WO2015173664A1

WO2015173664A1 - Process for the preparation of (5s)-n-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

Info

Publication number: WO2015173664A1
Application number: PCT/IB2015/052188
Authority: WO
Inventors: Vijaykumar Jagdishwar Patil; Velupillai LOGANATHAN
Original assignee: Wockhardt Limited
Priority date: 2014-05-14
Filing date: 2015-03-25
Publication date: 2015-11-19

Abstract

A process for preparation of compound of Formula (I) is provided.

Description

PROCESS FOR THE PREPARATION OF (55)-^V-{3-[3,5-DIFLUORO-4- (4-HYDROXY-4-METHOXYMETHYL-PIPERIDIN-l-YL)-PHENYL]-2- OXO-OXAZOLIDIN-5-YLMETHYL}-ACETAMIDE

RELATED PATENT APPLICATIONS

This application claims priority to Indian Patent Application No. 1637 MUM/2014 filed on May 14, 2014, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

FIELD OF THE INVENTION

The invention relates to a process for preparation of geminally disubstituted piperidino phenyloxazolidinone compound having antimicrobial activity.

BACKGROUND OF THE INVENTION

Oxazolidinone represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and β-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001 ; 358: 1975-82).

Various oxazolidinones and their methods of preparation are disclosed in the literature. International Publication No. WO 1995/25106 discloses substituted piperidino phenyloxazolidinones and International Publication No. WO 1996/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. US Patent Publication No. 2004/0063954, International Publication Nos. WO 2004/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use. Pyrrolidinyl/piperidinyl phenyl oxazohdinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230. International Publication No. WO 1996/35691 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives. Diazepeno phenyloxazolidinone derivatives are disclosed in the International Publication No. WO 1999/24428. International Publication No. WO 2002/06278 discloses substituted aminopiperidino phenyloxazolidinone derivatives.

Various other methods of preparation of oxazolidinones are reported in US Patent No. 7087784, US Patent No. 6740754, US Patent No. 4948801 , US Patent No. 3654298, US Patent No. 5837870, Canadian Patent No. 681830, J. Med. Chem., 32, 1673 (1989), Tetrahedron, 45, 1323 (1989), J. Med. Chem., 33, 2569 (1990), Tetrahedron Letters, 37, 7937-40 (1996) and Organic Process Research and Development, 11 , 739-741(2007).

Indian Patent Application No. 2534/MUM/2007 discloses a process for the preparation of substituted piperidino phenyloxazolidinones. International Publication No. WO2012/059823 further discloses the process for the preparation of phosphoric acid mono- (L-{4-[(5)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}4- methoxymethyl piperidine-4-yl)ester.

US Patent No. 8217058 discloses (5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4- methoxymethyl-piperidin-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide as an antibacterial agent and its process for preparation.

The present invention provides an improved process for preparation of (55)-N-{3-[3,5- difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-2-oxo-oxazolidin-5- ylmethylj-acetamide (I). SUMMARY OF THE INVENTION

Accordingly, there is provided a novel process for preparation of (55)-N-{ 3-[3,5- difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin- l -yl)-phenyl]-2-oxo-oxazolidin-5- ylmethylj -acetamide (I).

Formula (I)

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. All references including patents, patent applications, and literature cited in the specification are expressly incorporated herein by reference in their entirety.

The inventors have surprisingly discovered a single step improved process for the preparation of (5S)-N- { 3-[3 ,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l -yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl} -acetamide (I). Formula (I)

The term "Ac" as used herein refers to acetyl.

The term "polar aprotic solvent" as used herein refers to solvents which do not contain acidic hydrogen and also do not act as a hydrogen bond donor. Typical, non-limiting examples of polar aprotic solvents according to the invention include acetonitrile, dime thy Iformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, acetone, N-methyl-2-pyrrolidone, N-methylmorpholine, acetylacetone, γ-butyrolactone or a mixture thereof.

In one general aspect, there is provided a process for preparation of a compound of Formula (I),

Formula (I)

said process comprising, reacting a compound of Formula (II) with a compound of Formula (III) in presence of a base and a polar aprotic solvent.

Formula (III)

Typically, (5S)-N- { 3-[3 ,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin- 1 -yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl} -acetamide (I) is obtained by reacting a [3,5-difluoro-4- (4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-carbamic acid benzyl ester (II) with acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) in presence of a base and a suitable polar aprotic solvent. Compound of Formula (II) is prepared by following the general procedure disclosed in IN2007 /MUM/2534. Compound of Formula (III) is prepared as per the method disclosed in Organic Process Research and Development 2003, 7, 533-546. Typical, non-limiting examples of bases include butyl lithium, sodium teri-butoxide, potassium tert- butoxide, lithium feri-butoxide or lithium diisopropylamide. Typical, non-limiting examples of polar aprotic solvents include tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or a mixture thereof. In some embodiments, a compound of Formula (I) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) in presence of lithium feri-butoxide as a base and tetrahydrofuran as a solvent.

