WO2016041505A1

WO2016041505A1 - Tedizolid phosphate, intermediate and preparation method thereof

Info

Publication number: WO2016041505A1
Application number: PCT/CN2015/089820
Authority: WO
Inventors: 朱益忠; 张喜全; 刘飞; 顾红梅; 朱波; 汤剑秋; 汤松; 王路路
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2014-09-17
Filing date: 2015-09-17
Publication date: 2016-03-24

Abstract

Provided is a preparation method for tedizolid phosphate, an intermediate thereof of formula VII and a preparation method for the intermediates of formulae V, VII, IX and X. The preparation method has a short route, mild reaction conditions and is green and environmentally friendly. Dibenzyl diisopropylamino phosphite is used as a phosphorylation agent, avoiding the production of dimeric products and enabling a higher yield of the preparation method.

Description

Terbutazol phosphate, intermediate thereof and preparation method thereof

Technical field

The invention belongs to the field of medicinal chemical industry, and in particular relates to tertidazole phosphate, an intermediate thereof and a novel preparation method thereof.

Background technique

Tedizolidphosphate, (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyl Oxazolidine-2-one dihydrogen phosphate (Formula I) for the treatment of Gram-positive bacterial infections, such as acute bacterial skin infections, MRSA-induced infections and pulmonary infections.

At present, there are two main methods for preparing the disclosed tertazol phosphate:

Route 1: CN1894242 discloses the following preparation method:

The first step of the route uses a toxic organotin reagent, and the second step of the condensation reaction produces the key intermediate (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridine-5- The yield of 3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one is as low as 26%, and the third step is to prepare (R)-[3-(4-(2-(2-) Methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidine] bis(tetrabutyl ester) methyl phosphate is carried out at -78 ° C. Moreover, the reaction time is long, and the last step requires the use of trifluoroacetic acid having a pungent odor and strong corrosiveness. Therefore, the total yield of the route is low, the production cost is high, the reaction conditions are harsh, the production cycle is long, and the reagents used are toxic or irritating, corrosive, and are not suitable for industrial production.

Route 2: CN102177156 discloses the following synthetic route:

The route is long by the starting material synthesis reaction route, wherein the second step of the boronation reaction needs to be carried out at a low temperature of -72 ° C and the yield of the obtained product 4-(benzyloxycarbonylamino)-2-fluorobenzeneboronic acid is only 66%. And it is very impure. The fourth step of the ring-forming reaction is cumbersome and the reaction time is long. The final step of phosphorylation uses the highly toxic fuming liquid phosphorus oxychloride. Therefore, the route is not suitable for industrial mass production.

The method for synthesizing the tertidamine phosphate disclosed in the prior art has many drawbacks, and therefore a new method for preparing tertazolam phosphate is still required.

Summary of the invention

In a first aspect, the invention relates to a novel process for the preparation of terbutazol phosphate (a compound of formula I).

In a second aspect, the invention relates to an intermediate compound of formula VII of a compound of formula I and a process for the preparation thereof.

In a third aspect, the invention relates to a process for the preparation of a compound of formula V of the compound of formula I.

In a fourth aspect, the invention relates to a process for the preparation of a compound of formula IX of the compound of formula I.

In a fifth aspect, the invention relates to a process for the preparation of a compound of formula X of the compound of formula I.

detailed description

Method for preparing compound of formula I

In a first aspect, the present invention provides a process for the preparation of a compound of formula I, which comprises reacting a compound of formula VII with a benzyl group as follows:

Further, as an embodiment of the benzyl removal reaction, the benzyl removal reaction can be carried out in the presence of a catalyst and a hydrogen source.

Wherein the catalyst is selected from the group consisting of Pd(OH) ₂ /C, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(OH) ₂ or Raney nickel, preferably Pd/C.

Wherein the hydrogen source is selected from the group consisting of H ₂ , HCOOH, HCOONH ₄ , NH ₂ NH ₂ or cyclohexene, preferably H ₂ .

The preparation of the compound of the formula I can be carried out by selecting a suitable reaction solvent selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, Composition of valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO a solvent or a mixed solvent of several solvents in the group, preferably a solvent selected from the group consisting of ethyl acetate, butyl acetate and C ₁ -C ₈ alcohol or several solvents The mixed solvent is most preferably a solvent selected from the group consisting of ethyl acetate, methanol and ethanol or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is methanol.

As another embodiment of the benzyl removal reaction, the benzyl removal reaction can be carried out in the presence of trifluoroacetic acid.

The preparation of the compound of the formula I can be carried out by selecting a suitable reaction solvent selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, water, C ₁ -C ₈ alcohol, 1,4. - dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene A solvent or a mixed solvent of several solvents of a group consisting of toluene, xylene, DMF, DMAC and DMSO, preferably dichloromethane.

Optionally, the preparation of the compound of formula I further comprises the step of purifying the reaction product with an organic solvent including, but not limited to, petroleum ether, diethyl ether, diisopropyl ether, cyclohexane, dichloromethane, chloroform. , carbon tetrachloride, C ₁ -C ₈ alcohol, 1,4-dioxane, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, ethyl acetate, butyl acetate, A solvent or a mixed solvent of several solvents in a group consisting of tetrahydrofuran, acetonitrile, benzene, toluene and xylene. In a specific embodiment, the organic solvent is ethanol.

Further, as a specific embodiment, the method for preparing the compound of the formula I further comprises: reacting the compound of the formula V and the compound of the formula VI in the presence of a catalyst and an oxidizing agent to prepare the compound of the VII,

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or, R ₁ and R ₂ are each independently Selected from a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy substituted benzyl, preferably R ₁ and R _{2 are} both isopropyl or ethyl, most preferably R ₁ and R _{2 are} both isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the reaction solvent is selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and a solvent or a mixed solvent of several solvents in a group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO, preferably For methylene chloride,

Among them, the compound of the formula VI is preferably dibenzyl diisopropylaminophosphite.

Still further, as a specific embodiment, the method for preparing the compound of formula I further comprises: preparing the compound of formula V according to the following steps:

(1) a compound of the formula III is reacted with a borating reagent in the presence of a palladium catalyst and a base,

(2) the product of step (1) is reacted with a compound of formula IV in the presence of a palladium catalyst and a base,

Wherein X ₁ and X ₂ are each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent of the step (1) is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,

More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd (OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein said base in step (1) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium,

Wherein the palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd (OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein the base of the step (2) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide and lithium diisopropylamide from C ₁ -C ₈ . One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine Preferred is potassium acetate.

Further, as another specific embodiment, the method for preparing the compound of the formula I further comprises: preparing the compound of the formula V by reacting the compound of the formula X with a compound of the formula III in the presence of a palladium catalyst and a base,

Wherein X _{1 is} selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

The compound of formula III is preferably (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (formula VIII),

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide from C ₁ -C ₈ One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably Barium carbonate,

Wherein, the reaction solvent is selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, a solvent or a mixture of several solvents in the group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO, and NMP Solvent,

Among them, the preparation of the compound of the formula V is carried out under the protection of N ₂ or Ar.

