US20070265451A1

US20070265451A1 - Process for the preparation of oxazolidinones and method of use thereof

Info

Publication number: US20070265451A1
Application number: US11/811,623
Authority: US
Inventors: Rawle Hollingsworth; Guijun Wang; Raghavakaimal Padmakumar; Jianmin Mao; Huiping Zhang; Zongmin Dai; Kanakamma Puthuparampil
Original assignee: Michigan State University MSU
Current assignee: Michigan State University MSU
Priority date: 2001-10-18
Filing date: 2007-06-11
Publication date: 2007-11-15
Also published as: WO2003106413A2; US20080146458A1; JP2005519996A; WO2003106413A3; EP1578723A4; CA2464109A1; US7390825B1; EP1578723A2; AU2002367959A8; AU2002367959A1

Abstract

A process for preparing N-(substituted)-C-(substituted methyl)-oxazolidinones, C-(substituted methyl)-oxazolidinones, and N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably chiral, from optically active C-(protected oxymethyl)-oxazolidinones is described. The process can be used to produce combinatorial libraries of the above substituted oxazolidinones in a two or three step reaction comprising a plurality of reagents differing in numbers of carbons or particular substituted oxazolidinones. A number of substituted oxazolidinones produced using the above process have been discovered to have antimicrobial activity.

Description

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 60/330,266 filed Oct. 18, 2001, and U.S. Provisional Application No. 60/330,268 filed Oct. 18, 2001.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A “COMPUTER LISTING APPENDIX SUBMITTED ON A COMPACT DISC”

Not Applicable.

BACKGROUND OF THE INVENTION

(1) Field of the Invention
The present invention relates to a process for preparing N-(substituted)-C-(substituted methyl)-oxazolidinones, C-(substituted methyl)-oxazolidinones, and N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably chiral, from optically active C-(protected oxymethyl)-oxazolidinones. The process can be used to produce combinatorial libraries of the above substituted oxazolidinones in a two or three step reaction comprising a plurality of reagents differing in numbers of carbons or particular substituted oxazolidinones. A number of substituted oxazolidinones produced using the above process have been discovered to have antimicrobial activity.
(2) Description of Related Art
Oxazolidinones, particularly substituted oxazolidinones such as 3-(substituted)-5-alkylaminomethyl- and 3-(substituted)-5-acylaminomethyl-2-oxazolidinones, are an important class of drug substances which are used for a wide variety of drug applications. These applications include use as antibacterial agents and in therapies for treating behavior disorders (Bowersock et al., Antimicrob. Agents Chemotherp. 44: 1367-1369 (2000); Skold, Acta Vet. Scand. Suppl. 93: 23-36 (2000); Diekema and Jones, Drugs 59: 7-16 (2000); Genin et al., J. Med. Chem. 43: 953-970 (2000); Johnson et al., J. Antimicrob. Chemother. 45: 225-230 (2000); Schulin et al., Antimicrob. Agents Chemotherp. 43: 2873-2876 (1999); Cynamon et al., Antimicrob. Agents Chemotherp. 43: 1189-1191 (1999); Chen and Reamer, Organic Letts. 1: 293-294 (1999); Brenner et al., Clin Therapeut. 22: 411-419 (2000); Clemett and Markham, Drugs 59: 815-827 (2000); Brickner et al., J. Med. Chem. 39: 673-679 (1996); Barry, Antimicrob. Agents Chemotherp. 32: 150-152 (1988); Slee et al., Antimicrob. Agents Chemotherp. 31: 1791-1797 (1987); Manninen et al., Abs. Paps. Amer. Chem. Soc. 212: 389-ORGN, Part 2, (Aug. 25, 1996)).
There are several methods for making the oxazolidinone nucleus in 3-(substituted)-5-alkylaminomethyl- and 3-(substituted)-5-acylaminomethyl-2-oxazolidinones. The general structure of 3-(substituted)-5-(substituted methyl)-2-oxazolidinone is

wherein R₁is alkyl, aryl, heteroalkyl, heteroaryl, or mixture thereof, or hydrogen or hydroxy, and R₂is alkyl, aryl, heteroalkyl, heteroaryl, or mixture thereof. The following disclose processes for preparing oxazolidinones and substituted oxazolidinones.
U.S. Pat. No. 6,288,238 B1 to Hollingsworth and Wang disclose a process for preparing 5-hydroxymethyl-2-oxazolidinones in one step from 3,4-boronic acid ester protected 3,4-dihydroxybutyramides.
U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang discloses a process for preparing 5-trityloxymethyl-2-oxazolidinones and suggests a scheme for the alkylation of N-lithio-N-substituted carbamates with oxiranes such as glycidyl butyrate as shown in Scheme 1.

Glycidyl equivalents such as epichlorohydrin can be used instead of glycidyl butyrate.
Schaus and Jacobsen (Tetrahedron Letts. 37: 7937-7940 (1996)) teach using optically active N-oxiranylmethylacetamides to prepare chiral 3-(substituted)-5-acetamidomethyl-2-oxazolidinones in one step by the alkylation of N-lithio-N-aryl (or alkyl) carbamates as shown in Scheme 2.
However, the above processes do not allow for the rapid synthesis of a plurality of substituted oxazolidinones at the same time in the same reaction. Thus, producing a plurality of substituted oxazolidinones for drug screening is slow and cumbersome which affects the rate in which new and useful drugs can be discovered. Therefore, there remains a need for a rapid and simple process that can produce a plurality of substituted oxazolidinones at the same time in the same reaction. Being able to produce a plurality of drug candidates in a short period of time would accelerate the rate at which new and useful drugs and other compounds are discovered. The present invention provides a simple and rapid process for synthesizing substituted oxazolidinones.
Strains of Gram positive bacteria resistant to the present repertoire of antibiotics have been increasing in prevalence over the past several decades (Skold, Acta Vet. Scand. Suppl. 93: 23-36 (2000)). Resistant Gram positive that have been commonly encountered include among others those in the staphylococci, streptococci, pneumococci, and enterococci families. Because of the increasing prevalence of these antibiotic resistant bacterial strains, there is a clear need for new antimicrobial agents.
Several species of substituted oxazolidinones have been discovered to be effective antimicrobial agents against particular antibiotic resistant strains of Gram positive bacteria. Linezolid (Clemett and Markham, Drugs 59: 815-827 (2000); Johnson et al., J. Antimicrob. Chemother. 45: 225-230 (2000)) is a substituted oxazolidinone which has been approved for the treatment of microbial infections. The structure of linezolid is shown below.

A number of other substituted oxazolidinones with varying degrees of antibacterial activity against Gram positive and in some cases Gram negative bacteria are also known (Barry, Antimicrob. Agents Chemotherp. 32: 150-152 (1988); Brickner et al., J. Med. Chem. 39: 673-679 (1996); Genin et al., J. Med. Chem. 43: 953-970 (2000); Slee et al., Antimicrob. Agents Chemotherp. 31: 1791-1797 (1987)).
Most, if not all, of the known substituted oxazolidinones which have been found to have antibacterial activity have the structure shown below wherein the R₃substituent is aryl and the relative stereochemistries of the groups on the chiral center (C-5) is as indicated.
A comparison of the structures for all of the known substituted oxazolidinones which have antimicrobial activity, the general consensus has arisen that there are at least three elements of these substituted oxazolidinones which are critical for biological activity. The first element is that when the oxazolidinone ring is oriented as shown below such that all the ring atoms are in one plane, the carbonyl oxygen points up, the ring nitrogen is to the left, and the 5-substituent is to the right, then of the two possible orientations for the 5-substituent (distal or proximal), the proximal substituent is required for biological activity.

The second element is that the 3-substituent is an aryl. The third element is that the 5-substituent is an alkylamino methyl or an acetamidomethyl group. No substituted oxazolidinone which has antibacterial activity has been found which does not have all three of the above elements.
Because microorganisms will eventually develop resistance to antibiotics, there is a continual need for new antibiotics. The present invention provides families of novel substituted oxazolidinones which have antimicrobial activity but which have structures which do not conform to the consensus structure thought to be necessary for antimicrobial activity.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing N-(substituted)-C-(substituted methyl)-oxazolidinones, C-(substituted methyl)-oxazolidinones, and N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably chiral, from optically active C-(protected oxymethyl)-oxazolidinones. The process can be used to produce combinatorial libraries of the above substituted oxazolidinones in a two or three step reaction comprising a plurality of reagents differing in numbers of carbons or particular substituted oxazolidinones.
Therefore, the present invention provides a process for producing a library of substituted oxazolidinones which comprises (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I); and (b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group and replaces it with another group from the second reagent to produce the library of substituted oxazolidinones.
In a further embodiment of the above process, the second reagent is a reducing agent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone to provide a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II) as the library of substituted oxazolidinones.
In a further embodiment of the above process, the mixture of (II) is further reacted with a third reagent containing a plurality of compounds reactive with the hydroxymethyl in an anhydrous organic solvent to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones. Preferably, the anhydrous organic solvent further includes pyridine. In particular embodiments, the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones or a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.
The present invention further provides a process for producing a library of substituted oxazolidinones which comprises (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I); (b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinones to produce a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II); and (c) reacting the mixture of (II) produced in step (b) in an anhydrous organic solvent with a third reagent containing a plurality of compounds reactive with the hydroxymethyl of the mixture of (II) to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones. Preferably, the anhydrous organic solvent in step (c) further includes pyridine. In particular embodiments, the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones or a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.
In a further embodiment of the above processes, substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.
In a further embodiment of the above processes, the substituted oxazolidinones in the library are separated chromatographically.
In a preferred embodiment of the above process, the protecting group is a trityl group.
In a further embodiment of the above processes, under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity, preferably, the alkali is an ionic hydride, most preferably, the ionic hydride is sodium hydride, and under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst, preferably, the palladium catalyst is Pd(OAc)₂.
In a further embodiment of the above processes, the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I) produced in step (a) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.
In a still further embodiment of the above processes, the N-(substituted)-C-hydroxymethyl-oxazolidinones (II) produced in step (b) are purified by removing the solvent.
In a still further embodiment of the above processes, the N-(substituted)-C-(substituted methyl)-oxazolidinones (III) produced in step (c) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.
In a further embodiment of the above processes, the present invention provides a process for preparing a library of substituted oxazolidinones which comprises reacting a C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent including pyridine with a reagent containing a plurality of compounds reactive with the hydroxy group to produce a mixture of substituted oxazolidinones as the library of substituted oxazolidinones.
In a further embodiment of the above processes, the reaction produces a mixture of 5-(substituted methyl)-2-oxazolidinones, a mixture of 4-(substituted methyl)-2-oxazolidinones, a mixture of N-(substituted)-C-(hydroxymethyl)-2-oxazolidinones, or a mixture of N-(substituted)-C-(substituted methyl)-2-oxazolidinones.
In a further embodiment of the above processes, substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.
In a further embodiment of the above processes, the substituted oxazolidinones in the library are separated chromatographically.
The present invention further provides a library of substituted oxazolidinones selected from the group consisting of N-(substituted)-C-(substituted methyl)-oxazolidinones, N-(substituted)-C-hydroxymethyl-oxazolidinones, and C-(substituted methyl)-oxazolidinones.
In a further embodiment of the library, substituted in N-(substituted) includes at least 10 different individual groups.
In a further embodiment of the library, substituted in C-(substituted) includes at least 10 different individual groups.
In a further embodiment of the library, the library is a mixture of N-(substituted)-C-hydroxymethyl-2-oxazolidinones or a mixture selected from the group consisting of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones and 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.
In a further embodiment of the library, substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.
The present invention further provides a method of screening substituted oxazolidinones for biological activity which comprises (a) providing a library of the substituted oxazolidinones wherein the substituted oxazolidinones are selected from the group consisting of N-(substituted)-C-(substituted methyl)-oxazolidinones, N-(substituted)-C-hydroxymethyl-oxazolidinones, and C-(substituted methyl)-oxazolidinones; (b) chromatographically separating the substituted oxazolidinones in the library; and (c) testing the separated substituted oxazolidinones for the biological activity.
In a further embodiment of the above method, substituted in N-(substituted) includes at least 10 different individual groups.
In a further embodiment of the above method, substituted in C-(substituted methyl) includes at least 10 different individual groups.
In a further embodiment of the above method, the substituted oxazolidinones is a mixture of N-(substituted)-C-hydroxymethyl-2-oxazolidinones or a mixture selected from the group consisting of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones, 3-(substituted)-4-(substituted methyl)-2-oxazolidinones, 5-(substituted methyl)-2-oxazolidinones, and 4-(substituted methyl)-2-oxazolidinones.
In a further embodiment of the above method, substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.
The present invention further provides a substituted oxazolidinone with biological activity obtained by the above method.
The present invention further provides a process for producing a substituted oxazolidinone which comprises (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a compound which is reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce an N-(substituted)-C-(protected oxymethyl)-oxazolidinone; (b) reacting the N-(substituted)-C-(protected oxymethyl)-oxazolidinone in an aqueous organic solvent with a second reagent with a second reagent which replaces the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone with a hydrogen to produce an N-(substituted)-C-hydroxymethyl-oxazolidinone; and (c) reacting the N-(substituted)-C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent with a third reagent containing a compound reactive with the hydroxy group to produce N-(substituted)-C-(substituted methyl)-oxazolidinones as the substituted oxazolidinone.
In a further embodiment of the above process, the anhydrous organic solvent in step (c) further includes pyridine.
In a further embodiment of the above process, substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.
In a further embodiment of the above process, the protecting group is a trityl group.
In a further embodiment of the above process, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of hydrogen, acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R₂is selected from the group consisting of acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, and mixture thereof, or a hydrogen, wherein hetero is an atom selected from the group consisting of O, N, P, and S; and y is a heteroatom selected from the group consisting of O, N, and S.
In a further embodiment of the above process, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R₂is selected from the group consisting of alkyl, acyl, aryl, and thio; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R₂is selected from the group consisting of alkyl, acyl, aryl, and thio; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, acyl, thio, and aryl, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, acyl, thio, and aryl, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, or heterocycle, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle and R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers; or, the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle and R₂is selected from the group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2, or 3 chiral centers.
In a further embodiment of the above process, under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity, preferably, the alkali is an ionic hydride, most preferably, the ionic hydride is sodium hydride.
In a further embodiment of the above process, under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst, preferably, the palladium catalyst is Pd(OAc)₂.
In a further embodiment of the above process, the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinone produced in step (a) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.
In a further embodiment of the above process, the N-(substituted)-C-hydroxymethyl-oxazolidinone produced in step (b) is purified by removing the solvent.
In a further embodiment of the above process, the N-(substituted)-C-(substituted methyl)-oxazolidinone produced in step (c) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.
The present invention further provides a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of hydrogen, acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R₂is selected from the group consisting of acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, and mixture thereof, or a hydrogen, wherein hetero is an atom selected from the group consisting of O, N, P, and S; and y is a heteroatom selected from the group consisting of O, N, and S.
The present invention further provides a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R₂is selected from the group consisting of alkyl, acyl, aryl, and thio; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R₂is selected from the group consisting of alkyl, acyl, aryl, and thio; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl, acyl, thio, and aryl, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl, acyl, thio, and aryl, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2 or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, or heterocycle, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle and R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers; or, a substituted oxazolidinone which has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, or heterocycle and R₂is selected from the group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2, or 3 chiral centers.
The present invention further provides an antimicrobial composition comprising a carrier and one or more substituted oxazolidinones of the formula

wherein R₁is selected from the group consisting of hydrogen, acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl, sulfonyl, thio, and mixture thereof, or a hydrogen; R₂is selected from the group consisting of acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, and mixture thereof, or a hydrogen, wherein hetero is an atom selected from the group consisting of O, N, P, and S; and y is a heteroatom selected from the group consisting of O, N, and S.

OBJECTS

Therefore, it is the object of the present invention to provide a process for producing substituted oxazolidinones which are substituted at the N-position or the C-position, or both.
It is a further object of the present invention to provide a process for producing a library of substituted oxazolidinones comprising a plurality of oxazolidinones substituted at the N-position, a plurality of oxazolidinones substituted at the C-position, or a plurality of oxazolidinones substituted at both the N-position and the C-position.
These and other objects of the present invention will become increasingly apparent with reference to the following drawings and preferred embodiments.

DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the conversion of 5-trityloxymethyl-2-oxazolidinone to 3-(2,5-dimethoxyphenacyl)-5-trityloxymethyl-2-oxazolidinone.
FIG. 1B shows the conversion of 3-(2,5-dimethoxyphenacyl)-5-trityloxymethyl-2-oxazolidinone to 3-(2,5-dimethoxyphenacyl)-5-hydroxymethyl-2-oxazolidinone.
FIG. 1C shows the conversion of 3-(2,5-dimethoxyphenacyl)-5-hydroxymethyl-2-oxazolidinone to a library of ten 3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones.
FIG. 2 shows the ten chlorides used in the O-functionalization.
FIG. 3 shows an HPLC profile of the library of ten 3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones prepared as shown in FIGS. 1A to 1C.
FIG. 4 shows the structure of the ten 3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones identified in FIG. 3.

DETAILED DESCRIPTION OF THE INVENTION

All patents, patent applications, government publications, government regulations, and literature references cited in this specification are hereby incorporated herein by reference in their entirety. In case of conflict, the present description, including definitions, will control.
The present invention provides a novel process for preparing collections or combinatorial libraries of substituted oxazolidinones. In particular, the present invention provides a process for preparing libraries of optically active or chiral N-(substituted)-C-(substituted methyl)-oxazolidinones, N-(substituted)-C-(methyl)-oxazolidinones, and C-(substituted methyl)-oxazolidinones bearing alkyl or aryl substituents in the N-substituted position (3-position) and a methyl group substituted with a heteroatom such as O, N, or S in the C-substituted position (4- or 5-position) and wherein the heteroatom is further substituted with hydrogen or acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, or mixture thereof.
In a preferred embodiment, the substituted oxazolidinones comprising the library are optically active or chiral N-(substituted)-C-(substituted methyl)-2-oxazolidinones, N-(substituted)-C-(methyl)-2-oxazolidinones, and C-(substituted)-2-oxazolidinones bearing alkyl or aryl substituents in the N-substituted position (3-position) and a methyl group substituted with a heteroatom in the C-substituted position (4- or 5-position) and wherein the heteroatom is further substituted with hydrogen or acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, or mixture thereof.
As used herein, the term “substituted” refers to groups other than hydrogen substituted at the N-position or the methyl at the C-position. Preferably, the substituting group is an organic group. Therefore, when the N-position is substituted, it is substituted with a group such as acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, or mixture thereof. When N is not referred to as being “substituted”, the N has a hydrogen at the N-position. When the C-position methyl is substituted, it is referred to as “substituted methyl” wherein “substituted” is a group such as acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, or mixture thereof.
The general structure of these substituted oxazolidinones is shown below

wherein R₁is an acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thio, or mixture thereof, or a hydrogen, R₂is an acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, or mixture thereof, or a hydrogen (when N is not substituted by an organic group), and y is a heteroatom selected from the group consisting of O, N, and S. The heteroatom comprising R₁or R₂can include one or more atoms selected from the group consisting of O, P, S, N, Al, and Si.
The above genus comprises at least eight families of substituted oxazolidinones. The first family (Family I) comprises substituted oxazolidinones with the following general structure

wherein R₁is alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, or thio and R₂is alkyl, acyl, aryl, or thio.
The second family (Family II) comprises substituted oxazolidinones with the following general structure

wherein R₁is alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, or thio and R₂is alkyl, acyl, aryl, or thio.
The third family (Family III) comprises substituted oxazolidinones with the following general structure

wherein R₁is alkyl, acyl, thio, or aryl, R₂is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, and X is F, NO₂, Cl, Alkyl, or aryl.
The fourth family (Family IV) comprises substituted oxazolidinones with the general structure

wherein R₁is alkyl, acyl, thio, or aryl, R₂is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, and X is F, NO₂, Cl, Alkyl, or aryl.
The fifth family (Family V) comprises substituted oxazolidinones with the general structure

wherein R₁is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, R2 is alkyl, aryl, acyl, thio, or heterocycle, and X is F, NO₂, Cl, Alkyl, or aryl.
The sixth family (Family VI) comprises substituted oxazolidinones with the general structure

wherein R₁is alkyl, aryl, acyl, thio, or heterocycle, R₂is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers, and X is F, NO₂, Cl, Alkyl, or aryl.
The seventh family (Family VII) comprises substituted oxazolidinones with the general structure

wherein R₁is alkyl, aryl, acyl, thio, or heterocycle and R₂is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers.
The eighth family (Family VIII) comprises substituted oxazolidinones with the general structure

