Process for preparing intermediates of eribulin

Abstract

The present invention provides a method for preparing a compound of formula I, which involves using compound 3A or compound 3B as starting material, selectively acylating it with bioenzyme A or selectively hydrolyzing it with bioenzyme B, and then reacting the hydroxyl group of the desired configuration with an acid anhydride under the influence of an organic base and a catalyst to obtain compound 5. In this invention, by increasing the water solubility of the intermediate product, separation of the two configurations can be achieved using extraction separation, with an ee value of 99% or more. This method for preparing a compound of formula I is simple, has high conversion, good selectivity, and low cost, making it suitable for industrial scale production.

Description

[Technical Field]

[0001] This application claims priority to a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on July 29, 2022, bearing application number 202210904052.6 and entitled "Method for preparing intermediates of eribulin," the entire contents of which are incorporated herein by reference.

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing an intermediate of eribulin. [Background technology]

[0003] Eribulin mesylate is a synthetic analog of halichondrin B, which contains the biologically active macrocyclic moiety of halichondrin B. Halichondrin B is a polyether macrolide that has demonstrated potent anticancer effects in both cell and animal models. Eribulin mesylate inhibits mitosis of cell tubulin, causing irreversible G2 / M cell cycle arrest and disruption of the mitotic spindle, leading to prolonged mitotic arrest followed by apoptosis and suppression of cell proliferation. Eribulin mesylate injection, developed by Eisai Inc., was approved for sale in the United States by the U.S. FDA in November 2010 under the trade name Halaven. The approved indication is for patients with metastatic breast cancer who have received at least two prior metastatic cancer treatment regimens. Results of a subset-based analysis indicate that eribulin mesylate can be used actively and effectively in the treatment of triple-negative metastatic breast cancer, a malignant form of breast cancer often associated with a poor prognosis. In many countries, eribulin mesylate has been considered a third-line drug and even a subsequent drug therapy for metastatic breast cancer, and during treatment, this drug is the only chemotherapy agent that can effectively improve patient survival. Eribulin mesylate is currently the only drug in this field with good clinical and commercial prospects.

[0004] The structure of the initial intermediate of eribulin is shown in Formula I below. [ka]

[0005] The prior art synthesis method for the compound of formula I is as follows: The process scheme for synthesizing the initial intermediate I of eribulin drug substance from Eisai Co., Ltd., the original manufacturer of eribulin drug substance, is as follows: [ka] Here, TBDPS is t-butyldiphenylsilyl.

[0006] Compound I has chirality at the tosyl-protected hydroxy carbon, and the synthesis process initially yields a racemic mixture. Literature (e.g., Synlett (2013), 24(3), 327-332, WO2005118565) has reported that compound 3 can be separated to obtain a single configuration using a chiral simulated moving bed (SMB) system. However, this method has low preparative efficiency, is expensive, and is unsuitable for scale-up. Another literature (Org. Lett., Vol. 10, No. 14, 2008) has reported that a single configuration product can be obtained under the catalysis of a chiral ligand and metal chromium, but this method is expensive. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Patent Application Publication No. 2005 / 118565 Brochure [Non-patent literature]

[0008] [Non-Patent Document 1] Synlett(2013),24(3),327-332 [Non-patent document 2] Org.Lett.,Vol.10,No.14,2008 Summary of the Invention [Problem to be solved by the invention]

[0009] The technical problem to be solved by the present invention is to provide a method for preparing the compound of formula I, which is completely different from the prior art. This preparation method has mild reaction conditions, is environmentally friendly, uses a novel route, is simple in post-treatment and purification, and the purity of the compound of formula I obtained is high, the operation is simple, the conversion rate is high, the selectivity is good, and the cost is low, which is advantageous for industrial scale-up. The compound of formula I can be used in the preparation of eribulin drug. [Means for solving the problem]

[0010] The present invention provides a method for preparing chiral compounds I by enzymatic methods, comprising the steps of: The method includes method 1 or method 2, In the method 1, a compound represented by formula 3A is used as a raw material, and is subjected to an acylation reaction with an acylating reagent under the action of a biological enzyme A to obtain compound 4 and compound I, and the mixture of compound 4 and compound I is selectively separated; [ka] In the method 2, the compound represented by formula 3B is used as a raw material, and is hydrolyzed under the action of a biological enzyme B and a base to obtain the compound 4 and the compound I, and the mixture of the compound 4 and the compound I is selectively separated; [ka] where R1 is a C1-C substituted or unsubstituted group with Ra. 12a straight-chain or branched-chain acyl group, a benzoyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently a C1-C6 straight-chain or branched-chain alkyl group, a C1-C6 straight-chain or branched-chain alkoxy group, a hydroxy group, an amino group, a halogen atom, a nitro group, a cyano group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a C1-C6 thioalkyl group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a phenyl group, and a C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N, and S; R1 is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group, and more preferably an acetyl group, a propionyl group, a butyryl group, a benzoyl group, or an acryloyl group; The biological enzyme A is a lipase or an esterase, The bioenzyme A is any one selected from lipase AK, Pseudomonas fluorescens-derived lipase, recombinant Candida Antarctica lipase B derived from Aspergillus oryzae immobilized on Immobead 150, Candida Antarctica lipase B immobilized on acrylic resin, lipase AS, lipase PS, thermophilic fungus-derived lipase, Candida rugosa-derived lipase, lipase AYS, triacylglycerol lipase, Mucor miehei-derived lipase, and Rhizopus oryzae-derived lipase; The bioenzyme A is preferably lipase AK, lipase from Pseudomonas fluorescens, or Novozym 435, which is Candida antarctica lipase B immobilized on an acrylic resin; The biological enzyme B is a lipase, an esterase, or a hydrolase, The bioenzyme B includes lipase TL, lipase PS-30 from Pseudomonas cepacia, lipase QLM, lipase from Thermomyces lanuginosus, lipase P2 from Pseudomonas cepacia, lipase PS from Pseudomonas stutzeri, lipase RS from Rhizopus, lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger, lipase A from Achromobacter, lipase AS1 from Alcaligenes, lipase AS2 from Alcaligenes, lipase C2 from Candida cylindracea, lipase C1 from Candida cylindracea, lipase TL IM, lipase TL 100L, lipase B from Candida antarctica, and CHIRAZYME. E-1 porcine liver esterase, lipase from Pseudomonas sp. L-6, Candida antarctica lipase A, Candida rugosa lipase L-3, and pancreatic lipase; In the method, the bioenzyme B is preferably lipase TL or lipase PS-30 derived from Pseudomonas cepacia.

[0011] The present invention relates to a method for preparing a chiral compound I, comprising the steps of: The method includes separating a mixture of compound 4 and compound I; The separating step includes the following 3) or 4): 3) Separating the mixture of Compound 4 and Compound I by column chromatography to obtain Compound I; 4) Step a: under the action of a catalyst and an organic base, compound I in a mixture of compound 4 and compound I is selectively esterified with an acid anhydride, and then separated to obtain compound 4 and compound 5; Step b: compound 5 is hydrolyzed to obtain compound I, and the reaction scheme is as follows: [ka] where R1 is a C1-C substituted or unsubstituted group with Ra. 12a straight-chain or branched-chain acyl group, a benzoyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N, and S; R1 is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group; R2 is [ka] That is the method.