Still further, as another specific embodiment, the method for preparing the compound of formula I further comprises: reacting a compound of formula IX with a compound of formula X in the presence of a palladium catalyst and a base to prepare the compound of formula VII,

Wherein the base is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably carbonic acid Sodium or potassium carbonate, most preferably sodium carbonate;

Among them, the compound of the formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methylphosphonic acid bis(benzyl ester).

Further, as a specific embodiment, the method for preparing the compound of the formula I further comprises: reacting the compound of the formula III and the compound of the formula VI in the presence of a catalyst and an oxidizing agent to prepare the compound of the formula IX,

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R ₁ and R ₂ are each independently Selected from a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy-substituted benzyl group, preferably at the same time R ₁ and R ₂ is isopropyl or ethyl, most preferably R ₁ and R ₂ simultaneously isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

Preferred is 1H-tetrazole,

Wherein the compound of formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester), a compound of formula III Preferred is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one.

Further, as a specific embodiment, the method for preparing the compound of the formula I further comprises: reacting the compound of the formula IV with a borating reagent in the presence of a palladium catalyst and a base to prepare the compound of the formula X,

Wherein X _{2 is} selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent is selected from the group consisting of pinacol borate,

More preferably, it is a benzoic acid pinacol ester,

Wherein the base is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium.

In the following, six specific embodiments of the preparation method of the compound of the formula I will be described in detail.

As a first specific embodiment, the method of preparing a compound of formula I comprises:

(1) a compound of the formula IX is reacted with a compound of the formula X in the presence of a palladium catalyst and a base to prepare a compound of the formula VII,

(2) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

In a particular embodiment, the compound of formula IX is (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester) (Formula XII),

Wherein the base of the step (1) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide and lithium diisopropylamide from C ₁ -C ₈ . One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine Kind, preferably sodium carbonate or potassium carbonate, most preferably sodium carbonate,

Wherein, the step (1) can be carried out by selecting a suitable reaction solvent according to requirements, including but not limited to water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid Butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC a solvent in a group consisting of DMSO and NMP or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is a mixed solvent of 1,4-dioxane and water.

Optionally, the reaction of step (1) can be carried out under the protection of N ₂ or Ar.

Wherein the catalyst of the step (2) is selected from the group consisting of Pd(OH) ₂ /C, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(OH) ₂ or Raney nickel, preferably Pd/C.

Wherein, the hydrogen source of the step (2) is selected from the group consisting of H ₂ , HCOOH, HCOONH ₄ , NH ₂ NH ₂ or cyclohexene, preferably H ₂ .

Wherein, the step (2) can be carried out by selecting a suitable reaction solvent selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, Butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and a solvent in a group consisting of DMSO or a mixed solvent of several solvents, preferably a solvent or a group selected from the group consisting of ethyl acetate, butyl acetate, and C ₁ -C ₈ alcohol The mixed solvent of the solvent is most preferably a solvent selected from the group consisting of ethyl acetate, methanol and ethanol or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is methanol.

Optionally, the reaction can be carried out under the protection of N ₂ or Ar.

As a method for preparing the compound of the above formula IX, the compound of the formula III and the compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent,

Wherein X _{1 is} selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br.

In a particular embodiment, the compound of formula IX is (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester) (Formula XII), the compound of formula III is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (formula XI),

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R ₁ and R ₂ are each independently Selected from a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ -C An alkyl group of ₄ or a C ₁ -C ₄ alkoxy-substituted benzyl group. Preferably, R ₁ and R _{2 are} both isopropyl or ethyl, most preferably R ₁ and R _{2 are} both isopropyl.

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

It is preferably 1H-tetrazole.

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, peroxyacetic acid, peroxybenzoic acid or t-butyl hydroperoxide (TBHP), preferably m-chloroperoxybenzoic acid (mCPBA). .

The preparation of the compound of the formula IX can be carried out by selecting a suitable reaction solvent selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, Composition of valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO A solvent in a group or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is dichloromethane.

In a particular embodiment, the compound of formula VI is dibenzylaminodiphosphite (formula II),

As a method for preparing the above compound of the formula X, the method comprises: reacting a compound of the formula IV with a borating reagent in the presence of a palladium catalyst and a base,

Wherein X _{2 is} selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br.

In a particular embodiment, the compound of formula IV is 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (Formula XIII).

The borating agent is selected from the group consisting of pinacol borate

More preferably, it is a benzoic acid pinacol ester.

The palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex.

The base is selected from the C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine is preferably potassium acetate.

The preparation of the compound of the formula X can be carried out by selecting a suitable solvent, including but not limited to water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, pentane. Acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO and NMP A solvent of a group or a mixed solvent of several solvents. In a specific embodiment, the solvent is DMSO.

As a second specific embodiment, the method for preparing a compound of formula I comprises:

i) reacting a compound of formula III with a boronating reagent in the presence of a palladium catalyst and a base,

Ii) reacting the product of step i) with a compound of formula IV in the presence of a palladium catalyst and a base to prepare a compound of formula V,

Iii) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

Iv) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

Wherein X ₁ and X ₂ are each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br.

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R ₁ and R ₂ are each independently Selected from a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ - An alkyl group of C ₄ or a C ₁ -C ₄ alkoxy-substituted benzyl group. Preferably, R ₁ and R _{2 are} both isopropyl or ethyl, most preferably R ₁ and R _{2 are} both isopropyl.

The boriding agent of step i) is selected from the group consisting of pinacol borate

More preferably, it is a benzoic acid pinacol ester.

The palladium catalyst of the step i) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex .

The base of the step i) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, potassium hydroxide, One or more of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine or ethylenediamine is preferably potassium acetate.

The palladium catalyst of the step ii) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex .

The base of the step ii) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, potassium hydroxide from C ₁ -C ₈ . One or more of the group consisting of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably cesium carbonate.

The catalyst of step iii) is 1H-tetrazole or

It is preferably 1H-tetrazole.

The oxidizing agent of step iii) is selected from m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, peroxyacetic acid, peroxybenzoic acid or t-butyl hydroperoxide (TBHP), preferably m-chloroperoxybenzoic acid ( mCPBA).

The catalyst of step iv) is selected from the group consisting of Pd(OH) ₂ /C, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(OH) ₂ or Raney nickel, preferably Pd/C.

The hydrogen source of step iv) is selected from the group consisting of H ₂ , HCOOH, HCOONH ₄ , NH ₂ NH ₂ or cyclohexene, preferably H ₂ .

As a third specific embodiment, the preparation method of the compound of formula I includes:

i) a compound of the formula III and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula IX,

Ii) a compound of the formula IV is reacted with a boronating reagent in the presence of a palladium catalyst and a base to prepare a compound of the formula X,

Iii) a compound of the formula IX is reacted with a compound of the formula X in the presence of a palladium catalyst and a base to prepare a compound of the formula VII,

The catalyst of step i) is 1H-tetrazole or

It is preferably 1H-tetrazole.