wherein R₁is alkyl, aryl, acyl, thio, or heterocycle and R₂is a C-3, C-4, or C-5 chiral synthon with 1, 2, or 3 chiral centers.
Examples of the C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers include, but are not limited to, (R)-3-acetoxy-4-bromobutyric acid, (S)-3-acetoxy-4-bromobutyric acid, (R)-3-Acetoxy-4-bromobutiryl chloride, (S)-3-Acetoxy-4-bromobutiryl chloride, (R)-2-Acetoxy-1,4-dibromobutane, (S)-2-Acetoxy-1,4-dibromobutane, (R)-3-Acetoxy-gamma-butyrolactone, (S)-3-Acetoxy-gamma-butyrolactone, (R)-4-Acetoxy-2-thioxopyrrolidine, (S)-4-Acetoxy-2-thioxopyrrolidine, (R)-4-Acetylthio-2-pyrrolidinone, (S)-4-Acetylthio-2-pyrrolidinone, (R)-4-Amino-1,3-butanediol, (S)-4-Amino-1,3-butanediol, (R)-3-Amino-1,2-dihydroxypropane, hydrochloride, (S)-3-Amino-1,2-dihydroxypropane, hydrochloride, (R) -4-Amino-3-hydroxy-1-trityloxy-butane, (S)-4-Amino-3-hydroxy-1-trityloxy-butane, (R)-4-Amino-3-hydroxybutanoic acid, (S)-4-Amino-3-hydroxybutanoic acid, (S)-4-Aminomethyl-2,2-dimethyl-1,3-dioxolane, (R)-3-Amino-1,2-propanediol, (S)-3-Amino-1,2-propanediol, (S)-N-Benzyl-3,4-dihydroxybutyramide, (R)-1-Benzyl-4-hydroxy-2-pyrrolidinone, (S)-1-Benzyl-4-hydroxy-2-pyrrolidinone, (R)-1-Benzyl-3-mesyloxy pyrrolidine, (S)-1-Benzyl-3-mesyloxy pyrrolidine, (R)-1-Benzyl-3-pyrrolidinol, (S)-1-Benzyl-3-pyrrolidinol, (R)-3-Bromo-1-(bromomethyl)propyl-methoxymethyl, (S)-3-Bromo-1-(bromomethyl)propyl-methoxymethyl ether, (R)-4-Bromo-1,3-butanediol, (S)-4-Bromo-1,3-butanediol, (R)-4-Bromo-1,3-diacetoxy-butane, (S)-4-Bromo-1,3-diacetoxy-butane, (R)-3-Bromo-1,2-dihydroxypropane, (S)-3-Bromo-1,2-dihydroxypropane, (R)-4-Bromo-1,2-epoxybutane, (S)-4-Bromo-1,2-epoxybutane, (R)-5-Bromo-4-(methoxymethoxy)-peritanenitrile, (S)-5-Bromo-4-(methoxymethoxy)-pentanenitrile, (4R)-4-Bromomethyl-2-phenyl-1,3-dioxane, (4S)-4-Bromomethyl-2-phenyl-1,3-dioxane, (R)-1,3-Butanediol, (S)-1,3-Butanediol, (R)-1,2,4-Butanetriol, (S)-1,2,4-Butanetriol, (R)-1,2,4-Butanetriol trimesylate, (S)-1,2,4-Butanetriol trimesylate, (R)-4-Cyano-1,2-epoxybutane, (S)-4-Cyano-1,2-epoxybutane, 1,3-Dehydro-2-deoxy-N-acetylneuraminic acid, (R)-1,4-Dibromo-2-butanol, (S)-1,4-Dibromo-2-butanol, (R)-3,4-Dihydroxybutyramide, (S)-3,4-Dihydroxybutyramide, (R)-2,2-Dimethyl-4-aminomethyl-1,3-dioxane, (S)-2,2-Dimethyl-4-aminomethyl-1,3-dioxane, (R)-2,2-Dimethyl-1,3-dioxolane-4-acetamide, (S)-2,2-Dimethyl-1,3-dioxolane-4-acetamide, (R)-2,2-Dimethyl-1,3-dioxolane-4-acetic acid, methyl ester, (S)-2,2-Dimethyl-1,3-dioxolane-4-acetic acid, methyl ester, (R)-2,2-Dimethyl-1,3-dioxolane-4-acetonitrile, (S)-2,2-Dimethyl-1,3-dioxolane-4-acetonitrile, (R)-2,2-Dimethyl-1,3-dioxolane-4-propanol, (S)-2,2-Dimethyl-1,3-dioxolane-4-propanol, (3R)-1,3-Dioxane-2-methyl-4-carboxylic acid, (3S)-1,3-Dioxane-2-methyl-4-carboxylic acid, (R)-1,4-Ditosyloxy-2-butanol, (S)-1,4-Ditosyloxy-2-butanol, (3R)-3-(1-Ethoxyethoxy)-gamma-butyrolactone, (3S)-3-(1-Ethoxyethoxy)-gamma-butyrolactone, (2R)-2-(1-Ethoxyethoxy)-1,4-butanediol, (2S)-2-(1-Ethoxyethoxy)-1,4-butanediol, Ethyl (R)-4-bromo-3-hydroxybutanoate, Ethyl (S)-4-bromo-3-hydroxybutanoate, Ethyl (R)-4-chloro-3-hydroxybutanoate, Ethyl (S)-4-chloro-3-hydroxybutanoate, (R)-4-cyano-3-hydroxybutanamide, (S)-4-cyano-3-hydroxybutanamide, Ethyl (R)-4-cyano-3-hydroxybutanoate, Ethyl (S)-4-cyano-3-hydroxybutanoate, Ethyl (R)-3,4-epoxybutanoate, Ethyl (S)-3,4-epoxybutanoate, Ethyl (R)-3-hydroxy-decanoate, Ethyl (S)-3-hydroxy-decanoate, Ethyl (R)-3-hydroxy-tetradecanoate, Ethyl (S)-3-hydroxy-tetradecanoate, Ethyl (R)-4-iodo-3-hydroxybutanoate, Ethyl (S)-4-iodo-3-hydroxybutanoate, (R)-4-(4-Fluorophenoxy)methyl butyrolactone, (S)-4-(4-Fluorophenoxy)methyl butyrolactone, (1S,3R)-3-Hydroxy-cyclopentanecarboxylic acid, (1S,3S)-3-Hydroxy-cyclopentanecarboxylic acid, (R)-4-Hydroxy-1-cyclopentene-1-carboxylic acid, (S)-4-Hydroxy-1-cyclopentene-1-carboxylic acid, (R)-4-Hydroxy-2-pyrrolidinone, (S)-4-Hydroxy-2-pyrrolidinone, (4R)-4-(2-Hydroxyethyl)-2-phenyl-1,3-dioxolane, (4S)-4-(2-Hydroxyethyl)-2-phenyl-1,3-dioxolane, (R)-2-Hydroxy-gamma-butyrolactone, (S)-2-Hydroxy-gamma-butyrolactone, (R)-3-Hydroxy-gamma-butyrolactone, (S)-3-Hydroxy-gamma-butyrolactone, (R)-4-Hydroxymethyl butyrolactone, (S)-4-Hydroxymethyl butyrolactone, (R)-4-Hydroxy-2-pyrrolidinethione, (S)-4-Hydroxy-2-pyrrolidinethione, (R)-3-Hydroxytetrahydrofuran, (S)-3-Hydroxytetrahydrofuran, (R)-4-Mercapto-2-pyrrolidinone, (S)-4-Mercapto-2-pyrrolidinone, (R)-2-(Methoxy-1-methylethoxy)-butanediol, (S)-2-(1-Methoxy-1-methylethoxy)-butanediol, Methyl (R)-4,5-dihydroxyisopropylidenepentanoate, Methyl (S)-4,5-dihydroxyisopropylidenepentanoate, Methyl (R)-2-phenyl-1,3-dioxolane-4-acetate, Methyl (S)-2-phenyl-1,3-dioxolane-4-acetate, Methyl (R)-3-hydroxy-4-trityloxy-butanoate, Methyl (S)-3-hydroxy-4-trityloxy-butanoate, (R)-3-Pyrrolidinol, (S)-3-Pyrrolidinol, (R)-3-Chloro-1,2-propanediol, (S)-3-Chloro-1,2-propanediol, (2S)-(+)-glycidal tosylate, Benzyl (R)-glycidyl ether, (R)-3-chlorolactic acid, Ethyl (S)-4-chloro-3-hydroxybutanoate, (S)-3-Hydroxybutyrolactone, (R)-2-hydroxybutyrolactone, (S)-2-Hydroxybutyrolactone, (R)-2-Chlrobutyric acid, (R)-2-bromobutyric acid, (S)-1-iso-propylaminopropanediol, (S)-1-tert-Butylaminopropanediol, (R)-1-cyclohexyl-ethyl-amine, (R)-Ethyl-nipecotate, (S)-Ethyl-nipecotate, (R)-Glycetol-3-phosphate, alpha-Glycerophosphatidylcholine, alpha-glycerophosphatidylethanolamine, (R)—O-Isopropylidene glycerol, (S)—O-Isopropylidene glycerol, (R)—O-Isopropylidene glycerol mesylate, (S)—O-Isopropylidene glycerol mesylate, (R)—O-Isopropylidene glycerol tosylate, (S)—O-Isopropylidene glycerol tosylate, (R)—O-methyl-O-isopropylidene glycerate, (R)-2-tetrahydrofuroic acid, (R)-1-Tosyl-glycerol, and (S)-1-Tosyl-glycerol.
The process for synthesis of the substituted oxazolidinones preferably uses an optically active C-protected oxazolidinone as the starting material, preferably a 5-(protected hydroxymethyl)-oxazolidinone such as 5-trityloxymethyl-oxazolidinone wherein the trityl is triphenylmethyl. Most preferably, the protected oxazolidinone is a 5-(protected hydroxymethyl)-2-oxazolidinone which in a further preferred embodiment is a 5-trityloxymethyl-2-oxazolidinone. The synthesis of 5-trityloxymethyl-2-oxazolidinone and its use are disclosed in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang. The structure of 5-trityloxymethyl-2-oxazolidinone is shown below.
The general process for producing a library of substituted oxazolidinones comprises the following steps. First, a C-(protected oxymethyl)-oxazolidinone is N-arylated with a mixture of compounds comprising a plurality of different aryl acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, or phenacyl bromides under Buchwald conditions (Yin and Buchwald, Org. Letts 2: 1101-1104 (2000)) or by simple alkylation under nitrogen. This produces a plurality of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I).
For example, under simple alkylation conditions, a C-(protected oxymethyl)-oxazolidinone is dissolved in an organic solvent such as tetrahydrofuran (THF) containing a strong base (alkali) which preferably does not have substantial reducing activity or which has reducing activity which is suppressed at low temperatures. Hydrides are strong bases which are suitable for the reaction. Preferably, the strong base is an ionic hydride such as an alkali hydride. Most preferred is sodium hydride which is a powerful base without substantial reducing activity. Other strong bases which may be used include lithium hydride, potassium hydride, rubidium hydride, cesium hydride, sodium alcoholates, sodium amide, and metallic sodium. In general, about 1 equiv. of the strong base (alkali), preferably sodium hydride, is added to the solvent containing the C-(protected oxymethyl)-oxazolidinone. In the case of sodium hydride, which is insoluble in organic solvents, the sodium hydride is provided as a suspension in an organic solvent such as hexane. After allowing the mixture containing the protected oxazolidinone and strong base to incubate at about 0° C. for about 10 minutes with stirring under an inert atmosphere such as nitrogen, the mixture is warmed to room temperature and stirred for about two hours and a mixture of n different arylating reagents, preferably in a molar ratio of about 1 to 1 to 1 to 2 (C-(protected oxymethyl)-oxazolidinone to mixture), is added. The reaction is incubated at room temperature with stirring for a time (about eight hours) sufficient to arylate the N at the 3-position with the n different arylating reagents to produce n N-(substituted)-C-(protected oxymethyl)-oxazolidinones. The reaction is then quenched by adding an aqueous solution containing an acid such as NH₄Cl and the N-(substituted)-C-protected oxymethyl)-oxazolidinones are recovered by extracting the quenched reaction with the organic solvent, drying the extract over a drying agent such as anhydrous Na₂SO₄, and concentrating the extract under reduced pressure (in vacuo). The N-(substituted)-C-(protected oxymethyl)-oxazolidinones are preferably purified by chromatography.
Under Buchwald conditions, the C-(protected oxymethyl)-oxazolidinone and about 1 to 2 equiv. of a mixture of n different arylating reagents are incubated with a Pd(OAc)₂catalyst in an organic solvent such as tetrahydrofuran (THF) under an inert atmosphere such as argon at a temperature between about 45° to 110° C. for a time sufficient to arylate the N at the 3-position with the n different arylating reagents to produce n N-(substituted)-C-(protected oxymethyl)-oxazolidinones (in general, about eight hours as determined by gas chromatography). The reaction is then cooled to room temperature, diluted with an organic solvent such as dichloromethane, filtered, and concentrated under reduced pressure (in vacuo). The N-(substituted)-C-(protected oxymethyl)-oxazolidinones are preferably purified by chromatography.
Next, the N-arylated oxazolidinones (N-substituted) are deprotected in the usual fashion by hydrogenolysis using H₂and a palladium catalyst or an acid such as to produce a library of n N-(substituted)-C-hydroxymethyl-oxazolidinones (II). For example, the N-arylated oxazolidinones, preferably purified by chromatography or the like, are incubated in an aqueous solvent such as wet dichloromethane (CH₂Cl₂) (about 8:1 CH₂Cl₂:H₂O) further containing an acid such as trifluoroacetic acid (CF₃CO₂H) at room temperature for a time sufficient (about four hours) to deprotect the C-hydroxymethyl. Preferably, the C-protecting group in the above reaction is a triphenylmethyl group. The reaction is quenched by adding triethylamine or other quenching agent and the deprotected oxazolidinone concentrated under reduced pressure (in vacuo). The concentrated deprotected oxazolidinone is preferably further purified by chromatography.
In a further step, the n N-(substituted)-C-hydroxymethyl-oxazolidinones (II) are O-functionalized with a mixture of n different alkylation, acylation, sulfonylation, halogenation, or other such species. For example, a mixture containing a plurality of different acyl, alkyl, aryl, heteroalkyl, heteroacyl, heteroaryl, heterocycle., phenacyl, aryl sulfonyl, amides thereof, thiols thereof, or other such species, or the O of the hydroxymethyl is replaced by N-aryl, N-sulfonyl, N-sulfide, or other N-species, or the O of the hydroxymethyl is replaced by a thioalkyl, thioaryl, or other thio-species. Methods for converting the hydroxyl group to a nitrogen containing function can be done by any of the methods which are known. These include mesylation or tosylation followed by displacement with ammonia, azide, benzylamine, or other nitrogen nucleophiles as taught for example in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang or U.S. Pat. No. 5,837,870 to Pearlman et al. For example, n substituted oxazolidinones (II), preferably purified by chromatography or the like, are then incubated in an organic solvent such as dry dichloromethane containing about 1 equiv. pyridine and about 1 equiv. of a mixture of n different acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thios and amides thereof, or other such species halides at room temperature for time sufficient (about 12 to 16 hours) to functionalize the C-hydroxymethyl at the 4- or 5-position. Afterwards, the reaction is quenched by addition of ammonium chloride, extracting the organic layer with dichloromethane, drying the organic layer extract over a drying agent such as anhydrous Na₂SO₄, and concentrating under reduced pressure (in vacuo). The above process generates a library of n²N-(substituted)-C-(substituted methyl)-oxazolidinones (III). For example, if ten different aryl bromides reagents are used in the first step and ten different halide reagents in the second step, 100 N-(substituted)-C-(substituted)-oxazolidinones (III) are obtained.
Each of the products (I, II, or III) produced above can be separated chromatographically and each separately evaluated as drug or antimicrobial candidates.
The process takes advantage of the ease of reaction of the nitrogen atom at the 3-position in C-(protected oxymethyl)-oxazolidinones which enables both arylation and alkylation sequences for substituting the N to be used. A further advantage is that in one or two steps, the protecting group can be removed and the hydroxyl group functionalized. In the same scheme, the oxygen substituent at the C-position methyl can be replaced with halo, thio, phenoxy, azido, or substituted nitrogen groups under standard Mitsunobu conditions (Mitsunobu, Synthesis 1 (1981)). Alternatively, the hydroxyl group can be first converted to a sulfonate, halo, or other such activating group.
Thus, the process involves essentially two steps, the first step is generating a first library of n N-(substituted)-C-hydroxymethyl-oxazolidinones from a C-protected oxazolidinone and the second step is O-functionalizing acylating the C-hydroxymethyl to generate a library of n²N-(substituted)-C-(substituted methyl)-oxazolidinones.
In a preferred embodiment, the first library comprises at least 10 different N-(substituted)-C-hydroxymethyl-oxazolidinones prepared by reacting C-(protected oxymethyl)-oxazolidinones with at least 10 different N-arylating reagents and the second library comprises at least 100 different N-(substituted)-C-(substituted)-oxazolidinones prepared by reacting the ten N-(substituted)-C-hydroxymethyl-oxazolidinones with at least ten different O-functionalizing acylating reagents. In other embodiments of the library, the substituted oxazolidinones comprise a plurality of molecules with N-position substitutions and a single substitution group at the C-position of the molecules or a plurality of molecules with C-position substitutions and a single substitution group at the N-position of the molecules. A further embodiment of the library can comprise substituted oxazolidinones with either N-position substitutions only (N-(substituted)-C-(methyl)-oxazolidinones) or C-position substitutions only (C-(substituted methyl)-oxazolidinones. The particular library embodiment chosen depends on the particular objectives of the drug or antimicrobial screening program.
In a preferred embodiment, the oxazolidinone is 2-oxazolidinone. In a further preferred embodiment as shown in Scheme 3 below, the C-(protected hydroxymethyl)-2-oxazolidinone is C-trityloxymethyl-2-oxazolidinone. The C-trityloxymethyl-2-oxazolidinone is N-arylated (N at position 3) with a mixture of n different aryl acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, or phenacyl bromides, or other such bromides under Buchwald conditions (Yin and Buchwald, Org. Letts. 2: 1101-1104 (2000)) or simple alkylation under nitrogen to produce N-(substituted)-C-trityloxymethyl-2-oxazolidinones. The trityl (Tr) group is then removed by hydrogenation to produce a library of n N-(substituted)-C-hydroxymethyl-2-oxazolidinones.
In a further step, the N-(substituted)-C-hydroxymethyl-2-oxazolidinones are O-functionalized acylated with a mixture of n different acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, amides thereof, or other such species halides, or the O of the hydroxymethyl is replaced by N-aryl, N-sulfonyl, N-sulfide, or other N-species, or the O is replaced by a thioalkyl, thioaryl, or other thio-species. This generates a library of n²N-(substituted)-C-(substituted methyl)-2-oxazolidinones. For example, if ten aryl bromides reagents are used in the first step and ten halide species reagents in the second step, a total of 100 N-(substituted)-C-(substituted methyl)-2-oxazolidinones are made. In one embodiment, the starting oxazolidinone is 4-(protected oxymethyl)-2-oxazolidinone, preferably 4-trityloxymethyl-oxazolidinone, and the n library comprises 3-(substituted)-4-hydroxymethyl-2-oxazolidinone and the n²library comprises 3-(substituted)-4-(substituted methyl)-2-oxazolidinone. In a preferred embodiment, the starting oxazolidinone is 5-(protected oxymethyl)-2-oxazolidinone, preferably 5-trityloxymethyl-oxazolidinone, and the n library comprises 3-(substituted)-5-hydroxymethyl-2-oxazolidinone and the n²library comprises 3-(substituted)-5-(substituted methyl)-2-oxazolidinone.
The novel process allows for the rapid synthesis of a plurality of substituted oxazolidinones including but not limited to 3-(substituted)-5-(substituted methyl)-oxazolidinones, 3-(substituted)-4-(substituted methyl)-oxazolidinones, 3-(substituted)-5-(substituted methyl)-2-oxazolidinones, 3-(substituted)-4-(substituted methyl)-2-oxazolidinones, 3-(substituted)-5-hydroxymethyl-oxazolidinones, 3-(substituted)-4-hydroxymethyl-oxazolidinones, 3-(substituted)-5-hydroxymethyl-2-oxazolidinones, and 3-(substituted)-4-hydroxymethyl-2-oxazolidinones. The number of substituted oxazolidinones synthesized by the novel process depends on the number of substituting reagents included in the process. Therefore, the use of substituting reagents such as sulfur, nitrogen, and oxygen nucleophiles on the primary hydroxyl group and the amine group of the oxazolidinones affords access to a plurality of families of optically active compounds in a single process which is fast and simple.
The substituted oxazolidinones produced by the above process can be separated using standard chromatography methods and the separated substituted oxazolidinones screened for biological activity including antimicrobial activity or for usefulness as a drug or an intermediate for synthesizing a drug. Technologies and methods for screening compounds in combinatorial libraries are well known in the art.
For any particular substituted oxazolidinone which has useful characteristics, biological activities, or which is a useful intermediate for the synthesis of other compounds, the above process for making the combinatorial library is modified to a process for making the particular substituted oxazolidinone. The modified process differs from the process for preparing the library in that the plurality of reagents shown in Scheme 3 and described above is replaced with the particular reagents which will result in the synthesis of the particular substituted oxazolidinone. Thus, the general method involves the following steps: (1) substituting the N-group of optically active C-protected oxazolidinone, preferably trityloxy-2-oxazolidione, by simple alkylation under nitrogen or N-arylating under Buchwald conditions to produce an N-substituted oxazolidinone, (2) removing the C-protecting group, and (3) substituting the hydrogen of the C-4 or C-5 hydroxymethyl with an alkylation, acylation, arylation, sulfonylation, or other such species halide, or substituting the hydroxy group with a thioalkyl, thioaryl, or other thio-group species to replace the O of the hydroxymethyl with S, or substituting the hydroxy group under conditions with an N-acyl, N-sulfonyl, N-sulfide, or other N-group species to replace the O of the hydroxymethyl with N. The above process enables particular substituted oxazolidinones of any one of the eight families (Families I to VIII) to be prepared.
When libraries comprising substituted oxazolidinones prepared according to the process of the present invention were tested for antimicrobial activity, many of the substituted oxazolidinones in the libraries with the genus structure were discovered to have antimicrobial activity against gram positive and Gram negative bacteria. In particular, many of the substituted oxazolidinones were found to be active against Gram positive bacteria such as those of the genera Staphlococcus and Enterococcus and Gram negative bacteria such as those of the genera Escherichia with 90 to 100% Minimum Inhibitory Concentrations (MIC_90-100) of less than 10 μg/mL. The discovery that many of the novel substituted oxazolidinones had antibacterial activity was surprising since the novel substituted oxazolidinones do not contain all three elements considered necessary for antibacterial activity. Thus, the novel substituted oxazolidinones represent an new class of antimicrobial agents which are active against a variety of bacteria, in particular, Gram positive bacteria such as Staphylococcus aureus, Pseudomonas aeriginose, pneumococci (Streptococcus pneumoniae), enterococci (Enterococcus faecium, Enterococcus faecalis, Enterococcus gallinarum), Groups A, B, C, and G streptococci, Streptococcus oralis, and Streptococcus sanguis and Gram negative bacteria such as Escherichia coli.
Preferably, the substituted oxazolidinones with antimicrobial activity are embraced by the species of Families I to VIII. Tables 2 and 3 show examples of substituted oxazolidinones produced as disclosed herein which have been shown to have antimicrobial activity. Tables 1 and 2 show the results of analyses of the antimicrobial activity for several of the substituted oxazolidinones. The substituted oxazolidinones which are particularly useful antimicrobials have an MIC_90-100against at least one gram positive bacteria of about 300 μg/mL or less, preferably, of about 100 μg/mL or less, most preferably, of about 10 μg/mL or less. Because particular strains of these bacteria species have developed antibiotic resistance, the novel substituted oxazolidinones are particularly useful for use against the antibiotic resistant strains of bacteria such as those shown in Table 1.
To inhibit or prevent a bacterial infection from developing in a human or animal or to treat a bacterial infection in a human or animal patient, compositions comprising a carrier and one or more of the novel substituted oxazolidinones disclosed herein can be administered to the human or animal intravenously; by injection; orally by tablet, capsule, or liquid suspension; or topically.
For intravenous administration, one or more of the novel substituted oxazolidinones is dissolved in dimethyl sulfoxide or other pharmaceutically acceptable organic solvent, which is then diluted to about 5% (v/v) in a carrier which is a sterile isotonic solution. A suitable isotonic solution includes sodium citrate, citric acid, and dextrose wherein the Na+content is about 0.38 mg/mL (1.7 mEq/100 mL). Linezolid in the above isotonic solution has been approved for human use by the U.S. Food and Drug Administration. The intravenous solution can be applied as 15- to 20-minute infusions or by continuous infusion over an extended time period through a catheter surgically implanted through the patient's vein. In particular embodiments, the one or more novel substituted oxazolidinones is combined with one or more antibiotics or other antibacterial agents.
For injection, one or one or more of the novel substituted oxazolidinones is dissolved in dimethyl sulfoxide or other pharmaceutically acceptable organic solvent, which is then diluted to about 5% (v/v) in a carrier which is a sterile isotonic solution or sterile distilled water. The solution can be administered subcutaneously, intramuscularly, or peritoneally. In particular embodiments, one or more the substituted oxazolidinones is combined with one or more antibiotics or other antibacterial agents.
For oral administration, one or more of the novel substituted oxazolidinones is mixed with a pharmaceutically acceptable carrier and the mixture compressed into a tablet, which can be film coated, or encapsulated within a pharmaceutically acceptable capsule. For example, one or more of the novel oxazolidinones are admixed with a carrier which includes as the inactive ingredients: corn starch, microcrystalline cellulose, hydroxy propylcellulose, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and carnauba wax. The admixture is formed into tablets or encapsulated in capsules. Each tablet or capsule contains about 0.1 mEq Na⁺. Linezolid in a carrier which includes the above inactive ingredients has been approved for human use by the U.S. Food and Drug Administration. In particular embodiments, one or more of the substituted oxazolidinones is combined with one or more antibiotics or other antibacterial agents.
Alternatively, the novel substituted oxazolidinones are administered orally as a suspension. In this embodiment, one or more of the novel substituted oxazolidinones is provided in a pharmaceutically acceptable flavored granule or powder carrier for constitution into a suspension for oral administration. For example, one or more of the novel substituted oxazolidinones are admixed with a granule or powder which includes as the inactive ingredients: sucrose, citric acid, sodium citrate, microcrystalline cellulose, carboxy methyl cellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors. Linezolid in a granule or powder containing the above inactive ingredients has been approved for human use by the U.S. Food and Drug Administration. In particular embodiments, one or more of the substituted oxazolidinones is combined with one or more antibiotics or other antibacterial agents.
For topical administration, one or more of the substituted oxazolidinones can be provided in an ointment, a lotion, a cream, or a gel. In particular embodiments, one or more of the substituted oxazolidinones is combined with one or more steroids, one or more antibiotics or other antibacterial agents, or both.
The following examples are intended to promote a further understanding of the present invention.