In some other embodiments, a compound of Formula (II) is reacted with a compound of Formula (III) in presence of an initiator. The term "initiator" as used herein refers to a compound which initiates or facilitates the chemical reaction. Typical, non-limiting examples of an initiator include methanol, ethanol or iso-propanol. In some embodiments, a compound of Formula (II) is reacted with a compound of Formula (III) in presence of methanol as initiator. In some embodiments, a compound of Formula (I) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) at a temperature of about of 10°C to 15°C.

In some embodiments, there is provided a process for preparation of a compound of Formula (I),

Formula (I)

said process comprising, reacting a compound of Formula (II) with a compound of Formula (III) in presence of lithium teri-butoxide, tetrahydrofuran and methanol at a temperature of 10°C to 15°C.

In some embodiments, there is provided a process for preparation of a compound of Formula (I) as shown in Scheme 1

(I I) (I N)

Scheme 1

In some embodiments, there is provided a process for preparation of a compound of Formula (I) having purity of at least about 97% as determined by HPLC.

In some embodiments, there is provided a compound of Formula (I) having purity of at least about 97% as determined by HPLC.

In some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula (I) having a purity of at least about 97% as determined by HPLC. In some embodiments, the said pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients. Typically, compound of Formula (III) is prepared by a process disclosed in Scheme 2. 5-epichlorohydrin (IV) is reacted with benzaldehyde (V) in presence of aqueous ammonia. The obtained reaction mixture is further treated with hydrochloric acid to obtain l-amino-3- chloro-propan-2-ol hydrochloride (VI). The compound of Formula (VI) is then reacted with acetic anhydride in presence of pyridine to obtain a compound of Formula (III).

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention. Example 1

Preparation of (55)-iV-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (I)

To a stirred solution of lithium teri-butoxide (59.1 g, 0.74 mol) in tetrahydrofuran (500 ml) was added a solution of [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l- yl)-phenyl]-carbamic acid benzyl ester (II) (100 g, 0.25 mol) in 500 ml of tetrahydrofuran slowly at room temperature. The resulting mixture was stirred for 3 hours at room temperature (formation of lumps observed). The reaction mixture was cooled to temperature of 10°C to 15°C and acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) (95.2 g, 0.49 mol) was added in one lot, after 5 minutes methanol (2.36 g, 0.075 mol) was added in one portion. The resulting mixture was stirred further at temperature of 10°C to 15°C. After 5 hours the reaction mixture was allowed to warm to room temperature and stirring continued further for 16 hours. An aqueous solution of saturated ammonium chloride (100 ml) was added to the reaction mixture, the resulting mixture was stirred well and the solvent evaporated under reduced pressure (35°C, 150 mm Hg). The residual mixture was diluted with water (1 L stirred well and filtered under suction, the residual solid was washed with additional fresh water (100 ml). The residual mass was suspended in acetone (500 ml), stirred well and the mixture diluted with hexane (1 L), slowly. The mixture was stirred further for 1 hour and filtered under suction. The residual solid was washed with a 2:1 mixture of acetone and water (100 ml). The residual solid was dried at 45°C, for 3.5 hour at 4 mm Hg, to obtain the 78 g of (55)-N-{3- [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l -yl)-phenyl]-2-oxo-oxazolidin-5- ylmethylj -acetamide (I) as white solid, in 77% yield.

Analysis:

Mass: 414 (M+l ); for Molecular Weight: 413 and Molecular Formula:

Melting Point: 178-179°C; 1H NMR (400 MHz, DMSO): δ 8.18-8.21 (m, 1H), 7.19-7.25 (d, 2H), 4.07-4.71 (m, 1H), 4.32 (s, 1H), 4.02-4.07 (t, 1H), 3.64-3.68 (t, 1H), 3.14 (s, 2H), 2.81-2.83 (d, 2H), 1.81 (s, 3H), 1.63-1.69 (t, 2H), 1.42-1.45 (d, 2H);

Purity as determined by HPLC: 97.65%.