The oxidizing agent of step i) is selected from m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide (TBHP), preferably m-chloroperoxybenzoic acid ( mCPBA).

The boriding agent of step ii) is selected from the group consisting of pinacol borate

More preferably, it is a benzoic acid pinacol ester.

Said step ii) is a base selected from the C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, hydroxide One or more selected from the group consisting of sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably It is potassium acetate.

The palladium catalyst of the step iii) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex .

Said step iii) is a base selected from the C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, hydroxide One or more selected from the group consisting of sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably Most preferred is sodium carbonate or potassium carbonate.

As a fourth specific embodiment, the method for preparing a compound of formula I comprises:

(1) a compound of the formula X is reacted with a compound of the formula III in the presence of a palladium catalyst and a base to prepare a compound of the formula V,

(2) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

(3) a compound of the formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of the formula I,

In a particular embodiment, the compound of formula III is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (formula VIII),

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; or R ₁ and R ₂ are each independently selected a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkoxy-substituted benzyl. Preferably, R ₁ and R _{2 are} both isopropyl or ethyl, most preferably R ₁ and R _{2 are} both isopropyl.

Wherein the palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd (OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.

Wherein said base in step (1) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine It is preferably cesium carbonate.

The step (1) may be carried out by selecting a suitable reaction solvent according to requirements, including but not limited to water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyl Acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO A solvent or a mixed solvent of several solvents in a group consisting of NMP. In a specific embodiment, the reaction solvent of step (1) is DMSO.

Optionally, the step (1) reaction can be carried out under the protection of N ₂ or Ar.

Wherein the catalyst of the step (2) is selected from 1H-tetrazole or

It is preferably 1H-tetrazole.

Wherein the oxidizing agent of the step (2) is selected from m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide (TBHP), preferably m-chloroperoxy Benzoic acid (mCPBA).

The step (2) may be carried out by selecting a suitable reaction solvent selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid. , valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO A solvent or a mixed solvent of several solvents in the composition group. In a specific embodiment, the reaction solvent is dichloromethane.

Wherein the catalyst of the step (3) is selected from the group consisting of Pd(OH) ₂ /C, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(OH) ₂ or Raney nickel, preferably Pd/C.

Wherein, the hydrogen source of the step (3) is selected from the group consisting of H ₂ , HCOOH, HCOONH 4 , NH ₂ NH ₂ or cyclohexene, preferably H ₂ .

The step (3) may be carried out by selecting a suitable reaction solvent selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid. , valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO One solvent or a mixed solvent of several solvents in the group consisting of one solvent or several solvents selected from the group consisting of ethyl acetate, butyl acetate and C ₁ -C ₈ alcohols. The mixed solvent is most preferably a solvent selected from the group consisting of ethyl acetate, methanol and ethanol or a mixed solvent of several solvents. In a specific embodiment, the solvent is methanol.

As a fifth specific embodiment, the method for preparing a compound of formula I comprises:

i) a compound of the formula IV is reacted with a boronating reagent in the presence of a palladium catalyst and a base to prepare a compound of the formula X,

Ii) a compound of the formula X is reacted with a compound of the formula III in the presence of a palladium catalyst and a base to prepare a compound of the formula V,

More preferably, it is a benzoic acid pinacol ester.

Said step i) a base selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, hydroxide One or more selected from the group consisting of sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably It is potassium acetate.

Said step ii) is a base selected from the C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, hydroxide One or more selected from the group consisting of sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably It is barium carbonate.

The catalyst of step iii) is 1H-tetrazole or

It is preferably 1H-tetrazole.

As a sixth specific embodiment, the method for preparing a compound of formula I comprises:

Iv) a compound of formula VII is reacted in the presence of trifluoroacetic acid to prepare a compound of formula I,

More preferably, it is a benzoic acid pinacol ester.

The base of the step i) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, potassium hydroxide from C ₁ -C ₈ . One or more of the group consisting of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably potassium acetate.

The catalyst of step iii) is 1H-tetrazole or

It is preferably 1H-tetrazole.

The compound of the formula VI in the present embodiment can be obtained commercially, or can be produced by a method of the prior art, for example, by the following method.

For example, the compound of formula II can be obtained commercially, or can be prepared by the following method.

It should be understood that the compound of the formula II, the compound of the formula VI, the compound of the formula IX, the compound of the formula VII or the compound of the formula XII of the present invention also encompasses a compound in which the benzene ring on the benzyl group is mono- or polysubstituted, as long as the above reaction can be carried out. Substituents include, but are not limited to, halogen, hydroxy, amino, cyano, carboxy, sulfonyl, decyl, trifluoromethyl, nitro, phenyl, benzyl, benzyloxy, pyridyl, piperidinyl, hydroxymethyl group, hydroxyethyl, hydroxypropyl, optionally substituted with halogen or C ₁ -C ₆ alkoxy-substituted C ₁ -C ₆ alkyl, optionally substituted by halogen or C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkane Alkylcarbonyloxy, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkoxy or C ₃ -C ₇ cycloalkylmethoxy.

It should be understood that the palladium catalyst of the present invention may also be various palladium complex compounds prepared from various palladium catalysts and ligands including, but not limited to, PCy ₃ , AsPh ₃ , n-Bu ₃ P, (MeO) ₃ P, Ph ₂ P(CH ₂ ) ₂ PPh ₂ (dppe) or Ph ₂ P(CH ₂ ) ₃ PPh ₂ (dppp).

C ₁ -C _n as used herein includes C ₁ -C ₂ , C ₁ -C ₃ , ... C ₁ -C _n . For example, "C ₁ -C ₈ " means that the moiety has 1-8 carbon atoms, that is, contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms. , 6 carbon atoms, 7 carbon atoms or 8 carbon atoms, and C ₁ -C ₂ and C ₃ -C ₇ are also the same. Thus, for example, "a sodium alkoxide of C ₁ -C ₈ " means a sodium alkoxide having from 1 to 8 carbon atoms, that is, the sodium alkoxide contains one carbon atom, two carbon atoms, three carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms or 8 carbon atoms; and, for example, "C ₁ -C ₆ alkyl" means an alkyl group having 1 to 6 carbon atoms, that is, The alkyl group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, more specifically, for example, "C ₁ -C ₄ alkyl group" It means an alkyl group having 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The "dppf" described in the present invention is 1,1'-bis(diphenylphosphino)ferrocene.

The "dba" described in the present invention is dibenzylideneacetone.

The "PCy ₃ " described in the present invention is tricyclohexylphosphine.

The "dppe" described in the present invention is 1,2-bis(diphenylphosphino)ethane.

The "dppp" described in the present invention is 1,3-bis(diphenylphosphino)propane.

Intermediate formula VII compound and preparation method thereof

In a second aspect, the present invention provides a compound of formula VII,

The invention also provides a process for the preparation of a compound of formula VII.