EXAMPLE 1

This example illustrates the preparation of (S)-5-trityloxymethyl-2-oxazolidinone using the process disclosed in U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang.
In a flask, (S)-3,4-dihydroxybutyramide (11.9 g, 0.10 moles) was dissolved in 50 mL of tetrahydrofuran (THF) to which 50 mL of dimethylformamide and 10 mL pyridine was added followed by 30.6 g (0.11 moles) of trityl chloride. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred for 36 hours at room temperature. Afterwards, the reaction mixture was filtered to remove the solids. The liquid was concentrated under reduced pressure to remove most of the solvent. The concentrate was poured into ice water, stirred for about half an hour, and then the water layer was removed from the organic layer containing the 3-Hydroxy-4-trityloxy butyramide. The product was a semi-crystalline liquid which was dried in vacuo. Afterwards, the excess trityl chloride was washed away by tituration with hexane.
The 3-hydroxy-4-trityloxy butyramide (3.61 g, 0.01 moles) was dissolved in 30 mL THF. Fifteen mL of a 13% sodium hypochlorite solution was added and the mixture was stirred vigorously. Next, 1.6 g of sodium hydroxide dissolved in 10 mL of water was added. The reaction was stirred at 55-60° C. for eight hours after which time the conversion to 5-trityloxymethyl-2-oxazolidinone was completed as indicated by TLC and 1H-NMR spectroscopy. The organic layer was separated from the aqueous layer and saved. The aqueous layer was extracted three times with THF. The saved organic layer and the THF extracts were combined and then concentrated to remove the solvent. The residue was taken up in dichloromethane and the solution dried over sodium sulfate. Afterwards, the solution was concentrated to remove the solvent and the oxazolidinone was obtained as a white crystalline product (3.4 g, yield 95%). Normally, this crude product did not need further purification.

EXAMPLE 2

This comparative example illustrates the N-arylation of 5-trityloxymethyl-2-oxazolidinone to produce (S)-3-(2-nitro)phenyl-5-trityloxymethy)-2-oxazolidinone using the procedure disclosed in Shakespeare, Tetrahedron Lett. 40: 2035-2038 (1999).
To 36 mg of 5-trityloxymethyl-2-oxazolidinone, 30 mg (1.5 equivs) 1-bromo-2-nitrobenzene, 2.4 mg (0.1 equivs) palladium (II) acetate, 5.5 mg (0.1 equivs) 1,1′-bis(diphenylphosphino)-ferrocene, 16 mg (0.15 equivs) potassium t-butoxide, and 1 mL toluene were added under a nitrogen atmosphere. The mixture was heated at 110° C. for 14 hours after which time the mixture was resolved by thin-layer chromatography (TLC) comprising silica with dichloromethane as the eluant.
The TLC indicated complete conversion to a single product: (S)-3-(2-nitro)phenyl-5-trityloxymethyl-2-oxazolidinone. The mixture was cooled and diluted with dichloromethane. The dark brown organic solution was washed with 5% sodium carbonate, concentrated, and chromatographed on silica gel using dichloromethane as the eluant. The product (47 mg, 98%) was obtained as a pale yellow solid which crystallized from chloroform:methanol as off-white crystals with a melting point of 236-237° C. The product was analyzed by ¹H-NMR, ¹³C NMR, IR, MS, and HRMS.
¹H-NMR (300 MHz, CDCl₃) δ 8.03 (dd, 1H, J=8.0, 2.1 Hz), 7.65 (td, 1H, J=8.0, 2.1 Hz), 7.46-7.53 (m, 6H), 7.44 (td, 1H, J=8.0, 2.1 Hz), 7.20-7.36 (m, 10H), 4.83 (m, 1H), 4.07 (t, 1H, J=8.5 Hz), 3.89 (t, 1H, J=8 Hz), 3.58 (dd, 1H, J=11.8, 4.5 Hz), 3.36 (dd, 1H, J=11.8, 4.5 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 176.4, 143.5, 134.1, 131.7, 127.6, 87.5, 73.4, 64.0, 49.4. IR cm⁻¹3057, 2924, 1760, 1607, 1532, 1489, 1449, 1411, 1355. MS (electron impact) m/z 57, 71, 91, 105, 131, 165, 243, 259, 403, 463, 480 (M⁺). HRMS (electron impact) analyzed for C₂₉H₂₄N₂O₅: theoretical MW 480.1685, observed MW 480.1683.

EXAMPLE 3

This example illustrates the preparation of a library of substituted 2-oxazolidinones, which are members of Family II, according to the process of the present invention. In this example, (S)-5-trityloxymethyl-2-oxazolidinone is N-acylated with 2,5-dimethoxyphenacyl bromide, detritylated, and then acylated with ten different acyl halides or anhydrides to produce a library of n=10 3-(2,5-dimethoxyphenacyl)-5-(substituted methyl)-2-oxazolidinones.
In the first step (FIG. 1A), (S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone was produced in a reaction comprising (S)-5-trityloxymethyl-2-oxazolidinone and the aryl bromide: 2,5-dimethoxyphenacyl bromide. To a solution of 3.59 g (10 mmoles) of(S)-5-trityloxymethyl-2-oxazolidinone (MW 359.2) in 40 mL THF at 4° C., 400 mg (10 mmoles) NaH (MW 24) as a 60% suspension in hexane was added. The reaction mixture was stirred for about 10 minutes under nitrogen at 0° C. and then warmed up to room temperature and stirred for an additional two hours. Then, 2.59 g (10 mmoles) of 2-bromo-4′dimethoxyacetophenone (MW 259.1) was added and the reaction mixture stirred at room temperature for about eight hours. Afterwards, the reaction was quenched by adding 20 mL 20% NH₄Cl. The organic layer was removed and saved. The aqueous layer was extracted two times with 40 mL aliquots of THF. The THF extracts were combined with the saved organic layer and the mixture dried with 2.5 g anhydrous Na₂SO₄. The mixture was then concentrated in vacuo to provide a crude product. The crude product was purified by flash column chromatography using 40% EtOAc:Hexane followed by 60% EtOAc:Hexane. This produced 2.73 g (51% yield) of the (S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone (product) (MW 537.6). The product was compared to the starting material by TLC using 40% EtOAC/Hexane as the solvent. The Rf of the starting material was 0.2 and the Rf of the product was 0.4.
In the second step (FIG. 1B), the trityl group was removed from the (S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone. To 1.07 g (2.0 mmoles) of (S)-3-(2,5-dimethocyphenacyl)-5-trityloxymethyl-2-oxazolidinone in wet CH₂Cl₂(8 mL CH₂Cl₂, 1 mL H₂O), 0.14 mL CF₃CO₂H (210 mg, 1.8 mmoles) (MW 114.02) was added and the reaction mixture stirred for about four hours. Afterwards, the reaction was quenched by adding 0.2 mL triethylamine and the reaction mixture concentrated in vacuo. The residue was purified by flash chromatography to produce 472 mg (80% yield) of (S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone (product) (MW 295.29). The product was compared to the starting material by TLC using 80% EtOAC:Hexane as the solvent. The Rf of the starting material was 0.7 and the Rf of the product was 0.1.
In the third step (FIG. 1C), the library of ten substituted 2-oxazolidinones was produced in a reaction comprising the (S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone and the ten different acetyl chlorides shown in FIG. 2. To about 295 mg (1.0 mmoles) of (S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone in dry CH₂Cl₂(8 mL CH₂Cl₂), 1.0 equiv. (1.1 mmoles) of pyridine was added and the reaction mixture stirred at room temperature. To this reaction mixture was added 1.0 equiv. of a mixture of ten different acetyl chlorides. The reaction was stirred overnight at room temperature. Afterwards, TLC of an aliquot indicated that complete conversion of the (S)-3-(2,5-dimethocyphenacyl)-5-hydroxymethyl-2-oxazolidinone to (S)-3-(2,5-dimethocyphenacyl)-5-(substituted methyl)-2-oxazolidinone had occurred. Therefore, about 3 mL of 20% NH₄Cl was added to the reaction mixture and the organic layer removed and saved. The aqueous layer was extracted two times with 40 mL aliquots of CH₂Cl₂. The CH₂Cl₂extracts were combined with the saved organic layer and the mixture dried with 2.5 g anhydrous Na₂SO₄. The mixture was then concentrated in vacuo to provide a crude product. The crude product was analyzed by ¹H-NMR, ¹³C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent system.
An HPLC profile of the (S)-3-(2,5-dimethocyphenacyl)-5-(substituted methyl)-2-oxazolidinone products made is shown in FIG. 3. The products represented by the peaks in the HPLC are shown in FIG. 4. This example illustrates the principle of the present invention. As shown by this example, providing n=10 acetyl halides in a single reaction produces 10 (S)-3-(2,5-dimethocyphenacyl)-5-(substituted methyl)-2-oxazolidinone products. If n=10 aryl bromides had been used as well to arylate the N at the 3-position, the process would have generated 100 (S)-3-(substituted)-5-(substituted methyl)-2-oxazolidinone products.

EXAMPLE 4

The substituted oxazolidinone (S)-3-(3,3-dimethyl-2-butone)-5-(4-nitro-benzenesulfonyloxymethyl)-2-oxazolidinone
is prepared as follows.
In the first step, (S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone is produced in a reaction comprising (S)-5-trityloxymethyl-2-oxazolidinone and BrCH₂COC(CH₃)₃. To a solution of about 10 mmoles of (S)-5-trityloxymethyl-2-oxazolidinone in 40 mL tetrahydrofuran (THF) at 4° C., 10 mmoles NaH as a 60% suspension in hexane is added. The reaction mixture is stirred for about 10 minutes under nitrogen at 0° C. and then warmed up to room temperature and stirred for an additional two hours. Then, about 10 mmoles of BrCH₂COC(CH₃)₃is added and the reaction mixture stirred at room temperature for about eight hours. Afterwards, the reaction is quenched by adding 20 mL 20% NH₄Cl. The organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of THF. The THF extracts are combined with the saved organic layer and the mixture dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide (S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone as a crude product. The crude product is purified by flash column chromatography using 40% EtOAc:Hexane followed by 60% EtOAc:Hexane. The product is compared to the starting material by TLC using 40% EtOAC/Hexane as the solvent.
In the second step, the trityl group is removed from the (S)-3-(3,3-dimethyl-2-butone)-5-trityloxymethyl-2-oxazolidinone. To about 2.0 mmoles of the crude product in wet CH₂Cl₂(8 mL CH₂Cl₂, 1 mL H₂O), 0.14 mL CF₃CO₂H (1.8 mmoles) is added and the reaction mixture stirred for about four hours. Afterwards, the reaction is quenched by adding 0.2 mL triethylamine and the reaction mixture concentrated in vacuo. The residue is purified by flash chromatography to produce (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone. The product can be compared to the starting material by TLC using 80% EtOAC:Hexane as the solvent to determine the yield.
In the third step, the (S)-3-(3,3-dimethyl-2-butone)-5-(4-nitro-benzenesulfonyloxymethyl)-2-oxazolidinone is produced in a reaction comprising the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and nitrobenzenesulfonyl chloride. To about 1.0 mmoles of the ((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in dry CH₂Cl₂(8 mL CH₂Cl₂), 1.0 equiv. (1.1 mmoles) of pyridine is added and the reaction mixture stirred at room temperature. To this reaction mixture is added 1.0 equiv. of compound nitrobenzenesulfonyl chloride. The reaction is stirred overnight at room temperature. Afterwards, an aliquot of the reaction is analyzed by TLC to determine whether complete conversion of the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to the substituted oxazolidinone has occurred. Thereafter, about 3 mL of 20% NH₄Cl is added to the reaction mixture and the organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of CH₂Cl₂. The CH₂Cl₂extracts are combined with the saved organic layer and the mixture is dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide a crude product of the substituted oxazolidinone. The crude product is analyzed by ¹H-NMR, ¹³C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent system and is further purified by standard chromatography methods.

EXAMPLE 5

The substituted oxazolidinone (S)-3-(3,3-dimethyl-2-butone)-5-(4-isocyanobenzenesulfonyloxymethyl)-2-oxazolidinone

is prepared as follows.
(S)-3-(3,3-dimethyl-2-butone)-5-hydroxymethyl-2-oxazolidinone is prepared as in Example 4. Then the (S)-3-(3,3-dimethyl-2-butone)-5-(4-isocyanobenzenesulfonyloxymethyl)-2-oxazolidinone is produced in a reaction comprising the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and isocyanobenzenesulfonyl chloride as follows.
To about 1.0 mmoles of the ((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in dry CH₂Cl₂(8 mL CH₂Cl₂), 1.0 equiv. (1.1 mmoles) of pyridine is added and the reaction mixture stirred at room temperature. To this reaction mixture is added 1.0 equiv. of isocyanobenzenesulfonyl chloride. The reaction is stirred overnight at room temperature. Afterwards, an aliquot of the reaction is analyzed by TLC to determine whether complete conversion of the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to the substituted oxazolidinone has occurred. Thereafter, about 3 mL of 20% NH₄Cl is added to the reaction mixture and the organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of CH₂Cl₂. The CH₂Cl₂extracts are combined with the saved organic layer and the mixture is dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide a crude product of the substituted oxazolidinone. The crude product is analyzed by ¹H-NMR, ¹³C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent system and is further purified by standard chromatography methods.

EXAMPLE 6

The substituted oxazolidinone (S)-3-(3,3-dimethyl-2-butone)-5-(7-chloro-2,1,3-benzoxadiazole-4-sulfonyloxymethyl)-2-oxazolidinone (34)

is prepared as follows.
(S)-3-(3,3-dimethyl-2-butone)-5-hydroxymethyl-2-oxazolidinone is prepared as in Example 4. The substituted oxazolidinone 34 is then produced in a reaction comprising the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone and 7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride as follows.
To about 1.0 mmoles of the ((S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone in dry CH₂Cl₂(8 mL CH₂Cl₂), 1.0 equiv. (1.1 mmoles) of pyridine is added and the reaction mixture stirred at room temperature. To this reaction mixture is added 1.0 equiv. of compound 7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. The reaction is stirred overnight at room temperature. Afterwards, an aliquot of the reaction is analyzed by TLC to determine whether complete conversion of the (S)-3-(3,3-dimethyl-2-butanone)-5-hydroxymethyl-2-oxazolidinone to the substituted oxazolidinone 34 has occurred. Thereafter, about 3 mL of 20% NH₄Cl is added to the reaction mixture and the organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of CH₂Cl₂. The CH₂Cl₂extracts are combined with the saved organic layer and the mixture is dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide a crude product of the substituted oxazolidinone 34. The crude product is analyzed by ¹H-NMR, ¹³C NMR, HPLC, and TLC using a EtOAc:hexane (2:1) solvent system and is further purified by standard chromatography methods.

EXAMPLE 7

The substituted oxazolidinone (S)-3-(3-butene-2-one)-5-(7-chloro-2,1,3-benzoxadiazole-4-sulfonyloxymethyl)-2-oxazolidinone

is prepared as follows.
In the first step, (S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone is produced in a reaction comprising (S)-5-trityloxymethyl-2-oxazolidinone and BrCHCHCOCH₃. To a solution of about 10 mmoles of (S)-5-trityloxymethyl-2-oxazolidinone in 40 mL tetrahydrofuran (THF) at 4° C., 10 mmoles NaH as a 60% suspension in hexane is added. The reaction mixture was stirred for about 10 minutes under nitrogen at 00 C and then warmed up to room temperature and stirred for an additional two hours. Then, about 10 mmoles of BrCHCHCOCH₃is added and the reaction mixture stirred at room temperature for about eight hours. Afterwards, the reaction is quenched by adding 20 ML 20% NH₄Cl. The organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of THF. The THF extracts are combined with the saved organic layer and the mixture dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide (S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone as a crude product. The crude product is purified by flash column chromatography using 40% EtOAc:Hexane followed by 60% EtOAc:Hexane. The product is compared to the starting material by TLC using 40% EtOAC/Hexane as the solvent.
In the second step, the trityl group is removed from the (S)-3-(3-butene-2-one)-5-trityloxymethyl-2-oxazolidinone as in Example 4 to produce (S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone.
In the third step, the substituted oxazolidinone is produced in a reaction comprising the (S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone and 7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. To about 1.0 mmoles of the ((S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone in dry CH₂Cl₂(8 mL CH₂Cl₂), 1.0 equiv. (1.1 mmoles) of pyridine is added and the reaction mixture stirred at room temperature. To this reaction mixture is added 1.0 equiv. of 7-chloro-2,1,3-benzoxadiazole-4-sulfonyl chloride. The reaction is stirred overnight at room temperature. Afterwards, an aliquot of the reaction is analyzed by TLC to determine whether complete conversion of the (S)-3-(3-butene-2-one)-5-hydroxymethyl-2-oxazolidinone to the substituted oxazolidinone has occurred. Thereafter, about 3 mL of 20% NH₄Cl is added to the reaction mixture and the organic layer is removed and saved. The aqueous layer is extracted two times with 40 mL aliquots of CH₂Cl₂. The CH₂Cl₂extracts are combined with the saved organic layer and the mixture is dried with 2.5 g anhydrous Na₂SO₄. The mixture is then concentrated in vacuo to provide a crude product of the substituted oxazolidinone. The crude product is analyzed by ¹H-NMR, ¹³C NMR, HPLC, and TLC using an EtOAc:hexane (2:1) solvent system and is further purified by standard chromatography methods.