[0012] The present invention relates to an intermediate compound, the structure of which is [ka] and * represents a chiral carbon, and R is a C1-C substituted or unsubstituted by Ra. 12 a linear or branched acyl group, a C3-C6 linear or branched alkenoyl group substituted or unsubstituted by Ra; [ka] and the substituents Ra of each group are each independently selected from a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxy group, an amino group, a halogen atom, a nitro group, a cyano group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a C1-C6 thioalkyl group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a phenyl group, and a C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N, and S; Preferably, when the chiral carbon represented by * is in the S configuration, the structure of the intermediate compound is [ka] and R1 is a substituted or unsubstituted C1-C 12 a straight-chain or branched-chain acyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N, and S; R1 is preferably a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group or an acryloyl group; The intermediate compound is preferably [ka] and When the chiral carbon represented by * is in the R configuration, the structure of the intermediate compound is [ka] and R2 is [ka] and The intermediate compound is preferably [ka] is an intermediate compound DETAILED DESCRIPTION OF THE INVENTION

[0013] In a first aspect, the present invention provides a method for preparing chiral compound I by an enzymatic method, comprising method 1 or method 2, In the method 1, a compound represented by formula 3A is used as a raw material, and is subjected to an acylation reaction with an acylating reagent under the action of a biological enzyme A to obtain compound 4 and compound I, and the mixture of compound 4 and compound I is selectively separated; [ka] In the method 2, the compound represented by formula 3B is used as a raw material, and is hydrolyzed under the action of a biological enzyme B and a base to obtain compound 4 and compound I, and the mixture of compound 4 and compound I is selectively separated; [ka] where R1 is a C1-C substituted or unsubstituted group with Ra. 12 a straight-chain or branched-chain acyl group, a benzoyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18wherein R1 is selected from heteroaromatic groups, heteroatoms in the heteroaromatic groups are selected from O, N and S, and R1 is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group, more preferably an acetyl group, a propionyl group, a butyryl group, a benzoyl group, or an acryloyl group.

[0014] In a further improvement of the present invention, the bioenzyme A is a lipase or an esterase, and the bioenzyme A is selected from the group consisting of Lipase AK (Lipase AK "Amano"), Lipase from Pseudomonas fluorescens (Amano Lipase), Lipase B Candida antarctica immobilized on Immobead 150, recombinant from Aspergillus oryzae (Lipase B Candida antarctica immobilized on Immobead 150, recombinant from Aspergillus oryzae), Lipase B Candida antarctica immobilized on acrylic resin (CAL-B lipase immobilized on acrylic resin (Novozym 435)), Lipase AS (Lipase AS "Amano"), Lipase PS (Lipase PS "Amano" SD), Lipase from Thermomyces The bioenzyme A is any one selected from the group consisting of lipase from Candida lanuginosus, lipase from Candida rugosa, lipase AYS (Lipase AYS "Amano"), triacylglycerol lipase, lipase from Mucor miehei, and lipase from Rhizopus oryzae, and the bioenzyme A is preferably lipase AK (Lipase AK "Amano"), lipase from Pseudomonas fluorescens (Amano Lipase from Pseudomonas fluorescens), or Novozym 435, which is Candida Antarctica lipase B immobilized on acrylic resin (CAL-B lipase (Novozym 435) immobilized on acrylic resin).

[0015] In a further improvement of the present invention, the biological enzyme B in method 2 is a lipase, an esterase or a hydrolase, such as lipase TL, lipase PS-30 from Pseudomonas cepacia, lipase QLM, lipase from Thermomyces lanuginosus, lipase P2 from Pseudomonas cepacia, lipase PS from Pseudomonas stutzeri, lipase RS from Rhizopus sp., lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger, lipase A from Achromobacter sp., lipase B from Alcaligenes sp., lipase TL from Pseudomonas cepacia, lipase QLM from Pseudomonas cepacia, lipase P2 from Pseudomonas stutzeri, lipase RS from Rhizopus sp., lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger, lipase A from Achromobacter sp., lipase B from Alcaligenes sp., lipase AN from Aspergillus niger ... B from Alcaligenes sp., lipase AN from Aspergillus niger, lipase B from Alcaligenes sp., lipase B from Alcaligenes sp., lipase AN from Alcaligenes sp., lipase B from Alcaligenes sp., lipase B from Alcaligenes sp., lipase B from Alcaligenes sp., lipase B from Alcaligenes sp., lipase B from Alcaligenes sp., lipase C from Alcal Lipase AS1 from Alcaligenes sp., Lipase AS2 from Alcaligenes sp., Lipase C2 from Candida cylindracea, Lipase C1 from Candida cylindracea, Lipase lipozym TL IM, Lipase lipozym TL 100L, Candida antarctica lipase B (CALB), CHIRAZYME E-1 porcine liver esterase, Lipase from Pseudomonas sp. L-6, Candida antarctica lipase A (CALA), Candida rugosa lipase (L-3), or Pancreatic Lipase USP Grade.

[0016] In a further refinement of the present invention, the acylating reagent of Method 1 is selected from vinyl esters and isopropenyl esters, wherein the vinyl esters are C1-C substituted or unsubstituted with Rc. 12 vinyl esters of linear or branched chain acids, vinyl benzoate, and vinyl esters of C3-C6 linear or branched chain olefinic acids substituted or unsubstituted by Rc, wherein the isopropenyl ester is selected from the group consisting of vinyl esters of C1-C6 linear or branched chain olefinic acids substituted or unsubstituted by Rc. 12isopropenyl esters of straight-chain or branched-chain acids, isopropenyl benzoate, and isopropenyl esters of C3-C6 straight-chain or branched-chain olefinic acids substituted or unsubstituted by Rc. The substituents Rc in each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18 heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S;

[0017] As a further improvement of the present invention, the acylating reagent of method 1 is preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl isobutyrate, isopropenyl isobutyrate, vinyl 2-methylbutyrate, isopropenyl 2-methylbutyrate, vinyl 3-methylbutyrate, isopropenyl 3-methylbutyrate, vinyl pivalate, isopropenyl pivalate, vinyl 2-methylvalerate, isopropenyl 2-methylvalerate, vinyl 3-methylvalerate, isopropenyl 3-methylvalerate vinyl 4-methylvalerate, isopropenyl 4-methylvalerate, vinyl caproate, isopropenyl caproate, vinyl laurate, isopropenyl laurate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate, or isopropenyl acrylate, and more preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate, or isopropenyl acrylate.

[0018] In Method 1 provided by the present invention, Bioenzyme A can selectively acylate an alcohol of Formula 3A with Bioenzyme A to produce a single isomeric acylated compound of Formula 4. The compound of Formula I can then be easily separated from the compound of Formula 4. The acylation reaction is carried out in an organic solvent. The enantiomeric excess of the product of Formula I is preferably at least 96% ee, more preferably at least 99% ee. The enzyme is immobilized on a carrier to facilitate enzyme recovery and post-reaction processing. The enzyme is characterized by high selectivity, good stability, high enzymatic activity, and low cost.

[0019] In a further improvement of the present invention, the acylation reaction of Method 1 is carried out in an organic solvent A. The organic solvent A is one or any combination of alkane-based, aromatic hydrocarbon-based, chloroalkane-based, nitrile-based, and ether-based solvents. For example, the alkane-based solvent is one or any combination of n-hexane, cyclohexane, n-pentane, cyclopentane, and n-heptane. The aromatic hydrocarbon-based solvent is one or any combination of toluene, xylene, and chlorobenzene. The chloroalkane-based solvent is dichloromethane and chloroform. The nitrile-based solvent is one or any combination of acetonitrile, propionitrile, and benzonitrile. The ether-based solvent is one or any combination of petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether (MTBE). The organic solvent A is preferably one selected from petroleum ether, ethyl ether, methyl tert-butyl ether, dichloromethane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene, and acetonitrile, or any combination thereof, and more preferably one selected from n-hexane and n-heptane, or a combination thereof.