Hereinafter, two specific embodiments of the preparation method of the VII compound are described as follows:

As a first embodiment of the method for preparing a compound of formula VII, the method comprises: reacting a compound of formula V with a compound of formula VI in the presence of a catalyst, an oxidizing agent,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

It is preferably 1H-tetrazole.

The preparation of the compound of the formula VII can be carried out by selecting a suitable reaction solvent selected from the group consisting of water, a C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid. a group consisting of acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO A solvent or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is dichloromethane.

The compound of the above formula V can be produced by any one of the following two production methods.

As a first specific embodiment of the preparation method of the compound of formula V, the method comprises:

In a particular embodiment, the compound of formula III is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one.

In a particular embodiment, the compound of formula IV is 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine.

The borating agent of the step (1) is selected from the group consisting of pinacol borate

More preferably, it is a benzoic acid pinacol ester.

The palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex Things.

The palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex Things.

The base of the step (1) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, and hydroxide. One or more of the group consisting of potassium, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine is preferably potassium acetate.

Said base of step (2) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine is preferably cesium carbonate.

The preparation of the compound of the formula V can be carried out by selecting a suitable reaction solvent including, but not limited to, water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid. , valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO and A solvent of a group consisting of NMP or a mixed solvent of several solvents. In a specific embodiment, the solvent of step (1) is DMSO, and the solvent of step (2) is a mixed solvent of 1,4-dioxane and water.

Optionally, the reaction of step (1) and step (2) can be carried out under the protection of N ₂ or argon.

As a second specific embodiment of the preparation method of the above compound of the formula V, the method comprises: reacting a compound of the formula X with a compound of the formula III in the presence of a palladium catalyst and a base to prepare a compound of the formula V,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ is preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex.

Wherein the base is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide (LDA), hydrogen from C ₁ -C ₈ . One or more of the group consisting of sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine or ethylenediamine, Preference is given to cesium carbonate.

The preparation of the compound of the formula V can be carried out by selecting a suitable reaction solvent including, but not limited to, water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid. , valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO and A solvent in a group consisting of NMP or a mixed solvent of several solvents. In a specific embodiment, the solvent of step (1) is DMSO, and the solvent of step (2) is a mixed solvent of 1,4-dioxane and water.

Optionally, the preparation of the compound of formula V can be carried out under the protection of N ₂ or Ar.

A second embodiment of the process for the preparation of a compound of formula VII, which comprises reacting a compound of formula IX with a compound of formula X in the presence of a palladium catalyst and a base to prepare a compound of formula VII,

Wherein the base is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably carbonic acid Sodium or potassium carbonate, most preferably sodium carbonate.

Wherein, the preparation of the compound of the formula VII can be carried out by selecting a suitable reaction solvent including, but not limited to, water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, and the like. Butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, A solvent or a mixed solvent of several solvents in a group consisting of DMSO and NMP. In a specific embodiment, the reaction solvent is a mixed solvent of 1,4-dioxane and water.

Optionally, the preparation of the compound of formula VII can be carried out under the protection of N ₂ or Ar.

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

It is preferably 1H-tetrazole.

As a method for preparing the above compound of the formula X, it may include: reacting the compound of the formula IV with a borating reagent in the presence of a palladium catalyst and a base,

The borating agent is selected from the group consisting of pinacol borate

More preferably, it is a benzoic acid pinacol ester.

The preparation of the compound of the formula X can be carried out by selecting a suitable solvent including, but not limited to, water, a C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, and the like. Valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO and NMP A solvent of the group consisting of or a mixed solvent of several solvents. In a specific embodiment, the reaction solvent is DMSO.

Method for preparing intermediate formula V compound

As a specific embodiment, the preparation method of the intermediate compound of formula V comprises: preparing the compound of formula V according to the following steps:

More preferably, it is a benzoic acid pinacol ester.

Wherein said base in step (1) is selected from the group consisting of C ₁ -C ₈ sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium.

Wherein the palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh ₃ ) ₄ , Pd (OAc) ₂ , PdCl ₂ (dppf), Pd ₂ (dba) ₃ or Pd(dba) ₂ , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.

As another specific embodiment, the preparation method of the intermediate formula V compound comprises: preparing the compound of the formula V by reacting the compound of the formula X with the compound of the formula III in the presence of a palladium catalyst and a base,

Wherein the base is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide from C ₁ -C ₈ One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably Barium carbonate.

Wherein, the solvent for the reaction is selected from the group consisting of water, C ₁ -C ₈ alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, and ring. a solvent or a group of a group consisting of pentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO, and NMP a solvent mixture;

Method for preparing intermediate formula IX compound

In a fourth aspect, the present invention relates to a process for the preparation of a compound of the formula IX of the compound of the formula I, which comprises reacting a compound of the formula III and a compound of the formula VI in the presence of a catalyst and an oxidizing agent to prepare the compound of the formula IX,

Wherein R ₁ and R ₂ are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R ₁ and R ₂ are each independently Selected from a phenyl group optionally substituted by halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; or R ₁ and R ₂ are each independently selected from halogen, C ₁ -C The alkyl group of ₄ or the C ₁ -C ₄ alkoxy-substituted benzyl group, preferably R ₁ and R _{2 are} both isopropyl or ethyl, most preferably R ₁ and R _{2 are} both isopropyl.

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or

It is preferably 1H-tetrazole.

Method for preparing intermediate formula X compound

In a fifth aspect, the present invention relates to a process for the preparation of a compound of the formula X of the compound of the formula I, which comprises reacting a compound of the formula IV with a boronating reagent in the presence of a palladium catalyst and a base to prepare the compound of the formula X,

More preferably, it is a benzoic acid pinacol ester.

The intermediates and final products of each step of the preparation method of the present invention have high purity. In addition, the use of dibenzylaminophosphite dibenzyl ester as the phosphorylating agent can also avoid the production of dimerization products, resulting in a higher yield of the preparation process of the present invention. The preparation method of the invention has a short route, mild reaction conditions, and avoids the use of toxic, irritating and strong corrosive agents, and is environmentally friendly; Avoid the use of ultra-low temperature reaction, easy to operate and high production efficiency. Therefore, the preparation method of the present invention is particularly adapted to industrial production.

Example

The invention is exemplified by the following examples, which are merely examples and are not intended to limit the invention, and all of the techniques based on the invention are within the scope of the invention.

Example 1 Preparation of tertazolidin phosphate (compound of formula I)

Step 1 (R)-3-(4-(2-(2-Methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyloxazolidine-2- Preparation of ketones (compounds of formula V)

DMSO (100 ml), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (10 g, 34.5 mmol), boronic acid frequency was added to a 250 ml reaction flask. Alcohol ester (17.52 g, 69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.41 g, 1.73 mmol) and potassium acetate (13.5 g) , 138 mmol), heated to 80 ° C under nitrogen, and reacted for 14 hours. The heating was stopped, the temperature was lowered to room temperature, and the mixture was combined with water and ethyl acetate. The organic layer was combined and evaporated.