EXAMPLE 8

The substituted oxazolidinones were tested for antimicrobial activity as follows.
The following American Type Culture Collection (ATCC, 10801 University Boulevard, Manassas, Va.) quality control strains were selected for the initial screening of the antimicrobial properties of the substituted oxazolidinones as suggested by the NCCLS: Enterococcus faecalis 29212, Escherichia coli 25922, Pseudomonas aeruginosa 27853, and Staphylococcus aureus 29213. See, NCCLS document M7-A5. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. Volume 20, Number 2. January 2000, (ISBN 1-56238-394-9) and Lorian V. Antibiotics. Laboratory Medicine. 4th ed. Baltimore: Williams and Wilkins, pp. 52-111 (1996). For subsequent testing, the following strains have been used: Staphylococcus aureus NRS4 (992; HIP5836; New Jersey) (Smith et al., New Engl. J. Med. 340: 493-501 (1999); Tenover et al., J. Clin. Microbiol. 36: 1020-1027 (1998)), Staphylococcus aureus NRS3 (963sm; HIP5827; Michigan) (Smith et al., ibid.; Tenover et al., ibid.), Staphylococcus aureus NRS103 (Becker) (Karakawa and Vann, Sem. Infect. Dis. 4: 285 (1982), Staphylococcus aureus NRS102 (Reynolds) Karakawa and Vann, ibid; McMurray et al., JID 162: 759-762 (1990)), Staphylococcus epidermidis NRS101 (ATCC 35984), Streptococcus pneumoniae (ATCC 49619), Enterococcus faecalis (ATCC 51299), and Staphylococcus aureus (ATCC 43300.
Stock cultures of these strains were obtained by seeding colonies from overnight streak plates (Tryptic Soy Agar II (TSAII) and 5% sheep's blood (SB) agar plates: Becton Dickinson, CA#2211261) into sterile Mueller-Hinton Broth (MHB)(Becton Dickinson, CA#211443) and growing the suspensions to mid-late log phase in 13 mL screw-cap tubes. Glycerol (Sigma, CA#G-6279) was sterilized by autoclaving for 15 minutes at 121° C. in 6 mL volumes, and then stored at 2-8° C. This was diluted to 20% in dH₂O, and then added 1:1 (250 μL:250 μL, 10% final glycerol concentration) to the logarithmically growing bacterial suspension of each strain. Tubes were frozen and stored at −70° C. Purity of the stock cultures was tested by thawing one tube of each strain in a water bath at 37° C. and plating them on TSAII with 5% SB. Plates were incubated overnight at 37° C. and colonies were examined for morphology. Growth curves and approximate CFU/mL were also obtained.
DMSO susceptibility determinations were performed as follows. DMSO (Alfa Aesar, CA#22914) was diluted to 2× the final starting concentration of 20% in MHB, pH 7.36 (this was the consistent pH value of MHB) (should be between 7.2-7.4 according to NCCLS). Two-fold serial dilutions were performed in 15 mL conical tubes and poured into sterile reservoirs. Using an 8-channel micropipetman, 50 μL from each reservoir was transferred to every well in the corresponding column (1-11) of a sterile 96-well, U-bottom microplate (Nalge Nunc, Intl., CA#262162). As a positive growth control, 50 μL of MHB alone was added to each well of Column 12. Bacteria were grown overnight on TSAII +5%SB, and 3-4 colonies were seeded into 6 mL of sterile MHB in 13 mL screw cap tubes. Tubes were grown at 35° C. to mid-log phase, and were diluted to an optical density of 0.12 at 625 nm (or approx. 1×10⁸CFU/mL), using 0.9% sterile saline. This solution was further diluted 1:100 with 0.9% sterile saline (1×10⁶CFU/mL), and 50 μL was added to each well for a final inoculum of 1×10⁵CFU/mL. As a negative growth control, well H12 was inoculated only with 0.9% sterile saline. The plate was tightly fitted with sealing tape (Corning Costar, CA#3095) and was incubated for a period of 18 hours at 35° C., after which growth was observed. 2.5% DMSO was determined to be the smallest concentration of DMSO to exhibit no visual effects on bacterial growth as compared with the positive controls for all strains tested. This was confirmed by performing colony counts to assess cell viability in the presence of DMSO. For each strain, 10 μL was removed from one of the inoculated wells containing 2.5%, 0.15%, and 0% DMSO (after mixing). This was diluted 1:100000 in sterile 0.9% DMSO, plated on TSAII +5%SB, and grown overnight at 35° C. Plates were then observed for differences in the number of viable colonies (theoretically, each colony arises from a single cell) based on the varying concentrations of DMSO. No differences were observed.
High purity substituted oxazolidinones prepared according to the method of the present invention and a ZYVOX standard (ZYVOX is a trade name for linezolid available from Pharmacia Corporation) were provided by Synthon Corporation, Monmouth Junction, N.J. Compounds were dissolved at 10 mg/mL in DMSO, as after a dilution of approx. 39.0 to reach the desired final starting concentration of 256 ug/ml, the concentration of DMSO is approximately 2.5%. Compounds were then stored at room temperature (25° C.) in the dark.
Antimicrobial susceptibility screening was as follows. All compounds were initially screened for activity in duplicate at 256 μg/mL (2.5% DMSO), including ZYVOX, the positive control for antimicrobial activity. A single well of bacterially inoculated 2.5% DMSO served as a positive control for bacterial growth, while a well of DMSO inoculated with of 50 μL of sterile 0.9% saline served as a negative growth control. Controls were prepared on every microplate, so that 46 was the maximum number of compounds that were screened per plate. Broth was pipetted into sterile microcentrifuge tubes, to which the compounds were then added (1:19.53 dilution or 2× final concentration). Each tube was vortexed, and 50 μL was immediately transferred to the microplate wells for each strain. Solubility was assessed by visual observation. MB (medium broth solubility) was recorded if the solution appeared only slightly cloudy. LB (low broth solubility) was recorded if the solution was extremely cloudy, and especially if larger, clumpy precipitates formed. Bacteria were grown as described above, although absorbance was measured at 650 nm and bacteria were diluted to an initial OD of 0.12-0.15. Bacteria were then further diluted 1:100 with 0.9% sterile saline. Within 15 minutes of this final dilution, 50 μL of this suspension was added to each well for a final volume of 0.1 L, and a final bacterial concentration of 1×10⁵CFU/mL (except for the negative control well). Plates were grown as above and all observations were recorded.
Compounds exhibiting activity at this concentration were then screened for their MICs (minimum inhibitory concentration) in duplicate, at concentrations ranging from 256-0.25 μg/mL (columns 1-11) using the broth microdilution method. Two-fold dilutions were obtained using an 8-channel micropipetman and tips were changed between each column transfer, after mixing 10 times and expelling the maximum amount of fluid. The MIC was defined as the lowest concentration of test compound that inhibited visible growth after a period of 18 hours incubation at 35° C. Bacteria were prepared, and the microwell plates were incubated as described above. In addition, bacteria were routinely sampled before addition to the wells. From the pre-well concentration, samples were diluted 1:200 with 0.9% sterile saline. At this concentration, 100 μL was plated and the remaining sample was diluted 1:10. 100 μL of this was then also spread-plated onto TSAII +5% SB and grown overnight at 35° C. Colonies were counted and multiplied by the dilution factor to obtain starting CFU/mL. As a positive MIC control, ZYVOX was tested in parallel for each strain, and the dilution of 5% (2× final concentration) DMSO served as a positive growth control. To control for variation between the volume transferred by each tip of the 8-channel micropipetman, 5% (2× final concentration) DMSO was added to column 12 using the micropipetman. All wells, but that of the negative control (H12), were inoculated with the same bacterial suspension resulting in a final starting concentration of 1×10⁵CFU/mL. The negative control was inoculated with 0.9% sterile saline.
At this time, a total of 1625 substituted oxazolidinones have been successfully screened for activity at 256 pg/mL (Compounds 1422, 1474, 147$, 1595 were absent). Of these, 71 were tested against Staphylococcus aureus (Gram positive), 60 were tested against Enterococcus faecalis (Gram positive), and one compound tested against Escherichia coli (Gram negative) have proven effective with MICs at or below 256 μg/mL.

Tables 1 and 2 show the antimicrobial activity for several of the substituted oxazolidinones. Table 1 further shows that several were also able to inhibit the growth of myeloid, erythroid, and megakaryocytic cells. Table 3 shows several substituted oxazolidinones which have been found to be particularly antimicrobial. In general, many of the substituted oxazolidinones were as effective as ZYVOX. Thus, the results show that many of the substituted oxazolidinones prepared according to the process herein have antimicrobial applications, in particular, as antimicrobial agents against drug resistant strains of gram positive bacteria.

TABLE 1


In Vitro Antimicrobial Test Results for Several Substituted Oxazolidinones

		Bone Marrow Cell Growth Inhibition
	MIC_90-100(μg/mL)	(IC₅₀μg/mL)

SA

EF

MR SA

VS EF

MR SA

Pen. R SA

Ref SA

Myeloid

Erythroid

Megakaryocytic

Strain	ATCC	ATCC	New	Michigan	ATCC	ATCC	Reynolds	Becker
	29212	29213	Jersey		51299	43300
Compound
1687	2	2	2	2			3	3	20	0.01	6
1705	2	4	3	2	8	4	32	4	5	0.5	0.08
1715	2	4	3	3	8	4	32	8	5	0.7	0.08
1808	4-8	2	4	3	2	8	16	16
1809	4-8	4	3	3	2	4	8	4
2278	4	2	4	4			8	8
2405	2	2	4	2			8	4
2428	4	4	4-8	4-8			32	16
1021	16-32	250	256	256	>256	100			20	20	0.9
1192	4-8	250	256	256	>256	128			5	0.05	0.6
126	8-16	250	256	256	256	256			5	0.02	9.0
207	64-125	250							0.8	0.2	3.0
253	8-16	250	256	256	>256	>256			30	7	10.0
971	4-8	250	256	256	>256	100			40	>0.01	30.0
ZYVOX	2	2	2	2	0.5	1	1	1	20	0.08	4

VR is vancomycin resistant,
VS is vancomycin sensitive,
MR is methicillin resistant,
MS is methicillin sensitive,
SA is Staphylococcus aureus, and
EF is Entercoccus faecalis.

TABLE 2


		MIC_(90-100)(ug/mL)	MIC_(90-100)(ug/mL)
COMPOUND	COMPOUND #	SA-ATCC 29213	EF-ATCC 29212


34	250

108	62.5

110	31.3

126	15.6

235	62.5

236	31.3

250	250

253	15.6

254	125

255	62.5	250

260	250

266	15.6

272	250

276	125	250

285	62.5	250

291	250

294	31.3	250

323	250	125

324	62.5	250

334	62.5

369	250	31.3

388	125

401	250	62.5

533	125

589	125

669	62.5

674	250	125

695	62.5

771	15.6

860	64

870	16

905	256

921	256

924	256

929	64

942	32

952	32

971	8

1001	64	125

1021	32

1026	256

1058	256

1063	16

1066	256

1081	256

1097	32

1160	128

1192	8

1196	256	128

1210	256

1141	64	128

1629	256	64

1631	16	16

1632	16	64

1808	8	2

1809	8	4

1960	32	8

1965	32	8

1985	8	124

1998	16	64

2017	16	8

2019	16	32

2020	64	124

2023	64	32

2025	64	32

TABLE 3


External ID	internal ID	Structure


SCC 001	126

SCC 002	207

SCC 003	253

SCC 004	971

SCC 005	1021

SCC 006	1192

SCC 007	1687

SCC 008	1705

SCC 009	1715

SCC 010	1808

SCC 011	1809

SCC 012	2278

SCC 013	2405

SCC 014	2428

SCC 015	2570

Standard	Zyvox

EXAMPLE 9

This example shows the synthesis of various examples of the substituted oxazolidinones.
A. Sulphonates and esters
1. Synthesis of Precursors

N-Ethyl 5-hydroxymethyl-2-oxazolidinone

To a solution containing the oxazolidinone (5.0 g, 13.9 mmol) in dry THF (50 mL) was added potassium-t-butoxide (2.03 g, 18.1 mmol, 1.3 equiv) at RT and stirred under N₂atm for 0.5 h. To this solution was added ethyl iodide (3.25 g, 20.8 mmol, 1.5 equiv) and stirred for 2h after which TLC (1:1 hex-EtOAc) showed completion of reaction. The reaction was quenched by adding satd. NH₄Cl solution. THF was removed on rotovap and residue diluted with CH₂Cl₂(100 mL). Organic layer washed with brine and dried (MgSO₄). Removal of solvent gave a light yellow oil. This crude product was taken in CH₂Cl₂(50 mL). Added trifluroacetic acid (4.75 g, 41.7 mmol, 3.0 equiv)-water (1.0 g, 55.5 mmol, 4 equiv) dropwise and stirred for 2 h. The solvent was removed on rotovap and residue purified by flash column chromatography (silica gel, EtOAc) to get the product as a colorless oil (1.3 g, 66% in two steps).
¹H NMR(CDCl₃, 200 MHz): δ 4.6 (m, 1H), 4.1 (s, 1H), 3.88 (dd, 1H)3.6 (m, 5H), 1.2 (t, 3H). ¹³C NMR (CDCl₃, 50 MHz): δ 157.86, 73.45, 62.69, 45.01, 38.59, 12.22.
A similar procedure was followed for the alkylation of the oxazolidinone with B12 (R&S), B38(R&S), B39, E11(R&S), E16(R&S), E81(R&S), G3(R&S), G4-oxa-C4, W14, W15, W17, W19 and W23.

N-isopropyl-5-trityloxymethyl-2-oxazolidinone

To a solution containing the oxazolidinone (15.0 g, 41.7 mmol) in dry THF (150 mL) was added potassium-t-butoxide (8.4 g, 75.0 mmol, 1.8 equiv) at RT and stirred under N₂atm for 0.5 h. To this solution was added isopropyl iodide (7.8 g, 45.9 mmol, 1.1 equiv) and stirred at 70° C. for 15 h. The reaction was quenched by adding satd. NH₄Cl solution. THF was removed on rotovap and residue diluted with CH₂Cl₂(200 mL). Organic layer washed with brine and dried (MgSO₄). Removal of solvent gave a light yellow oil. The residue was purified by flash column chromatography (silica gel, hexane-EtOAc, 4:1) to get the product as a colorless solid (15.0 g, 90%).
¹H NMR(CDC₁, 200 MHz): δ 7.3 (m, 15H), 4.56 (m, 1H), 4.1 (m, 1H), 3.3 (m, 4H), 1.1 (m, 6H). ¹³C NMR (CDCl₃, 50 MHz): δ 157.0, 143.4, 128.6, 127.9, 127.2, 86.8, 71.9, 64.0, 44.6, 41.6, 19.8, 19.6.

Synthesis of ethyl (2-bromo)-t-butyl ketone (class G4)

To a suspension of SnBr₂(242 mg, 5 mol %) in CH₂Cl₂(5.0 mL) was added pinacolone trimethylsilyl enol ether (3.0 g, 17.4 mmol) in CH₂Cl₂(2.0 mL) followed by bromomethyl methylether (3.26 g, 26.1 mmol, 2.1 mL, 1.5 equiv) in CH₂Cl₂(2.0 mL). Stirred at RT for 3.5 h after which TLC showed complete conversion. The solvent was removed on rotovap to get an orange yellow liquid. The crude product was passed through a short pad of silica packed in hexane and the product was eluted with 5% EtOAc-hexanes as a pale yellow liquid (2.65 g, 79%). ¹H NMR(CDCl₃, 200 MHz): δ 3.54(t, 2H), 3.06(t, 2H), 1.12(s, 9H). ¹³C NMR (CDCl₃, 50 MHz): δ 212.4, 43.9, 39.6, 26.0.

Homologation of t-butylacetyl chloride

t-Butylacetyl chloride (4.0 g, 29.7 mmol) was added dropwise to a solution of trimethylsilyldiazomethane (37.1 mL, 74.3 mmol) in CH₃CN-THF (100 mL, 1:1) at 0° C. added the t-butylacetyl chloride (4.0 g, 29.7 mmol) dropwise and then refrigerated for 40 h. Solvent was removed on rotovap and residue diluted with CH₂Cl₂(100 mL). Washed with satd. NaHCO₃(50 mL) solution followed by brine, dried (MgSO₄) and concentrated to an yellow liquid (4.5 g). This product was taken in THF (25 mL) and cooled to 0° C. and added HBr (48%) (8.4g, 104.0 mmol, 3.5 equiv) dropwise. After the addition, reaction mixture stirred at that temp for 30 min. Diluted with CH₂Cl₂(75 mL) and washed with satd. NaHCO₃(50 mL) followed by brine, dried (MgSO₄) and concentrated to an yellow liquid. Purified by column chromatography (silica gel) and the product was eluted with 2-4% EtOAc-hexane. Pale yellow liquid (3.3 g, 82.5%).
₁H NMR (CDCl₃, 200 MHz): δ 3.84(s, 2H), 2.48(s, 2H), 0.98(s, 9H). ¹³C NMR (CDCl₃, 50 MHz): δ 200.8, 51.7, 36.2, 31.1, 29.4.
Following a similar procedure W14, W15, W19, W23 were prepared from corresponding acid chlorides.

Synthesis of C4-Oxazolidinone

4,4-dibenzylamino-1,3-(S)butanediol

R.B charged with LiBr (14.8 g, 170.8 mmol, 4.0 equiv), NaBH₄(6.37 g, 170.8 mmol, 4.0 equiv) and THF (125 mL) and stirred at 50° C. for 2 h. Added the ester (14.0 g, 42.7 mmol, 1.0 equiv) in THF (25 mL) slowly and stirring continued for 2 h (TLC no SM). Reaction mixture cooled to RT and added satd. NH₄Cl dropwise (cool in ice-bath) till no gas evolution. Most of the THF was removed on rotovap and residue diluted with EtOAc (250 mL). Washed with brine, dried (MgSO₄) and concentrated to a colorless oil and purified by column chromatography (70% EA-hexane). Product obtained as a colorless syrup (yield: 9.2 g, 77%).
¹H NMR(CDCl₃, 200 MHz): δ 7.2(m, 10H), 3.8(m, 6H), 3.4(d, 2H), 2.4(m, 2H), 1.6(m, 2H). ¹³C NMR (CDCl₃, 50 MHz): δ 138.3, 128.9, 128.3, 127.2, 66.8, 60.7, 59.5, 58.4, 36.3.

4-Amino-1,3-(S)butanediol

THF-MeOH (30+40 mL) suspension containing the diol (9.0 g, 31.5 mmol) and wet Pd(OH)₂(10%, 3.5 g) was hydrogenated under 40 psi (2.81 kgf/cm²) for 20 h. The solution warmed and the hot solution filtered through a short pad of celite. Washed several times with methanol (towards the end few drops of TEA added). Removal of solvent gave a colorless oil (3.3 g, quantitative).

4-(Benzyloxycarbonyl)-amino-1,3-(S)butanediol

R. B. charged with the amine (3.3 g, 31.3 mmol, 1.0 equiv) and THF-H₂O (20+40 mL). Added Na₂CO₃(4.0 g, 37.8 mmol, 1.2 equiv) and cooled to 5° C. Added CbzCl (6.45 g, 37.8 mmol, 5.4 mL, 1.2 equiv) dropwise keeping temp. below 5° C. and stirred at that temp. for 3 h. Diluted with water (100 mL) and extracted into EtOAc (3×100 mL). Washed with brine, dried (MgSO₄) and concentrated to a colorless oil which solidified on keeping (9.0 g).
¹H NMR(CDCl₃, 200 MHz): δ 7.2(s, 5H), 5.6(s, 1H), 5.0(s, 2H), 3.5(m, 7H), 1.6(m, 2H). ¹³C NMR (CDCl3, 50 MHz): δ 157.1, 136.2, 128.4, 128.0, 127.9, 70.2, 66.8, 60.4, 46.9, 35.7.

4-(Benzyloxycarbonyl)-amino-1(O-trityl)-3-(S)butanediol

Reaction mix. containing the crude diol (˜9.0 g, 31.5 mmol, 1.0 equiv), TrCl (10.5 g, 37.6 mmol, 1.2 equiv) and TEA (7.96 g, 78.6 mmol, 2.5 equiv) in CH₂Cl₂(100 mL) stirred at RT for 21 h. The reaction mixture washed with water, brine and dried (MgSO₄) and concentrated to a pale yellow oil (20.0 g).

