CN115894496A - A kind of preparation method of ticagrelor and its intermediate - Google Patents

Abstract

The invention provides a brand new synthesis method of ticagrelor and a key intermediate (S) -1- (3,4-difluorophenyl) -alpha-alcohol thereof. The method takes 1- (3,4-difluorophenyl) -alpha-alcohol ester as a raw material to prepare (S) -1- (3,4-difluorophenyl) -alpha-alcohol through enzyme resolution (hydrolysis); the resulting compound of another configuration can be used to prepare (S) -1- (3,4-difluorophenyl) -alpha-alcohol by (hydrolysis), sulfonylation, waldenstein conversion and hydrolysis. The method has the advantages of simple operation, cheap and easily obtained raw materials and reagents, mild reaction conditions, high yield and environmental friendliness, thereby realizing industrial production.

Description

A preparation method of ticagrelor and its intermediates

Technical Field

The present invention belongs to the field of medicine and fine chemicals. Specifically, the present invention relates to a method for synthesizing a key intermediate of ticagrelor.

Background Art

Ticagrelor is a new type of small molecule anticoagulant with selective effects. It was approved for marketing by the European Union and the U.S. Food and Drug Administration (FDA) in December 2010 and July 2011, respectively. The drug can act reversibly on the ADP P2Y12 receptor, has a significant inhibitory effect on ADP-induced platelet aggregation, and has a rapid onset of action after oral administration. It is clinically used to reduce the incidence of thrombotic cardiovascular events in patients with acute coronary syndrome.

(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine is a key intermediate in the synthesis of ticagrelor. There are two methods for synthesizing it in the prior art: one is to synthesize racemic 2-(3,4-difluorophenyl)cyclopropylamine and then obtain (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine by splitting; this will lose half of the raw materials, causing great waste, and the efficiency of the synthesis is also very low. The other is to synthesize chiral (S)-(3,4-difluorophenyl)-α-alcohol intermediates or S-(3,4-difluorophenyl) oxirane as raw materials to synthesize (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine.

In the method of WO 2008018822A1, o-difluorobenzene is used as a raw material to prepare 2-chloro-1-(3,4-difluorophenyl)ethanone through Friedel-Crafts reaction, and then 2-chloro-1-S-(3,4-difluorophenyl)ethanol is prepared through chiral reduction; the disadvantage of this method is that it uses expensive chiral oxazolidinone catalyst and toxic borane dimethyl sulfide complex, and also uses explosive material sodium hydride. The specific process route is as follows:

The method disclosed in WO2011017108A uses E-3-(3,4-difluorophenyl)allylic acid as a raw material to synthesize E-3-(3,4-difluorophenyl)allyl chloride, which is then reacted with chiral oxazoloborane and then converted into a chiral compound by catalytic reaction. The disadvantage of this method is that expensive chiral oxazoloborane and palladium catalyst are used. The specific synthesis route is as follows:

The method disclosed in WO2013124280 uses o-difluorobenzene as a raw material to prepare 2-chloro-1-(3,4-difluorophenyl)ethanone through Friedel-Crafts reaction, and then uses expensive ligands for reduction to produce (S)-4-(3,4-difluorophenyl)-4-hydroxybutyronitrile. The disadvantage of this method is that relatively expensive ligands are used in the chiral reduction, and the ligands are not recyclable, the overall yield is low, the environmental pollution is large, the cost is high, and it is not suitable for industrial production.

In the method disclosed in WO2011132083, o-difluorobenzene is used as a raw material to prepare 3-chloro-1-(3,4-difluorophenyl)acetone through Friedel-Crafts reaction, which is then nitrated with sodium nitrite and sodium iodide, and then asymmetric reduced with CBS catalyst to prepare (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol; this route uses expensive chiral reducing agents and expensive and highly toxic sodium iodide, and is not suitable for industrial production.

The method disclosed in CN102775314A uses 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxy-benzo-triazole, dicyclohexylcarbodiimide and other condensing agents and 4-dimethylaminopyridine catalyst for kinetic resolution. This method is costly and pollutes the environment, and also wastes 50% of the raw materials.

In the method disclosed in CN106906249A, 3-chloro-1-(3,4-difluorophenyl)acetone is prepared from o-difluorobenzene as a raw material, and 2-chloro-1-S-(3,4-difluorophenyl)ethanol is prepared by carbonyl reductase reduction; the disadvantage of this method is that the biological activity of the enzyme is not high and the amount used is large. The specific process route is as follows:

Although there are many studies on the preparation of (S)-1-(3,4-difluorophenyl)-α-ol in the prior art, the published synthesis methods have many disadvantages, such as low yield, difficulty in separation and purification, large-scale use of expensive chiral reagents, heavy pollution and high cost. These unfavorable factors limit industrial production.

Therefore, there is an urgent need in the art for other methods for preparing (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates to reduce their synthesis costs, thereby reducing the preparation cost of ticagrelor.

Summary of the invention

The purpose of the present invention is to provide a new preparation method for (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates, which should not only have a simple process but also be low-cost and environmentally friendly, thereby reducing the production cost of ticagrelor and being suitable for industrial production.

In a first aspect, the present invention provides a method for preparing ticagrelor, the method comprising the following steps:

(1-1) Using 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially performing a Friedel-Crafts reaction and a reduction reaction to obtain a compound of formula I, and then performing an acylation reaction of the hydroxyl group to obtain a compound of formula II;

(1-2a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br);

R ₂ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

(1-3) preparing ticagrelor by multi-step reaction using the compound represented by formula III;

Alternatively, the method comprises the following steps:

(2-1) Using 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially performing Friedel-Crafts reaction, substitution reaction, and reduction reaction to obtain a compound of formula i, and then performing acylation of the hydroxyl group to obtain a compound of formula ii;

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

(2-2) enzymatically decomposing the compound of formula ii obtained in step (2-1), thereby obtaining the compound of formula iii and the compound of formula iv;

(2-3a) hydrolyzing the compound represented by formula iv obtained in step (2-2) to obtain the compound represented by formula v;

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

(2-4) Using the compound represented by formula v, ticagrelor is prepared through a multi-step reaction.

In a preferred embodiment, in the step (1-1), the compound represented by formula I is acylated to form an ester by a hydroxyl group to obtain a compound represented by formula II;

In step (2-1), the compound represented by formula i is subjected to acylation of the hydroxyl group to form an ester to obtain the compound represented by formula ii.

In a preferred embodiment, the solvent used in the acylation reaction of step (1-1) or (2-1) is acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane;

The base used in the acylation reaction is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine;

The acyl chloride used in the acylation reaction is C _1-6 alkyl acyl chloride, acryloyl chloride, benzoyl chloride or phenylacetyl chloride, preferably acetyl chloride;

In the acylation reaction, the molar ratio of the compound represented by formula I or the compound represented by formula I, the base and the acyl chloride is 1:(1-2):(1-1.2), preferably 1:1.1:1;

The temperature of the acylation reaction is 10-30°C, preferably 10-20°C;

The acylation reaction time is 1 to 5 hours, preferably 2 hours.

In a specific embodiment, the enzyme used in step (1-2a) or (2-2) is a hydrolase, including but not limited to lipase, protease or esterase;

Preferably, the lipase is Candida antarctica lipase, Candida cylindrica lipase, Candida cepacia lipase PS, lipase TL, koji enzyme lipase, lipase AS1, etc.;

The protein enzymes are chymosin, cathepsin, papain and subtilisin, etc.;

The esterase is porcine liver esterase PL, esterase RO, Aspergillus oryzae TL recombinant, Escherichia coli esterase BS1 recombinant, Escherichia coli esterase BS2 recombinant, etc.;

More preferably, the hydrolase is Candida cepacia lipase PS or Candida antarctica lipase.

In a preferred embodiment, the concentration of the compound of formula II in step (1-2a) is 5-20%, preferably about 10%; the weight ratio of the compound of formula II to the hydrolase is 1-20:1, preferably 10:1; or

In step (2-2), the concentration of the compound represented by formula ii is 5-20%, preferably about 10%; the weight ratio of the compound represented by formula ii to the hydrolase is 1-20:1, preferably 10:1.

In a preferred embodiment, in step (1-2a) or (2-2), the temperature of the enzyme resolution reaction is 15 to 40°C, preferably 25 to 30°C.

In a preferred embodiment, in step (1-2a) or (2-2), the pH of the enzymatic resolution reaction is 6 to 9, preferably 7 to 7.5.

In a preferred embodiment, in step (1-2a) or (2-2), the enzymatic resolution reaction time is about 12 to 30 hours, preferably about 18 hours.

In a specific embodiment, after step (1-2a), the method further comprises using the compound of formula IV obtained in step (1-2a) to prepare the compound of formula III through hydrolysis reaction, sulfonylation reaction, Walden configuration conversion reaction, and hydrolysis reaction; or

After step (2-3a), the method further comprises using the compound of formula iii obtained in step (2-2) to undergo sulfonylation reaction, Walden configuration conversion reaction, and hydrolysis reaction to prepare the compound of formula v.

