Method for preparing eribulin intermediates

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 the Chinese patent application filed with the China National Intellectual Property Administration on July 29, 2022, application number 202210904052.6, with the title of the invention "Method for preparing an intermediate of eribulin," all of which are incorporated herein by reference.

[0002] This invention belongs to the field of drug chemistry and, more specifically, relates to a method for preparing eribulin intermediates. [Background technology]

[0003] Eribulin mesylate is a synthetic analog of halichondrin B, possessing the bioactive macrocyclic moiety of halichondrin B. Halichondrin B is a polyether macrolide that exhibits potent anticancer effects in both cell and animal models. Eribulin mesylate can inhibit tubulin mitosis in cells, thereby causing irreversible cell cycle G2 / M phase arrest and mitotic spindle disruption, leading to apoptosis after prolonged mitotic arrest and suppression of cell proliferation. Eribulin mesylate injection was developed by Eisai Inc. and approved for sale in the United States by the FDA in November 2010 under the brand name Halaven. The approved indication is for patients with metastatic breast cancer who have previously received at least two metastatic cancer treatment regimens. Subset-based analysis results indicate that eribulin mesylate can be used aggressively and effectively in the treatment of triple-negative metastatic breast cancer, a malignant breast cancer that often has a poor prognosis. In many countries, eribulin mesylate has been considered a third-line, and even later, drug therapy for treating metastatic breast cancer. However, during treatment, this drug is the only chemotherapeutic agent that can effectively improve patient survival rates. Eribulin mesylate is currently the only drug in this field with a favorable clinical and market outlook.

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

[0005] The conventional method for synthesizing the compound represented by formula I is as follows: The process scheme for synthesizing the initial intermediate I of the eribulin active pharmaceutical ingredient, as used by Eisai Co., Ltd., the original manufacturer of the eribulin active pharmaceutical ingredient, is as follows: [ka] Here, TBDPS is t-butyldiphenylsilyl.

[0006] Compound I has a tosyl-protected hydroxyl carbon that possesses chirality, and in the synthesis process, a racemic mixture is first obtained. Literature (Synlett (2013), 24(3), 327-332, WO2005118565, etc.) reports that a single stereochemistry can be obtained by separating the compound represented by formula 3 using a chiral pseudo-mobile bed (SMB), but this method has low preparation efficiency, high cost, and is unfavorable for scaling up production. Furthermore, literature (Org. Lett., Vol.10, No.14, 2008) reports obtaining a product with a single stereochemistry under the catalytic action of a chiral ligand and metallic chromium, but this method is also costly. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Brochure for International Patent Application Publication No. 2005 / 118565 [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 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] The technical problem that this invention aims to solve is to provide a method for preparing a compound represented by formula I that is completely different from the prior art. This preparation method has mild reaction conditions, is environmentally friendly, has a novel pathway, is easy to work with and purify, the compound represented by formula I obtained has high purity, is simple to operate, has a high conversion rate, good selectivity, is low cost, and is advantageous for large-scale industrial production. The compound represented by formula I can be used in applications in the preparation of eribulin drugs. [Means for solving the problem]

[0010] The present invention relates to a method for preparing chiral compound I by an enzymatic method, The above method includes method 1 or method 2, In the above method 1, a compound represented by formula 3A is used as a raw material and is subjected to an acylation reaction with an acylation reagent under the action of biological enzyme A to obtain compound 4 and compound I, and a mixture of compound 4 and compound I is selectively separated. [ka] In the above method 2, a compound represented by formula 3B is used as a raw material and subjected to a hydrolysis reaction under the action of biological enzyme B and a base to obtain compound 4 and compound I, and a mixture of compound 4 and compound I is selectively separated, [ka] Here, R1 is a C1-C that is either substituted with Ra or unsubstituted. 12The substituents are linear or branched acyl groups, benzoyl groups, or Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, and each group's substituent Ra can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group, and C3-C 18 A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S. R1 is preferably an acetyl group, propionyl group, butyryl group, isobutyryl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, 2-methylvaleryl group, 3-methylvaleryl group, 4-methylvaleryl group, hexanoyl group, lauroyl group, benzoyl group, or acryloyl group, and more preferably an acetyl group, propionyl group, butyryl group, benzoyl group, or acryloyl group. The aforementioned biological enzyme A is a lipase or esterase. The aforementioned biological enzyme A is one selected from lipase AK, lipase derived from Pseudomonas fluorescein, Candida antarcticalipase B, a recombinant derived from Aspergillus oryzae immobilized on Imobead 150, Candida antarcticalipase B immobilized on acrylic resin, lipase AS, lipase PS, lipase derived from thermophilic fungus, lipase derived from Candida rugoza, lipase AYS, triacylglycerol lipase, lipase derived from Mucormiehei, and lipase derived from Rhizopus oryzae. The aforementioned biological enzyme A is preferably lipase AK, lipase derived from Pseudomonas fluorescein, or Novozym 435, which is Candida antarcticalipase B immobilized on acrylic resin. The aforementioned biological enzyme B is a lipase, esterase, or hydrolase. The aforementioned biological enzyme B includes lipase TL, lipase PS-30 derived from Pseudomonas cepacia, lipase QLM, lipase derived from Thermomyces lanuginosa, lipase P2 derived from Pseudomonas cepacia, lipase PS derived from Pseudomonas statzeri, lipase RS derived from Rhizopus, lipase PS derived from Pseudomonas cepacia, lipase AN derived from Aspergillus niger, lipase A derived from Achromobacter, lipase AS1 derived from Alcaligenes, lipase AS2 derived from Alcaligenes, lipase C2 derived from Candida syrindrasse, lipase C1 derived from Candida syrindrasse, lipase TL IM, lipase TL 100L, Candida antarcticalipase B, and CHIRAZYME. E-1 is selected from porcine liver esterase, lipase derived from Pseudomonas L-6, Candida antarcticalipase A, Candida rugosalilipase L-3, and pancreatic lipase. The method is characterized in that the biological enzyme B is preferably lipase TL or lipase PS-30 derived from Pseudomonas cepacia.