Example 2

Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III)

Step-I: Preparation of l-amino-3-chloro-propan-2-ol hydrochloride (VI)

Benzaldehyde (118.67 g, 1.03 mol) was dissolved in ethanol (297 ml) under stirring and the solution was cooled to 18-19°C. To this solution aqueous ammonia solution (25%) (101.58 ml) was added slowly, followed by slow addition of S-epichlorohydrin (100 g, 1 mol). The resulting mixture was warmed to 40°C and stirred for 7 hours. The mixture was allowed to cool to room temperature and stirred further. After 16 hours, the reaction mixture was concentrated to 50% volume under reduced pressure. Toluene (228 ml) was added to the reaction mixture followed by addition of aqueous hydrochloric acid (162 ml of concentrated hydrochloric acid diluted with 152 ml of water). The mixture thus obtained for 3 hours at 45°C, the resulting mixture was allowed to cool to room temperature and the toluene layer separated. The toluene layer was further extracted with water (56 ml). The combined aqueous layer was diluted with ethanol (56 ml) and the mixture evaporated under reduced pressure. This process was repeated again. To the final concentrate was added ethanol (180 ml), stirred for 10 minutes and the mixture cooled to -28°C to -30°C and maintained at this temperature for 2 hours. The separated solid was filtered under suction and the residue washed with cold (-30°C) ethanol (50 ml). The residue was dried at 45°C, under reduced pressure (4 mm Hg) for 3 hours, to obtain 96 g of l-amino-3-chloro-propan-2-ol hydrochloride (VI) as white solid in 61% yield.

Analysis: Mass: 110 (M+l) as free base; for Molecular Weight: 145.5 and Molecular Formula:

1H NMR (400 MHz, D₂0): δ 4.02-4.08 (m, 1H), 3.51-3.61 (m, 2H), 3.12-3.16 (dd, 1H), 2.93 -2.99 (dd, 1H).

Step-II: Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III).

A stirred solution of dichloromethane (220.8 ml) containing the step-I salt (96 g, 0.66 mol) was cooled to 18-20°C. Acetic anhydride (154.78 g, 1.5175 mol) was added slowly (slight exothermic). Pyridine (67.76 g, 0.8577 mol) was added slowly (exothermic) while maintaining the temperature at 18-20°C. The resulting mixture was heated to 40°C for 5 hours. The reaction mixture was allowed to cool to room temperature and stirring continued for further 16 hours. The reaction mass was cooled to 3-6°C and diluted with 170 ml of fresh water. To this was added an aqueous solution of potassium carbonate (191.2 g of K₂CO₃ in 382 ml water). The reaction mixture was further diluted with additional dichloromethane (170 ml) and water (425 ml). The reaction mass was stirred well and the dichloromethane layer separated. The aqueous layer was further extracted with 2x170 ml dichloromethane. The combined dichloromethane layer was washed with aqueous sodium chloride solution (13.6 g of sodium chloride in 493 ml water). The solvent was evaporated till a volume of 170 ml and the residual layer was diluted with toluene (340 ml), stirred well and the solvent was evaporated completely at 40°C under reduced pressure (4 mm Hg). To the residue ethyl acetate (170 ml) and hexane (187 ml) were added and the mixture stirred for 30 minute. The separated solid was filtered under suction and the residue washed with 50 ml of a 1 :1 mixture of ethyl acetate and hexane. The solid obtained was dried under reduced pressure (4 mm Hg) at 45°C for 3.5 hours, to obtain 96 g of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) as a white solid, in 75% yield.

Analysis:

Mass: 194 (M+l); for Molecular Weight: 193 and Molecular Formula: C₇Hi₂ClN0₃; 1H NMR (400 MHz, CDC1₃): 5 5.69 (s, 1H), 5.0-5.1 (m, 1H), 3.4-3.7 (m, 4H), 2.1 (s, 3H), 1.9 (s, 3H).

Claims

1. A process for preparation of a compound of Formula (I),

Formula (I)

Formula (I II)

2. A process according to Claim 1 , wherein the base is selected from a group consisting of butyl lithium, sodium teri-butoxide, potassium teri-butoxide, lithium tert- butoxide or lithium diisopropylamide.

3. A process according to Claim 2, wherein the base is lithium teri-butoxide.

4. A process according to Claim 1 , wherein the polar aprotic solvent is selected from tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile or dimethylsulfoxide.

5. A process according to Claim 4, wherein the polar aprotic solvent is tetrahydrofuran.

6. A process according to Claim 1, wherein compound of Formula (I) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) in presence of an initiator.

7. A process according to Claim 6, wherein the initiator is selected from the group consisting methanol, ethanol or iso-propanol.

8. A process according to Claim 7, wherein the initiator is methanol.

9. A process according to Claim 1, wherein compound of Formula (I) is obtained by reacting a compound of Formula (II) with a compound of Formula (III) at a temperature of 10°C to 15°C.

10. A compound of Formula (I) having purity of at least about 97% as determined by HPLC.

11. A pharmaceutical composition comprising a compound of Formula (I) according to Claim 10.

12. A process for preparation of a compound of Formula (I),

Formula (I)

said process comprising, reacting a compound of Formula (II) with a compound of Formula (III) in presence of lithium feri-butoxide, tetrahydrofuran and methanol at a temperature of 10°C to 15°C.