5-trityloxyethyl-2-oxazolidinone

The above crude product (20 g, ˜31.5 mmol based on purity) taken in anhydrous THF (150 mL) and treated with KtBuO (7.84 g, 70 mmol, 2.2 equiv) and stirred at RT for 7 h. Diluted with water (100 mL), bulk of the THF removed on rotovap. Residue extracted with EtOAc (3×100 mL), washed with brine, dried (MgSO4) and concentrated to a light brown oil. Purified by column chromatography (40% EtOAc-hexane) to get a pale yellow foamy oil which solidifies (10.7 g, 91% in three steps).
¹H NMR(CDCl₃, 200 MHz): δ 7.25(m, 15H), 5.75(s, 1H), 4.8(m, 1H), 3.6(t, 1H), 3.2(t, 3H), 2.0(m, 2H). ¹³C NMR (CDCl₃, 50 MHz): δ 159.6, 143.8, 128.5, 127.8, 127.0, 86.9, 75.0, 59.3, 46.0, 35.2.

N-(4-nitrophenyl)-5-trityloxymethyl-2-oxazolidinone

The reaction mixture containing the oxazolidinone (5.0 g, 13.9 mmol), 4-bromonitrobenzene (4.2 g, 20.8 mmol,. 1.5 equiv), 1,1′bis(diphenylphosphinoferrocene) (0.77 g, 1.39 mmol, 0.1 equiv), Pd(OAc)₂(0.31g, 1.39 mmol, 0.1 equiv) and sodium-t-butoxide (2.0 g, 20.8 mmol, 1.5 equiv) in dry toluene (130 mL) was stirred under N₂atm at 110° C. for 8 h. The solvent was removed on rotovap and the dark residue was chromatographed on silica gel using 30% EtOAc-hexane to get the product as a dark yellow foamy solid (2.7 g, 41%).
¹H NMR(CDCl₃, 200 MHz): δ 8.2(d, 2H), 7.6(d, 2H), 7.2(m, 15H), 4.8(m, 1H), 4.2(t, 1H), 3.9(m, 1H), 3.8(dd, 1H), 3.4(dd, 1H). ¹³C NMR (CDCl₃, 50 MHz): δ 155, 145, 144, 129.5, 129.3, 129, 126, 118, 87, 72, 64, 47.
2. Synthesis of Library-Sulphonates and Esters
0.1 mM solution of the oxazolidinone in CH₂Cl₂(25 mL) was prepared. From the above std. soln. syringed out 1.0 mL each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28 μL/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the stock solution (0.10 mM) of acid/sulphonyl chlorides into respective vials. The vial capped, the solution mixed well and kept aside at RT (20 h). All compounds purified by prep. TLC. (EtOAc-hexane). Silica gel band containing the product was taken in CH₃CN (15.0 mL). Filtered and washed with more CH₃CN (3 mL), and solvent removed on-rotovap. The product obtained was transferred to small vials using CH₂Cl₂, all samples air dried and finally dried in vacuo. All samples were analyzed by LCMS.

Oxazolidinones and sulphonyl/acid chlorides used:
B12: K2, K4, K5, K8, K9, K10, K11, E112
B12(R): K2, K10, K21, K22, K23, K83, E112
B38: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E0, E1, E4, E7, E8, E9, E10, E11, E15, E16, E112
B38(R): K10, E112, E117, E120, E124, E136, E154,
B39: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E0, E1, E4, E7, E8, E9, E10, E11, E15, E16, E112
E11: K2, K4, K5, K8, K9, K10, K11, E112
E11(R): K2, K10, K21, K22, K23, K83, E112
E16: K00, K0, K1, K2, K3, K4, K5, K6, K7, K8, K9, K10, K11, E14, E0, E1, E4, E7, E8, E9, E10, E11, E15, E16, E112
E16(R): K2, K10, K21, K22, K23, K83, E8, E112
E81: K4, K5, K8, K9, K10, K11, E112
E81(R): K2, K10, K21, K22, K23, K83, E112
G4: K2, K4, K5, K8, K10, K11, K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83, K90, K91, K92, K93, K94, K95, K96, K97, E4, E11, E81, E82, E90, E107, E112, E113, E117, E159, E164, E168
G4(R): K10, K21, K22, K23, K83,
G5: K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12, K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102, K117, E8, E11, E81, E82, E90, E107, E112, E113, E117, E120, E124, E136, E154, E159, E164, E168, E183, E184
G5(R): K10, K11, K12, K21, K22, K23, K83
G9(R): K2, K90, K91, K92, K93, K9.4, K95, K96, K97, K98, K99, K100, K101, K102, K117,
G12: K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12, K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102, K104, K105, K106, K107, K109, K110, K112, K113, K114, K115, K117,
G12(R): K2, K101, K102, K117, E112, E183, E184
G13(R): K00, K0, K1, K2, K3, K4, K5, K8, K9, K10, K11, K12, K21, K22, K23, K27, K30, K52, K54, K55, K56, K59, K60, K66, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102, K104, K105, K106, K107, K109, K110, K112, K113, K114, K115, E112, E183
W14: K101, K102, K104, K105, K106, K107, K109, K110, K112, K113, K114, K115, E112, E183
W15: K10, K21, K22, K23, K83, E8, E11, E81, E82, E90, E107, E112, E113, E117, E120, E124, E136, E154, E159, E164, E168
W17: K2, K4, K9, K10, K11, K12, K21, K27, K29, K30, K31, K52, K53, K54, K55, K56, K59, K60, K61, K66, K70 E8, E11, E81, E82, E90, E107, E112, E113, E159, E164, E168
W19: K10, K11, K12, K21, K22, K23, K83 E8, E11, E81, E82, E90, E107, E112, E113, E117, E120, E124, E136, E154, E157, E159, E164, E168
W23: K2, K4, K9, K10, K11, K21, K22, K23, K27, K29, K30, K31, K52, K53, K54, K55, K56, K59, K60, K61, K66, K70, K83, E8, E11, E81, E82, E90, E107, E112, E113, E117, E120, E124, E136, E154, E157, E159, E164, E168
G12-oxa-C4: K2, K10, K11, K93, K95, K96, K97, K100, K101, K102, K104, K105, K106, K107, K109, K110, K112, K115, K117, E183, E184
G3-oxa-C4: K2, K10, K11, K93, K95, K96, K97, K100, K101, K102, K104, K105, K106, K107, K109, K110, K112, K115, K117, E183, E184

Amines

A. Amides and Sulphonamides
1. Synthesis of Precursors

(5R)-methanesulphonyloxymethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)

To an ice-cooled solution of the oxazolidinone (5.0 g, 22.6 mmol, 1.0 equiv) in CH₂Cl₂(50 mL) was added TEA (4.57 g, 45.1 mmol, 2.0 equiv) followed by MsCl (3.36 g, 29.3 mmol, 1.3 equiv) dropwise and then stirred for 2 h. Diluted with CH₂Cl₂(50 mL), washed with water (25 mL), brine, dried (MgSO₄) and concentrated to get an oil which solidified on keeping (6.5 g, 97%).
¹H NMR (CDCl₃, 200 MHz): δ 7.4 (s, 5H), 5.25 (m, 1H), 4.7 (m, 1H), 4.4 (m, 2H), 3.4 (m, 2H), 3.15 (s, 3H), 1.65(d, 3H). ¹³C NMR (CDCl₃, 50 MHz): δ 156.1, 138.9, 128.5, 127.8, 126.7, 69.8, 68.8, 51.5, 41.3, 37.4, 16.0.

(5R)-Azidomethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)

Reaction mixture containing the mesylate (6.5 g, 21.7 mmol) and NaN3 (2.12 g, 32.6 mmol, 1.5 equiv) in DMSO (60 mL) was stirred at 80° C. for 3 h under N₂atm. Then cooled to RT, diluted with water (100 mL) and CH₂Cl₂(150 mL). Organic layer washed with brine, dried (MgSO₄) and concentrated to a pale yellow liquid. Crude product filtered through a short pad of silica using 40% EtOAc-hexane. Colorless oil which crystallized on keeping (5.0 g, 94%).
¹H NMR (CDCl₃, 200 MHz): δ 7.4 (s, 5H), 5.3 (m, 1H), 4.6 (m, 1H), 3.4 (m, 4H), 1.66 (d, 3H). ¹³C NMR (CDCl₃, 50 MHz): δ 156.4, 139.0, 128.6, 127.8, 126.8, 71.1, 53.1, 51.4, 42.3, 16.0

(5R)-Aminomethyl-3-[(1R)-phenylethyl-oxazolidine-2-one)

R.B charged with Pd-C (10%, 500 mg) and ethanol (10 mL). Added oxazolidinone (2.0 g) in ethanol (10 mL). Flushed with H₂three times and stirred under H₂overnight (17 h). Filtered through a short celite pad and washed with methanol. Solvent removed on rotovap to a light orange oil. Purified by silica gel column (20-50% MeOH in EtOAc) to get a light orange oil which solidifies on keeping (1.1 g, 62%).
¹H NMR (CDCl₃, 200 MHz): δ 7.4 (s, 5H), 5.3 (m, 1H), 4.6 (m, 1H), 3.4 (m, 2H), 3.1 (t, 2H), 2.8 (s, 2H), 1.66 (d, 3H). ¹³C NMR (CDCl₃, 50 MHz): δ 157.1, 139.4, 128.6, 127.8, 126.9, 73.7, 58.0, 51.4, 42.6, 16.2.
Amines belonging to classes G3, G5, G9, G12, B38 (both isomers), G3-oxa-C4, G12-oxa-C4 were prepared in a similar manner.

2. Library-Synthesis
0.1 mM Solution of the oxazolidinone in CH₂Cl₂(25 mL) was prepared. From the above std. soln. syringed out 1.0 mL each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28 μL/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the stock solution (0.10 mM) of acid/sulphonyl chlorides into respective vials. The vial capped, the solution mixed well and kept aside at RT (20. h). All compounds purified by prep. TLC. (EtOAc-hexane). Silica gel band containing the product was taken in CH₃CN (15.0 mL). Filtered and washed with more CH₃CN (3 mL), and solvent removed on rotovap. The product obtained was transferred to small vials using CH₂Cl₂, all samples air dried and finally dried in vacuo. All samples were analyzed by LCMS.
Other Amines used for the library: G3(R), G5(R), G5(S), G12(R), G9(R), G9(S), G13(S).
Sulphonyl/acid chlorides used:

B38: K1, K9, K10, K11, K21, K22, K23, K83, E112
G12-oxa-C4: K2, K93, K95, K96, K97, K99, K100, K101, K102, K117, E183, E184
G12: K2, K93, K95, K96, K97, K99, K100, K101, K102, K117, E183, E184
G9(R): E183, E184
G9(S): E183, E184
G5: K00, K0, K1, K2, K3, K4, K5, K8, K10, K11, K12, K21, K22, K23, K83, K90, K91, k92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102, K117,E183, E112, E184
G5(R): K2, K93, K95, K96, K97, K99, K100, K101, K102, K117, E183, E184
G3(R): K2, K93, K95, K96, K97, K100, K101, K102, K117, E183, E184
G13(R): K00, K0, K1, K2, K5, K9, K10, K11, K12, K21, K22, K23, K52, K60, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100, K101, K102, E183,
B. Urea Type Compounds

Oxazolidinone (0.1 mmol, 14 mg) in CH₂Cl₂(1.0 mL) treated with the respective isocyante (0.1 mmol) In cases where the solution was not homogeneous 0.5 mL THF was also added. Reaction mixture kept at RT for 16 h and purified by prep. TLC (hexane-EtOAc). All products were analyzed by LCMS.
Other amines used for the library: G12(R), G12(S), G5(S), G9(R), G9(S),
Isocyanates used for the library:

G12(R): DD2, DD3, DD4, DD5, DD6, DD7
G12: DD2, DD3, DD4, DD5, DD6, DD7
G5: DD2, DD3, DD4, DD5, DD6, DD7
G5(R): DD2, DD3, DD4, DD5, DD6, DD7
G12-oxa-C4: DD2, DD3, DD4, DD5, DD6, DD7
G9(R): DD2, DD3, DD4, DD5, DD6, DD7
G9(S): DD2, DD3, DD4, DD5, DD6, DD7
G3: DD2, DD3, DD4, DD5, DD6, DD7
C. Sulphenyl Compounds

0.1 mM solution of the oxazolidinone in CH₂Cl₂(5 mL) was prepared. From the above std. soln. syringed out 1.0 mL each (0.10 mmol) into 3 mL capped vials. Added triethylamine, 28 μL/vial (0.2 mmol, 2.0 equiv). Added 1.0 mL (0.10 mmol) of the stock solution (0.10 mM) of sulphenyl chlorides into respective vials. The vial capped, the solution mixed well and kept aside at RT (20 h). All compounds purified by prep. TLC. (EtOAc-hexane). Silica gel band containing the product was taken in CH₃CN(15.0 mL). Filtered and washed with more CH₃CN (3 mL), and solvent removed on rotovap. The product obtained was transferred to small vials using CH₂Cl₂, all samples air dried and finally dried in vacuo. All samples were analyzed by LCMS.
Amines used for the library: G5, G12, G9, G9(R), G12-oxa-C4
Oxazolidinones and sulphenyl chlorides used:

G5: BB3, BB5, BB7, BB9
G5(R): BB3, BB5, BB7, BB9
G12: BB3, BB5, BB7, BB9
G12(R): BB3, BB5, BB7, BB9
G9: BB3, BB5, BB7, BB9
G9(R): BB3, BB5, BB7, BB9
G12-oxa-C4: BB3, BB5, BB7, BB9
D. Substituted Aryl Amines-Buchwald Coupling

The reaction mixture containing the aminooxazolidinone (50 mg, 0.35 mmol), CuI (3.3 mg, 5 mol %), K₃PO₄(148.6 mg, 0.70 mmol, 2 equiv), ethyleneglycol (43.4 mg, 0.70 mmol) and the aryl iodide (0.52 mmol, 1.5 equiv) in isopropanol (1.5 mL) was stirred at 70° C. for 24 h. Reaction mixture was cooled and filtered. Filtrate purified by prep. TLC. Products were analyzed by LCMS.
Other amines used for library: G5(R), G9(R), G9(S), G12(R)

Oxazolidinones and aryl iodides used:

G9(S): AA6, AA7, AA9, AA11, AA12 AA16, AA17, AA18, AA26, AA35
G9(R): AA6., AA7, AA9, AA16, AA17, AA18, AA26, AA35
G12(R): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA27, AA35
G12(S): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA35
G5(R): AA6, AA7, AA9, AA16, AA17, AA18, AA26, AA35

Ether Derivatives

5-Tosyloxymethyl-N-isopropyl-2-oxazolidinone

CH₂Cl₂(25 mL) solution containing the oxazolidinone (2.3 g, 14.4 mmol, 1.0 equiv) was cooled in ice-bath. Added TEA (3.65 g, 36.1 mmol, 2.5 equiv) followed by TsCl (4.1 g, 21.5 mmol, 1.5 equiv) in small portions. Stirring continued at 0° C-RT (7 h). Diluted with more CH₂Cl₂(50 mL), washed with 1N HCl (50 mL), water, brine, dried (MgSO₄) and concentrated to a brown liquid. Crude product passed through a silica gel column (60% EtOAc-hexane) to get the product as a colorless solid (4.3 g, 96%).
¹H NMR(CDCl₃, 200 MHz): δ 7.5 (ABq, 4H), 4.6 (m, 1H), 4.0 (m, 3H), 3.5 (t, 1H), 3.3 (dd, 1H), 2.39 (s, 3H), 1.2 (m, 6H). ¹³C NMR (CDCl₃, 50 MHz): δ 155.8, 145.2, 131.9, 129.9, 127.7, 69.5, 68.7, 44.7, 40.9, 21.4, 19.4, 19.3.
3.0 mL vial charged with 1-naphthol (12.7 mg, 0.09 mmol, 1.1 equiv) and THF (1.0 mL). Added KtBuO (13.4 mg, 0.12 mmol, 1.5 equiv). Stirred for 30 min. at RT. Added the tosylate (25 mg, 0.08 mmol, 1.0 equiv) in THF (1 mL). Stirred at RT for 2.0 h. Purified by prep. TLC (EtOAc-hexane) to get the pure product. Analyzed by LCMS.
Other libraries synthesized
To a solution containing the oxazolidinone (14.4 mg, 0.1 mmol), PPh₃-polystyrene (120 mg,1.2 equiv, loading 1.0 mmol/g), phenol (0.1 mmol, 1.0 equiv) and CH₂Cl₂(1.0 mL). Added DIAD/DEAD (1.2 equiv) in THF (1.0 mL) slowly. Stirred gently for 24 h. The crude product was purified by prep. TLC (hexane-EtOAc).
Other libraries synthesized: G9, G5
Alcohols/phenols used:

B38: M1, M2, M3, M4, M5, M6, M14, M37, M38,
B39: M3, M5, M35, M38
G5: M39, M42, M43, M44, M45, M46, M47
G12(S): M1, M2, M3, M4, M5, M6, M11, M13, M14, M24, M30, M34, M35, M37, M38, M39, M40, M41, M42, M43, M44, M45, M46, M47
G12(R): M40, M41
G9(R): M1, M2, M3, M4, M5, M6, M11, M13, M14, M24, M30, M34, M35, M37 ,M38, M39, M40, M41,

Sulphonylchlorides (K):

Phenols (M):

Aryl Iodides (AA):

Sulphenyl Chlorides (BB), Isocyantes (DD):

Experimental
1. Preparation of the Precursors of Libraries.
General Methods. Column chromatography was performed on silica gel. TLC was performed on silica gel GF254. NMR spectra were recorded with an Varian VXR-200 NMR spectrometer ¹H NMR and ¹³C NMR spectra were recorded at either 200 MHz or 50 MHz. LC-MS was carried out at PE-Sciex AP150EX single quadrapole instrument.
Typical Reactions for preparation of the alcohols (3):
Method A:
A solution of t-BuOK (50 mL, 50 mmol, 1 M) in THF was dropped into a solution of starting material 1 (18 g, 50 mmol) in dry THF (120 mL) under nitrogen at rt in 5 min. The mixture was stirred for 10 min at rt. Methyl bromoacetate (7.65 g, 50 mmol) was dropped into the flask in 5 min. The mixture was stirred for 1 h at rt. 10% NH₄Cl (20 mL) and hexanes (40 mL) were added, respectively. The organic phase is separated. The solvents were evaporated to give a crude product, without purification for next step. The crude product was dissolve into DCM (100 mL). Water (1.8 mL, 100 mmol) and TFA (8.55 g, 75 mmol) were added to the flask. The mixture was stirred for 2 h at rt. Removal of volatile materials gave a residue, which was co-evaporated with CH3CN (2×60 mL) to remove the trace water. Column chromatography purification (1:1 ethyl acetate/hexanes, then ethyl acetate) afforded a pure product (3a) (5.2 g, 55%) NMR: □_H3.4-4.1 (7H, m), 3.66 (3H, s), 4.5-4.7 (1H, m) ppm, □_C: 44.98, 46.10, 52.17, 62.61, 74.08, 158.20 (C═O), 168.92 (C═O, ester) ppm.
3b: yield: 36%, NMR: δ_H2.9 (1H, br,s), 3.46-3.86 (4H, m), 4.02 (2H, s,), 4.54-4.70 (1H, m), 5.14 (2H, s), 7.2-7.3 (5H, m) ppm.
3e: yield: 8.1%. 5H 2.5 (1H, br), 3.51- 3.94 (4H, m), 3.79 (3H, s), 4.67 (2H, s), 4.5-4.7 (1H, m), 7.1-7.5 (4H, m) ppm.
Method B:
NaH (0.4 g, 10 mmol, 60%) was added in portions into a solution of starting material 1 (3.59 g, 10 mmol) in dry THF (40 mL) under nitrogen at rt in 10 min. The mixture was stirred for 1 h at rt. Bromopinacolone (1.79 g, 10 mL) was dropped into the flask in 10 min. The mixture was stirred overnight at rt. 10 % NH4Cl (10 mL) and hexanes (20 mL) were added, respectively. The organic phase is separated. The solvents were evaporated to give a crude product, without purification for next step. The crude product was dissolve into DCM (30 mL). Water (0.36 mL, 20 mmol) and TFA (1.71 g, 15 mmol) were added to the flask. The mixture was stirred for 1 h at rt. Removal of volatile materials gave a residue, which was co-evaporated with CH3CN (2×30 mL) to remove the trace water. Column chromatography purification (3:1 ethyl acetate/hexanes, then ethyl acetate) afforded a pure product (3c) (1.68 g, 78%). NMR: δ_H1.14 (9H, s), 3.36-3.9(6H, m), 4.18 (2H, s), 4.54-4.7 (1H, m) ppm, δ_C: 26.08, 43.10, 46.30, 48.21, 63.11, 74.05, 158.45 (C═O), 209.60 (C═O, ketone) ppm.
3d: yield: 8.1%. δ_H2.5 (1H, br), 3.56-3.9(4H, m), 4.66 (2H, s), 4.5-4.7 (1H, m) 7.43, 7.47, 7.84, 7.88 (4H, AB) ppm.
Method C:
A solution of t-BuOK (10 mL, 10 mmol, 1 M) in THF was dropped into a solution of starting material 1 (3.59 g, 10 mmol) in dry THF (40 mL) under nitrogen at rt in 5 min. The mixture was stirred for 1 h at rt. A solution of methyl bromoacetamide (1.52 g, 10 mL) in THF was dropped into the flask in 10 min. The mixture was stirred overnight at rt. Con. NH₄Cl (5 mL) and brine (5 mL) were added, respectively. The organic phase is separated. The solvents were evaporated to give a crude product. Flash column chromatography (hexanes/ethyl acetate 1:1) gave a pure product. To a solution of the pure material in DCM (30 mL) was added TFA (1.71 g, 15 mmol) and water (0.36 g). The mixture was stirred for 1 h at rt. Removal of volatile materials gave a residue, which was partitioned in water (50 mL) and t-BuOMe (20 mL). The separated aqueous layer was washed with t-BuOMe (20 mL). Water was evaporated to give a residue, which was co-evaporated with CH3CN (2×30 mL) to remove the trace water. A product (3f) (0.91 g, 48%) obtained, without further purification for next step.
3g: yield: 99%. δ_H2.91, 2.96 (6H, 2 s), 3.5-3.9 (4H, m), 3.92-4.16 (2H, AB), 4.41 (1H, br), 4.5-4.7 (1H, m) ppm.
3h: yield: 74%. δ_H3.25-3.61 (13H, m), 4.04 (2H, s), 4.5-4.7 (1H, m) ppm.
3i: yield: 99%.
3j: yield: 81%.
2. Preparation of Libraries:
A. parallel Synthesis:
Typical reaction procedures (Reaction scales might be various accordingly):
Library 4-esters: To a solution of an acyl chloride (E) (0.1 mmol) in dry DCM (1 mL) were add a solution of 3 (0.1 mmol, 0.1 M) in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing overnight at rt. The reaction was completed. The product was purified with preparative TLC.
Library 4-sulfonates: To a solution of a sulfonyl chloride (K) (0.1 mmol) in dry DCM (1 mL) were add a solution of 3 (0.1 mmol, 0.1 M) in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing overnight at rt. The reaction was completed. The product was purified with preparative TLC.
Library 4-ethers: To a mixture of 3 (0.1 mmol), a phenol (M) (0.1 mmol) and Ph3P-polystyrene (0.1 g, 0.1 mmol Ph₃P) in dry DCM (1 mL) was add a solution of DEAD (1 mL, 0.1 M). The mixture was standing at rt for three days. The reaction was completed. The product was purified with preparative TLC.