In a specific embodiment, after step (1-2a), the following steps are also included:

(1-2b) hydrolyzing the compound represented by formula IV obtained in step (1-2a) to obtain the compound represented by formula V;

(1-2c) subjecting the compound represented by formula V obtained in step (1-2b) to a sulfonylation reaction to obtain a compound represented by formula VI;

(1-2d) subjecting the compound represented by formula VI obtained in step (1-2c) to Walden configuration transformation to obtain a compound represented by formula VII;

(1-2e) hydrolyzing the compound represented by formula VII obtained in step (1-2d) to obtain a compound represented by formula III;

In the formula, R ₁ is as described above; R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ );

Alternatively, after step (2-3a), the following steps are also included:

(2-3b) subjecting the compound represented by formula iii obtained in step (2-2) to a sulfonylation reaction to obtain a compound represented by formula vi;

(2-3c) subjecting the compound represented by formula ⅵ obtained in step (2-3b) to Walden configuration transformation to obtain a compound represented by formula ⅶ;

(2-3d) hydrolyzing the compound represented by formula ⅶ obtained in step (2-3c) to obtain the compound represented by formula V;

wherein R ₃ is as described above; R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is selected from: H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ ).

In a preferred embodiment, the solvent used in the hydrolysis reaction of step (1-2b), (1-2e) or step (2-3a), (2-3d) is water, methanol, ethanol, isopropanol or a combination thereof, preferably methanol;

The hydrolysis reagent used is concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate;

The temperature of the hydrolysis reaction is 40 to 80°C, preferably 45 to 50°C;

The hydrolysis reaction time is 3 to 10 hours, preferably about 5 hours.

In a preferred embodiment, the solvent used in the sulfonylation reaction of step (1-2c) or (2-3b) is acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane;

The base used in the sulfonylation reaction is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine;

The sulfonyl chloride used in the sulfonylation reaction is C _1-6 alkylsulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride;

In the sulfonylation reaction, the molar ratio of the compound represented by formula V or the compound represented by formula III, the base and the sulfonyl chloride is 1: (1-2): (1-1.2), preferably 1:1.2:1;

The temperature of the sulfonylation reaction is 0-20°C, preferably 0-5°C;

The sulfonylation reaction time is 1 to 5 hours, preferably 2 hours.

In a specific embodiment, the C _1-6 fatty acid salt used in the Walden configuration transformation reaction of step (1-2d) or (2-3c) is preferably cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, and most preferably cesium acetate;

The solvent used in the Walden configuration conversion reaction is DMF, DMSO or acetonitrile, preferably DMF;

The molar ratio of the compound represented by formula VI or the compound represented by formula VI to the fatty acid salt in the Walden transformation is 1:1 to 4, preferably 1:1.5;

The temperature of the Walden configuration conversion reaction is 20 to 50°C, preferably 22 to 26°C;

The Walden configuration conversion reaction time is 10 to 30 hours, preferably 12 hours.

In a second aspect, the present invention provides a method for preparing (S)-1-(3,4-difluorophenyl)-α-ol, wherein the (S)-1-(3,4-difluorophenyl)-α-ol is a compound represented by formula III, and the method comprises the following steps:

(1-1) Using 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially performing a Friedel-Crafts reaction and a reduction reaction to obtain a compound of formula I, and then performing an acylation reaction of the hydroxyl group to obtain a compound of formula II;

(1-2a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br);

R ₂ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

Alternatively, the (S)-1-(3,4-difluorophenyl)-α-alcohol is a compound represented by formula v, and the method comprises the following steps:

(2-1) Using 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially performing Friedel-Crafts reaction, substitution reaction, and reduction reaction to obtain a compound of formula i, and then performing acylation of the hydroxyl group to obtain a compound of formula ii;

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

(2-2) enzymatically decomposing the compound of formula ii obtained in step (2-1), thereby obtaining the compound of formula iii and the compound of formula iv;

(2-3a) hydrolyzing the compound represented by formula iv obtained in step (2-2) to obtain the compound represented by formula v;

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ .

In a specific embodiment, after step (1-2a), the method further comprises using the compound of formula IV obtained in step (1-2a) to prepare the compound of formula III through hydrolysis reaction, sulfonylation reaction, Walden configuration conversion reaction, and hydrolysis reaction; or

After step (2-3a), the method further comprises using the compound of formula iii obtained in step (2-2) to undergo sulfonylation reaction, Walden configuration conversion reaction, and hydrolysis reaction to prepare the compound of formula v.

In a specific embodiment, after step (1-2a), the following steps are also included:

(1-2b) hydrolyzing the compound represented by formula IV obtained in step (1-2a) to obtain the compound represented by formula V;

(1-2c) subjecting the compound represented by formula V obtained in step (1-2b) to a sulfonylation reaction to obtain a compound represented by formula VI;

(1-2d) subjecting the compound represented by formula VI obtained in step (1-2c) to Walden configuration transformation to obtain a compound represented by formula VII;

(1-2e) hydrolyzing the compound represented by formula VII obtained in step (1-2d) to obtain a compound represented by formula III;

In the formula, R ₁ is as described in claim 1; R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ );

Alternatively, after step (2-3a), the following steps are also included:

(2-3b) subjecting the compound represented by formula iii obtained in step (2-2) to a sulfonylation reaction to obtain a compound represented by formula vi;

(2-3c) subjecting the compound represented by formula ⅵ obtained in step (2-3b) to Walden configuration transformation to obtain a compound represented by formula ⅶ;

(2-3d) hydrolyzing the compound represented by formula ⅶ obtained in step (2-3c) to obtain the compound represented by formula V;

Wherein R ₃ is as described in claim 1; R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is selected from: H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ ).

In a third aspect, the present invention provides a compound represented by formula II

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br);

R ₂ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ; or

Compound represented by formula II

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ .

In a fourth aspect, the present invention provides use of a compound represented by formula II or a compound represented by formula II in the preparation of ticagrelor.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventor unexpectedly found that starting from a specific starting compound, (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates can be directly obtained by enzyme resolution, and then the byproducts of the enzyme resolution can be further converted into the desired (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates by configuration transformation, thereby enabling the simple and low-cost production of (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates and the final ticagrelor. On this basis, the present invention was completed.

The inventors of the present invention creatively selected a process route that is simple to operate and easy to industrialize based on the consideration of industrial production, based on the study of multiple synthetic routes and reaction conditions of (S)-1-(3,4-difluorophenyl)-α-alcohols, a key drug intermediate of ticagrelor, i.e., (S)-1-(3,4-difluorophenyl)-α-alcohol esters are used as raw materials for enzymatic separation to prepare (S)-1-(3,4-difluorophenyl)-α-alcohols; and the obtained compound of another configuration can be hydrolyzed, sulfonylated, Walden transformed and hydrolyzed to prepare (S)-1-(3,4-difluorophenyl)-α-alcohols.

The present invention relates to the use of enzyme splitting and configuration conversion technology in the preparation of ticagrelor intermediates, and specifically relates to the preparation of ticagrelor intermediate (S)-1-(3,4-difluorophenyl)-α-ol by enzyme splitting and (hydrolysis) of 1-(3,4-difluorophenyl)-α-ol ester; and the preparation of ticagrelor intermediate (S)-1-(3,4-difluorophenyl)-α-ol by (hydrolysis), sulfonylation, configuration inversion and hydrolysis of split by-products.

In a specific embodiment, it includes:

(1) The key intermediate of ticagrelor, (S)-2-chloro-1-(3,4-difluorophenyl)ethanol, is prepared by enzymatic resolution of ethyl 2-chloro-1-(3,4-difluorophenyl)acetate; in addition, another compound obtained by enzymatic resolution, ethyl 2-chloro-1R-(3,4-difluorophenyl)acetate, is hydrolyzed, sulfonylated, subjected to Walden transformation and hydrolysis to prepare (S)-2-chloro-1-(3,4-difluorophenyl)ethanol.

(2) The key intermediate of ticagrelor, (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol, is prepared by enzymatic cleavage of 1-(3,4-difluorophenyl)-3-nitro-propyl acetate and hydrolysis. In addition, another compound (R)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol obtained by enzymatic cleavage is prepared by sulfonylation, Walden configuration transformation and hydrolysis to prepare (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol.

(3) The key intermediate of ticagrelor, (S)-1-(3,4-difluorophenyl)-4-hydroxybutyronitrile, is prepared by enzymatic cleavage of 1-(3,4-difluorophenyl)-3-cyano-propyl acetate and hydrolysis. In addition, another compound (R)-1-(3,4-difluorophenyl)-3-cyano-propyl acetate obtained by enzymatic cleavage is prepared by sulfonylation, Walden configuration transformation and hydrolysis to prepare (S)-1-(3,4-difluorophenyl)-4-hydroxybutyronitrile.

Through a large number of experiments and discussions on the reaction conditions of each step in the synthesis process, the synthesis yield and quality were improved, the synthesis cycle was shortened, the synthesis cost was reduced, and finally more reasonable process conditions were determined. The entire reaction route is relatively simple, the raw materials and reagents used are cheap and easy to obtain, the reaction conditions are mild, the yield is high, and it is environmentally friendly, thus enabling industrial production.

The method for synthesizing (S)-1-(3,4-difluorophenyl)-α-alcohol and ticagrelor of the present invention comprises:

1. In step (1-1), the compound represented by formula I is used as a raw material, and the hydroxyl group is acylated to form an ester to obtain the compound represented by formula II. The specific chemical reaction equation of the method is as follows:

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br); R ₂ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH＝CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

Specifically, in the acylation reaction, the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base used is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the molar ratio of the compound of formula I, the base and the acyl chloride is 1:(1-2):(1-1.2), preferably 1:1.1:1; the temperature of the acylation reaction is 10-30°C, preferably 10-20°C; the time of the acylation reaction is 1-5 hours, preferably 2 hours.