[0020] As a further improvement of the present invention, the ratio of the mass of compound 3A to the volume of organic solvent A in method 1 is 1 g:1-15 mL, more preferably 1 g:5-8 mL.

[0021] As a further improvement of the present invention, the acylation reaction temperature in Method 1 is 30 to 80° C., preferably 55 to 60° C. In this temperature range, the enzyme has high activity, a fast reaction rate, and high efficiency.

[0022] As a further improvement of the present invention, the mass ratio of Compound 3A to Bioenzyme A in Method 1 is 1:0.005-0.3, preferably 1:0.01-0.3, and more preferably 1:0.05-0.2.

[0023] As a further improvement of the present invention, the molar ratio of compound 3A to the acylating reagent in Method 1 is 1:1 to 20, preferably 1:2 to 10, and more preferably 1:3 to 6. When the acylating reagent of the present invention is used in combination with a biological enzyme, the S-configuration compound in racemic compound 3A can be selectively acylated to obtain compound 4, resulting in a high reaction yield and good isomeric purity.

[0024] In a further refinement of the present invention, the product obtained by the enantioselective acylation of the present invention comprises a mixture of the compound of formula I in the R configuration and the compound of formula 4 in the S configuration. Similarly, enantioselective enzymatic hydrolysis produces a mixture containing the compound of formula I in the R configuration and the compound of formula 4 in the S configuration. The optical purity of the compound of formula I obtained by the optical resolution method of the present invention is generally at least 96% ee, preferably at least 97% ee, more preferably at least 98% ee, and most preferably at least 99% ee.

[0025] In a further improvement of the present invention, the hydrolysis reaction of Method 2 is carried out in water and an organic solvent B. The organic solvent B includes one or any combination of an alkane, an aromatic hydrocarbon, a chloroalkane, a nitrile, and an ether solvent. For example, the alkane is one or any combination of an alkane selected from n-hexane, cyclohexane, n-pentane, cyclopentane, and n-heptane. The aromatic hydrocarbon is one or any combination of an alkane selected from toluene, xylene, and chlorobenzene. The chloroalkane is one or any combination of an alkane selected from dichloromethane and chloroform. The nitrile is one or any combination of an alkane selected from acetonitrile, propionitrile, and benzonitrile. The ether is one or any combination of an alkane selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether (MTBE). The organic solvent B is preferably one or any combination of an alkane selected from toluene, xylene, methyl tert-butyl ether, and acetonitrile.

[0026] In a further improvement of the present invention, the base is selected from an organic base and an inorganic base. The organic base is one selected from diethylamine, triethylamine (TEA), diisopropylamine, morpholine, N-methylmorpholine, piperazine, and N-methylpiperazine, or any combination thereof. The inorganic base includes, for example, one selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides, or any combination thereof. Preferably, the base is one selected from alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates, or any combination thereof, more preferably, the base is an alkali metal carbonate. The base is preferably one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and potassium carbonate, or any combination thereof, most preferably, one selected from sodium carbonate and potassium carbonate, or any combination thereof. The base of the present invention, when used in combination with the biological enzyme B, can selectively hydrolyze and react the R configuration of the racemic compound 3B to obtain compound I, resulting in a high reaction yield and good isomeric purity.

[0027] As a further improvement of the present invention, the mass ratio of Compound 3B to Bioenzyme B in Method 2 is 1:0.005-0.3, preferably 1:0.01-0.3, and more preferably 1:0.05-0.2.

[0028] As a further improvement of the present invention, the molar ratio of compound 3B to base in method 2 is 1:1-10, preferably 1:1-8, more preferably 1:1-4.

[0029] As a further improvement of the present invention, the ratio of the mass of compound 3B to the volume of organic solvent B in method 2 is 1 g:1-15 mL, more preferably 1 g:3-8 mL.

[0030] As a further improvement of the present invention, the hydrolysis reaction temperature in Method 2 is 30 to 80° C., preferably 35 to 40° C. In this temperature range, the enzyme has high activity, a fast reaction rate, and high efficiency.

[0031] As a further improvement of the present invention, the method for selectively separating a mixture of compound 4 and compound I includes the following steps 1) or 2): 1) A mixture of Compound 4 and Compound I is separated by column chromatography to obtain Compound I. 2) Step a: In the presence of a catalyst and an organic base, compound I in a mixture of compound 4 and compound I is selectively esterified with an acid anhydride, and then separated to obtain compound 4 and compound 5. Step b: Compound 5 is hydrolyzed to obtain compound I. The reaction scheme is as follows: [ka] where R1 is a C1-C substituted or unsubstituted group with Ra. 12 a straight-chain or branched-chain acyl group, a benzoyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N and S; R1 is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group; and R2 is [ka] is.

[0032] In a further improvement of the present invention, the separation by column chromatography is carried out by silica gel column chromatography using a solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1 as an eluent.

[0033] In a further refinement of the present invention, the catalyst in step a is 4-dimethylaminopyridine (DMAP).

[0034] As a further improvement of the present invention, the molar ratio of compound I to catalyst in step a is 1:0.1-0.5, preferably 1:0.2-0.3.

[0035] In a further improvement of the present invention, the organic base in step a is one selected from diethylamine, triethylamine, diisopropylamine, pyridine, α-methylpyridine, 1,2-dimethylpyridine, 4-hydroxy-2-methylpyridine, γ-trimethylpyridine, quinoline, and dimethylquinoline, or any combination thereof, and the organic base in step a is preferably one selected from triethylamine, diisopropylamine, pyridine, and α-methylpyridine, or any combination thereof. The molar ratio of compound I to the organic base in step a is 1:1-10, preferably 1:1-5, and more preferably 1:3-5. The temperature of the esterification reaction is 0-50°C, preferably 10-30°C.

[0036] In a further improvement of the present invention, the acid anhydride in step a is [ka] The molar ratio of the compound I to the acid anhydride is 1:1 to 10, preferably 1:1 to 5, and more preferably 1:1.1 to 1.8.

[0037] In a further improvement of the present invention, the esterification reaction in step a is carried out in a reaction solvent C. The reaction solvent C comprises one or any combination of aromatic hydrocarbons, chloroalkanes, nitrile solvents, and ether solvents. For example, the aromatic hydrocarbon solvent is one or any combination of toluene, xylene, and chlorobenzene. The chloroalkane solvent is one or any combination of dichloromethane and chloroform. The nitrile solvent is one or any combination of acetonitrile, propionitrile, and benzonitrile. The ether solvent is one or any combination of petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether. The reaction solvent C is preferably one or any combination of toluene, xylene, methyl tert-butyl ether, and acetonitrile.

[0038] In a further improvement of the present invention, the separation in step a includes common separation steps, such as separation, extraction, washing with water, or concentration. The present invention is not particularly limited to the solvent used for separation or extraction, and any combination thereof may be used, selected from alkane-based, chloroalkane-based, and ether-based solvents. For example, the alkane-based solvent may be selected from n-hexane, cyclohexane, n-pentane, cyclopentane, and n-heptane, or any combination thereof. The chloroalkane-based solvent may be selected from dichloromethane and chloroform, or any combination thereof. The ether-based solvent may be selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether (MTBE), or any combination thereof.

[0039] In a further refinement of the present invention, the hydrolysis in step b is carried out in water and an organic solvent D. Any organic solvent that does not have a deleterious effect is suitable for the hydrolysis reaction. The organic solvent D is selected from organic solvents that do not have a deleterious effect. The organic solvent D is preferably selected from the reaction solvent C in the above step a. Preferably, the hydrolysis is carried out in water and acetonitrile. The reaction temperature is preferably room temperature.