Libraries:



Entry	MW	mMol

(1) 4a-esters:

E0	140.57	0.1
E1	182.65	0.1
E2	252.62	0.1
E3	252.62	0.1
E4	186.66	0.1
E5	212.53	0.1
E6	194.54	0.1
E7	198.60	0.1
E8	212.63	0.1
E9	256.08	0.1
E12	178.02	0.1
E13	178.02	0.1
E14	211.98	0.1
E15	131.52	0.1
E16	130.53	0.1
E17	130.53	0.1
E37	274.08	0.1
E40	154.60	0.1
E49	190.63	0.1
E55	175.03	0.1
E90	181.04	0.1
E92	215.48	0.1
E99	216.73	0.1
E113	229.06	0.1
E117	223.68	0.1
E120	207.61	0.1
E124	176.00	0.1
E136	200.67	0.1
E154	309.07	0.1
E157	226.66	0.1
E159	293.67	0.1
E164	319.76	0.1
E168	192.60	0.1

(2) 4a-sulfonates:

K0	190.65	0.1
K00	190.65	0.1
K1	211.07	0.1
K2	221.62	0.1
K3	206.65	0.1
K5	182.65	0.1
K6	254.71	0.1
K8	290.65	0.1
K9	195.62	0.1
K10	253.06	0.1
K11	327.71	0.1
K12	227.67	0.1
K16	438.33	0.1
K17	180.62	0.1
K21	218.62	0.1
K23	234.69	0.1
K29	238.65	0.1
K30	252.67	0.1
K31	363.21	0.1
K52	279.79	0.1
K53	249.70	0.1
K54	317.69	0.1
K55	249.70	0.1
K56	330.74	0.1
K59	301.12	0.1
K60	259.74	0.1
K61	306.82	0.1
K66	237.66	0.1
K70	256.71	0.1
K76	262.72	0.1
K83	234.69	0.1
K90	194.61	0.1
K91	255.52	0.1
K92	232.73	0.1
K93	244.62	0.1
K94	245.51	0.1
K96	256.06	0.1
K97	289.62	0.1
K98	302.86	0.1
K100	235.65	0.1
K101	217.63	0.1
K102	201.63	0.1
K104	229.06	0.1
K105	279.07	0.1
K106	245.51	0.1
K107	212.60	0.1
K109	312.62	0.1
K110	240.71	0.1
K111	330.74	0.1
K112	230.59	0.1
K113	242.69	0.1
K114	262.72	0.1
K115	243.67	0.1

(3) 4a-ethers:

Materials	MW	mMol

M1	173	0.1
M2	128.55	0.1
M3	112.10	0.1
M5	162.11	0.1
M6	137.18	0.1
M11	95.1	0.1
M14	148.16	0.1
M24	161.16	0.1
M25	349.23	0.1
M30	160.17	0.1
M34	213.15	0.1
M35	146.14	0.1
M37	211.21	0.1
M38	189.25	0.1

	Entry	MW	mMol

(4) 4b-sulfonates:

K0	190.65	0.1
K00	190.65	0.1
K1	211.07	0.1
K2	221.62	0.1
K3	206.65	0.1
K5	182.65	0.1
K6	254.71	0.1
K8	290.65	0.1
K10	253.06	0.1
K11	327.71	0.1
K12	227.67	0.1
K21	218.62	0.1
K23	234.69	0.1
K56	330.74	0.1
K70	256.71	0.1
K76	262.72	0.1
K83	234.69	0.1
K90	194.61	0.1
K91	255.52	0.1
K92	232.73	0.1
K93	244.62	0.1
K94	245.51	0.1
K96	256.06	0.1
K97	289.62	0.1
K98	302.86	0.1
K100	235.65	0.1
K101	221.62	0.1
K102	201.63	0.1
K104	229.06	0.1
K105	279.07	0.1
K106	245.51	0.1
K107	212.60	0.1
K109	312.62	0.1
K110	240.71	0.1
K111	330.74	0.1
K112	230.59	0.1
K113	242.69	0.1
K114	262.72	0.1
K115	243.67	0.1

(5) 4c-esters:

E0	140.57	0.25
E00	120.58	0.25
E1	182.65	0.25
E2	252.62	0.20
E4	186.66	0.25
E5	212.53	0.25
E6	194.54	0.25
E7	198.60	0.25
E8	212.63	0.25
E10	108.52	0.25
E11	104.53	0.25
E12	178.02	0.25
E13	178.02	0.25
E14	211.98	0.25
E15	131.52	0.25
E16	130.53	0.25

(6) 4c-sulfonates:

K0	190.65	0.15
K00	190.65	0.15
K1	211.07	0.15
K2	221.62	0.15
K3	206.65	0.15
K4	217.63	0.15
K5	182.65	0.15
K6	254.72	0.15
K8	290.65	0.15
K9	195.62	0.15
K10	253.06	0.15
K11	327.71	0.15
K12	227.67	0.15

(7) 4d-esters:

E7	198.60	0.09
E10	108.52	0.09
E11	104.53	0.09
E15	131.52	0.09

(8) 4d-sulfonates:

K5	182.65	0.09
K8	290.65	0.09
K10	253.06	0.09
K11	327.71	0.09

(9) 4e-esters:

E0	140.57	0.075
E1	182.65	0.075
E4	186.66	0.075
E8	212.63	0.075
E7	198.60	0.075
E10	108.52	0.075
E11	104.53	0.075
E15	131.52	0.075
E16	130.53	0.075

(10) 4e-sulfonates:

K0	190.65	0.075
K00	190.65	0.075
K1	211.07	0.075
K2	221.62	0.075
K3	206.65	0.075
K4	217.63	0.075
K5	182.65	0.075
K6	254.72	0.075
K8	290.65	0.075
K9	195.62	0.075
K10	253.06	0.075
K11	327.71	0.075
K12	227.67	0.075

	Entry	MW	Wt/V	mMol

(11) 4f-esters:

	E183	185.56		0.1
	E184	230.56		0.1

(12) 4f-sulfonates:

K2	221.62	0.1
K96	256.06	0.1
K101	221.62	0.1
K106	245.51	0.1
K117	221.62	0.1

(13) 4g-sulfonates:

K0	190.65	0.1
K00	190.65	0.1
K1	211.07	0.1
K2	221.62	0.1
K4	217.63	0.1
K5	182.65	0.1
K6	254.71	0.1
K8	290.65	0.1
K10	253.06	0.1
K11	327.71	0.1
K12	227.67	0.1
K19	229.09	0.1
K21	218.62	0.1
K22	253.07	0.1
K23	234.69	0.1
K30	252.67	0.1
K52	279.79	0.1
K54	317.69	0.1
K55	249.70	0.1
K56	330.74	0.1
K59	301.12	0.1
K60	259.74	0.1
K66	237.66	0.1
K69	181.60	0.1
K70	256.71	0.1
K76	262.72	0.1
K83	234.69	0.1
K90	194.61	0.1
K91	255.52	0.1
K92	232.73	0.1
K93	244.62	0.1
K94	245.51	0.1
K95	266.62	0.1
K96	256.06	0.1
K97	289.62	0.1
K98	302.86	0.1
K99	266.57	0.1
K100	235.65	0.1
K101	217.63	0.1
K104	229.06	0.1
K105	279.07	0.1
K106	245.51	0.1
K107	212.60	0.1
K109	312.62	0.1
K110	240.71	0.1
K111	330.74	0.1
K112	230.59	0.1
K113	242.69	0.1
K115	243.67	0.1

(14) 4h-esters:

Entry	MW	mMol

E0	140.57	0.1
E1	182.65	0.1
E2	252.62	0.1
E3	252.62	0.1
E4	186.66	0.1
E5	212.53	0.1
E6	194.54	0.1
E7	198.60	0.1
E8	212.63	0.1
E9	256.08	0.1
E12	178.02	0.1
E13	178.02	0.1
E14	211.98	0.1
E15	131.52	0.1
E16	130.53	0.1
E17	130.53	0.1
E37	274.08	0.1
E40	154.60	0.1
E49	190.63	0.1
E55	175.03	0.1
E90	181.04	0.1
E92	215.48	0.1
E99	216.73	0.1
E113	229.06	0.1
E117	223.68	0.1
E120	207.61	0.1
E124	176.00	0.1
E136	200.67	0.1
E154	309.07	0.1
E157	226.66	0.1
E159	293.67	0.1
E164	319.76	0.1
E168	192.60	0.1

(15) 4h-sulfonates:

Entry	MW	Wt/V	mMol

K0	190.65		0.1
K00	190.65		0.1
K1	211.07		0.1
K2	221.62		0.1
K3	206.65		0.1
K4	217.63		0.1
K5	182.65		0.1
K6	254.71		0.1
K8	290.65		0.1
K9	195.62		0.1
K10	253.06		0.1
K11	327.71		0.1
K12	227.67		0.1
K19	229.09		0.1
K21	218.62		0.1
K23	234.69		0.1
K27	247.95		0.1
K30	252.67		0.1
K52	279.79		0.1
K53	249.70		0.1
K54	317.69		0.1
K55	249.70		0.1
K56	330.74		0.1
K59	301.12		0.1
K60	259.74		0.1
K61	306.82		0.1
K66	237.66		0.1
K69	181.60		0.1
K70	256.71		0.1
K76	262.72		0.1
K83	234.69		0.1

(16) 4h-ethers:

Materials	MW	Wt/V	mMol

M1	173		0.1
M2	128.55		0.1
M3	112.10		0.1
M5	162.11		0.1
M6	137.18		0.1
M14	148.16		0.1
M24	161.16		0.1
M34	213.15		0.1
M35	146.14		0.1

	Entry	MW	Wt/V	mMol

(17) 4i-sulfonates:

K0	190.65	0.1
K00	190.65	0.1
K1	211.07	0.1
K2	221.62	0.1
K3	206.65	0.1
K5	182.65	0.1
K6	254.71	0.1
K8	290.65	0.1
K10	253.06	0.1
K11	327.71	0.1
K12	227.67	0.1
K16	438.33	0.1
K19	229.09	0.1
K21	218.62	0.1
K22	253.07	0.1
K23	234.69	0.1
K52	279.79	0.1
K60	259.74	0.1
K70	256.71	0.1
K76	262.72	0.1
K83	234.69	0.1
K90	194.61	0.1
K91	255.52	0.1
K92	232.73	0.1
K93	244.62	0.1
K94	245.51	0.1
K96	256.06	0.1
K97	289.62	0.1
K98	302.86	0.1
K100	235.65	0.1
K101	221.62	0.1
K102	201.63	0.1
K104	229.06	0.1
K105	279.07	0.1
K106	245.51	0.1
K107	212.60	0.1
K109	312.62	0.1
K110	240.71	0.1
K111	330.74	0.1
K112	230.59	0.1
K113	242.69	0.1
K115	243.67	0.1

(18) 4j-sulfonates:

K0	190.65	0.1
K1	211.07	0.1
K2	221.62	0.1
K3	206.65	0.1
K8	290.65	0.1
K21	218.62	0.1
K60	259.74	0.1
K70	256.71	0.1
K83	234.69	0.1
K90	194.61	0.1
K91	255.52	0.1
K93	244.62	0.1
K94	245.51	0.1
K97	289.62	0.1
K98	302.86	0.1
K100	235.65	0.1
K101	221.62	0.1
K102	201.63	0.1

B. Combinatorial synthesis.

Procedure: To a solution of 3c (4.0 mmol), DMAP (9.8 mg, 0.08 mmol), pyridine (576.8 mg. 8.0 mmol) in CH₂Cl₂(15 mL) was drop a solution of the acyl chlorides in CH₂Cl₂(5 mL) into the flask in 5 min. The mixture was stirred at rt. for 24 h, washed with 1 N NaHCO₃and dried over Na₂SO₄. Removal of the solvents gave a crude product (1.35 g). The products were separated with HPLC (4.6×25 cm, C-18 Column; flow rate: 1.0 mL/min; 0 min: H₂O(70), CH₃CN(12), CH₃OH (18); 20 min: H₂O(50), CH₃CN(20), CH₃OH (30); 22 min: H₂O(50), CH₃CN(0), CH₃OH (50); 55 min: H₂O(17), CH₃CN(0), CH₃OH (83); post run; 10 min).

(19) 4c-esters:



Entry	MW	mMol

E0	140.57	0.25 mmol
E00	120.58	0.25 mmol
E1	182.65	0.25 mmol
E2	252.62	0.25 mmol
E4	186.66	0.25 mmol
E5	212.53	0.25 mmol
E6	194.54	0.25 mmol
E7	198.60	0.25 mmol
E8	212.63	0.25 mmol
E10	108.52	0.25 mmol
E11	104.53	0.25 mmol
E12	178.02	0.25 mmol
E13	178.02	0.25 mmol
E14	211.98	0.25 mmol
E15	131.52	0.25 mmol
E16	130.53	0.25 mmol

1. Preparation of Precursors of Libraries:
Azide 5: To a solution of 3c (0.52 g, 2.4 mmol) and Ph₃P (0.79 g, 3.0 mmol) in THF was dropped DEAD (0.56 g, 3.2 mmol) and DPPA (0.83 g, 3.0 mmol) at 0° C., respectively. The mixture was allowed to warm to rt. The mixture was stirred at rt for 2 h. Removal of volatile materials gave a residue, which was purified by column chromatography to afford a pure product (5) (0.5 g, 87%).
Amine 6: To a solution of 5 (0.48 g, 2.0 mmol) in THF was added Ph₃P (0.63 g, 2.4 mmol) at rt. The mixture was stirred at rt overnight. Removal of volatile materials gave a residue. 90% MeOH (20 mL) was added to the flask. The solution was stirred at rt for 2 h. Removal of the solvents gave a residue, which was purified by column chromatography to afford a pure product (6) (0.2 g, 47 %) δ_H1.17 (9H, s), 1.41. (2H, br), 2.8-3.2 (2H, m), 3.2-3.6 (2H, m), 4.07, 4.16, 4.22, 4.31 (2H, AB), 4.48-4.64 (1H, m) ppm.
2. Preparation of Libraries (Parallel Synthesis):
Procedure: To a solution of a sulfonyl chloride (K) (0.1 mmol) in dry DCM (1 mL) were add a solution of 6 (0.1 mmol, 0.1 M) in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing at rt for 6 h. The reaction was completed. The product was purified with preparative TLC.

(20) Library 7-sulfonamides:



Entry	Materials MW	Wt/V	mMol

K2	221.62	mg	0.1
K4	217.63	mg	0.1
K5	182.65	mg	0.1
K8	290.65	mg	0.1
K9	195.62	mg	0.1
K10	253.06	mg	0.1
K11	327.71	mg	0.1
K12	227.67	mg	0.1
K21	218.62	mg	0.1
K22	253.06	mg	0.1
K23	234.68	mg	0.1
K83	234.68	mg	0.1

1. Preparation of Precursors of Libraries:
Alcohol 9: A solution of t-BuOK (10 mL, 10 mmol, 1 M) in THF was dropped into a solution of starting material 1 (3.59 g, 10 mmol) in dry THF (40 mL) under nitrogen at rt in 5 min. The mixture was stirred for 10 min at rt. Bromoacetonitrile (1.2 g, 10 mmol) was dropped into the flask in 5 min. The mixture was stirred for 1 h at rt. 10 % NH₄Cl (20 mL) and hexanes (40 mL) were added, respectively. The organic phase is separated. The solvents were evaporated to give a crude product, without purification for next step. The crude product was dissolve into DCM (30 mL). Water (0.36 mL, 20 mmol) and TFA (1.71 g, 15 mmol) were added to the flask. The mixture was stirred for 2 h at rt. Removal of volatile materials gave a residue, which was co-evaporated with CH₃CN (2×30 mL) to remove the trace water. Column chromatography purification (1:1 ethyl acetate/hexanes, then ethyl acetate) afforded a pure product (9) (0.59 g, 38 %). δ_H2.49 (1H, br), 3.35-3.66 (4H, m), 4.36 (1H, s), 4.5-4.7 (1H, m) ppm.
2. Preparation of Libraries (Parallel Synthesis):
Procedure: (1) Esters: To a solution of an acyl chloride (E) (0.1 mmol) in dry DCM (1 mL) were add a solution of 9 (0.1 mmol, 0.1 M) in N-methylmorpholine and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing overnight at rt. The reaction was completed. The product was purified with preparative TLC.
(21) Library 10 -esters:

Entry MW Wt/V mMol

E183 185.56 0.1

E184 230.56 0.1

(2) Sulfonates: To a solution of a sulfonyl chloride (K) (0.1 mmol) in dry DCM (1 mL) were add a solution of 9 (0.1 mmol, 0.1 M) in N-methylmorpholine and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing at rt for 6 h. The reaction was completed. The product was purified with preparative TLC.
(22) Library 10-sulfonates:

Entry MW Wt/V mMol

K2 221.62 0.1

K96 256.06 0.1

K101 221.62 0.1

K106 245.51 0.1

K117 221.62 0.1
1. Preparation of Precursors of Libraries:
Compound 11: NaH (0.44 g, 11 mmol, 60%) was added in portions into a solution of starting material 1 (3.59 g, 10 mmol) in dry HMPA (30 mL) under nitrogen at rt in 10 min. The mixture was stirred for 1 h at rt. (MeO)₂CCH₃CH₂Br (1.83 g, 10 mL) was dropped into the flask in 10 min. The mixture was stirred overnight at rt, then heated to 80° C. for two days. The reaction was cooled down to rt. Con. NH₄Cl (10 mL) and brine (10 mL) were added. The mixture was extracted by t-BuOMe (2×30 mL). The organic phase was dried over Na₂SO₄. was separated. Removal of volatile materials gave a residue, which was purified by column chromatography (4:1 ethyl acetate/hexanes) to afford a pure product (11) (2.0 g, 45 %) δ_H1.25 (3H, s), 3.1-3.7 (6H, m), 3.18 (6H, s), 4.5-4.7 (1H, m) ppm.
Compound 12: To a solution 11 (1.8 g, 3.9 mmol) in DCM (20 mL) was added TFA (1.71 g, 15 mmol) and water (0.36 g). The mixture was stirred for 1 h at rt. Removal of volatile materials gave a residue, which was partitioned in water (30 mL) and t-BuOMe (20 mL). The separated aqueous layer was washed with t-BuOMe (20 mL). Water was evaporated to give a residue, which was co-evaporated with CH₃CN (2×30 mL) to remove the trace water. A product (12) (0.43 g, 64%) obtained, without further purification for next step. δ_H2.15 (3H, s), 3.47-3.90 (5H, m), 4.06 (1H, s), 4.59-4.72 (1H, m) ppm.
2. Preparation of Libraries (Parallel Synthesis):
Sulfonates: To a solution of a sulfonyl chloride (K) (0.1 mmol) in dry DCM (1 mL) were add a solution of 12 (0.1 mmol, 0.1 M) in DCM and triethyl amine (20.2 mg, 0.2 mmol). The mixture was standing overnight at rt. The reaction was completed. The product was purified with preparative TLC.