2. In step (1-2a), the compound represented by formula II is split by enzyme to obtain the S-type compound represented by formula III and the R-type compound represented by formula IV. The specific chemical reaction equation of the method is as follows:

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br); R ₂ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH＝CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ ;

Specifically, the method comprises: mixing a hydrolase, a buffer, and an optional base, then adding a compound shown in formula II, maintaining pH=6-9 with an optional base at 15-40° C., and reacting for 12-30 hours to obtain an S-type compound shown in formula III and an R-type compound shown in formula IV.

The enzyme utilized in the method is a hydrolase, including but not limited to lipase, proteinase or esterase;

Preferably, the lipase is antarctic Candida lipase, a cylindrical Candida lipase, a lipase PS of Candida cepacia, a lipase TL, a koji enzyme lipase, a lipase AS1, etc. Preferably, the proteinase is chymosin, cathepsin, papain, and subtilisin, etc. Preferably, the esterase is a pig liver esterase PL, an esterase RO, a recombinant Aspergillus oryzae TL, a recombinant Escherichia coli esterase BS1, a recombinant Escherichia coli esterase BS2, etc. More preferably, the hydrolase is a lipase PS of Candida cepacia or antarctic Candida lipase.

The concentration of the compound represented by formula II is usually 5-20%, preferably about 10%. The weight ratio of the compound represented by formula II to the hydrolase is 1-20:1, preferably 10:1. The hydrolase can generally be reused 5-15 times, preferably 8 times, without affecting the separation results, and is suitable for industrial-scale application.

The activity of an enzyme is usually related to temperature. In a specific embodiment, the temperature of the enzyme resolution reaction is controlled between 15 and 40°C, preferably between 25 and 30°C.

The enzymatic resolution reaction time is generally about 12 to 30 hours, preferably about 18 hours.

Enzymes are usually used in combination with buffers to provide a pH suitable for enzyme activity. In a specific embodiment, the buffer has a pH of 6 to 9, preferably pH 7 to 7.5; the solvent used for enzyme resolution is water, the buffer molar concentration is 0.001 to 0.2 mol/L, preferably the molar concentration is 0.01 mol/L; the buffer salt is sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen acetate, potassium hydrogen acetate or a combination thereof, preferably disodium hydrogen phosphate.

The pH of the enzymatic resolution reaction is generally controlled by adding a base, which may be an alkali metal hydroxide, carbonate or bicarbonate, preferably sodium hydroxide or potassium hydroxide.

After the enzyme resolution reaction is completed, solvent extraction is usually required, and the extraction solvent is ethyl acetate, dichloromethane, toluene or dichloroethane, preferably dichloromethane.

The effect of pH value on enzyme splitting reaction is as follows:

In a specific embodiment, ethyl 2-chloro-1-(3,4-difluorophenyl)acetate is used as a substrate, lipase PS of Candida cepacia is used, the temperature is controlled at 25-30° C., and the reaction is carried out for 18 hours.

3. A method for preparing a compound of formula III by enzymatically resolving a byproduct R-type compound of formula IV, the method comprising:

(1-2b) Using the R-type compound represented by formula IV as a raw material, hydrolyzing the compound represented by formula V to obtain the R-type compound;

(1-2c) sulfonylating the R-type compound of formula V obtained in step (1-2b) to obtain the R-type compound of formula VI;

(1-2d) subjecting the R-type compound of formula VI obtained in step (1-2c) to Walden transformation to obtain the S-type compound of formula VII;

(1-2e) The S-type compound of formula VII obtained in step (1-2d) is hydrolyzed to obtain the S-type compound of formula III.

The specific synthetic route of the method described is as follows:

In the formula, R ₁ is selected from halogen (preferably F, Cl or Br); R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is selected from: H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ );

In the hydrolysis reaction of step (1-2b) or step (1-2e), the solvent used is usually water, methanol, ethanol, isopropanol or a combination thereof, preferably methanol; the hydrolysis reagent is usually concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate; the hydrolysis reaction temperature is 40 to 80°C, preferably 45 to 50°C; the hydrolysis reaction time is 3 to 10 hours, preferably about 5 hours.

In the sulfonylation reaction of step (1-2c), the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base used is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the sulfonyl chloride used is methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride; the molar ratio of the compound of formula V, the base and the sulfonyl chloride is 1:(1-2):(1-1.2), preferably 1:1.2:1; the temperature of the sulfonylation reaction is 0-20°C, preferably 0-5°C; the time of the sulfonylation reaction is 1-5 hours, preferably 2 hours.

In the Walden configuration conversion reaction of step (1-2d), the fatty acid salt used is cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, preferably cesium acetate; the solvent used is DMF, DMSO or acetonitrile, preferably DMF; the molar ratio of the compound of general formula VI to the fatty acid salt is 1:1-4, preferably 1:1.5; the temperature of the Walden configuration conversion reaction is 20-50°C, preferably 22-26°C; the time of the Walden configuration conversion reaction is 10-30 hours, preferably 12 hours.

4. In step (2-1), the compound represented by formula i is used as a raw material, and the hydroxyl group is acylated to form an ester to obtain the compound represented by formula ii. The specific chemical reaction equation of the method is as follows:

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ .

Specifically, in the acylation reaction, the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base used is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the molar ratio of the compound represented by formula I, the base and the acyl chloride is 1:(1-2):(1-1.2), preferably 1:1.1:1; the temperature of the acylation reaction is 10-30°C, preferably 10-20°C; the time of the acylation reaction is 1-5 hours, preferably 2 hours.

5. In step (2-2), the compound represented by formula ii is enzymatically resolved to prepare the S-type compound represented by formula iv and the R-type compound represented by formula iii. The specific reaction equation of the method is as follows:

Wherein, R ₃ is selected from NO ₂ or CN;

R ₄ is selected from: C _1-6 alkyl (preferably CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ ), CH═CH ₂ , C ₆ H ₅ or CH ₂ C ₆ H ₅ .

In a specific embodiment, the method comprises: mixing a hydrolase, a buffer, and an optional base, then adding a compound shown in formula ii, maintaining pH = 6 to 9 with an optional base at 15 to 40°C, and reacting for 12 to 30 hours to obtain an R-type compound shown in formula iii and an S-type compound shown in formula iv.

In a specific embodiment, the hydrolase used in the method is a lipase, a proteinase or an esterase. Preferably, the lipase is an antarctic Candida lipase, a cylindraceous Candida lipase, a lipase PS of Candida cepacia, a lipase TL, a distiller's yeast lipase, a lipase AS1, etc. Preferably, the proteinase is chymosin, cathepsin, papain and subtilisin, etc. Preferably, the esterase is a pig liver esterase PL, an esterase RO, an Aspergillus oryzae TL recombinant, an Escherichia coli esterase BS1 recombinant, an Escherichia coli esterase BS2 recombinant, etc. More preferably, the hydrolase is a lipase PS of Candida cepacia or antarctic Candida lipase.

The concentration of the compound represented by formula II is usually 5-20%, preferably about 10%. The weight ratio of the compound represented by formula II to the hydrolase is 1-20:1, preferably 10:1. The hydrolase can generally be reused 5-15 times, preferably 8 times, without affecting the separation results, and is suitable for industrial-scale application.

The activity of an enzyme is usually related to temperature. Therefore, in a specific embodiment, the temperature of the enzyme resolution reaction is controlled between 15 and 40°C, preferably between 25 and 30°C.

The enzymatic resolution reaction time is generally about 12 to 30 hours, preferably about 18 hours.

Enzymes are usually used in combination with buffers to provide a pH suitable for enzyme activity. In a specific embodiment, the pH of the buffer is 6 to 9, preferably pH 7 to 7.5; the solvent used is water, the molar concentration of the buffer is 0.001 to 0.2 mol/L, preferably, the molar concentration is 0.01 mol/L; the buffer salt is sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen acetate, potassium hydrogen acetate or a combination thereof, preferably disodium hydrogen phosphate.

The pH of the enzymatic resolution reaction is generally controlled by adding a base, which may be an alkali metal hydroxide, carbonate or bicarbonate, preferably sodium hydroxide or potassium hydroxide.

After the enzyme resolution reaction is completed, solvent extraction is usually required. The extraction solvent used is ethyl acetate, dichloromethane, toluene or dichloroethane, preferably dichloromethane.

Generally, in the hydrolysis reaction of the compound represented by S-type formula iv to prepare the compound represented by S-type formula v, the solvent is water, methanol, ethanol, isopropanol or a combination thereof, preferably, the solvent is ethanol; the hydrolysis reagent is concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate, preferably, the hydrolysis reagent is concentrated hydrochloric acid; the hydrolysis reaction temperature is 40 to 80°C, preferably, the reaction temperature is 45 to 50°C; the reaction time is 3 to 10 hours, preferably, the reaction time is about 5 hours.

6. A method for preparing an S-type compound of formula v by hydrolyzing an S-type compound of formula iv by enzymatic resolution and preparing an S-type compound of formula v by enzymatic resolution of a byproduct R-type compound of formula iii, the method comprising:

(2-3a) Using the S-type compound of formula iv, the enzymatic cleavage product of step (2-2), as a raw material, hydrolyze to prepare the S-type compound of general formula v.