[0040] In a further improvement of the present invention, the hydrolysis in step b is carried out in an inorganic base. The inorganic base is one selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides, or any combination thereof. Preferably, the base is one selected from alkali metal hydroxides and alkaline earth metal hydroxides, or any combination thereof, more preferably, the base is an alkali metal hydroxide. Preferably, the base is one selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, or any combination thereof, more preferably, one selected from sodium hydroxide and potassium hydroxide, or any combination thereof.

[0041] As a further improvement of the present invention, the molar ratio of compound 5 to inorganic base in step b is 1:1-20, preferably 1:1-4.

[0042] In a second aspect, the present invention provides a method for preparing chiral compound I, said method comprising separating a mixture of compound 4 and compound I, said separating step comprising: 3) separating the mixture of Compound 4 and Compound I by column chromatography to obtain Compound I; or 4): Step a) selectively esterifying compound I in a mixture of compound 4 and compound I with an acid anhydride under the action of a catalyst and an organic base, followed by separation to obtain compound 4 and compound 5; and Step b) hydrolyzing compound 5 to obtain compound I, wherein the reaction scheme is as follows: [ka] where R1 is a C1-C substituted or unsubstituted group with Ra. 12 a straight-chain or branched-chain acyl group, a benzoyl group, or a substituted or unsubstituted C3-C6 straight-chain or branched-chain alkenoyl group, and the substituents Ra of each group are each independently a C1-C6 straight-chain or branched-chain alkyl group, a C1-C6 straight-chain or branched-chain alkoxy group, a hydroxy group, an amino group, a halogen atom, a nitro group, a cyano group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a C1-C6 thioalkyl group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a phenyl group, and a C3-C 18 heteroaromatic groups, wherein the heteroatoms in the heteroaromatic groups are selected from O, N and S; R1 is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group; and R2 is [ka] That is, The present invention provides a method for detecting a temperature difference between a plurality of electrodes.

[0043] In a further improvement of the present invention, the reaction conditions for each step of compound I in the second embodiment can refer to the parameters for the reaction conditions for each step in the first embodiment of the present invention. When sequentially adding compounds, whether a mixture of compound I and compound 4 is obtained by the acylation reaction of compound 3A with bioenzyme A, or a mixture of compound I and compound 4 is obtained by the hydrolysis reaction of compound 3B with bioenzyme B, will not affect the reaction with acid anhydride in the next step a, as long as they are added accurately based on the theoretical yield of 50% or the amount detected by high performance liquid chromatography (HPLC).

[0044] As a further improvement of the present invention, compound 4 can be hydrolyzed and then directly converted to compound I by referring to the method in Synlett (2013), 24(3), 327-332, the entire contents of which are incorporated herein by reference.

[0045] In a further improvement of the present invention, the preparation of the mixture of compound 4 and compound I comprises selectively acylating or hydrolyzing compound 3A or compound 3B under the action of bioenzyme A or bioenzyme B, respectively, to obtain the mixture of compound 4 and compound I. The reaction scheme is as follows: [ka]

[0046] As a further improvement of the present invention, the reaction conditions for preparing the mixture of compound 4 and compound I in the second aspect can refer to the reaction conditions for each step in the first aspect of the present invention described above.

[0047] In a third aspect, the present invention provides a key intermediate for preparing compound I. In some embodiments, the key intermediate compound C is represented as follows: [ka] * represents a chiral carbon, and R is a C1-C substituted or unsubstituted by Ra. 12 a linear or branched acyl group, a C3-C6 linear or branched alkenoyl group substituted or unsubstituted by Ra; [ka] is.

[0048] Here, the substituents Ra of each group are each independently selected from the group consisting of a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxy group, an amino group, a halogen atom, a nitro group, a cyano group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a C1-C6 thioalkyl group, a C1-C6 amido group, a C3-C6 cycloalkyl group, a phenyl group, and a C3-C 18 heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S;

[0049] Preferably, when the chiral carbon represented by * is in the S configuration, the structure is [ka] and where R1 is a C1-C substituted or unsubstituted group with Ra. 12 a straight-chain or branched-chain acyl group, or a C3-C6 straight-chain or branched-chain alkenoyl group substituted or unsubstituted by Ra, wherein the substituents Ra of each group are each independently selected from C1-C6 straight-chain or branched-chain alkyl groups, C1-C6 straight-chain or branched-chain alkoxy groups, hydroxy groups, amino groups, halogens, nitro groups, cyano groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, C1-C6 thioalkyl groups, C1-C6 amido groups, C3-C6 cycloalkyl groups, phenyl groups, and C3-C 18 Heteroaromatic groups are selected from heteroatoms in the heteroaromatic groups, and the heteroatoms in the heteroaromatic groups are selected from O, N and S. R1 is preferably a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, or an acryloyl group.

[0050] As a further improvement of the present invention, the key intermediate compound is [ka] It is selected from, but not limited to:

[0051] When the chiral carbon represented by * is in the R configuration, the structure is [ka] and Here, R2 is [ka] is.

[0052] As a further improvement of the present invention, the key intermediate compound is [ka] It is selected from, but not limited to:

[0053] In a third aspect, the present invention provides a method for preparing an eribulin drug, the method comprising the method provided in the first aspect of the invention or the method provided in the second aspect of the invention.

[0054] Compared with the prior art, the present invention provides a novel method for preparing the compound of formula I, which has mild reaction conditions, is environmentally friendly, has a novel route, is simple in post-treatment and purification, and the purity of the compound of formula I obtained is high, the operation is simple, the conversion rate is high, the selectivity is good, and the cost is low, which is favorable for industrial scale-up production. The compound of formula I can be used in the preparation of eribulin drug. The advantages of the method for preparing compound I are as follows: 1) Racemic Compound 3 (including Compound 3A or Compound 3B) of the present invention can be separated by selectively resolving Compound 3 of the present invention with a selected bioenzyme (biozyme A or B) using column chromatography, without the need for costly SMB procedures or the catalytic action of a chiral ligand and metal chromium, followed by standard filtration. Compared with preparation by SMB chromatography, the preparation method of the present invention is easier to operate and scale up, and also shortens the production cycle and improves production capacity. 2) The bioenzymes screened in the present invention are characterized by high selectivity, excellent stability, high enzymatic activity, and can be recovered and reused at low cost. 3) The present invention has been found to utilize the difference in polarity to selectively acylate compound I using a biological enzyme, achieving a racemic compound resolution with a yield of over 93% and an ee value of over 99%. 4) More specifically, the present invention uses a bioenzyme resolution method to selectively protect the unwanted configuration with an acyl group to reduce the polarity of the intermediate product, and then uses an acid anhydride to react with the hydroxyl group of the desired configuration under the action of an organic base and a catalyst, thereby increasing the water solubility of the intermediate product. The unwanted configuration (the product protected with an acyl group) is then removed by extraction with a low-polarity solvent. This allows the separation of the two configurations to be achieved without the need for column chromatography purification, with an ee value of over 99%. [Example]

[0055] In the following, the technical solutions of the present invention will be further described with reference to specific examples, in order to facilitate understanding of the content of the present invention for those skilled in the art, but the following content does not limit the scope of protection and spirit of the claims of the present invention. Unless otherwise specified, the raw materials, reagents or solvents used in the present invention are all purchased from commercial sources, and the experimental methods with specific conditions not specifically specified are carried out under ordinary operating conditions in this field.