The concentrated product of the above step was added to a 250 ml reaction flask, and 1,4-dioxane (100 ml) and 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (8.28) were added. g, 34.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.56 g, 0.69 mmol) and aqueous cesium carbonate solution (50 ml, containing 33.72 g Barium carbonate, 103.5 mmol), heated to 70 ° C under nitrogen, reacted for 3 hours, and extracted with dichloromethane. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, evaporated .

^{1 H NMR (500MHz, DMSO-} d6): δ8.9328 (s, 1H), 8.2019 (m, 2H), 7.7153 (m, 2H), 7.5227 (m, 1H), 5.1824 (t, 1H), 4.7675 ( m, 1H), 4.4782 (s, 3H), 4.1671 (t, 1H), 3.9184 (m, 1H), 3.7203 (m, 1H), 3.6122 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): δ 163.75, 159.1925, 154.147, 149.235, 144.983, 140.434, 136.91, 131.475, 130.69, 121.918, 118.483, 113.89, 105.292, 73.314, 61.507, 45.907, 39.519.

ESI-MS [M+H] ⁺ : 371.1264.

Step 2 (R)-[3-(4-(2-(2-Methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl Preparation of bis(benzyl ester) methyl phosphate (compound of formula VII)

Dichloromethane (100 ml), 1H-tetrazole (5.97 g, 85.2 mmol) and compound of formula V (10.5 g, 28.4 mmol) were added to a 500 ml three-necked flask, and diisopropylaminophosphoric acid was added dropwise at a temperature below 30 ° C. Dibenzyl ester (19.6 g, 56.8 mmol) was reacted for 30 min at 25-30 °C. The temperature was lowered to 0-10 ° C, 85% m-chloroperoxybenzoic acid (8.08 g, 39.8 mmol) was added, and the reaction was carried out at 5-10 ° C for 30 min.

The reaction solution was washed successively with saturated NaHCO ₃ twice, washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give 14.89g of the title compound in a yield of 83.1%, HPLC purity by 99.62% (area Normalization method).

^{1 H NMR (500MHz, DMSO-} d6): δ8.9318 (s, 1H), 8.241 (m, 1H), 8.1938 (m, 1H), 7.7457 (t, 1H), 7.6669 (1,1H), 7.4924 ( 1,1H), 7.3442 (1,10H), 5.0336 (1,5H), 4.4859 (s, 3H), 3.3063 (m, 3H), 3.9175 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): 5163.811, 159.234, 153.752, 149.343, 145.068, 140.087, 137.079, 135.778, 131.5, 130.75, 128.358, 127.733, 122.037, 118.804, 114.055, 105.463, 70.977, 68.741, 67.288, 45.698 , 39.53.

ESI-MS [M+H] ⁺ : 631.1852.

Step 3 Preparation of tertazolidin phosphate (compound of formula I)

Methanol (1000 ml), a compound of formula VII (12.8 g) and 10% Pd/C (50% water, 1.28 g) were added to a 2 L reaction flask, and hydrogenated at 50 ° C for 12 h under normal pressure, filtered, and evaporated to give 8.78 g of title. The compound was obtained in a yield of 96.0%, and the purity by HPLC was 99.66% (area normalization method).

^{1 H NMR (500MHz, DMSO-} d6): δ8.9367 (s, 1H), 8.2052 (m, 2H), 7.72 (m, 2H), 7.5162 (m, 1H), 4.99 (m, 1H), 4.4961 ( s, 3H), 4.2546 (t, 1H), 4.1714 (m, 1H), 4.1035 (m, 1H), 3.9521 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): δ 163.854, 159.2905, 153.925, 149.382, 145.069, 140.286, 137.083, 131.558, 130.87, 122.044, 118.764, 114.079, 105.509, 71.467, 65.457, 45.833, 39.549.

ESI-MS m/z [M+H] ⁺ : 451.0927.

Example 2 Preparation of tertazolidin phosphate (compound of formula I)

Step 1 Preparation of (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester) (compound of formula IX)

Dichloromethane (50 ml), 1H-tetrazole (7.24 g, 103.41 mmol) and (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazole were added to a 250 ml three-necked flask. Alkan-2-one (10.0 g, 34.47 mmol), dibenzyl diisopropylammonium phosphite (23.81 g, 68.94 mmol) was added dropwise at a temperature below 30 ° C, and the temperature was maintained at 25-30 ° C for 30 min, and the temperature was lowered. At 0-10 ° C, 85% m-chloroperoxybenzoic acid (9.8 g, 48.26 mmol) was added and the reaction was carried out at 5-10 ° C for 30 min.

The reaction solution was washed successively with saturated NaHCO ₃ twice, once with saturated NaCl solution and dried over anhydrous Na ₂ SO _4, filtered, concentrated in vacuo and purified by column chromatography to afford 17.11g of the title compound in a yield of 90.2%, HPLC purity detection 99.24% (area normalization method).

^{1 H NMR (500MHz, DMSO-} d6): δ7.6892 (m, 1H), 7.6387 (dd, 1H), 7.3240 (m, 11H), 5.034 (m, 4H), 4.9644 (m, 1H), 4.3203 ( m, 1H), 4.2576 (m, 1H), 4.1594 (m, 1H), 3.8409 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): δ 159.1, 157.168, 153.666, 139.254, 135.737, 135.684, 133.364, 128.361, 128.331, 128.285, 127.737, 127.67, 114.991, 106.1081, 70.899, 68.744, 68.703, 67.201, 45.652 , 39.499.

ESI-MS [M+H] ⁺ : 550.0425.

Step 2 Preparation of B-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]boronic acid (compound of formula X)

To a 250 ml reaction flask was added DMSO (100 ml), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (10.0 g, 41.66 mmol), and benzoic acid pinacol ester (12.69 g, 49.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.7 g, 2.08 mmol) and potassium acetate (16.35 g, 166.64 mmol), N Under the protection of ₂ , the temperature was raised to 80 ° C and the reaction was carried out for 3 h. Methylene chloride / water extraction, the organic phase was washed with saturated NaCl solution resulting was separated, dried over anhydrous Na ₂ SO ₄ dried, filtered, concentrated in vacuo and purified by column chromatography to give 8.11g solid, yield 95.0%, HPLC purity detection 98.2% (area normalization method).

¹ H NMR (500 MHz, DMSO-d6): δ s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s

¹³ C NMR (125 MHz, DMSO-d6): 5163.901, 154.885, 148.290, 143.277, 121.612, 84.278, 24.575.

ESI-MS [M+H] ⁺ : 206.0845.