(2-3b) using the R-type compound represented by formula iii, a byproduct of the enzymatic resolution in step (2-2), as a raw material for sulfonylation reaction to obtain the R-type compound represented by formula vi;

(2-3c) converting the R-type compound represented by formula ⅵ obtained in step (2-3b) into the Walden configuration to obtain the S-type compound represented by formula ⅶ;

(2-3d) The S-type compound of formula ⅶ obtained in step (2-3c) is hydrolyzed to obtain the S-type compound of formula V.

The specific synthetic route of the method described is as follows:

wherein R ₃ is selected from: NO ₂ or CN; R ₅ is selected from: C _1-6 alkyl (preferably CH ₃ ), C ₆ H ₅ or p-CH ₃ C ₆ H ₄ ; R ₆ is selected from: H, C _1-6 alkyl (preferably CH ₃ or CH ₂ CH ₃ );

In the sulfonylation reaction of step (2-3b), the solvent used is usually acetonitrile, toluene, dichloromethane, ethyl acetate, tetrahydrofuran or a combination thereof, preferably dichloromethane; the base used is triethylamine, N,N-dimethylethylamine, N,N-diisopropylethylamine, imidazole or pyridine, preferably triethylamine; the sulfonyl chloride used is methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride, preferably methanesulfonyl chloride; the molar ratio of the compound represented by R type formula iii, the base and the sulfonyl chloride is 1:(1-2):(1-1.2), preferably 1:1.2:1; the temperature of the sulfonylation reaction is 0-20°C, preferably 0-5°C; the time of the sulfonylation reaction is 1-5 hours, preferably 2 hours.

In the Walden configuration conversion reaction of step (2-3c), the fatty acid salt used is usually cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, preferably cesium acetate; the solvent used is DMF, DMSO or acetonitrile, preferably DMF; the molar ratio of the R-type formula ⅵ compound to the fatty acid salt is 1:1 to 4, preferably 1:1.5; the temperature of the Walden configuration conversion reaction is 20 to 50°C, preferably 22 to 26°C; the Walden configuration conversion reaction is 10 to 30 hours, preferably 12 hours.

In the hydrolysis reaction of step (2-3d), the solvent used is usually water, methanol, ethanol, isopropanol or a combination thereof, preferably ethanol; the hydrolysis reagent used is concentrated hydrochloric acid, aqueous hydrogen bromide solution, sodium carbonate or potassium bicarbonate, preferably concentrated hydrochloric acid; the hydrolysis reaction temperature is 40 to 80° C., preferably 45 to 50° C.; the hydrolysis reaction time is 3 to 10 hours, preferably about 5 hours.

7. Ticagrelor can be synthesized using the compound represented by formula III or the compound represented by formula V. The compound represented by formula III is preferably (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1; the compound represented by formula V is preferably (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 2 and (S)-4-(3,4-difluorophenyl)-4-hydroxybutyronitrile 3. The intermediate compound (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine 4 can be simply and conveniently synthesized through the intermediate compound 1, the intermediate compound 2 or the intermediate compound 3. The specific synthesis route is as follows:

The intermediate compound (1R, 2S)-2-(3, 4-difluorophenyl) cyclopropylamine 4 can be further reacted in two steps to synthesize ticagrelor. The specific synthesis route is as follows:

Advantages of the present invention:

1. The present invention provides a novel preparation method of (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates;

2. The preparation method of the (S)-1-(3,4-difluorophenyl)-α-alcohol intermediate of the present invention has simple process, readily available raw materials, low cost and is environmentally friendly;

3. The intermediate of the present invention has high chiral purity, effectively recovers by-products, and has a high yield.

4. The method of the present invention for preparing (S)-1-(3,4-difluorophenyl)-α-alcohol intermediates can reduce the production cost of ticagrelor, which is very beneficial to large-scale industrial production.

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

Example 1. Preparation of 2-chloro-1-(3,4-difluorophenyl)ethanone 5

Under nitrogen protection, 100 g of o-difluorobenzene, 120 g of aluminum chloride and 200 mL of dichloromethane were added into a reaction bottle, stirred, cooled to 5-15°C, 99 g of chloroacetyl chloride was added dropwise, and the temperature was controlled not to exceed 40°C. After the addition was completed, the reaction was kept at 30-40°C for 4-5 hours.

The reaction solution was cooled, and the temperature was controlled at 20-40°C, and the mixture was added dropwise to a mixed solution of 25 mL of concentrated hydrochloric acid and 500 mL of water. After the addition was completed, the mixture was stirred until the solid was dissolved and separated for extraction. The aqueous phase was extracted with 100 mL of dichloromethane*2, and the organic phases were combined, washed with 100 mL of water, washed once with 200 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-chloro-1-(3,4-difluorophenyl)ethanone 5 (164 g. The yield was about 98%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ5.2 (2H, s), 7.6 (1H, dd), 7.8 (1H, m), 8.0 (1H, dd).

Example 2. Preparation of 2-chloro-1-(3,4-difluorophenyl)ethanol 6

Put 100g 2-chloro-1-(3,4-difluorophenyl)ethanone 5 and 400mL anhydrous ethanol into a reaction bottle, control the temperature at 10-20℃, add 6g sodium borohydride in batches, and after the addition, heat to 25-30℃ and stir for 2h. Concentrate the ethanol in the reaction solution under reduced pressure, add 200mL water, extract the aqueous phase with 200mL*2 dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 2-chloro-1-(3,4-difluorophenyl)ethanol 6 (100g, yield 99%).

Example 3. Preparation of ethyl 2-chloro-1-(3,4-difluorophenyl)acetate 7

100 g of 2-chloro-1-(3,4-difluorophenyl)ethanol, 500 mL of dichloromethane and 58 g of triethylamine were placed in a reaction bottle. Under nitrogen protection, the temperature was controlled at 10-20°C, and 40.8 g of acetyl chloride solution was added dropwise. After the addition was completed, stirring was continued for 2 h.

After the reaction, 200 mL of 5% dilute hydrochloric acid solution was added, and the mixture was separated and extracted. The aqueous phase was extracted with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 2-chloro-1-(3,4-difluorophenyl)acetate 7 (120 g, yield 98.5%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ2.15 (3H, s), 3.70-3.72 (1H, m), 3.75-3.77 (1H, m), 5.45-5.47 (1H, m), 7.02-7.25 (3H, m). MS (ESI): m/z ＝235[M+H] ⁺ .

Example 4. Preparation of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 by enzymatic resolution

(1) Prepare 440 mL of 0.01 M disodium hydrogen phosphate solution, and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. Add 44 g of ethyl 2-chloro-1-(3,4-difluorophenyl)acetate 7, 4.4 g of lipase PS from Candida cepacia and disodium hydrogen phosphate buffer into a reaction flask, heat to 25-30° C. for reaction, and maintain the pH at 7-7.5 with 10% sodium hydroxide solution. After about 18 hours of reaction, the pH does not change much, filter, wash the filter cake with 200 mL of dichloromethane, separate and extract, extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily crude liquid product, which is purified by silica gel column chromatography to obtain (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 (17.33 g, ee value 99.6%, yield 48.5%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.774(1H,s), 3.56-3.64(1H,m), 3.72-3.76 (1H,m), 4.90-4.92(1H,m), 7.27-7.42(3H,m). MS(ESI):m/z＝174.9[M-OH] ⁺

Silica gel column chromatography was used to purify ethyl 2-chloro-1R-(3,4-difluorophenyl)acetate 8 (22 g, ee value 99%, yield 50%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.15 (3H, s), 3.70-3.72 (1H, m), 3.75-3.77 (1H, m), 5.45-5.47 (1H, m), 7.02-7.25 (3H, m). MS (ESI): m/z=235 [M+H] ⁺ .

(2) Prepare 440 mL of 0.01 M disodium hydrogen phosphate solution and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. Compound 44g ethyl 2-chloro-1-(3,4-difluorophenyl)acetate 7, 4.4g Antarctic Candida lipase and disodium hydrogen phosphate buffer were put into a reaction flask, heated to 25-30°C for reaction, and pH was maintained at 7-7.5 with 10% sodium hydroxide solution. The pH did not change much after about 18 hours of reaction, filtered, and the filter cake was washed with 200mL dichloromethane (), separated and extracted, the aqueous phase was extracted with 100mL dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily liquid crude product, which was purified by silica gel column chromatography to obtain (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 (17.1g, ee value 99.4%, yield 48%) and ethyl 2-chloro-1R-(3,4-difluorophenyl)acetate 8 (22g, ee value 99%, yield 50%).

Example 5. Preparation of (R)-2-chloro-1-(3,4-difluorophenyl)ethanol 9 by hydrolysis

10 g of ethyl 2-chloro-1R-(3,4-difluorophenyl)acetate 8, 15 mL of concentrated hydrochloric acid and 50 mL of ethanol were placed in a reaction flask, the temperature was raised to t=45-50°C and the reaction was carried out for 5-6 hours, the mixture was concentrated under reduced pressure, 30 mL of water was added, the mixture was extracted with 40 mL of dichloromethane*2, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to obtain a dichloromethane solution of (R)-2-chloro-1-(3,4-difluorophenyl)ethanol 9.