(23) Library 13-sulfonates:



Entry	MW	Wt/V	mMol

K2	221.62		0.1
K5	182.65		0.1
K6	254.71		0.1
K10	253.06		0.1
K11	327.71		0.1
K12	227.67		0.1
K19	229.09		0.1
K21	218.62		0.1
K22	253.07		0.1
K23	234.69		0.1
K54	317.69		0.1
K60	259.74		0.1
K83	234.69		0.1
K90	194.61		0.1
K91	255.52		0.1
K92	232.73		0.1
K93	244.62		0.1
K94	245.51		0.1
K96	256.06		0.1
K97	289.62		0.1
K98	302.86		0.1
K99	266.57		0.1
K100	235.65		0.1
K101	217.63		0.1
K102	201.63		0.1

Reaction Procedure:
Amine Compound Synthesis:
Method 1:

a). Alkylation:

Materials d MW Wt/V mMol

SM 359.42 14.8 g 41

60% NaH 24 2.0 g 50

G3 2.28 141.94 3.6 mL 61.5

THF 140 mL

Procedure:

- 1. To a solution of oxazolidinone and THF, sodium hydride power was added under N2 protection, and ice bath.
- 2. The mixture was stirred for half hour at 0° C., then let it warm up to room temperature.
- 3. G3 was added into the solution slowly, and the reaction was stirred for overnight.
- 4. The reaction was quenched with water and extracted with Ethyl acetate/hexane mixture. The combined organic layer was washed with NH₄Cl, brine and dried over Na₂SO₄.
- 5. The organic solvents were removed by water Rota-vap and the crude residue was carried on next step without purification.

b). Deprotection:

Materials d MW Wt/V mMol equiv

SM 373.17 crude 41

TFA 1.48 114.02 4.7 mL 62 1.5

water 18 1.5 mL 82 2.0

CH₂Cl₂ 10 mL

Procedure:

1. The mixture was stirred for 3 h at room temperature.
2. The reaction was quenched by three drops of triethyl amine and dried over Na₂SO₄.
3. The solvents were removed by Rota-vap and the residue was purified by column chromatography. The elute solvents: 2/1=hexane /EtOAc to 1/2=hexane/EtOAc,
then use pure EtOAc.

c). Tosylation and Azidelation:

Materials d MW Wt/V mMol Equiv

SM 131.13 3.93 30 1

MsCl 1.48 114.55 3.01 39 1.3

Et₃N 101 5.8 mL 42 1.4

CH₂Cl₂

THF

DMSO

NaH₃ 65 3.1 g 48 1.6

Procedure:

1). Starting material was treated with methanesulfonyl chloride in the presence of triethylamine in methylene chloride.
2) The reaction mixture was stirred at ice bath for 3 hours.
3). The reaction was washed with water and the organic layer was dried over Na₂SO₄.
4). The organic solvent was removed to give the residue, which was treated with sodium azide in DMSO,
5) The result solution was heated up to 80° C. for two hours, then diluted with water and extracted with methylene chloride.
6). The organic layer was dried over Na₂SO₄.
7). The solvent was removed and the crude was purified by flash column chromatography to afford azide compound.
d). Hydrogenation
Oxazolidinone: 3.4 g
Pd-C (10%): 800 mg
EtOH: 30 mL
- 1. Hydrogenation bottle was charged with azide compound and EtOH.
- 2. Flushed with N₂
- 3. Pd—C was deactivated with two drops of water then added into the reaction mixture.
- 4. Reaction was run for overnight under hydrogenater with 30 Psi (2 atmosphere)
- 5. TLC showed complete conversion and the reaction mixture was filtered under water pump.
- 6. The residue (2.46 g) was obtained and used to carry on next step without purification.
  Library Design:

Oxazolidinones: RC2, SP40 (0.08 nM) in CH₂Cl₂
Acid chlorides: E0, E2, E8, E92, E124, E154, E157, E159, E117, E120, E164, E136
Parallel Synthesis Procedure:

1). Oxazolidinones (0.16 nM) were made and transferred into small vials.
2). To those vials Et3N (1.5 equiv) was added.
3). After 20 mins, acid chlorides or sufonyl chlorides were added into the reaction vials.
4). The compounds were isolated by CombiFlash, sq 16× open access purification system.
Library:

Oxazolidinones: RC2, SP40 (0.08 nM) in CH₂Cl₂
Sufonyl chlorides: K2, K3, K4, K10, K21, K22, K23, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K99, K100
Parallel Synthesis Procedure:

1). Oxazolidinones (0.16 nM) were made and transferred into small vials.
2). To those vials Et3N (1.5 equiv) was added.
3). After 20 mins, acid chlorides or sufonyl chlorides were added into the reaction vials.
4). The compounds were isolated by para-TLC (2/1=EtOAC/Hexane).

Nitrogen linkage library compound synthesis

Library Design:
Oxazolidinone: amine
Acid Chloride: E0, E2, E8, E92, E124, E154, E157, E159, E117, E120, E164, E136
Sufonyl chlorides: K2, K3, K4, K10, K21, K22, k23, K83, K90, K91, K92, K93, K94, K95, K96, K97, K98, K100
Parallel Synthesis Procedure:

1). Oxazolidinones (0.01 nM) were made and transferred into small vials.
2). To those vials Et3N (1.5 equiv) was added.
3). After 20 mins, acid chlorides or sufonyl chlorides were added into the reaction vials.
4). The compounds were isolated by para-TLC (2/1=EtOAC/Hexane).
Library:

Oxazolidinones: SG3, SC3, and SC5 (0.08 nM) in CH₂Cl₂
Acid chlorides: E0, E2, E8, E92, E124, E154, E157, E159, E117, E120, E164, E136
Parallel Synthesis Procedure:

1). Oxazolidinones (0.16 nM) were made and transferred into small vials.
2). To those vials Et3N (1.5 equiv) was added.
3). After 20 mins, acid chlorides or sufonyl chlorides were added into the reaction vials.
4). The compounds were isolated by para-TLC (2/1=EtOAC/Hexane).
Ether Type of Linkages:

Library Design:

Oxazolidinones: SG3, SC5
M compounds: M1, M2, M3, M4, M5, M6, M6, M11, M14, M14, M24, M30 M34, M35, M37, M38 DEAD=0.10 nM in THF (MW 174

Ph₃P-polystyrene 1 mmol/g 100 mg for each compound 0.1 mMol
THF 1 mL
Procedure:
- 1. The vials were charged with starting material, THF, CH₂Cl₂and Ph₃P-polystrene.
- 2. A solution of DEAD was added into the reaction mixture.
- 3. The reactions were stand for overnight.
- 4. Separated by pre-TLC.
  N-Aryl Linkage:

Using Buchwald Reaction:

Materials	d	MW	Wt/V	mMol	equiv

SM	359.42	1.0	g	2.7	1
Bromo compound	202.01	0.76	g	3.7	1.3
Palladium(II) acetate	224.49	82	mg	0.36	0.13
sodium t-butoxide	96.11	0.4	g	4.16	1.5
Ferrocene	554.40	155	mg	0.27	0.1
Toluene		140	mL

Procedure:

- 1. A 100 mL flask loaded with oxazolidinone, bromo compound, palladium(II) acetate, 1,1′-bis(diphenylphosphino)-ferrocene and sodium t-butoxide and flashed by N2 protection for 10 mins.
- 2. Toluene was added and heated up to 110° C. for overnight and then diluted with dichloromethane after it cooled down to room temperature.

Buchwald Reaction:

Materials	d	MW	Wt/V	mMol	equiv

SM	359.42	6.0	g	16.7	1
Bromo compound	182.12	3.65	g	20	1.2
Palladium(II) acetate	224.49	487	mg	2.2	0.13
sodium t-butoxide	96.11	2.4	g	25	1.5
Ferrocene	554.40	926	mg	1.67	0.1
Toluene		140	mL

Procedure:

- 1.A 100 mL Round flask was loaded with oxazolidinone, bromo compound, palladium (II) acetate, 1,1′-bis(diphenylphosphino)-ferrocene and sodium t-butoxide and flashed by N₂protection for 10 mins.
- 2. Toluene was added and heated up to 110° C. for overnight and then cool down to room temperature, diluted with dichloromethane.
- 3. filtered by celite.
- 4. Separated by column. EtOAc/Hexane=¼ elute solvent.

Synthesis of 3-trityloxy-2-hydroxy-propylamine

Procedure:

- 1. To a 500 mL Round flask was charged with 18 g SM and 90 mL of isopropyl alcohol 10 mL of MeOH then 50 mL of LiOH saturated solution.
- 2. The mixture was heated under reflux overnight at ˜70° C.
- 3. Cool down to room temperature and solvents were removed on Rota-vap.
- 4. Extract with EtOAc (1×50mL, and 1×50 mL).
- 5. The combined EtOAc layers was washed with saturated NaCl, and dried with anhydrous Na₂SO₄.
- 6. The solid was filtered and solution was divided into three parts and concentrated them separately. Total 18.05 g, 100% yield was obtained.
  Amine Oxazolidinone Formation:
  Method 2:

a). Hydrazine Formation:

Materials d MW Wt/V mMol Equiv

SM 327.18 5.7 g 17.42 1

EtOH 10 mL

hydrazine 32 3 mL 26 1.5

- 1. To a round flask was Loaded hydrazine, EtOH and ester.
- 2. The reaction was heated up to reflux for overnight.
- 3. The solvents were removed by water rota-vap.
- 4. NMR showed there is no ester.

b). Curtius Rearrangement:

Materials d MW Wt/V mMol Equiv

SM 329.44 17.4 1

H₂SO₄ 98 2.04 g 20.8 1.2

NaNO₂ 69 2.4 34.8 2

water 17 mL

Procedure:

1). The hydrazide compound was dissolved in water (17 mL).
2). To the reaction mixture, concentrated sulfuric acid (2.04 g) diluted in water (10 mL) was added into the stirred solution.
3). The mixture was cooled in the ice bath and then NaNO2 was added.
4). The reaction mixture was stirred at 50° C. for 2 hrs.
Buchwald Reaction:
Org. Lett., Vol.2,No.8,2000

Pd-Catalyzed Amination of Activated Aryl Halides:

Materials d MW Wt/V mMol equiv

SM 359.42 454 mg 1.26 1

Bromo compound 202 305 mg 1.5 1.2

Pd(OAC)2 224.49 2.9 mg 0.013 0.01

Cesium carbonate 325.82 575 mg 1.8 1.4

Xantphos 578.63 10 mg 0.018 0.015

Procedure:

- 1. A 10 mL Round flask was loaded with oxazolidinone, bromo compound, palladium(II) acetate, Xantphos and Cesium carbonate.
- 2. The flask was back-filled N₂for 10 mins.
- 3. 1,4-dioxane was added and heated up to 100° C. for overnight and then cool down to room temperature, diluted with dichloromethane.
- 4. filtered by silicon gel.

5.

Oxazolidinone MW

SC2 169.18

SC3 184

SG2 173

B11 295.26

SG3 131.13

K2 221.62

K10 253.06

K6 254.72

Desired Products:

SC2K2, SC3K2, SC5K2, SC5K10, SG2K10, B11K6, SG3K2

0.2 nmol of starting material were used in the presence of 3 equivalent of triethylamine as base in 1 mL of dichloromethane. The reactions were stirred for overnight.
Remake some of the library compounds for testing according to the result on Mar. 14, 2002.

Oxazolidinone MW

SC3 184

SG2 173

SG3 131.13

K2 221.62

K10 253.06

K3 206.65

K23 234.68

K22 254.12

SG3-N 130.07

E8 212.63

Desired products:

SC3E8, SG3E8, SG3-N-E8, SG3-N-K2, SG3-N-K3,
Procedure:

0.1 nmol of starting material were used in the presence of 1.5 equivalent of triethylamine as base in 1 mL of dichloromethane. The reactions were stirred for overnight.
E112-Oxazolidione Library Compound Synthesis:
O-Linkage and N-Linkage:

Oxazolidinone MW

SC2 169.18

SC3 184

SG2 173

B11 295.26

B10 264

SG3 131.1

SG3-NH— 130.07

SC5 157

SC1 157

Desired Products:

SC3E112, SG3-N-E112, SG3 -E112, SC1E112, B11E112.

300 mg or ZD3-75-2
500 mg of Pd(OH)2
5 mL of THF
5 mL of MeOH

The reaction was stirred at room temperature 10 mins (see new spot and starting material on TLC, new spot is more polar) and 40 mins (see one new spot, which is less polar than starting material, and only one spot shown on TLC).
Variety of E112-Oxazolidione Library Compound Synthesis:

Oxazolidinone MW

RC2 169.18

B10 264

SG3 131.1

SC5 157

RC5 157

RC1 157

Desired Products:

RC2 E112 SB10E112 SG3 E112 SC5 E112 RC5E112 RC1E112 ZD3-87-E112 (387.36 or 567.49), ZD3-88-1 (206.24), ZD3-88-2 (206.24), ZD3-88-3 (206.24)
Exploring New Linkages:

1). Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides

Materials d MW Wt/V mMol equiv

SM 130.15 100 mg 1

Iodo compound 204.0 170 mg 1.1

CuI 190.44 7.6 mg 0.05

K₃PO₄ 212.5 322 mg 2

HO(CH₂)₂OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 80° C.
Results and Discussion:
Desired product was obtained by para-TLC. (2/1=EtOAc/Hexane).

Materials d MW Wt/V mMol equiv

SM 359.24 0.5 g 2.78 1

Pyrrolidine 0.2 mL

37% HCHO 0.2 mL

Ethanol

6 mL

Procedure:
A solution of SM, pyrrolidine and formaldehyde in ethanol (6 mL) was refluxed for 2 h. The solvent was evaporated.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 130.15 100 mg 1

Iodo compound 204.0 170 mg 1.1

CuI 190.44 7.6 mg 0.05

K₃PO₄ 212.5 322 mg 2

HO(CH₂)₂OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 80° C.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 130.15 100 mg 0.76 1

Iodo compound 234.0 211 mg 0.84 1.1

CuI 190.44 7.6 mg 0.05

K₃PO₄ 212.5 322 mg 2

HO(CH2)2OH 1.13 62.07 0.1 mL 2

Iospropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 90° C.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 130.15 40 mg 1

Iodo compound 218.0 72 mg 1.1

CuI 190.44 3 mg 0.05

K₃PO₄ 212.5 128 mg 2

HL(CH₂)₂OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 90° C.
CAN. J.CHEM.Vol.61, 411 (1983)

Materials d MW Wt/V mMol equiv

SM 359.42 0.68 g 2.78 1

Morpholine 87.12 0.4 mL

37% HCHO 0.4 mL

Ethanol

8 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 8 mL in ethanol was refluxed for 4 h. The solvent was evaporated.

Materials d MW Wt/V mMol equiv

SM 117 0.47 g

Pyrrolidine 0.2 mL

37% HCHO 0.4 mL

Ethanol

3 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 3 mL in ethanol was refluxed for 2 h. The solvent was evaporated.
Deprotection:

Materials d MW Wt/V mMol equiv

SM 442.55 24 mg 0.05 1

TFA one drop

H₂O one drop

CH₂Cl₂ 1 mL

Stir for overnight.

amine compound: 18 mg
D-glucose: 140
MeOH: 3 mL
Procedure:
To a schlenk tube was added Amine compound, D-glucose and MeOH. The reaction was heated up to 60° C. for overnight.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 130.15 40 mg 1

Iodo compound 218.0 72 mg 1.1

CuI 190.44 3 mg 0.05

K₃PO₄ 212.5 128 mg 2

HO(CH₂)₂OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 95° C. for overnight.
Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides
Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 130.15 40 mg 1

Iodo compound 248.0 72 mg 1.0

CuI 190.44 3 mg 0.05

K₃PO₄ 212.5 128 mg 2

HO(CH2)2OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

Procedure:
To a schlenk tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 95° C. for overnight.
The solution of 4 equiv of Hunig's base and 1 equiv of amine starting material in CH₃CN was stirred at 50° C. for overnight.
Reduction of Nitro Group

Materials d MW Wt/V mMol equiv

SM 417.46 70 mg 0.24 1

HCOONH₄ 63 56 0.88 3.6

Pd/C (Wt) 10

THF 0.4 mL

MeOH 0.4 mL

- 1. To a solution of oxazolidinone and THF-MeOH(1:1) was Ammonium formate and Pd—C.
- 2. The reaction was stirred at room temperature for 2 h.
- 3. Diluted with THF.
- 4. Filtered and washed several times with THF.
- 5. Filtrate concentrated to a dark yellow solid.

Reduction of Nitro Group

Materials d MW Wt/V mMol equiv

SM 269.23 120 0.45 1

Pd(OH)₂ 10%

THF

1 mL

MeOH

1 mL
The reaction was stirred at room temperature under H₂for 2 hrs.
Deprotection:

Materials d MW Wt/V mMol equiv

SM 458.55 800 mg 0.57 1

TFA 0.3 mL

H₂O 0.1 mL

CH₂Cl₂ 3 mL
AA6

AA7

AA8

AA9

AA12

Materials d MW Wt/V mMol equiv

SM 130.15 40 mg 0.31 1

CuI 190.44 3 mg 0.05

K₃PO₄ 212.5 128 mg 2

HO(CH₂)₂HO 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

AA Group: 0.31 mmol

AA6 77 mg

AA7 77 mg

AA9 91 mg

AA12 65 mg

Procedure:
To a test tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 80° C. for overnight.

Materials d MW Wt/V mMol equiv

SM 130.15 200 mg

CuI 190.44 15 mg

K₃PO₄ 212.5 640 mg

HO(CH₂)₂OH 1.13 62.07 0.5 mL

Isopropanol

2 mL

AA8 249 385 mg

Procedure:

To a test tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 90° C. for overnight.

	AA13


	AA14


	AA15


	AA16


	AA17


	AA18


	AA19

Materials	d	MW	Wt/V	mMol	equiv

SM		130.15	40	mg	0.31	1
CuI		190.44	3	mg		0.05
K₃PO₄		212.5	128	mg		2
HO(CH2)2OH	1.13	62.07	0.1	mL		2
Isopropanol			1	mL

AA Group: 0.31 mmol
AA13, AA14, AA15 77 mg; AA16, AA18 84 mg; AA17 68 mg; AA19 77 mg

Procedure:

To a small vial, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 80° C. for overnight.
CAN. J.CHEM.Vol.61, 411 (1983)

Materials d MW Wt/V mMol equiv

SM 296 0.1 g 0.4 1

Morpholine 87.12 0.1 mL

37% HCHO 0.1 mL

Ethanol 1.5 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 1.5 mL in ethanol was refluxed for 2 h. The solvent was evaporated.

Materials d MW Wt/V mMol equiv

SM 296.36 0.1 g

Pyrrolidine 0.1 mL

37% HCHO 0.1 mL

Ethanol 1.5 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 1.5 mL in ethanol was refluxed for 2 h. The solvent was evaporated.
Ether Type of Linkages:

Library Design:

Oxazolidinones: SG3, 130 mg in 5 mL of CHCl2. 0.5 mL was took for each reaction.
M compounds: M1, M4, M5, M11, M14, M24, M30, M35, M37, M38
DIAD=0.10 nM in THF (MW 202), 202 mg in 10 mL THF. 1 mL was for each reaction.
Ph3P-polystyrene 1 mmol/g 100 mg for each compound 0.1 mMol
Procedure:
- 1. The vials were charged with SM and Ph₃P-polystrene.
- 2. A solution of DIAD in THF was added into the reaction mixture.
- 3. The reactions were stirred for overnight.
  Ether Type of Linkages:
  
  Library Design:
Oxazolidinones: SG3, 130 mg in 5 mL of CHCl2. 0.5 mL was took for each reaction.
M compounds: M9, M13, M20, M21, M22, M23, M23, M29, M32, M33

DIAD=0.10 nM in THF (MW 202), 202 mg in 10 mL THF and 1.5 mL of DMPU as co-solvent. 1.2 mL was took for each reaction.

Ph₃P-polystyrene 1 mmol/g 100 mg for each

compound 0.1 mMol

Procedure:

- 1. The vials were charged with SM and Ph₃P-polystrene.
- 2. A solution of DIAD in THF was added into the reaction mixture.
- 3. The reactions were stirred for overnight.

Acid Hydrazide from Ester

Materials d MW Wt/V mMol Equiv

SM 217.26 2 g 9.2 1

EtOH 5 mL

hydrazine 32 588 mg 18.4 2

- 1. Loaded hydrazine and EtOH with a round flask and ester was added slowly.
- 2. The reaction was heated up to reflux for overnight.
- 3. The solvents were removed by water rota-vap.
- 4. NMR showed there is no ester.

Curtius Rearrangement:

Materials d MW Wt/V mMol Equiv

SM 203 9.2 1

H₂SO₄ 98 1.0 g 11 1.2

NaNO₂ 69 1.27 18.4 2

water 15 mL

Procedure:
1). The hydrazide compound was dissolved in water (7 mL), and concentrated sulfuric acid (1.0 g) diluted in water (3 mL) and added into the stirred solution. The mixture was cooled in the ice bath and then NaNO₂(in 5 mL water) was added slowly.
2). The reaction mixture was stirred at 50° C. for overnight.
Library:

SG3-N— MW 130.15

SG3 MW 131.13

For SG3: K107, K96, K100, K114, K115,K76
For SG3-N: K76, K96, K100, K101, K112, K114, K115. K2
Procedure:
0.10 mol of S
0.15 mmol of Et₃N
0.08 mmol of K compounds

Acid Hydrazide from Ester

Materials d MW Wt/V mMol Equiv

SM 343.46 16 g 46.6 1

EtOH 30 mL

hydrazine 32 2.2 g 70 1.5

- 1. Loaded hydrazine and EtOH with a schlenk tube and ester.
- 2. The reaction was heated up to 80° C. for overnight.
- 3. The solvents were removed by water rota-vap.
  Ether Type of Linkages:
  
  Library Design:
Oxazolidinones: SG3, 104 mg in 4 mL of CH₂Cl₂. 0.5 mL was took for each reaction.
M compounds: M2, M3, M6, M34, M38, M39, M40, M41,
DIAD=0.10 nM in THF (MW 202), 160 mg in 8 mL THF.