Step 3 (R)-[3-(4-(2-(2-Methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidine Preparation of bis(benzyl ester) methyl phosphate (compound of formula VII)

1,4-dioxane (60 ml), a compound of formula XII (17.0 g, 30.89 mmol), a compound of formula X (6.97 g, 33.98 mmol), [1,1'-bis(diphenyl) were added to a 250 ml reaction flask. Phosphine) ferrocene] palladium dichloride dichloromethane complex (0.51 g, 0.62 mmol), aqueous sodium carbonate (30 ml, containing 10.8 g of sodium carbonate, 101.94 mmol), heated to 70 ° C under N ₂ protection. After the reaction was carried out for 3 h, the mixture was extracted with methylene chloride, and the obtained organic phase was washed with a saturated NaCI solution, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and purified by column chromatography to give 15.31 g of solid, yield 78. The purity was 98.43% (area normalization method).

^{1 H NMR (500MHz, DMSO-} d6): δ8.9318 (s, 1H), 8.241 (m, 1H), 8.1938 (m, 1H), 7.7457 (t, 1H), 7.6669 (m, 1H), 7.4924 ( m, 1H), 7.3442 (m, 10H), 5.0336 (m, 5H), 4.4859 (s, 3H), 3.3063 (m, 3H), 3.9175 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): δ 163. 811, 159. 234, 153. 752, 149. 343, 145. 068, 140.087, 137.079, 135. 778, 131.5, 130.75, 128.358, 127.733, 122.037, 118.804, 114.055, 105.463, 70.977, 68.741, 67.288 , 45.698, 39.53.

ESI-MS [M+H] ⁺ : 631.1852.

Step 4 Preparation of tertazolidin phosphate (compound of formula I)

Methanol (1000 ml), a compound of the formula VII (12.0 g) and 10% Pd/C (50% water, 1.2 g) were added to a 2 L reaction flask, and hydrogenation was carried out at 50 ° C for 12 h under normal pressure, filtered, and concentrated in vacuo to give 8.21. The compound was obtained in a yield of 95.8%, and the purity by HPLC was 99.37% (area normalization method).

ESI-MS m/z [M+H] ⁺ : 451.0927.

Example 3 Preparation of tertazolidinyl phosphate (compound of formula I)

Step 1 Preparation of B-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridyl]boronic acid (compound of formula X)

¹³ C NMR (125 MHz, DMSO-d6): δ 163. 901, 154. 885, 148.290, 143.277, 121.612, 84.278, 24.575.

ESI-MS [M+H] ⁺ : 206.0845.

Step 2 (R)-3-(4-(2-(2-Methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyloxazolidine-2- Preparation of ketones (compounds of formula V)

1,4-dioxane (100 ml), compound of formula X (8 g, 39 mmol), (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one (11.3 g, 39 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.64 g, 0.78 mmol) and cesium carbonate Aqueous solution (60 ml, containing 41.93 g of cesium carbonate, 128.7 mmol), and warmed to 70 ° C under N ₂ and reacted for 3 h, and extracted with dichloromethane. The organic phase was washed with saturated NaCl solution resulting was separated, dried over anhydrous Na ₂ SO ₄ dried, filtered, concentrated in vacuo and purified by column chromatography to give 12.16g solid, yield 84.2%, HPLC purity of 98.39% is detected (area normalization law).

ESI-MS [M+H] ⁺ : 371.1264.

Dichloromethane (100 ml), 1H-tetrazole (5.67 g, 81.0 mmol) and the compound of formula V (10 g, 27.0 mmol) were added to a 500 ml three-necked flask, and diisopropylaminophosphite was added dropwise at a temperature below 30 ° C. Benzyl ester (18.65 g, 54.0 mmol) was reacted for 30 min at 25-30 °C. The temperature was lowered to 0-10 ° C, 85% m-chloroperoxybenzoic acid (7.67 g, 37.8 mmol) was added, and the reaction was carried out at 5-10 ° C for 30 min.

The reaction solution was washed successively with saturated NaHCO ₃ solution twice, washed with a saturated NaCl solution, dried over anhydrous Na ₂ SO _4, filtered, concentrated in vacuo and purified by column chromatography, to give 14.1g of the title compound in a yield of 82.8%, HPLC purity by It is 99.49% (area normalization method).

ESI-MS [M+H] ⁺ : 631.1852.

Step 4 Preparation of tertazolidin phosphate (compound of formula I)

Methanol (1000 ml), a compound of the formula VII (12 g, 19 mmol) and 10% Pd/C (50% water, 1.2 g) were added to a 2 L reaction flask, and hydrogenated at 50 ° C for 12 h under normal pressure, filtered, and concentrated in vacuo to give 8.22 g. The title compound, yield 96.1%, was found to be 99.51% by HPLC (area normalization).

ESI-MS m/z [M+H] ⁺ : 451.0927.

Example 4 Preparation of tertazolidinyl phosphate (compound of formula I)

ESI-MS [M+H] ⁺ : 371.1264.

ESI-MS [M+H] ⁺ : 631.1852.

Step 3 Preparation of tertazolidin phosphate (compound of formula I)

Methylene chloride (50 ml), trifluoroacetic acid (55 ml), a compound of the formula VII (12 g), 40-45 ° C, were dissolved in a 500 ml reaction flask, and the mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure at 40-45 ° C to dryness eluting with EtOAc (EtOAc). The yield was 95.0%, and the purity by HPLC was 99.23% (area normalization method).

^{1 H NMR (500MHz, DMSO-} d6): 58.9367 (s, 1H), 8.2052 (m, 2H), 7.72 (m, 2H), 7.5162 (m, 1H), 4.99 (m, 1H), 4.4961 (s, 3H), 4.2546 (t, 1H), 4.1714 (m, 1H), 4.1035 (m, 1H), 3.9521 (m, 1H).

¹³ C NMR (125 MHz, DMSO-d6): 5163.854, 159.2905, 153.925, 149.382, 145.069, 140.286, 137.083, 131.558, 130.87, 122.044, 118.764, 114.079, 105.509, 71.467, 65.457, 45.833, 39.549.

ESI-MS m/z [M+H] ⁺ : 451.0927.

Claims

A process for the preparation of a process of a compound of formula I, which comprises reacting a compound of formula VII with a benzyl group as follows:
The method of claim 1 wherein said benzyl removal reaction is carried out in the presence of a catalyst and a hydrogen source,

Wherein the catalyst is selected from the group consisting of Pd(OH) 2 /C, Pd/C, PdCl 2 , Pd(OAc) 2 , Pd(OH) 2 or Raney nickel, preferably Pd/C,

Wherein the hydrogen source is selected from the group consisting of H 2 , HCOOH, HCOONH 4 , NH 2 NH 2 or cyclohexene, preferably H 2 ,

Wherein the reaction solvent is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and a solvent or a mixed solvent of several solvents in a group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO, preferably a solvent selected from the group consisting of ethyl acetate, butyl acetate and C 1 -C 8 alcohol or a mixed solvent of several solvents, most preferably selected from the group consisting of ethyl acetate, methanol and A solvent or a mixed solvent of several solvents in the group consisting of ethanol is particularly preferably methanol.
The method of claim 1, wherein the benzyl removal reaction is carried out in the presence of trifluoroacetic acid,