Example 6. Preparation of 2-chloro-1R-(3,4-difluorophenyl)methanesulfonic acid ethyl ester by sulfonylation reaction

The dichloromethane solution (80 mL) of the (R)-2-chloro-1-(3,4-difluorophenyl)ethanol 9 prepared in the previous step and 5.2 g of triethylamine were put into a reaction flask, cooled to t=0-5°C, 4.9 g of methanesulfonyl chloride was added dropwise, and the reaction was carried out at t=0-5°C for 2 hours after the addition was completed. The reaction was completed by TLC detection, 40 mL of water was added, the organic phase was separated, the aqueous phase was extracted with 40 mL of dichloromethane, the organic phases were combined, washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid 2-chloro-1R-(3,4-difluorophenyl) methanesulfonic acid ethyl ester 10 (11.3 g, yield 98%). ¹ H-NMR (400MHz, CDCl ₃ ): δ3.15(3H,s), 3.70-3.72(1H,m), 3.75-3.77(1H,m), 5.89-6.01(1H,m), 7.02-7.25(3H,m). MS (ESI): m/z=175.2[M-OMs] ⁺ .

Example 7. Preparation of (S)-ethyl 2-chloro-1(3,4-difluorophenyl)acetate 11 by Walden inversion

Add 10 g of ethyl 2-chloro-1R-(3,4-difluorophenyl) methanesulfonate 10, 10.7 g of cesium acetate and 50 mL of DMF into a three-necked flask, react at 22-26° C. for about 12 hours, and detect the completion of the reaction by TLC. Filter to remove a small amount of salt, remove DMF by vacuum distillation, add 50 mL of dichloromethane, wash once with 30 mL of saturated brine, add anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily liquid (S)-ethyl 2-chloro-1(3,4-difluorophenyl)acetate 11 (8.24 g, yield 95%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ2.15 (3H, s), 3.70-3.72 (1H, m), 3.75-3.77 (1H, m), 5.45-5.47 (1H, m), 7.02-7.25 (3H, m). MS (ESI): m/z = 235 [M+H] ⁺ .

Example 8. Preparation of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 by hydrolysis

10 g of ethyl 2-chloro-1S-(3,4-difluorophenyl)acetate 11, 15 mL of concentrated hydrochloric acid and 50 mL of ethanol were placed in a reaction flask, heated to t=45-50°C and reacted for 5-6 hours, concentrated under reduced pressure, added with 30 mL of water, extracted the aqueous phase with 40 mL of dichloromethane*2, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 (8.2 g, ee value 99%, yield 98%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ2.774 (1H, s), 3.56-3.64 (1H, m), 3.72-3.76 (1H, m), 4.90-4.92 (1H, m), 7.27-7.42 (3H, m). MS (ESI): m/z=174.9[M-OH] ⁺ .

Example 9. Preparation of 3-chloro-1-(3,4-difluorophenyl)acetone 12

Under nitrogen protection, 100 g of o-difluorobenzene, 120 g of aluminum chloride and 200 mL of dichloromethane were put into a reaction bottle, stirred, cooled to 5-15°C, 111 g of chloropropionyl chloride was added dropwise, and the temperature was controlled not to exceed 40°C. After the addition was completed, the reaction was kept at 30-40°C for 4-5 hours.

The reaction solution was cooled. The temperature was controlled at 20-40°C and added dropwise to a mixed solution of 25 mL of concentrated hydrochloric acid and 500 mL of water. After the addition was completed, the mixture was stirred until the solid was dissolved and separated for extraction. The aqueous phase was extracted with 100 mL of dichloromethane*2. The organic phases were combined, washed once with 100 mL of water and once with 200 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-chloro-1-(3,4-difluorophenyl)acetone 12 (176 g, yield of about 98%).

Example 10. Preparation of 1-(3,4-difluorophenyl)-3-nitroacetone 13

Put 25g of 3-chloro-1-(3,4-difluorophenyl)acetone 12, 50mL of N,N-dimethylformamide, 5.5g of phloroglucinol and 0.25g of sodium iodide into a reaction bottle, control the temperature at 5-10℃, add 16.8g of sodium nitrite to the mixed solution in batches, stir at 5-10℃ for 30min, then heat the reaction solution to 25-30℃ and continue stirring for 3-4h. Then, the reaction solution was poured into 280 mL of water at 0-5°C in batches to quench, stirred for 30 min, and filtered. The filter cake was washed with ice water, and the crude product was dried under reduced pressure at 30-35°C. The crude product was dissolved in 75 mL of isopropanol at 50-60°C, cooled to 10-15°C and stirred for 2 h, cooled to 0-5°C and stirred for 2 h, filtered, and the filter cake was washed with 25 mL of isopropanol precooled at 0-5°C, and then washed with 25 mL of cyclohexane, and dried under reduced pressure at 30-35°C to obtain 1-(3,4-difluorophenyl)-3-nitropropane-1-ol 13 (19.7 g, yield 75.2%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.61 (2H, m), 4.82 (2H, m), 7.29 (1H, m), 7.82 (2H,m),7.80(1H,m). MS (ESI): m/z=216[M+H] ⁺ .

Example 11. Preparation of 4-(3,4-difluorophenyl)-4-oxobutyronitrile 14

20g 3-chloro-1-(3,4-difluorophenyl)acetone 12, 50mL ethyl acetate and 9.6g potassium tert-butoxide were placed in a reaction flask, heated at 70°C for 30 minutes, cooled to 25-30°C, and 50mL aqueous solution of 9.6g sodium cyanide was added dropwise. After the addition was completed, stirring was continued for 30 minutes, and 30mL ethanol was added and stirred for 3 hours. Separate extraction was performed, and the aqueous phase was extracted with 25mL ethyl acetate, and the organic phase was washed with 50mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(3,4-difluorophenyl)-4-oxobutyronitrile 14 (18.5g, yield 97%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.78-2.80 (2H, m), 3.34-3.36 (2H, m), 7.29 (1H, m), 7.74 (1H, m), 7.80 (1H, m). MS (ESI): m/z = 196 [M+H] ⁺ .

Example 12. Preparation of 1-(3,4-difluorophenyl)-3-nitropropane-1-ol 15

100g 2-chloro-1-(3,4-difluorophenyl)ethanone 13 and 400mL anhydrous ethanol were added to a reaction flask, the temperature was controlled at 10-20°C, 5.5g sodium borohydride was added in batches, and after the addition was completed, the temperature was raised to 25-30°C and stirred for 2h. The ethanol in the reaction solution was concentrated under reduced pressure, 200mL water was added, and the aqueous phase was extracted with 200mL dichloromethane*2, and the organic phases were combined and dried over anhydrous sodium sulfate. 2-chloro-1-(3,4-difluorophenyl)ethanol 15 (98g, yield 97%) was obtained by concentration under reduced pressure. ¹ H-NMR (400MHz,CDCl ₃ ):δ2.24-2.27(3H,m),4.44-4.47(1H,m),4.61-4.65(1H,m), 4.82-4.85(1H,m),7.07-7.15(3H,m). MS (ESI): m/z = 218 [M+H] ⁺ .

Example 13. Preparation of 1-(3,4-difluorophenyl)-3-nitro-propyl acetate 16

100 g of 2-chloro-1-(3,4-difluorophenyl)ethanol 15, 500 mL of dichloromethane, and 51.2 g of triethylamine were placed in a reaction flask, and 36.2 g of acetyl chloride solution was added dropwise under nitrogen protection and the temperature was controlled at 10-20°C. The mixture was stirred for 2 h after the addition was completed. After the reaction was completed, 200 mL of 5% dilute hydrochloric acid solution was added, and the mixture was separated and extracted. The aqueous phase was extracted with 100 mL of dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-(3,4-difluorophenyl)-3-nitro-propyl acetate 16 (113.4 g, with a yield of 95%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.15(3H,s), 2.43-2.48 (2H,m), 4.50-4.55(1H,m), 4.75-4.77(1H,m), 5.25-5.27(1H,m), 7.02-7.25(3H,m). MS (ESI): m/z=260[M+H] ⁺ .

Example 14. Preparation of (S)-1-(3,4-difluorophenyl)-3-nitro-propyl acetate by enzymatic resolution 17

(1) Prepare 400 mL of 0.01 M disodium hydrogen phosphate solution, and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. Add 40 g of 1-(3,4-difluorophenyl)-3-nitro-propyl acetate 16, 4.0 g of lipase PS from Candida cepacia, and disodium hydrogen phosphate buffer into a reaction flask, heat to 25-30° C. for reaction, and use 10% sodium hydroxide solution to maintain the pH at 7-7.5. After about 18 hours of reaction, the pH does not change much, filter, wash the filter cake with 200 mL of dichloromethane, separate and extract, extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily crude liquid, which is purified by silica gel column chromatography to obtain (S)-1-(3,4-difluorophenyl)-3-nitro-propyl acetate 17 (20 g, ee value 99%, yield 50%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.15(3H,s),2.43-2.48(2H,m),4.50-4.55(1H,m),4.75-4.77(1H,m),5.25-5.27(1H,m),7.02-7.25(3H,m). MS (ESI): m/z=260[M+H] ⁺ .

Silica gel column chromatography was used to purify (R)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 18 (16 g, ee value 99.4%, yield 48%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.24-2.27 (3H, m), 4.44-4.47 (1H, m), 4.61-4.65 (1H, m), 4.82-4.85 (1H, m), 7.07-7.15 (3H, m). MS (ESI): m/z=218 [M+H] ⁺ .