1 mL was for each reaction.

Ph₃P-polystyrene 1 mmol/g 100 mg for each

compound 0.1 mMol

Procedure:

Nitro Compounds with Special Linkages,

SG3—N— MW 130.15

SG3 MW 131.13

For SG3 and SG3—N: K117, BB3, BB5, E183

Procedure:

0.1 mmol of Starting material
0.15 mmol of Et₃N
0.08 mmol of K and B compounds
Exploration of different linkages

Alkylation:

For G16,

Materials MW Wt/V mMol Equiv

SM 359.42 1 g 2.78 1

G16 143.42 0.6 mL

t-BuOK 3 mL

THF

8 mL

For G14

Materials M Wt/V mMol Equiv

SM 359.42 1 g 2.78 1

G14 (d 2.1) 209.94 0.4 mL 4.17 1.5

t-BuOK 3 mL

THF

8 mL
Alkylation: (By NaH)

For G16,

Materials MW Wt/V mMol Equiv

SM 359.42 1 g 2.78 1

G16 143.42 0.6 mL

NaH (60%) 24 166 mg 4.17 1.5

THF 8 mL

For G14

Materials MW Wt/V mMol Equiv

SM 359.42 1 g 2.78 1

G14 (d 2.1) 209.94 0.4 mL 4.17 1.5

NaH (60%) 24 166 mg 4.17 1.5

THF 8 mL
Alkylation: (By NaH)

For G16,

Materials MW Wt/V mMol Equiv

SM 359.42 6.5 g 18.1 1

G15 (d 1.74) 170 2.5 mL

NaH (60%) 24 941.2 mg

THF 50 mL

Deprotection: (G15)

TFA 2 mL

H₂O 0.5 mL

CH2Cl2

5 mL
Deprotection: (combine 1 g of the reaction of G16 with BuOK and with NaH)

TFA 1 mL

H₂O 0.3 mL

CH₂Cl₂ 3 mL

Glycosylation:

5 mg of starting material
10 mg of sugar
1 mL of MeOH
Glycosylation
Deprotection:

SM 700 mg

TFA 1.2 mL

H₂O 0.3 mL

CH₂Cl₂ 3 mL
The mixture was stirred for two hours. The TLC showed no starting material left.

Library:



	SG3-N—	MW 130.15
	SG3	MW 131.13
	SC3	MW 183.20

	K100 (235.65), K101(221.62), K102(201.63), K103(339.51), K104 (229.06), K105 (279.06), K106 (245.51), K107 (212.60), K108 (372.67), K109 (312.62) K110 (240.71), K111 (330.74)

Procedure:

0.11 mol of S
0.15 mmol of Et₃N
0.08 mmol of K compounds
New Library Linkage:

Copper-Catalyzed Coupling of Alkylamines and Aryl Iodides

Organic Lett. 2002 Vol.4, No.4. page 581-584

Materials d MW Wt/V mMol equiv

SM 131 100 mg 1

Iodo compound 272.01 500 mg 1.8

CuI 190.44 19 mg 0.1

K₃PO₄ 212.5 322 mg 2

HO(CH₂)₂OH 1.13 62.07 0.15 mL 2

Isopropanol 1 mL

Procedure:
To a small vial, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 60° C. for overnight, and Isolated by parp-TLC.
CAN. J.CHEM.Vol.61, 411 (1983)

Materials d MW Wt/V mMol equiv

SM 359.42 0.1 g 2.78 1

Morpholine 87.12 0.1 mL

37% HCHO 0.05 mL

Ethanol 1.5 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 1.5-mL in ethanol was heated it up to 60° C. for overnight.
CAN. J.CHEM.Vol.61, 411 (1983)

Materials d MW Wt/V mMol equiv

SM 117.10 456 mg 3.9 1

Morpholine 87.12 1 mL

37% HCHO 0.4 mL

Ethanol

3 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 3 mL in ethanol was heated it up to 60° C. for overnight.

Materials d MW Wt/V mMol equiv

SM 117 443 mg 3.78 1

pyrrolidine 1 mL

37% HCHO 0.4 mL

Ethanol

3 mL

Procedure:
A solution of SM, morpholine and formaldehyde in 3 mL in ethanol was heated it up to 60° C. for overnight.

Materials d MW Wt/V mMol equiv

SM 130.15 40 mg 0.31 1

CuI 190.44 3 mg 0.05

K₃PO₄ 212.5 128 mg 2

HO(CH₂)₂OH 1.13 62.07 0.1 mL 2

Isopropanol 1 mL

AA Group: 0.31 mmol

AA20, AA21, AA22, AA23, AA24, AA25, AA26, AA27, AA28
Procedure:

To a test tube, CuI and K₃PO₄were added then the tube was back-filled with Nitrogen for 10 mins, and then rest of starting material were added, the reaction mixture was heated up to 65° C. for overnight.
Library Linkage:

Starting material: 22 mg for each reaction
K2, K90, K91, K92, K95, K96, K97, K100, K101, K102, K114, K117, E133, E184, BB3, BB5
Procedure:
0.1 mmol of starting material
0.15 mmol of Et₃N
0.1 mmol of K and BB or E compounds.
The reactions were stirred for overnight.
Buchwald Reaction:
Org. Lett., Vol.2,No.8,2000

Pd-Catalyzed Amination of Activated Ary Halides:

Materials	d	MW	Wt/V	mMol	equiv

SM	296.36	454	mg	1.6	1
Iodo compound	272	500	mg	1.8	1.2
Pd(OAC)₂	224.49	10	mg	0.016	0.01
Cesium carbonate	325.82	730	mg	2.24	1.4
Xantphos	578.63	14	mg	0.024	0.015
1,4-dioxane		3	mL

Procedure:

1. A 10 mL Round flask was loaded with oxazolidinone, bromo compound, palladium(II) acetate, Xantphos and Cesium carbonate and flashed by N2 protection for 10 mins.
2. 1,4-dioxane was added and heated up to 70° C. for overnight and then cool down to room temperature, diluted with dichloromethane.
Library Linkage:

Starting material: 22 mg for each reaction
K2, K90, K91, K92, K95, K96, K97, K100, K101, K102, K117, E183, BB3
Procedure:
0.2 mmol of starting material
0.15 mmol of Et₃N
0.2 mmol of K and BB or E compounds.
The reactions were stirred for overnight.

Alkylation: (By NaH)

For G16,

Materials MW Wt/V mMol Equiv

SM 359.42 50 g 139 1

G3 (d 2.28) 141.9 17 mL 278 2

NaH (60%) 24 10.3 g 257 1.8

THF 400 mL
NaH was added into the pre-cooled (by dry ice and acetone) the THF and SM solution, then stirred for two hours. G3 were added after re-cooled the reaction mixture.
Deprotection: (G3)

TFA 14 mL

H₂O 4 mL

CH₂Cl₂ 50 mL

Ether Type of Linkages:

Library Design:

Oxazolidinones: 25 mg (1.17 equiv) for each reaction.
M compounds: M1, M2, M3, M4, M5, M6, M11, M14, M24, M30, M34, M35, M37, M38, M39, M40, M41(1 equiv)
DIAD=0.10 nM in THF (MW 202), 400 mg in 17 mL THF.

1 mL was taken for each reaction.

Ph₃P-polystyrene 1 mmol/g 100 mg for each

compound 0.1 mMol

Procedure:

- 4. The vials were charged with SM and Ph₃P-polystrene.
- 5. A solution of DIAD in THF was added into the reaction mixture.
- 6. The reactions were stirred for overnight.

CAN. J.CHEM.Vol.61, 411 (1983)

Materials d MW Wt/V mMol equiv

SM 117.10 500 mg

Nitro compound 207.23 884 mg

37% HCHO 0.6 mL

Ethanol

6 mL

Procedure:
A solution of SM, nitro compound and formaldehyde in 3 mL in ethanol was heated it up to 65° C. for overnight.

Materials d MW Wt/V mMol equiv

SM 117 500 mg

pyrrolidine

1 mL

37% HCHO 0.6 mL

Ethanol

3 mL

Procedure:
A solution of SM, morpholine, and formaldehyde in 3 mL in ethanol was heated it up to 60° C. for overnight.
Alkylation: (By NaH)

For C18,

Materials MW Wt/V mMol Equiv

SM 359.42 0.5 g 1.39 1

C18 (d 1.5) 120 0.2 mL 2.78 2

NaH (60%) 24 100 mg 2.57 1.8

THF 4 mL
NaH was added into the pre-cooled (by dry ice and acetone) the THF and SM solution, then stirred for two hours. G3 were added after re-cooled the reaction mixture.
alkylation: (By NaH)

For C18,

Materials MW Wt/V mMol Equiv

SM 359.42 0.5 g 1.39 1

C19 149 414 mg 2.78 2

NaH (60%) 24 100 mg 2.57 1.8

THF 4 mL
NaH was added into the pre-cooled (by dry ice and acetone) the THF and SM solution, then stirred for two hours. C19 were added after re-cooled the reaction mixture.
Curtius Rearrangement:

Materials d MW Wt/V mMol Equiv

SM 329.44 26 79 1

H₂SO₄ 98 9.2 mL 95 1.2

NaNO₂ 69 8.2 g 118 1.5

water 100 mL

Procedure:
1). The hydrazide compound was dissolved in water (75 mL), and concentrated sulfuric acid (9.2 mL) diluted in water (25 mL) and added into the stirred solution. The mixture was cooled in the ice bath and then NaNO₂in water (20 mL) was added dropwise.
2). The reaction mixture was stirred at room temperature for overnight. Then was put on the water rota-vap without vacuum to shake for 6 hours at 50° C.
3). The reaction was neutralized by sodium carbonate and extracted with EtOAc three times, brine and dried over Na₂SO₄.
4). The solvents were removed by water rota-vap to afford residues.
5). Column chromatograph to isolate the desired compound.

Materials d MW Wt/V mMol Equiv

SM 329.44 4.5 g 1

H₂SO₄ 98 1.6 mL 1.2

NaNO₂ 69 1.4 g 1.5

water 30 mL

Procedure:
1). The hydrazide compound was dissolved in water (25 mL), and concentrated sulfuric acid (1.6 mL) diluted in water (5 mL) and added into the stirred solution. The mixture was cooled in the ice bath and then NaNO₂powder was added directly..
2). The reaction mixture was stirred at room temperature for overnight. Then was put on the water rota-vap without vacuum to shake for 6 hours at 50° C.
3). The reaction was neutralized by sodium carbonate and extracted with EtOAc three times, brine and dried over Na₂SO₄.
4). The solvents were removed by water rota-vap to afford residues.
5). Column chromatographed to isolate the desired compound.

300 mg of ZD3-75-2
500 mg of Pd (OH)₂
5 mL of THF
5 mL of MeOH
The reaction was stirred at room temperature 10 mins (see new spot and starting material on TLC, new spot is more polar) and 40 mins (see one new spot, which is less polar than starting material, and only one spot shown on TLC).

300 mg of ZD3-75-2
500 mg of Pd(OH)₂
5 mL of THF
5 mL of MeOH
The reaction was stirred at room temperature 10 mins (see new spot and starting material on TLC, new spot is more polar) and 40 mins (see one new spot, which is less polar than starting material, and only one spot shown on TLC).
To a solution of starting material in THF, Et3N was added then BB3 was added. The reaction was stirred for overnight. Isolated by parp-TLC (3/1=EtOAc/Hexane)
Library:

Oxazolidinone derivatives: SC1, H, SG3-N, RG3, RC3
(0.1 nmol CH₂Cl₂solution except H in THF)
Nitrobenzene derivatives: BB3, BB7, BB8, BB9 ((0.1 nmol CH2Cl2 solution except BB7 in THF)
Base: triethylamine (0.15 nmol)
The reactions were set up in the usual way and kept for overnight. Isolated by parp-TLC (3/1=EtOAc/Hexane).
Library
New M compounds:
Oxazolidinone derivatives: RG3, RC5, RC3
(0.1 nmol CH₂Cl₂solution)
Nitrobenzene derivatives: M42, M43, M44, M45, M46, M47 (0.1 nmol)

DIAD=0.10 nM in THF (MW 202), 1 equiv.

Ph₃P-polystyrene 1 mmol/g 100 mg for each

compound 0.1 mMol

Procedure:

- 7. The vials were charged with SM and Ph₃P-polystrene.
- 8. A solution of DIAD in THF was added into the reaction mixture.
  The reactions were stirred for overnight.
  The reactions were set up in the usual way and kept for overnight. Isolated by parp-TLC (3/1=EtOAc/Hexane).

Alkylation: (By t-BuOK)

Materials MW Wt/V mMol Equiv

SM 359.42 0.5 g 1.39 1

C18 (d 1.5) 120 0.2 mL 2.78 2

t-BuOK 3 mL 2.57 1.8

THF 5 mL
To a solution of SM and THF was added t-BuOK, then C19 was added. The reaction mixture was heated up to 60° C. in sealed tube.
Alkylation: (By t-BuOK)

For C19,

Materials MW Wt/V mMol Equiv

SM 359.42 0.5 g 1.39 1

C19 149 414 mg 2.78 2

t-BuOK 3 mL 2.57 1.8

THF 5 mL
To a solution of SM and THF was added t-BuOK, then C19 was added. The reaction mixture was heated up to 60° C. in sealed tube.
Alkylation: (By t-BuOK)

For C18,

Materials MW Wt/V mMol Equiv

SM 359.42 0.5 g 1.39 1

C18 (d 1.5) 120 0.2 mL 2.78 2

t-BuOK 3 mL 2.57 1.8

THF 5 mL
To a solution of SM and THF was added t-BuOK, then C19 was added. The reaction mixture was heated up to 60° C. in sealed tube.
Library Linkage:
Starting material: 22 mg for each reaction K2, K91, K92, K95, K96, K97, K100, K101, K117, E183, E184, BB3, BB7, BB9, BB5, K93, K98, K94, K106, AC2, AC3, AC5, AC7.
Procedure:

0.08 mol of starting material
0.15 mmol of Et₃N
0.09 mmol of K and BB, AC or E compounds.
The reactions were stirred for weekend.
Library linkage:
Starting material: 14 mg for each reaction.
AC1, AC4, AC8, AC9, AC10, AC11, AC12, MsCl
Procedure:
0.04 mmol of starting material
0.15 mmol of Et₃N
0.06 mmol of AC compounds.
The reactions were stirred for overnight.

While the present invention is described herein with reference to illustrated embodiments, it should be understood that the invention is not limited hereto. Those having ordinary skill in the art and access to the teachings herein will recognize additional modifications and embodiments within the scope thereof. Therefore, the present invention is limited only by the claims attached herein.

Claims

1. A process for producing a library of substituted oxazolidinones which comprises:

(a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I); and

(b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group and replaces it with another group from the second reagent to produce the library of substituted oxazolidinones.

2. The process of claim 1 wherein the second reagent is a reducing agent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone to provide a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II) as the library of substituted oxazolidinones.

3. The process of claim 2 wherein the mixture of (II) is further reacted with a third reagent containing a plurality of compounds reactive with the hydroxymethyl in an anhydrous organic solvent to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones.

4. The process of claim 3 wherein the anhydrous organic solvent further includes pyridine.

5. The process of claim 3 wherein the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones.

6. The process of claim 3 wherein the third reagent produces a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.

7. The process of claim 1 wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.

8. The process of claim 1, 2, or 3 wherein the substituted oxazolidinones in the library are separated chromatographically.

9. The process of claim 1, 2, or 3 wherein the substituted oxazolidinones in the library are separated chromatographically and then the separated substituted oxazolidinones are each screened for biological activity.

10. The process of claim 1 wherein the protecting group is a trityl group.

11. The process of claim 1 wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.

12. The process of claim 11 wherein the alkali is an ionic hydride.

13. The process of claim 12 wherein the ionic hydride is sodium hydride.

14. The process of claim 1 wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.

15. The process of claim 14 wherein the palladium catalyst is Pd(OAc)₂.

16. The process of claim 1 wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I) produced in step (a) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent and the substituted oxazolidinones produced in step (b) are purified by removing the solvent.

17. The process of claim 2 wherein the N-(substituted)-C-hydroxymethyl-oxazolidinones (II) are purified by removing the solvent.

18. The process of claim 3 wherein the N-(substituted)-C-(substituted methyl)-oxazolidinones (III) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.

19. A process for producing a library of substituted oxazolidinones which comprises:

(a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I);

(b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinones to produce a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II); and

(c) reacting the mixture of (II) produced in step (b) in an anhydrous organic solvent with a third reagent containing a plurality of compounds reactive with the hydroxymethyl of the mixture of (II) to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones.

20. The process of claim 19 wherein the anhydrous organic solvent in step (c) further includes pyridine.

21. The process of claim 19 wherein the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones.

22. The process of claim 19 wherein the third reagent produces a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.

23. The process of claim 19 wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.

24. The process of claim 19, 21, or 22 wherein the substituted oxazolidinones in the library are separated chromatographically.

25. The process of claim 19 wherein the protecting group is a trityl group.

26. The process of claim 19 wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.

27. The process of claim 26 wherein the alkali is an ionic hydride.

28. The process of claim 27 wherein the ionic hydride is sodium hydride.

29. The process of claim 19 wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.

30. The process of claim 29 wherein the palladium catalyst is Pd(OAc)₂.

31. The process of claim 19 wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I) produced in step (a) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.

32. The process of claim 19 wherein the N-(substituted)-C-hydroxymethyl-oxazolidinones (II) produced in step (b) are purified by removing the solvent.

33. The process of claim 19 wherein the N-(substituted)-C-(substituted methyl)-oxazolidinones (III) produced in step (c) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.

34. A process for preparing a library of substituted oxazolidinones which comprises:

reacting a C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent including pyridine with a reagent containing a plurality of compounds reactive with the hydroxy group to produce a mixture of substituted oxazolidinones as the library of substituted oxazolidinones.

35. The process of claim 34 wherein the reaction produces a mixture of 5-(substituted methyl)-2-oxazolidinones.

36. The process of claim 34 wherein the reaction produces a mixture of 4-(substituted methyl)-2-oxazolidinones.

37. The process of claim 34 wherein the reaction produces a mixture of N-(substituted)-C-(hydroxymethyl)-2-oxazolidinones.

38. The process of claim 34 wherein the reaction produces a mixture of N-(substituted)-C-(substituted methyl)-2-oxazolidinones.

39. The process of claim 34 wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.

40. The process of claim 34, 35, 36, 37, or 38 wherein the substituted oxazolidinones in the library are separated chromatographically.

41-53. (canceled)

54. A process for producing a substituted oxazolidinone which comprises:

(a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a compound which is reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce an N-(substituted)-C-(protected oxymethyl)-oxazolidinone;

(b) reacting the N-(substituted)-C-(protected oxymethyl)-oxazolidinone in an aqueous organic solvent with a second reagent with a second reagent which replaces the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone with a hydrogen to produce an N-(substituted)-C-hydroxymethyl-oxazolidinone; and

(c) reacting the N-(substituted)-C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent with a third reagent containing a compound reactive with the hydroxy group to produce N-(substituted)-C-(substituted methyl)-oxazolidinones as the substituted oxazolidinone.

55. The process of claim 54 wherein the anhydrous organic solvent in step (c) further includes pyridine.

56. The process of claim 54 wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.

57. The process of claim 54 wherein the protecting group is a trityl group.

58. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of hydrogen, acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R₂is selected from the group consisting of acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, and mixture thereof, or a hydrogen, wherein hetero is an atom selected from the group consisting of O, N, P, and S; and y is a heteroatom selected from the group consisting of O, N, and S.

59. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R₂is selected from the group consisting of alkyl, acyl, aryl, and thio.

60. The process of claim 54 wherein the substituted oxazolidinone has the formula

61. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, acyl, thio, and aryl, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl.

62. The process of claim 54 wherein the substituted oxazolidinone has the formula

63. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl.

64. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, or heterocycle, R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO₂, Cl, alkyl, and aryl.

65. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle and R₂is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers.

66. The process of claim 54 wherein the substituted oxazolidinone has the formula

wherein R₁is selected from the group consisting of 5 alkyl, aryl, acyl, thio, and heterocycle and R₂is selected from the group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2, or 3 chiral centers.

67. The process of claim 54 wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.

68. The process of claim 67 wherein the alkali is an ionic hydride.

69. The process of claim 68 wherein the ionic hydride is sodium hydride.

70. The process of claim 54 wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.

71. The process of claim 70 wherein the palladium catalyst is Pd(OAc)₂.

72. The process of claim 54 wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinone produced in step (a) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.

73. The process of claim 54 wherein the N-(substituted)-C-hydroxymethyl-oxazolidinone produced in step (b) is purified by removing the solvent.

74. The process of claim 54 wherein the N-(substituted)-C-(substituted methyl)-oxazolidinone produced in step (c) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.

75-84. (canceled)