[0056] In the present invention, the yield refers to the molar percentage of the actual yield relative to the theoretical yield of a product. "w" is the mass ratio, for example, 0.2w of the bioenzyme means that the mass ratio of the bioenzyme to the raw material (compound 3A / compound 3B) is 0.2.

[0057] Example 1 [ka]

[0058] Compound 3A (20.0 g, 44.70 mmol) was dissolved in 120 mL of n-heptane, vinyl acetate (15.4 g, 223.48 mmol), and the enzyme Lipase AK "Amano" (4.0 g, 0.2 wt.) were added. Under nitrogen gas protection, the internal temperature was raised to 55-60 °C and maintained at 55-60 °C until the ee value of compound I detected by HPLC was ≥ 99%, and the reaction was complete. The reaction solution was directly filtered, the filter cake was collected, and the filtrate was concentrated to obtain the crude product, which was separated by silica gel column chromatography, distilled under reduced pressure, and concentrated to dryness to obtain 10.5 g of compound 4-1, with a yield of 48.0%, and 9.44 g of compound I, with a yield of 47.2% and an ee value of 99.8%.

[0059] Compound 4-1 1 H-NMR (400MHz, CDCl3): δ=7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m ,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 25 H 33 BrO3Si] + 490.3,found 490.3.

[0060] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] +448.2,found 448.2.

[0061] <Example 2> The nuclear magnetic resonance of the obtained product was as follows, in the same manner as in Example 1, except that the synthesis route below was followed and the parameters were adjusted according to Table 1. [ka]

[0062] Compound 4-2 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.6 7(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J=12.0Hz),1.05(s,9H).LC-MS(ESI):m / z calcd for[C 26 H 35 BrO3Si] + 504.5,found 504.5.

[0063] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0064] Example 3 The nuclear magnetic resonance of the obtained product was as follows, in the same manner as in Example 1, except that the synthesis route below was followed and the parameters were adjusted according to Table 1. [ka]

[0065] Compound 4-3 1 H-NMR (400MHz, CDCl3): δ=8.07(d,2H,J=9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m, 1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 30 H 35 BrO3Si] + 552.4,found 552.4.

[0066] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0067] Example 4 The nuclear magnetic resonance of the obtained product was as follows, in the same manner as in Example 1, except that the synthesis route below was followed and the parameters were adjusted according to Table 1. [ka]

[0068] Compound 4-4の 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H,10.1Hz,4.4 Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5.47(s,1H),5.21-5.15(m,1H ),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.56(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m / z calcd for[1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for C 26 H 33 BrO3Si] + 504.5,found 504.5.

[0069] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0070] <Example 5>

change

[0071] Compound I (2.0 g, 4.47 mmol) was dissolved in 20 mL of acetonitrile, and pyridine (1.06 g, 13.41 mmol), 4-dimethylaminopyridine (DMAP) (0.11 g, 0.894 mmol), and succinic anhydride (0.67 g, 6.705 mmol) were added. The mixture was reacted under nitrogen gas at room temperature until the starting material disappeared by thin-layer chromatography (TLC). The reaction mixture was concentrated to give a pale yellow oil, which was separated by silica gel column chromatography, distilled under reduced pressure, and concentrated to dryness to give 2.35 g of compound 5-1 as a pale yellow oil in 96.0% yield.

[0072] 1 H-NMR (400MHz, CDCl3): δ=10.98(s,1H),7.67-7.65(m,4H),7.43-7.37(m,6H),5.61(s,1H),5.48(s,1H),5.24-5.1 8(m,1H),3.70-3.63(m,2H),2.74-2.54(m,6H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m / z calcd for[C 27 H 35 BrO5Si] + 548.3,found 548.3.

[0073] Example 6 The following synthesis route was followed in the same manner as in Example 5, except that the parameters were adjusted according to Table 2. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0074] 1H-NMR (400MHz, CDCl3): δ=10.98(s,1H),7.67-7.65(m,4H),7.43-7.37(m,6H),6.30(dd,2H,J=21.4,15.1Hz),5.61(s,1H),5.49(s ,1H),5.24-5.18(m,1H),3.70-3.63(m,2H),2.59-2.56(m,2H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m / z calcd for[C 27 H 33 BrO5Si] + 546.4,found 546.4.

[0075] Example 7 The following synthesis route was followed in the same manner as in Example 5, except that the parameters were adjusted according to Table 2. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0076] 1 H-NMR (400MHz, CDCl3): δ=10.98(s,1H),8.33-8.29(m,2H),7.91-7.87(m,2H),7.67-7.65(m,4H),7.43-7.37(m,6H),5.61(s,1H),5.4 9(s,1H),5.24-5.18(m,1H),3.70-3.63(m,2H),2.59-2.56(m,2H),1.79-1.72(m,1H),1.69-1.52(m,3H),1.05(s,9H),LC-MS(ESI):m / z calcd for[C 31 H 35 BrO5Si] + 596.2,found 596.2.

[0077] Example 8 [ka]

[0078] Compound 3B-1 (10.0 g, 20.43 mmol) was dissolved in 50 mL of toluene, and sodium carbonate (2.17 g, 20.43 mmol), lipase TL (1.0 g, 0.1 wt.), and water (1.5 g, 0.1 wt.) were added. The mixture was stirred under nitrogen gas at 35-40 °C until the ee of compound I (as determined by HPLC) reached 99% or higher. The reaction mixture was then directly filtered, and the filter cake was collected. The filtrate was washed with saturated brine. The organic phase was concentrated to give the crude product, which was separated by silica gel column chromatography to give 4.81 g of compound 4-1 (48.1% yield) and 4.37 g of compound I (47.8% yield, 99.8% ee.).

[0079] Compound 4-1 1 H-NMR (400MHz, CDCl3): δ=7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m ,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 25 H 33 BrO3Si] + 490.3,found 490.3.

[0080] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0081] Example 9 The following synthesis route was followed in the same manner as in Example 8, except that the parameters were adjusted according to Table 3. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0082] Compound 4-2 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2. 74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J=12.0Hz).LC-MS(ESI):m / z calcd for[C 26 H 35 BrO3Si] + 504.5,found 504.5

[0083] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0084] Example 10 The following synthesis route was followed in the same manner as in Example 8, except that the parameters were adjusted according to Table 3. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0085] Compound 4-3 1 H-NMR (400MHz, CDCl3): δ=8.07(d,2H,J=9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m, 1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 30 H 35 BrO3Si] + 552.4,found 552.4;

[0086] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0087] Example 11 The following synthesis route was followed in the same manner as in Example 8, except that the parameters were adjusted according to Table 3. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0088] Compound 4-4 11H-NMR (400 MHz, CDCl3): δ = 7.67 - 7.64 (m, 4H), 7.45 - 7.37 (m, 6H), 6.27 (dd, 1H, 10.1 Hz, 4.4 Hz), 6.05 (dd, 1H, 9.8 Hz, 7.6 Hz), 5.61 - 5.59 (m, 2H), (s, 1H), 5.47 (s, 1H), 5.21 - 5.15 (m, 1H), 3.71 - 3.62 (m, 2H), 2.74 - 2.67 (m, 1H) 2.61 - 2.56 (m, 1H), 1.80 - 1.72 (m, 1H), 1.68 - 1.54 (m, 3H), 1.07 (s, 9H). LC-MS (ESI): m / z calcd for [C 26 H 33 BrO3Si] + 502.5, found 502.5.