(2) Prepare 400 mL of 0.01 M disodium hydrogen phosphate solution and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. 40 g of 1-(3,4-difluorophenyl)-3-nitro-propyl acetate 16, 4.0 g of Candida antarctica lipase and disodium hydrogen phosphate buffer were put into a reaction flask, the temperature was raised to 25-30°C for reaction, and the pH was maintained at 7-7.5 with 10% sodium hydroxide solution. The pH did not change much after about 18 hours of reaction, and the filter cake was washed with 200 mL of dichloromethane. The aqueous phase was extracted with 100 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily liquid crude product, which was purified by silica gel column chromatography to obtain (S)-1-(3,4-difluorophenyl)-3-nitro-propyl acetate 17 (20 g, ee value 99%, yield 50%) and (R)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 18 (15.7 g, ee value 99.2%, yield 47%).

Example 15. Preparation of (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 2 by hydrolysis

10 g (S)-1-(3,4-difluorophenyl)-3-nitro-propyl acetate 17, 15 mL concentrated hydrochloric acid and 50 mL ethanol were placed in a reaction flask, heated to t=45-50°C for 5-6 hours, concentrated under reduced pressure, added with 30 mL water, extracted twice with 40 mL dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain oily liquid (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 2 (8 g, ee value 99%, yield 95%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ2.24-2.27 (3H, m), 4.44-4.47 (1H, m), 4.61-4.65 (1H, m), 4.82-4.85 (1H, m), 7.07-7.15 (3H, m). MS (ESI): m/z = 218 [M+H] ⁺ .

Example 16. Preparation of (R)-1-(3,4-difluorophenyl)-3-nitro-methanesulfonic acid propyl ester 19 by sulfonylation reaction

10 g of (R)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 18 and 80 mL of dichloromethane were put into a reaction flask, 5.6 g of triethylamine was added, the temperature was lowered to t=0-5°C, 5.27 g of methanesulfonyl chloride was added dropwise, and the reaction was carried out at t=0-5°C for 2 hours after the addition was completed. After TLC detection, the reaction was completed, 30 mL of water was added, and the liquids were separated and extracted. The aqueous phase was extracted with 30 mL of dichloromethane, the organic phases were combined, washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(3,4-difluorophenyl)-3-nitro-methanesulfonic acid propyl ester 19 (13.2 g, yield 97%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.45-2.48(2H,m),3.2(3H,s),4.61-4.65(1H,m),4.72-4.74(1H,m),5.82-5.85(1H,m),7.17-7.25(3H,m). MS (ESI): m/z=200[M-OMs] ⁺ .

Example 17. Preparation of (S)-1-(3,4-difluorophenyl)-3-nitro-propyl acetate by Walden inversion

10 g (R)-1-(3,4-difluorophenyl)-3-nitro-methanesulfonic acid propyl ester 19, 9.75 g cesium acetate and 50 mL DMF were put into a reaction bottle and reacted at 22-26° C. for about 12 hours. The reaction was completed by TLC detection. A small amount of salt was removed by filtration, and DMF was removed by vacuum distillation. 50 mL of dichloromethane was added, and the mixture was washed once with 30 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (S)-1-(3,4-difluorophenyl)-3-nitro-acetic acid propyl ester 17 (8.3 g, ee value 99.4%, yield 95%). ¹ H-NMR (400MHz, CDCl ₃ ): δ2.15(3H,s), 2.43-2.48(2H,m), 4.50-4.55(1H,m), 4.75-4.77(1H,m), 5.25-5.27(1H,m), 7.02-7.25(3H,m). MS (ESI): m/z=260[M+H] ⁺ .

Example 18. Preparation of 4-(3,4-difluorophenyl)-4-hydroxybutyronitrile 20

100g 4-(3,4-difluorophenyl)-4-oxobutyronitrile 14 and 400mL anhydrous ethanol were added to a reaction flask, the temperature was controlled at 10-20°C, 5.9g sodium borohydride was added in batches, and after the addition was completed, the temperature was raised to 25-30°C and stirred for 2h. The ethanol in the reaction solution was concentrated under reduced pressure, 200mL water was added, and the aqueous phase was extracted with 200mL dichloromethane*2. The organic phases were combined and dried over anhydrous sodium sulfate. 4-(3,4-difluorophenyl)-4-hydroxybutyronitrile 20 (98g, yield 97%) was obtained by concentration under reduced pressure. ¹ H-NMR (400MHz,CDCl ₃ ):δ1.96-2.01(2H,m),2.37-2.39(2H,m),2.54-2.57(1H,m),4.72-4.75 (1H,m),7.07-7.15(3H,m). MS (ESI): m/z = 198 [M+H] ⁺ .

Example 19. Preparation of 1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 21

100g 4-(3,4-difluorophenyl)-4-hydroxybutyronitrile 20, 500mL dichloromethane, and 56.5g triethylamine were added to a reaction bottle, and 39.8g acetyl chloride solution was added dropwise under nitrogen protection and the temperature was controlled at 10-20°C. Stirring was continued for 2h after the addition was completed. After the reaction was completed, 200mL of 5% dilute hydrochloric acid solution was added, and the liquids were separated and extracted. The aqueous phase was extracted with 100mL dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 21 (115.2g, yield 95%). ¹ H-NMR (400MHz, CDCl ₃ ): δ1.96-2.01(2H,m), 2.15 (3H,s), 2.33-2.35(1H,m), 2.44-2.46(1H,m), 5.05-5.07(1H,m), 7.02-7.25(3H,m). MS (ESI): m/z=240[M+H] ⁺ .

Example 20. Preparation of (S)-1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 22 by enzymatic resolution

(1) Prepare 400 mL of 0.01 M sodium dihydrogen phosphate solution, and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. Add 40 g of 1-(3,4-difluorophenyl)-3-cyano-propyl acetate 21, 4.0 g of lipase PS from Candida cepacia, and sodium dihydrogen phosphate buffer into a reaction flask, heat to 25-30° C. for reaction, and use 10% sodium hydroxide solution to maintain the pH at 7-7.5. After about 18 hours of reaction, the pH does not change much, filter, wash the filter cake with 200 mL of dichloromethane, separate and extract, extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily crude liquid, which is purified by silica gel column chromatography to obtain (S)-1-(3,4-difluorophenyl)-3-cyano-propyl acetate 22 (20 g, ee value 99%, yield 50%). ¹ H-NMR (400MHz, CDCl ₃ ): δ1.96-2.01(2H,m), 2.15(3H,s), 2.33-2.35(1H,m), 2.44-2.46(1H,m), 5.05-5.07(1H,m), 7.02-7.25(3H,m). MS (ESI): m/z=240[M+H] ⁺ .

Silica gel column chromatography was used to purify (R)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 23 (16 g, ee value 99.4, yield 48%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.96-2.01 (2H, m), 2.37-2.39 (2H, m), 2.54-2.57 (1H, m), 4.72-4.75 (1H, m), 7.07-7.15 (3H, m). MS (ESI): m/z=198 [M+H] ⁺ .

(2) Prepare 400 mL of 0.01 M disodium hydrogen phosphate solution and adjust the pH to 7.0-7.5 with dilute hydrochloric acid. 40 g of 1-(3,4-difluorophenyl)-3-cyano-propyl acetate 21, 4.0 g of Antarctic Candida lipase and disodium hydrogen phosphate buffer were put into a reaction flask, heated to 25-30°C for reaction, and pH was maintained at 7-7.5 with 10% sodium hydroxide solution. The pH did not change much after about 18 hours of reaction. The mixture was filtered, and the filter cake was washed with 200 mL of dichloromethane. The mixture was separated and extracted. The aqueous phase was extracted with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily liquid crude product. The crude product was purified by silica gel column chromatography to obtain (S)-1-(3,4-difluorophenyl)-3-cyano-propyl acetate 22 (20 g, ee value 99%, yield 50%) and (R)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 23 (15.6 g, ee value 99.4%, yield 47%).

Example 21. Preparation of (S)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 3 by hydrolysis

10 g (S)-1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 22, 15 mL concentrated hydrochloric acid and 50 mL ethanol were added to a reaction flask, heated to t=45-50°C for 5-6 hours, concentrated under reduced pressure, added with 30 mL water, extracted twice with 40 mL dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily liquid (S)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 3 (7.8 g, ee value 99, yield 95%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.96-2.01 (2H, m), 2.37-2.39 (2H, m), 2.54-2.57 (1H, m), 4.72-4.75 (1H, m), 7.07-7.15 (3H, m). MS (ESI): m/z = 198 [M+H] ⁺ .

Example 22. Preparation of (R)-1-(3,4-difluorophenyl)-3-cyano-methanesulfonic acid propyl ester 24 by sulfonylation reaction

10 g of (R)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 23 and 80 mL of dichloromethane were put into a reaction flask, 6.15 g of triethylamine was added, the temperature was lowered to t=0-5°C, 5.8 g of methanesulfonyl chloride was added dropwise, and the reaction was carried out at t=0-5°C for 2 hours after the addition was completed. After TLC detection, the reaction was completed, 30 mL of water was added, and the liquids were separated and extracted. The aqueous phase was extracted with 30 mL of dichloromethane, the organic phases were combined, washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(3,4-difluorophenyl)-3-cyano-methanesulfonic acid propyl ester 24 (13.2 g, yield 95%). ¹ H-NMR (400MHz, CDCl ₃ ): δ1.96-2.01(2H,m),2.37-2.39(1H,m),2.54-2.57(1H,m),3.2(3H,s),5.72-5.75(1H,m),7.07-7.15(3H,m). MS (ESI): m/z=180[M-OMs] ⁺ .