Wherein, the reaction solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, Acetone, butanone, pentanone, cyclopentanone, ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO A solvent or a mixed solvent of several solvents, preferably dichloromethane; preferably, the method includes a step of purifying the reaction product with an organic solvent.
The method according to any one of claims 1 to 3, further comprising: reacting a compound of the formula V and a compound of the formula VI in the presence of a catalyst or an oxidizing agent to prepare the compound of the VII,

Wherein R 1 and R 2 are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or, R 1 and R 2 are each independently Selected from a phenyl group optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or R 1 and R 2 are each independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy substituted benzyl, preferably R 1 and R 2 are both isopropyl or ethyl, most preferably R 1 and R 2 are both isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or
Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the reaction solvent is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and a solvent or a mixed solvent of several solvents in a group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO, preferably For methylene chloride,

Among them, the compound of the formula VI is preferably dibenzyl diisopropylaminophosphite.
The production method according to claim 4, wherein the method further comprises: preparing the compound of the formula V according to the following steps:

(1) a compound of the formula III is reacted with a borating reagent in the presence of a palladium catalyst and a base,

(2) the product of step (1) is reacted with a compound of formula IV in the presence of a palladium catalyst and a base,

Wherein X 1 and X 2 are each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent of the step (1) is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein said base in step (1) is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium,

Wherein the palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein the base of the step (2) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide and lithium diisopropylamide from C 1 -C 8 . One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine Preferred is potassium acetate.
The process according to claim 4, wherein the method further comprises: reacting a compound of the formula X with a compound of the formula III in the presence of a palladium catalyst and a base to prepare the compound of the formula V,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

The compound of formula III is preferably (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl
Oxazol-2-one (formula VIII),

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably carbonic acid cesium,

Wherein, the reaction solvent is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, a solvent or a mixture of several solvents in the group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO, and NMP Solvent,

Among them, the preparation of the compound of the formula V is carried out under the protection of N 2 or Ar.
The method according to any one of claims 1 to 3, further comprising reacting a compound of the formula IX with a compound of the formula X in the presence of a palladium catalyst and a base to prepare the compound of the formula VII,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably carbonic acid Sodium or potassium carbonate, most preferably sodium carbonate,

Wherein the compound of the formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-
Azolidinyl] bis(benzyl ester) methyl phosphate.
The process according to claim 7, wherein the method further comprises: reacting a compound of the formula III and a compound of the formula VI in the presence of a catalyst or an oxidizing agent to prepare the compound of the formula IX,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein R 1 and R 2 are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R 1 and R 2 are each independently Selected from a phenyl group optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or R 1 and R 2 are each independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy-substituted benzyl group, preferably at the same time R 1 and R 2 is isopropyl or ethyl, most preferably R 1 and R 2 simultaneously isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or
Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the compound of the formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-
Azolidyl] bis(benzyl ester) methyl phosphate, the compound of formula III is preferably (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyl
Azolidin-2-one.
The production method according to claim 7 or 8, wherein the method further comprises: reacting a compound of the formula IV with a borating agent in the presence of a palladium catalyst and a base to prepare the compound of the formula X,

Wherein X 2 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium.
The preparation method according to claim 2 or 7, the method comprising the steps of:

(1) a compound of the formula IX is reacted with a compound of the formula X in the presence of a palladium catalyst and a base to prepare a compound of the formula VII,

(2) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

Here, the definition of the catalyst and the hydrogen source is the same as the description of claim 2, and the definitions of the X 1 , the palladium catalyst, the base and the compound of the formula IX are as described in claim 7 .
The preparation method according to any one of claims 2, 4 and 5, comprising the steps of:

i) reacting a compound of formula III with a boronating reagent in the presence of a palladium catalyst and a base,

Ii) reacting the product of step i) with a compound of formula IV in the presence of a palladium catalyst and a base to prepare a compound of formula V,

Iii) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

Iv) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

Wherein the X 1 , X 2 , the borating agent, the palladium catalyst, and the base in the first step of the above reaction formula are as defined in claim 5; the catalyst, the oxidizing agent, and the R in the second step of the above reaction formula. 1 and R 2 are as defined in claim 4; the catalyst and hydrogen source in the third step of the above reaction formula are as defined in claim 2.
The preparation method according to any one of claims 2, 7, 8, and 9, the method comprising the steps of:

i) a compound of the formula III and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula IX,

Ii) a compound of the formula IV is reacted with a boronating reagent in the presence of a palladium catalyst and a base to prepare a compound of the formula X,

Iii) a compound of the formula IX is reacted with a compound of the formula X in the presence of a palladium catalyst and a base to prepare a compound of the formula VII,

Iv) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

Wherein the X 1 , the catalyst, the oxidizing agent, the R 1 , the R 2 and the compound of the formula IX in the step of preparing the compound of the formula IX are as defined in claim 8; the X in the step of preparing the compound of the formula X 2 , a boration reagent, a palladium catalyst, a base are defined as claimed in claim 9; a palladium catalyst, a base in the step of preparing a compound of the formula VII, a base as defined in claim 7; in the step of preparing the compound I The definition of the catalyst and hydrogen source is as defined in claim 2.
The preparation method according to any one of claims 2, 4, or 6, wherein the method comprises the steps of:

(1) a compound of the formula X is reacted with a compound of the formula III in the presence of a palladium catalyst and a base to prepare a compound of the formula V,

(2) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

(3) a compound of the formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of the formula I,

Wherein the definition of the X 1 , the palladium catalyst and the base in the first step of the above reaction formula is the same as defined in claim 6; the catalyst, the oxidizing agent, R 1 and R 2 in the second step of the above reaction formula are the same as defined in The catalyst and the hydrogen source in the third step of the above reaction formula are as defined in claim 2.
The preparation method according to any one of claims 2, 4, 6 and 9, comprising the steps of:

i) a compound of the formula IV is reacted with a boronating reagent in the presence of a palladium catalyst and a base to prepare a compound of the formula X,

Ii) a compound of the formula X is reacted with a compound of the formula III in the presence of a palladium catalyst and a base to prepare a compound of the formula V,

Iii) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

Iv) a compound of formula VII is prepared by reacting a catalyst with a hydrogen source to prepare a compound of formula I,

Wherein the X 2 , the borating agent, the palladium catalyst, and the base in the first step of the above reaction formula are as defined in claim 9; the X 1 , the palladium catalyst, and the alkali in the second step of the above reaction formula. The definition is the same as claim 6; the catalyst, the oxidizing agent, R 1 and R 2 in the third step of the above reaction formula are as defined in claim 4; the catalyst and hydrogen source in the fourth step of the above reaction formula; The definition is the same as in claim 2.
The preparation method according to any one of claims 3, 4 and 5, comprising the steps of:

i) reacting a compound of formula III with a boronating reagent in the presence of a palladium catalyst and a base,