[0089] For Compound I 1 1H-NMR (400 MHz, CDCl3): δ = 7.70 - 7.67 (m, 4H), 7.46 - 7.38 (m, 6H), 5.70 (s, 1H), 5.54 (s, 1H), 4.01 - 3.99 (m, 1H), 3.74 - 3.71 (m, 2H), 2.62 - 2.52 (m, 2H), 2.37 (s, 1H) 1.76 - 1.65 (m, 3H), 1.63 - 1.53 (m, 1H), 1.07 (s, 9H). LC-MS (ESI): m / z calcd for [C 23 H 31 BrO2Si] + 448.2, found 448.2.

[0090] <Example 12>

Chemical Structure

[0091] Compound 3A (20.0 g, 44.70 mmol) was dissolved in 100 mL of n-hexane, and vinyl acetate (19.24 g, 223.48 mmol) and the bioenzyme Lipase AK "Amano" (4.0 g, 0.2 w) were added. Under nitrogen gas protection, the internal temperature was raised to 55-60°C and maintained at 55-60°C until the ee value of compound I measured by HPLC reached 99% or higher, at which point the reaction was complete. The reaction mixture was directly filtered, and the filter cake was collected. The filtrate was concentrated to obtain the crude product. The crude product was dissolved in 40 mL of acetonitrile, and triethylamine (TEA) (7.92 g, 78.23 mmol), DMAP (0.55 g, 4.47 mmol), and succinic anhydride (3.35 g, 33.53 mmol) were added. The mixture was reacted at room temperature until the starting material spots disappeared by TLC observation. After the reaction was completed, n-heptane and water were added to the reaction mixture, and the n-heptane phase was collected. The acetonitrile / water phase was extracted again with n-heptane. The n-heptane phases were combined, and the n-heptane phase was concentrated under reduced pressure at 35-40 °C and dried to obtain 10.4 g of compound 4-1 in a yield of 47.6%.

[0092] Solid sodium hydroxide (3.58 g, 89.40 mmol) was added to the acetonitrile / aqueous phase and reacted at room temperature until the raw material spot disappeared by TLC observation. The mixture was separated, and the acetonitrile phase was collected. The acetonitrile phase was concentrated under reduced pressure at 35-40°C and dried to obtain 9.26 g of compound I, with a yield of 46.3% and an ee value of 99.7%.

[0093] Compound 4-1 1 H-NMR (400MHz, CDCl3): δ=7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m ,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 25 H 33 BrO3Si] +490.3, found 490.3.

[0094] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0095] Example 13 The following synthesis route was followed in the same manner as in Example 12, except that the parameters were adjusted according to Table 4. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0096] Compound 4-2 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.6 7(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J=12.0Hz),1.05(s,9H).LC-MS(ESI):m / z calcd for[C 26 H 35 BrO3Si] + 504.5,found 504.5.

[0097] Compound I 1H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0098] Example 14 The following synthesis route was followed in the same manner as in Example 12, except that the parameters were adjusted according to Table 4. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0099] Compound 4-3 1 H-NMR (400MHz, CDCl3): δ=8.07(d,2H,J=9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m, 1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 30 H 35 BrO3Si] + 552.4,found 552.4.

[0100] Compound I 1H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0101] Example 15 The following synthesis route was followed in the same manner as in Example 12, except that the parameters were adjusted according to Table 4. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0102] Compound 4-4 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H ,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5. 47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.5 6(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 26 H 33 BrO3Si] + 504.5,found 504.5.

[0103] Compound I 1H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0104] Example 16 [ka]

[0105] Compound 3A (20.0 g, 44.69 mmol) was dissolved in 100 mL of dichloromethane (DCM) and triethylamine (13.57 g, 134.07 mmol), DMAP (2.73 g, 22.34 mmol), and acetic anhydride (6.84 g, 67.035 mmol) were added. The reaction was continued under nitrogen gas protection at room temperature until the starting material disappeared by TLC. 50 mL of saturated brine was added to the reaction mixture, and the mixture was stirred and separated. The organic phase was concentrated to give the crude product as a pale yellow oil. The crude product was then slurried with 100 mL of n-heptane, filtered, and the filtrate was concentrated to give 21.34 g of compound 3B-1 as a pale yellow oil in 97.53% yield.

[0106] Compound 3B-1 1 H-NMR (400MHz, CDCl3): δ=7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m ,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 25H 33 BrO3Si] + 490.3,found 490.3.

[0107] Example 17 [ka]

[0108] Compound 3B-1 (10.0 g, 20.43 mmol) was dissolved in 50 mL of toluene, and sodium carbonate (2.17 g, 20.43 mmol), Pseudomonas cepacia lipase PS-30 (1.0 g, 0.1 w), and water (1.0 g, 0.1 w) were added. The mixture was stirred under nitrogen gas protection at 35-40 °C until the ee value of compound 5 (as determined by HPLC) reached 99% or higher, indicating completion of the reaction. The reaction mixture was directly filtered, the filter cake was collected, and the filtrate was washed once with 10 mL of saturated brine. The organic phase was concentrated to give the crude product. The crude product was dissolved in 20 mL of acetonitrile, and TEA (3.62 g, 35.75 mmol), DMAP (0.25 g, 2.043 mmol), and maleic anhydride (1.50 g, 15.32 mmol) were added. The reaction mixture was reacted at room temperature until the starting material spots disappeared by TLC observation. After the reaction was complete, 20 mL of n-heptane and 25 mL of water were added to the reaction mixture. The n-heptane phase was collected, and the acetonitrile / aqueous phase was extracted again with n-heptane. The n-heptane phases were combined, concentrated under reduced pressure at 35-40 °C, and dried to give 4.79 g of compound 4-1. The yield was 47.9%.

[0109] To the acetonitrile / aqueous phase, 1.63 g (40.86 mmol) of solid sodium hydroxide was added and the mixture was allowed to react at room temperature until the raw material spot disappeared by TLC observation. The mixture was then separated and the acetonitrile phase was collected. The acetonitrile phase was concentrated under reduced pressure at 35-40°C and dried to give 4.39 g of compound I, with a yield of 48.1% and an ee value of 99.8%.

[0110] Compound 4-1 1H-NMR (400MHz, CDCl3): δ=7.68-7.65(m,4H),7.45-7.37(m,6H),5.62(s,1H),5.48(s,1H),5.22-5.16(m,1H),3.72-3.63(m ,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),2.03(s,3H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 25 H 33 BrO3Si] + 490.3,found 490.3.

[0111] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0112] Example 18 The following synthesis route was followed in the same manner as in Example 16, except that the parameters were adjusted according to Table 5. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0113] Compound 3B-2 1H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2. 74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J=12.0Hz).LC-MS(ESI):m / z calcd for[C 26 H 35 BrO3Si] + 504.5,found 504.5.

[0114] Example 19 The following synthesis route was followed in the same manner as in Example 17, except that the parameters were adjusted according to Table 6. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0115] Compound 4-2 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),5.61(s,1H),5.47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2. 74-2.67(m,1H)2.61-2.56(m,1H),2.38-2.29(m,2H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.13(t,3H,J=12.0Hz).LC-MS(ESI):m / z calcd for[C 26 H 35 BrO3Si] + 504.5,found 504.5.

[0116] Compound I 1H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0117] Example 20 The following synthesis route was followed in the same manner as in Example 16, except that the parameters were adjusted according to Table 5. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0118] Compound 3B-3 1 H-NMR (400MHz, CDCl3): δ=8.07(d,2H,J=9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m, 1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 30 H 35 BrO3Si] + 552.4,found 552.4.