Example 23. Preparation of (S)-1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 22 by Walden inversion

10 g (R)-1-(3,4-difluorophenyl)-3-cyano-methanesulfonic acid propyl ester 24, 10.45 g cesium acetate and 50 mL DMF were put into a reaction bottle and reacted at 22-26°C for about 12 hours. The reaction was completed when detected by TLC. A small amount of salt was removed by filtration, and DMF was removed by vacuum distillation. 50 mL of dichloromethane was added, and the mixture was washed once with 30 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (S)-1-(3,4-difluorophenyl)-3-cyano-acetic acid propyl ester 22 (8.2 g, ee value 99.4%, yield 94%).

Example 24. Preparation of ethyl (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylate 25

17g of sodium tert-butoxide was suspended in 80mL of toluene, and 20.6g of phosphonoethyl triethyl was slowly added under nitrogen protection. The reaction was exothermic. After the addition was completed, the temperature was raised to 70-80°C, and 20mL of a toluene solution of 13.6g of (S)-2-chloro-1-(3,4-difluorophenyl)ethanol 1 was slowly added dropwise. After the addition was completed, the reaction solution continued to react at this temperature for 3-4h. TLC confirmed that the reaction was completed, the reaction solution was cooled to room temperature, 100ml of water was added, and the liquids were separated and extracted. The aqueous phase was extracted with 50mL of toluene, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow-brown oily liquid (1R, 2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid ethyl ester 25 (15.6g, yield 98%), with an HPLC purity of 86%. ¹ H-NMR (400MHz, CDCl ₃ ): δ1.23-1.27(1H,m), 1.28-1.32(3H,t), 1.58-1.63(1H,m), 1.84-1.88(1H,m), 2.46-2.51(1H,m), 4.16-4.22 (2H,m), 6.84-6. 93(2H,m),7.03-7.10(1H,m). MS (ESI): m/z=227[M+H] ⁺ .

Example 25. Preparation of (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxamide 26

(1)

15.2g of (1R, 2R)-2-(3,4-difluorophenyl) cyclopropylcarboxylic acid ethyl ester 25, 62g of 20% (g/g) ammonia methanol solution, 15g of methyl formate, and 30mL of 30% sodium methoxide solution were placed in a thick-walled pressure-resistant bottle and sealed. The temperature was raised to 70°C, the internal pressure was about 0.2Mpa, and the reaction was carried out for 10 hours. The reaction solution was cooled to room temperature. The temperature was controlled at 35-40°C, and 200mL of water was added dropwise under stirring for about 1 hour. Cooled to room temperature and crystallized at rest. Filtered, the filter cake was washed with 100mL of 30% methanol aqueous solution and 100mL of isopropyl ether. Drying in a constant temperature oven at 45°C gave an off-white solid (1R, 2R)-2-(3,4-difluorophenyl) cyclopropylcarboxamide 26 (10.5g, yield 79%). ¹ H-NMR (400MHz, CDCl ₃ ): δ1.17-1.24(1H,m), 1.57-1.68(2H,m), 2.44-2.51(1H,m), 5.2-5.7(2H,d), 6.81-6.88(2H,m), 6.9-7.01(1H,m). MS (ESI): m/z =198[M+H] ⁺ .

(2)

16.6 g (1R, 2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid 29 was dissolved in 160 mL toluene, 16.6 g thionyl chloride was added, the mixture was heated to reflux for 2 h, and the mixture was concentrated under reduced pressure. 20 mL toluene was added to dissolve the mixture, and the mixture was added dropwise to a mixed solution consisting of 30% aqueous ammonia (20.25 g), 50 mL water, and 115 mL ethyl acetate. The temperature was controlled at 15-30°C, and the addition was completed after 30 min. The mixture was stirred for 1-2 h, and the mixture was separated and extracted. The aqueous phase was extracted with 50 mL ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure to obtain an off-white solid (1R, 2R)-2-(3,4-difluorophenyl)cyclopropylcarboxamide 26 (14.35 g, yield 87%).

Example 26. Preparation of (1R,2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane 27

41.5 g of triphenylphosphine and 100 mL of toluene were put into a reaction bottle, the temperature was controlled at 5-10°C, and a solution of 30.7 g of diisopropyl azodicarboxylate in 70 mL of toluene was added dropwise. The solution was added after about 40 min. The stirring was continued for 40 min. The temperature was then controlled at 5-10°C, and a solution of 27.5 g of (S)-1-(3,4-difluorophenyl)-3-nitropropane-1-ol 2 in 70 mL of toluene was added dropwise. The solution was added after about 1 h. The reaction solution was stirred for 2 h. After TLC confirmed the completion of the reaction, 2 g of acetic acid was added dropwise, the temperature was controlled at 5-10°C and stirred for 30 min, the precipitated solid was filtered, the filter cake was washed with 30 mL of pre-cooled toluene, the toluene filtrate was combined, washed once with 100 mL of 10% hydrochloric acid aqueous solution and once with 100 mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily liquid crude product, which was then purified by reduced pressure distillation to obtain (1R, 2S)-2-(3,4-difluorophenyl)-1-nitrocyclopropane 27 (22.2 g, yield 88%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.6 (1H, m), 2.21 (1H, m), 3.1 (1H, m), 4.35 (1H, m), 6.89 (2H, m), 7.10 (1H, m). MS (ESI): m/z＝200[M+H] ⁺ .

Example 27. Preparation of (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarbonitrile 28

Dissolve 11.5g (S)-1-(3,4-difluorophenyl)-3-cyanopropane-1-ol 3 and 16.3mL triethylamine in 200mL tetrahydrofuran, control the temperature at 0-5℃, add 8.0g methanesulfonyl chloride dropwise, control the temperature at 25-30℃ and stir for 1h. Then control the temperature at 0-5℃, add 6.4g potassium tert-butoxide in batches, control the temperature at 25-30℃ and stir for 1h. Add 2M HCl aqueous solution (50mL), and add 50mL ethyl acetate*2 for extraction, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily liquid crude product, which is purified by column chromatography to obtain (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarbonitrile 28 (4.17g, yield 40%). ¹ H-NMR (400MHz, CDCl ₃ ): δ1.41(1H,m),1.53(1H,m),1.64(1H,m),2.60(1H,d),6.87(1H,m),6.92(1H,m),7.10(1H,m). MS (ESI): m/z=180[M+H] ⁺ .

Example 28. Preparation of (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid 29

7.7 g (1R, 2R)-2-(3, 4-difluorophenyl) cyclopropylcarbonitrile 28 and 4M lithium hydroxide aqueous solution (280 mL) were placed in a reaction flask and heated to reflux for 3.5 h. The mixture was cooled to 15-20°C, adjusted to pH = 2-3 with concentrated hydrochloric acid, extracted with 50 mL of dichloromethane*3, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1R, 2R)-2-(3, 4-difluorophenyl) cyclopropylcarboxylic acid 29 (8.12 g, yield 95%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.36 (1H, m), 1.68 (1H, m), 1.87 (1H, m), 2.57 (1H, m), 6.87 (1H, m), 6.92 (1H, m), 7.10 (1H, m).

Example 29. Preparation of (1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine 4

(1)

30 g (1R, 2R) -2- (3, 4-difluorophenyl) cyclopropylcarboxamide 26 and 200 mL of 30% sodium hydroxide solution were put into a reaction bottle, the temperature was controlled at 20-30°C, 250 g of 12% sodium hypochlorite solution was added, the reaction solution was stirred until the solid was dissolved, the temperature was quickly raised to 65-70°C for reaction for 1 h, the reaction solution was cooled to 10-20°C, and concentrated hydrochloric acid was added dropwise to adjust the pH to 8-9. The aqueous phase was extracted with 150 mL of ethyl acetate * 3, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily liquid (1R, 2S) -2- (3, 4-difluorophenyl) cyclopropylamine 4 (20.8 g, yield 80%). ¹ H-NMR (400MHz, CDCl ₃ ): δ0.88(1H,m),1.03(1H,m),1.71(2H,s),1.79(1H,m),2.47(1H,m),6.92(2H,m),6.97(1H,m). MS (ESI): m/z =170[M+H] ⁺ .

(2)

10g (1R, 2R)-2-(3,4-difluorophenyl) cyclopropylcarboxylic acid 29 and 100mL methanol were put into a hydrogenation reactor, 1g of 10% palladium carbon was added, and after replacing the hydrogen, the hydrogenation reaction was carried out at 50-55°C and 0.2-0.4Mpa. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and the filter cake was washed with 20mL methanol. The filtrate was combined and concentrated under reduced pressure to obtain a light yellow oily liquid (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine 4 (8.1g, yield 95%)

Example 30. Preparation of compound intermediate 31

Dissolve 16.9g (1R, 2S) -2- (3, 4-difluorophenyl) cyclopropylamine 4 and 19.5g potassium carbonate in 150mL water, control the temperature at 20 ~ 30 ° C, add 43g of compound 30 in 250mL toluene solution, and stir for 3h. After the reaction is completed, separate the liquids for extraction, extract the aqueous phase with 100mL toluene, combine the organic phases, wash once with 20mL saturated sodium chloride solution, and the resulting solution is a toluene solution of compound 31, which is directly used in the next step.