Ii) reacting the product of step i) with a compound of formula IV in the presence of a palladium catalyst and a base to prepare a compound of formula V,

Iii) a compound of the formula V and a compound of the formula VI are reacted in the presence of a catalyst or an oxidizing agent to prepare a compound of the formula VII,

Iv) a compound of formula VII is reacted in the presence of trifluoroacetic acid to prepare a compound of formula I,

Wherein the X 1 , X 2 , the borating agent, the palladium catalyst, and the base in the first step of the reaction formula are as defined in claim 5; the catalyst, the oxidizing agent, the R 1 and the second step in the reaction formula; R 2 is as defined in claim 4.
Intermediate compound of formula VII,
A process for the preparation of a compound of formula VII according to claim 16 which comprises reacting a compound of formula V and a compound of formula VI in the presence of a catalyst, an oxidizing agent to prepare said compound of formula VII,

Wherein R 1 and R 2 are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or, R 1 and R 2 are each independently Selected from a phenyl group optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or, R 1 and R 2 are each independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy substituted benzyl, preferably R 1 and R 2 are both isopropyl or ethyl, most preferably R 1 and R 2 are both isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or
Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the reaction solvent is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, cyclopentanone, and a solvent or a mixed solvent of several solvents in a group consisting of ketone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC and DMSO, preferably For methylene chloride,

Among them, the compound of the formula VI is preferably dibenzyl diisopropylaminophosphite.
The method of claim 17 further comprising: preparing said compound of formula V as follows:

(1) a compound of the formula III is reacted with a borating reagent in the presence of a palladium catalyst and a base,

(2) the product of step (1) is reacted with a compound of formula IV in the presence of a palladium catalyst and a base,

Wherein X 1 and X 2 are each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent of the step (1) is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein said base in step (1) is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium,

Wherein the palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein the base of the step (2) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide and lithium diisopropylamide from C 1 -C 8 . One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine Preferred is potassium acetate.
The method of claim 17 wherein said method further comprises: reacting a compound of formula X with a compound of formula III in the presence of a palladium catalyst and a base to prepare said compound of formula V,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

The compound of formula III is preferably (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (formula VIII),

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide from C 1 -C 8 One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably Barium carbonate,

Wherein, the solvent for the reaction is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, and ring. a solvent or a group of a group consisting of pentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO, and NMP a solvent mixture of solvents,

Among them, the preparation of the compound of the formula V is carried out under the protection of N 2 or Ar.
A process for the preparation of a compound of formula VII according to claim 16 which comprises reacting a compound of formula IX with a compound of formula X in the presence of a palladium catalyst and a base to prepare said compound of formula VII,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably carbonic acid Sodium or potassium carbonate, most preferably sodium carbonate,

Among them, the compound of the formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methylphosphonic acid bis(benzyl ester).
The method of claim 20, further comprising reacting a compound of formula III and a compound of formula VI in the presence of a catalyst, an oxidizing agent to produce said compound of formula IX,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein R 1 and R 2 are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R 1 and R 2 are each independently Selected from a phenyl group optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or R 1 and R 2 are each independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy-substituted benzyl group, preferably at the same time R 1 and R 2 is isopropyl or ethyl, most preferably R 1 and R 2 simultaneously isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or
Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the compound of formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester), a compound of formula III Preferred is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one.
The method according to claim 20 or 21, further comprising reacting a compound of the formula IV with a borating agent in the presence of a palladium catalyst and a base to prepare the compound of the formula X,

Wherein X 2 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium.
A process for the preparation of a compound of the formula V, which comprises: preparing the compound of the formula V according to the following procedure:

(1) a compound of the formula III is reacted with a borating reagent in the presence of a palladium catalyst and a base,

(2) the product of step (1) is reacted with a compound of formula IV in the presence of a palladium catalyst and a base,

Wherein X 1 and X 2 are each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent of the step (1) is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst of the step (1) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein said base in step (1) is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, LDA, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium,

Wherein the palladium catalyst of the step (2) is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd (OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex,

Wherein the base of the step (2) is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide and lithium diisopropylamide from C 1 -C 8 . One or more of the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine Preferred is potassium acetate.
A process for the preparation of a compound of the formula V, which comprises reacting a compound of the formula X with a compound of the formula III in the presence of a palladium catalyst and a base to prepare the compound of the formula V,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

The compound of formula III is preferably (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (formula VIII),

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of sodium carbonate, cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide from C 1 -C 8 One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably Barium carbonate,

Wherein, the solvent for the reaction is selected from the group consisting of water, C 1 -C 8 alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, methyl ethyl ketone, pentanone, and ring. a solvent or a group of a group consisting of pentanone, hexanone, cyclohexanone, diethyl ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene, toluene, xylene, DMF, DMAC, DMSO, and NMP a solvent mixture of solvents,

Among them, the preparation of the compound of the formula V is carried out under the protection of N 2 or Ar.
A process for the preparation of a compound of the formula IX, which comprises reacting a compound of the formula III and a compound of the formula VI in the presence of a catalyst or an oxidizing agent to prepare the compound of the formula IX,

Wherein X 1 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein R 1 and R 2 are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or t-butyl; or R 1 and R 2 are each independently Selected from a phenyl group optionally substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or R 1 and R 2 are each independently selected from halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy-substituted benzyl group, preferably at the same time R 1 and R 2 is isopropyl or ethyl, most preferably R 1 and R 2 simultaneously isopropyl,

Wherein the catalyst is selected from the group consisting of 1H-tetrazole or
Preferred is 1H-tetrazole,

Wherein the oxidizing agent is selected from the group consisting of m-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, peroxybenzoic acid or t-butyl hydroperoxide, preferably m-chloroperoxybenzoic acid.

Wherein the compound of formula IX is preferably (R)-[3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl bis(benzyl ester), a compound of formula III Preferred is (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one.
A process for the preparation of an intermediate compound of formula X, which comprises reacting a compound of formula IV with a boronating reagent in the presence of a palladium catalyst and a base to prepare the compound of formula X,

Wherein X 2 is selected from the group consisting of F, Cl, Br or I, preferably Br or I, most preferably Br,

Wherein the borating agent is selected from the group consisting of pinacol borate,

Triisopropyl borate, tripropyl borate, trimethyl borate or triethyl borate, preferably boronic acid pinacol ester,
More preferably, it is a benzoic acid pinacol ester,

Wherein the palladium catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, Pd(PPh 3 ) 4 , Pd(OAc) 2 , PdCl 2 (dppf), Pd 2 (dba) 3 or Pd(dba) 2 , preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex,

Wherein the base is selected from the group consisting of C 1 -C 8 sodium alkoxide, and cesium carbonate, lithium carbonate, sodium hydride, sodium amide, butyl lithium, lithium t-butoxide, lithium diisopropylamide, sodium hydroxide, One or more of the group consisting of potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, diethylamine and ethylenediamine, preferably acetic acid Potassium.