[0119] <Example 21> The following synthesis route was followed in the same manner as in Example 17, except that the parameters were adjusted according to Table 6. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0120] Compound 4-3 1 H-NMR (400MHz, CDCl3): δ=8.07(d,2H,J=9.2Hz),7.70-7.67(m,4H),7.55-7.31(m,9H),5.63(s,1H),5.49(s,1H),5.23-5.17(m, 1H),3.72-3.63(m,2H),2.75-2.68(m,1H),2.62-2.57(m,1H),1.81-1.72(m,1H),1.69-1.55(m,3H)1.06(s,9H).LC-MS(ESI):m / z calcd for[C 30 H 35 BrO3Si] + 552.4,found 552.4.

[0121] Compound I 1 H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2

[0122] <Example 22> The following synthesis route was followed in the same manner as in Example 16, except that the parameters were adjusted according to Table 5. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0123] Compound 3B-4 1H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H ,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5. 47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.5 6(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 26 H 33 BrO3Si] + 502.5,found 502.5.

[0124] Example 23 The following synthesis route was followed in the same manner as in Example 17, except that the parameters were adjusted according to Table 6. The nuclear magnetic resonance spectrum of the obtained product was as follows. [ka]

[0125] Compound 4-4 1 H-NMR (400MHz, CDCl3): δ=7.67-7.64(m,4H),7.45-7.37(m,6H),6.27(dd,1H ,10.1Hz,4.4Hz),6.05(dd,1H,9.8Hz,7.6Hz),5.61-5.59(m,2H),(s,1H),5. 47(s,1H),5.21-5.15(m,1H),3.71-3.62(m,2H),2.74-2.67(m,1H)2.61-2.5 6(m,1H),1.80-1.72(m,1H),1.68-1.54(m,3H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 26 H 33 BrO3Si] + 502.5,found 502.5.

[0126] Compound I 1H-NMR (400MHz, CDCl3): δ=7.70-7.67(m,4H),7.46-7.38(m,6H),5.70(s,1H),5.54(s,1H),4.01-3.99(m,1H),3.7 4-3.71(m,2H),2.62-2.52(m,2H),2.37(s,1H)1.76-1.65(m,3H),1.63-1.53(m,1H),1.07(s,9H).LC-MS(ESI):m / z calcd for[C 23 H 31 BrO2Si] + 448.2,found 448.2.

[0127] Tables 1 to 6 show relevant parameters in Examples 1 to 23 above.

[0128] [Table 1]

[0129] [Table 2]

[0130] [Table 3]

[0131] [Table 4]

[0132] [Table 5]

[0133] [Table 6]

Claims

1. 1. A method for preparing a chiral compound I by an enzymatic method, comprising the steps of: The method includes method 1 or method 2, In the method 1, a compound represented by formula 3A is used as a raw material, and is subjected to an acylation reaction with an acylating reagent under the action of a biological enzyme A to obtain compound 4 and compound I, and the mixture of compound 4 and compound I is selectively separated; 【Chemical 1】 In the method 2, the compound represented by formula 3B is used as a raw material, and is hydrolyzed under the action of a biological enzyme B and a base to obtain the compound 4 and the compound I, and the mixture of the compound 4 and the compound I is selectively separated; 【Chemistry 2】 Here, R １ is a substituted or unsubstituted C １ -C １２ A linear or branched acyl group, a benzoyl group, or a C substituted or unsubstituted with Ra ３ -C ６ A straight-chain or branched-chain alkenoyl group, and the substituents Ra of each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups, and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; R １ is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group, and more preferably an acetyl group, a propionyl group, a butyryl group, a benzoyl group, or an acryloyl group; The biological enzyme A is a lipase or an esterase, The bioenzyme A is any one selected from lipase AK, Pseudomonas fluorescens-derived lipase, recombinant Candida Antarctica lipase B derived from Aspergillus oryzae immobilized on Immobead 150, Candida Antarctica lipase B immobilized on acrylic resin, lipase AS, lipase PS, thermophilic fungus-derived lipase, Candida rugosa-derived lipase, lipase AYS, triacylglycerol lipase, Mucor miehei-derived lipase, and Rhizopus oryzae-derived lipase; The bioenzyme A is preferably lipase AK, lipase derived from Pseudomonas fluorescens, or Novozym 435, which is Candida antarctica lipase B immobilized on an acrylic resin; the biological enzyme B is a lipase, an esterase, or a hydrolase; The biological enzyme B includes lipase TL, lipase PS-30 derived from Pseudomonas cepacia, lipase QLM, lipase derived from Thermomyces lanuginosus, lipase P2 derived from Pseudomonas cepacia, lipase PS derived from Pseudomonas stutzeri, lipase RS derived from the genus Rhizopus, lipase PS derived from Pseudomonas cepacia, lipase AN derived from Aspergillus niger, lipase A derived from the genus Achromobacter, lipase AS1 derived from the genus Alcaligenes, lipase AS2 derived from the genus Alcaligenes, lipase C2 derived from Candida cylindracea, lipase C1 derived from Candida cylindracea, lipase TL IM, lipase TL 100L, Candida antarctica lipase B, and CHIRAZYME. E-1 porcine liver esterase, lipase from Pseudomonas sp. L-6, Candida antarctica lipase A, Candida rugosa lipase L-3, and pancreatic lipase; The method, wherein the bioenzyme B is preferably lipase TL or lipase PS-30 derived from Pseudomonas cepacia.

2. The acylating reagent of the method 1 is selected from vinyl esters and isopropenyl esters; The vinyl ester may be a C １ -C １２ vinyl esters of linear or branched chain acids, vinyl benzoate, and Rc-substituted or unsubstituted C ３ -C ６ selected from linear or branched vinyl esters of olefinic acids, The isopropenyl ester may be a C １ -C １２ isopropenyl esters of linear or branched chain acids, isopropenyl benzoate, and Rc-substituted or unsubstituted C ３ -C ６ is selected from isopropenyl esters of linear or branched chain olefinic acids; The substituents Rc in each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; The acylating reagent is preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl isobutyrate, isopropenyl isobutyrate, vinyl 2-methylbutyrate, isopropenyl 2-methylbutyrate, vinyl 3-methylbutyrate, isopropenyl 3-methylbutyrate, vinyl pivalate, isopropenyl pivalate, vinyl 2-methylvalerate, isopropenyl 2-methylvalerate, vinyl 3-methylvalerate, isopropenyl 3-methylvalerate, vinyl 4-methylvalerate, 4-methylvalerate, vinyl 4-methylvalerate, vinyl 4-methylvalerate, vinyl 4-methylbutyrate ...

2. The method of claim 1, wherein the vinyl ester is isopropenyl methylvalerate, vinyl caproate, isopropenyl caproate, vinyl laurate, isopropenyl laurate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate, or isopropenyl acrylate, and more preferably vinyl acetate, isopropenyl acetate, vinyl propionate, isopropenyl propionate, vinyl butyrate, isopropenyl butyrate, vinyl benzoate, isopropenyl benzoate, vinyl acrylate, or isopropenyl acrylate.

3. The acylation reaction of the method 1 is carried out in an organic solvent A, and the organic solvent A is one selected from alkane-based, aromatic hydrocarbon-based, chloroalkane-based, nitrile-based, and ether-based solvents, or any combination thereof. The organic solvent A is preferably one selected from petroleum ether, ethyl ether, methyl tert-butyl ether, dichloromethane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene, and acetonitrile, or any combination thereof, more preferably one selected from n-hexane and n-heptane, or a combination thereof; and / or In the method 1, the ratio of the mass of the compound 3A to the volume of the organic solvent A is 1 g:1-15 mL, more preferably 1 g:5-8 mL; and / or The acylation reaction temperature in the method 1 is 30 to 80°C, preferably 55 to 60°C, and / or In the method 1, the mass ratio of the compound 3A to the bioenzyme A is 1:0.005-0.3, preferably 1:0.01-0.3, more preferably 1:0.05-0.2, and / or The method according to claim 1, wherein the molar ratio of compound 3A to the acylating reagent in Method 1 is 1:1-20, preferably 1:2-10, more preferably 1:3-6.