Example 31. Preparation of Ticagrelor

The toluene solution of compound 31 obtained in the previous step was cooled to 10-15°C, and a mixed solution of 100 mL of concentrated hydrochloric acid and 150 mL of methanol was added in batches. The reaction mixture was stirred at 10-15°C for 2 h. After the reaction, the mixture was separated, the temperature was controlled at 10-15°C, the methanol/water solution containing the product was adjusted to pH 7.0-7.3 with a saturated sodium bicarbonate solution, 100 mL of ethyl acetate*3 was used to extract the water, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily liquid. 100 mL of ethyl acetate was added to the concentrate, heated to 60°C for dissolution, then cooled to about 50°C, 110 mL of n-hexane was added, cooled to 0-5°C, crystallized for 2h, filtered, and the filter cake was washed with a mixed solution of 22 mL of ethyl acetate and 25 mL of n-hexane precooled to 0°C, and dried under reduced pressure at 40-45°C to obtain ticagrelor (42 g, yield 80%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.83-0.86 and 0.94-1.09 (3H, m), 1.38-1.59 and 1.67-1.75(4H,m),2.06-2.14and 2.28(2H,s),2.61-2.70(1H,m),2.83-2.98(2H,m), 3.18-3.2(1H,m),3.52-3.54(4H,m),3.77(1H,s),3.99(1H,s ),4.58-4.88(2H,m),4.96- 5.04(1H,m),5.10-5.18(2H,m),7.10(1H,m),7.28-7.38(2H,m),8.97-8.99and 9.35 -9.37(1H,d),. MS (ESI): m/z=523[M+H] ⁺ .

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (10)

1. A process for preparing ticagrelor, the process comprising the steps of:

(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;

(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;

in the formula, R ₁ Selected from halogens (preferably F, cl or Br);

R ₂ selected from: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ ；

(1-3) preparing ticagrelor by utilizing the compound shown in the formula III through multi-step reaction;

alternatively, the method comprises the steps of:

(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;

in the formula, R ₃ Selected from NO ₂ Or CN;

R ₄ selected from: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ ；

(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;

(2-3 a) hydrolyzing the compound shown in the formula iv obtained in the step (2-2) to obtain a compound shown in a formula v;

in the formula, R ₃ Selected from NO ₂ Or CN;

R ₄ selected from the group consisting of: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ ；

(2-4) preparing ticagrelor by utilizing the compound shown in the formula v through multi-step reaction.

2. The method of claim 1, wherein the enzyme utilized in step (1-2 a) or (2-2) is a hydrolase, including but not limited to a lipase, a protease, or an esterase;

preferably, the lipase is candida antarctica lipase, candida cylindracea lipase, candida onion lipase PS, lipase TL, distillers yeast lipase, lipase AS1 and the like;

the protease is chymotrypsin, cathepsin, papain, subtilisin and the like;

the esterase is porcine liver esterase PL, esterase RO, an Aspergillus oryzae TL recombinant, an Escherichia coli esterase BS1 recombinant, an Escherichia coli esterase BS2 recombinant and the like;

more preferably, the hydrolase is a lipase PS from candida cepacia or a lipase from candida antarctica.

3. The method of claim 1 or 2, wherein the step (1-2 a) is further followed by hydrolysis, sulfonylation, waldenstein configuration transformation, and hydrolysis of the compound of formula IV obtained in step (1-2 a) to obtain a compound of formula III; or alternatively

And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).

4. The method of claim 3, further comprising, after step (1-2 a), the steps of:

(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;

(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;

(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Walton configuration transformation to obtain a compound represented by the formula VII;

(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;

in the formula, R ₁ As described above; r is ₅ Selected from: c _1-6 Alkyl (preferably CH) ₃ )、C ₆ H ₅ Or p-CH ₃ C ₆ H ₄ ；R ₆ Is H, C _1-6 Alkyl (preferably CH) ₃ Or CH ₂ CH ₃ )；

Or, the following steps are also included after the step (2-3 a):

(2-3 b) subjecting the compound represented by the formula iii obtained in the step (2-2) to a sulfonylation reaction to obtain a compound represented by the formula vi;

(2-3 c) carrying out Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;

(2-3 d) hydrolysing the compound of formula vii obtained in step (2-3 c) to give a compound of formula v;

wherein R is ₃ As described above; r ₅ Selected from: c _1-6 Alkyl (preferably CH) ₃ )、C ₆ H ₅ Or p-CH ₃ C ₆ H ₄ ；R ₆ Selected from: H. c _1-6 Alkyl (preferably CH) ₃ Or CH ₂ CH ₃ )。

5. The method of claim 4, wherein C used in the conversion of the Waldenstein configuration of step (1-2 d) or (2-3C) _1-6 The fatty acid salt is preferably cesium acetate, sodium acetate, potassium acetate, sodium formate, sodium propionate or potassium propionate, most preferably cesium acetate;

the solvent used in the Valden configuration transformation reaction is DMF, DMSO or acetonitrile, preferably DMF;

the molar ratio of the compound shown in the formula VI or the compound shown in the formula vi in the Valden configuration conversion to the fatty acid salt is 1:1-4, and 1.5 is preferred;

the temperature of the Waldenstein configuration conversion reaction is 20-50 ℃, and preferably 22-26 ℃;

the time for the conversion reaction of the Valden configuration is 10 to 30 hours, preferably 12 hours.

6. A method of preparing (S) -1- (3,4-difluorophenyl) - α -alcohol, said (S) -1- (3,4-difluorophenyl) - α -alcohol being a compound of formula III, said method comprising the steps of:

(1-1) taking 1,2-difluorobenzene and an acyl chloride compound as raw materials, sequentially carrying out Friedel-crafts reaction and reduction reaction to obtain a compound shown as a formula I, and then carrying out hydroxyl acylation to obtain a compound shown as a formula II;

(1-2 a) enzymatically resolving the compound of formula II obtained in step (1-1) to obtain a compound of formula III and a compound of formula IV;

in the formula, R ₁ Selected from halogens (preferably F, cl or Br);

R ₂ selected from: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ ；

Alternatively, the (S) -1- (3,4-difluorophenyl) - α -alcohol is a compound of formula v, comprising the steps of:

(2-1) taking 1,2-difluorobenzene and chloropropionyl chloride as raw materials, sequentially carrying out Friedel-crafts reaction, substitution reaction and reduction reaction to obtain a compound shown in a formula i, and carrying out hydroxyl acylation to obtain a compound shown in a formula ii;

in the formula, R ₃ Selected from NO ₂ Or CN;

R ₄ selected from: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ ；

(2-2) enzymatically resolving the compound of formula ii obtained in step (2-1) to obtain a compound of formula iii and a compound of formula iv;

(2-3 a) hydrolyzing the compound shown in the formula iv obtained in the step (2-2) to obtain a compound shown in a formula v;

in the formula, R ₃ Selected from NO ₂ Or CN;

R ₄ selected from: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ 。

7. The method of claim 6, wherein the step (1-2 a) is further followed by hydrolysis, sulfonylation, waldenstein configuration transformation, and hydrolysis of the compound of formula IV obtained in step (1-2 a) to obtain a compound of formula III; or

And (3) preparing the compound shown in the formula v by using the compound shown in the formula iii obtained in the step (2-2) through sulfonylation reaction, waldenstein configuration conversion reaction and hydrolysis reaction after the step (2-3 a).

8. The method of claim 7, further comprising, after step (1-2 a), the steps of:

(1-2 b) hydrolyzing the compound represented by the formula IV obtained in the step (1-2 a) to obtain a compound represented by the formula V;

(1-2 c) carrying out a sulfonylation reaction on the compound shown in the formula V obtained in the step (1-2 b) so as to obtain a compound shown in a formula VI;

(1-2 d) subjecting the compound represented by the formula VI obtained in the step (1-2 c) to a Walton configuration transformation to obtain a compound represented by the formula VII;

(1-2 e) hydrolyzing the compound represented by the formula VII obtained in the step (1-2 d) to obtain a compound represented by the formula III;

in the formula, R ₁ As claimed in claim 1; r is ₅ Selected from the group consisting of: c _1-6 Alkyl (preferably CH) ₃ )、C ₆ H ₅ Or p-CH ₃ C ₆ H ₄ ；R ₆ Is H, C _1-6 Alkyl (preferably CH) ₃ Or CH ₂ CH ₃ )；

Or, the following steps are also included after the step (2-3 a):

(2-3 b) carrying out a sulfonylation reaction on the compound shown in the formula iii obtained in the step (2-2) to obtain a compound shown in the formula vi;

(2-3 c) performing Waldenstein configuration conversion on the compound shown in the formula vi obtained in the step (2-3 b) to obtain a compound shown in the formula vii;

(2-3 d) hydrolyzing the compound of formula vii obtained in step (2-3 c) to obtain a compound of formula v;

wherein R is ₃ As claimed in claim 1; r ₅ Selected from the group consisting of: c _1-6 Alkyl (preferably CH) ₃ )、C ₆ H ₅ Or p-CH ₃ C ₆ H ₄ ；R ₆ Selected from the group consisting of: H. c _1-6 Alkyl (preferably CH) ₃ Or CH ₂ CH ₃ )。

9. A compound of formula II

In the formula, R ₁ Selected from halogen (preferably F, cl or Br);

R ₂ selected from the group consisting of: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ (ii) a Or

A compound of formula ii

In the formula, R ₃ Selected from NO ₂ Or CN;

R ₄ selected from the group consisting of: c _1-6 Alkyl (preferably CH) ₃ 、CH ₂ CH ₃ 、CH ₂ CH ₂ CH ₃ )、CH＝CH ₂ 、C ₆ H ₅ Or CH ₂ C ₆ H ₅ 。

10. Use of a compound of formula II or a compound of formula II for the preparation of ticagrelor.