4. The hydrolysis reaction of the method 2 is carried out in water and an organic solvent B, and the organic solvent B is one selected from an alkane-based solvent, an aromatic hydrocarbon-based solvent, a chloroalkane-based solvent, a nitrile-based solvent, and an ether-based solvent, or any combination thereof. The organic solvent B is preferably one selected from toluene, xylene, methyl tert-butyl ether, and acetonitrile, or any combination thereof; and / or the base is selected from an organic base and an inorganic base, the organic base is one selected from diethylamine, triethylamine, diisopropylamine, morpholine, N-methylmorpholine, piperazine, and N-methylpiperazine, or any combination thereof; the inorganic base is one selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides, or any combination thereof; the base is preferably one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and potassium carbonate, or any combination thereof, most preferably one selected from sodium carbonate and potassium carbonate, and / or any combination thereof; In the method 2, the mass ratio of the compound 3B to the bioenzyme B is 1:0.005-0.3, preferably 1:0.01-0.3, more preferably 1:0.05-0.2, and / or In Method 2, the molar ratio of compound 3B to the base is 1:1-10, preferably 1:1-8, more preferably 1:1-4, and / or In Method 2, the ratio of the mass of compound 3B to the volume of organic solvent B is 1 g:1-15 mL, more preferably 1 g:3-8 mL; and / or The method according to claim 1, wherein the hydrolysis reaction temperature in Method 2 is 30 to 80°C, preferably 35 to 40°C.

5. The method for selectively separating a mixture of the compound 4 and the compound I includes the following 1) or 2): 1) separating the mixture of Compound 4 and Compound I by column chromatography to obtain Compound I; 2) Step a: under the action of a catalyst and an organic base, the compound I in the mixture of the compound 4 and the compound I is selectively esterified with an acid anhydride, and then separated to obtain compounds 4 and 5; Step b: the compound 5 is hydrolyzed to obtain compound I, and the reaction scheme is as follows: 【Chemistry 3】 Here, R １ is a substituted or unsubstituted C １ -C １２ A linear or branched acyl group, a benzoyl group, or a C substituted or unsubstituted with Ra ３ -C ６ A straight-chain or branched-chain alkenoyl group, and the substituents Ra of each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups, and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; R １ is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group; R ２ teeth, 【Chemistry 4】 That is, 2. The method of claim 1.

6. A method for preparing chiral compounds I, comprising the steps of: The method includes separating a mixture of compound 4 and compound I; The separating step includes the following 3) or 4): 3) Separating the mixture of Compound 4 and Compound I by column chromatography to obtain Compound I; 4) Step a: under the action of a catalyst and an organic base, compound I in a mixture of compound 4 and compound I is selectively esterified with an acid anhydride, and then separated to obtain compound 4 and compound 5; Step b: compound 5 is hydrolyzed to obtain compound I, and the reaction scheme is as follows: 【Chemistry 5】 Here, R １ is a substituted or unsubstituted C １ -C １２ A linear or branched acyl group, a benzoyl group, or a C substituted or unsubstituted with Ra ３ -C ６ A straight-chain or branched-chain alkenoyl group, and the substituents Ra of each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; R １ is preferably an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group, a benzoyl group, or an acryloyl group; R ２ teeth, 【Chemistry 6】 That's the method.

7. The method according to claim 5 or 6, characterized in that the separation by column chromatography is carried out by silica gel column chromatography using a solution of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1, i.e., petroleum ether:ethyl acetate, as an eluent.

8. the catalyst in step a is 4-dimethylaminopyridine, and / or The molar ratio of compound I to the catalyst in step a is 1:0.1-0.5, preferably 1:0.2-0.3, and / or The organic base in step a is one selected from diethylamine, triethylamine, diisopropylamine, pyridine, α-methylpyridine, 1,2-dimethylpyridine, 4-hydroxy-2-methylpyridine, γ-trimethylpyridine, quinoline, and dimethylquinoline, or any combination thereof, preferably one selected from triethylamine, diisopropylamine, pyridine, and α-methylpyridine, or any combination thereof, and / or the molar ratio of compound I to the organic base in step a is 1:1-10, preferably 1:1-5, more preferably 1:3-5; the temperature of the esterification reaction is 0-50°C, preferably 10-30°C; and / or The acid anhydride in step a is 【Chemistry 7】 wherein the molar ratio of compound I to the acid anhydride is 1:1-10, preferably 1:1-5, more preferably 1:1.1-1.8; and / or The esterification reaction in step a is carried out in a reaction solvent C, and the reaction solvent C is one selected from aromatic hydrocarbons, chloroalkanes, nitrile solvents, and ether solvents, or any combination thereof, and the reaction solvent C is preferably one selected from toluene, xylene, methyl tert-butyl ether, and acetonitrile, or any combination thereof, and / or The hydrolysis in step b is carried out in water and an organic solvent D, which is selected from the reaction solvents C in step a, preferably the hydrolysis is carried out in water and acetonitrile, and the reaction temperature is preferably room temperature; and / or 7. The method according to claim 5 or 6, wherein the hydrolysis in step b is carried out in an inorganic base, and the inorganic base is one or any combination selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides, preferably one or any combination selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide, more preferably one or any combination selected from sodium hydroxide and potassium hydroxide.

9. An intermediate compound, wherein the structure of the intermediate compound is 【Chemistry 8】 and * represents a chiral carbon, and R represents a C substituted or unsubstituted by Ra. １ -C １２ A linear or branched acyl group, Ra substituted or unsubstituted C ３ -C ６ a straight-chain or branched-chain alkenoyl group, 【Chemistry 9】 and the substituents Ra of each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; Preferably, when the chiral carbon represented by * is in the S configuration, the structure of the intermediate compound is 【Chemistry 10】 and R １ is a substituted or unsubstituted C １ -C １２ A linear or branched acyl group or a C substituted or unsubstituted with Ra ３ -C ６ A straight-chain or branched-chain alkenoyl group, and the substituents Ra of each group are each independently C １ -C ６ A straight or branched chain alkyl group, C １ -C ６ A straight or branched chain alkoxy group, a hydroxy group, an amino group, a halogen, a nitro group, a cyano group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Thioalkyl group, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, phenyl groups and C ３ -C １８ heteroaromatic groups, wherein the heteroatoms in said heteroaromatic groups are selected from O, N and S; R １ is preferably a propionyl group, a butyryl group, an isobutyryl group, a 2-methylbutyryl group, a 3-methylbutyryl group, a pivaloyl group, a 2-methylvaleryl group, a 3-methylvaleryl group, a 4-methylvaleryl group, a hexanoyl group, a lauroyl group or an acryloyl group, The intermediate compound is preferably 【Chemistry 11】 and When the chiral carbon represented by * is in the R configuration, the structure of the intermediate compound is 【Chemistry 12】 and R ２ teeth, 【Chemistry 13】 and The intermediate compound is preferably 【Chemistry 14】 An intermediate compound.

10. A method for preparing an eribulin drug, comprising the method according to any one of claims 1-5, or the method according to any one of claims 6-8.

Images