[0011] The present invention relates to a method for preparing chiral compound I, The method described above includes the step of separating a mixture of compound 4 and compound I, The separation step includes step 3) or 4) below, 3) Separate 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 separated to obtain compound 4 and compound 5. Step b: Compound 5 is hydrolyzed to obtain compound I, and the reaction formula is as follows: [ka] Here, R1 is a C1-C that is either substituted with Ra or unsubstituted. 12The substituents are linear or branched acyl groups, benzoyl groups, or Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, and each group's substituent Ra can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group and C3-C 18 A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S. R1 is preferably an acetyl group, propionyl group, butyryl group, isobutyryl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, 2-methylvaleryl group, 3-methylvaleryl group, 4-methylvaleryl group, hexanoyl group, lauroyl group, benzoyl group, or acryloyl group. R2 is [ka] That is the method.

[0012] The present invention relates to an intermediate compound, wherein the structure of the intermediate compound is [ka] And, * represents a chiral carbon, and R represents a C1-C substituted or unsubstituted with Ra. 12 Linear or branched acyl groups, Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, [ka] The substituent Ra of each group can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group and C3-C 18A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S. Preferably, when the chiral carbon represented by * is in an S configuration, the structure of the intermediate compound is [ka] And, R1 is either substituted with Ra or unsubstituted with C1-C 12 The substituents are linear or branched acyl groups, or Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, and each group's substituent Ra can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group and C3-C 18 A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is 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] which is an intermediate compound. Mode for Carrying Out the Invention

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

[0014] As a further improvement of the present invention, biological enzyme A is a lipase or esterase, and biological enzyme A includes lipase AK (Lipase AK "Amano"), lipase from pseudomonas fluorescens (Amano Lipase from pseudomonas fluorescens), Candida antarctica immobilized on Immobead 150, recombinant from Aspergillus oryzae (Lipase B Candida antarctica immobilized on Immobead 150, recombinant from Aspergillus oryzae), Candida antarctica lipase B immobilized on acrylic resin (CAL-B lipase immobilized on acrylic resin (Novozym 435)), lipase AS (Lipase AS "Amano"), lipase PS (Lipase PS "Amano" SD), and lipase from thermophilic fungi (Lipase from Thermomyces). The biological enzyme A is selected from one of the following: Candida lanuginosus, lipase from Candida rugosa, lipase AYS ("Amano"), triacylglycerol lipase, lipase from Mucor miehei, and lipase from Rhizopus oryzae. The biological enzyme A is preferably lipase AK ("Amano"), lipase from pseudomonas fluorescens, or Novozym 435 (CAL-B lipase (Novozym 435) immobilized on acrylic resin), which is Candida antarcticalipase B.

[0015] As a further improvement of the present invention, the biological enzyme B in Method 2 is a lipase, esterase, or hydrolase, for example, 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 Rhizopus sp., lipase PS derived from Pseudomonas cepacia, lipase AN derived from Aspergillus niger, lipase A derived from Achromobacter sp., and Alcaligenes This includes lipase AS1 derived from Candida sp., lipase AS2 derived from Alcaligenes, lipase C2 derived from Candida cylindracea, lipase C1 derived from Candida cylindracea, lipase lipozym TL IM, lipase lipozym TL 100L, Candida antarctica lipase B (CALB), CHIRAZYME E-1 porcine liver esterase, lipase derived from Pseudomonas L-6, Candida antarctica lipase A (CALA), Candida rugosa lipase (L-3), or pancreatic lipase USP Grade.

[0016] As a further improvement of the present invention, the acylation reagent of Method 1 is selected from vinyl esters and isopropenyl esters, wherein the vinyl ester is Rc-substituted or unsubstituted C1-C 12 Selected from vinyl esters of linear or branched acids, vinyl benzoate, and vinyl esters of Rc-substituted or unsubstituted C3-C6 linear or branched olefinic acids, wherein the isopropenyl ester is Rc-substituted or unsubstituted C1-C 12The substituent Rc of each group is independently selected from isopropenyl esters of linear or branched acids, isopropenyl benzoate, and isopropenyl esters of C3-C6 linear or branched olefinic acids, with or without substitution by Rc. ,centre henyl group, and C3-C 18 A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S.

[0017] As a further improvement of the present invention, the acylation 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 The compounds are vinyl, 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] The biological enzyme A of Method 1 provided by the present invention can selectively acylate the alcohol of Formula 3A with biological enzyme A to produce the monoisomerized 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 enantiomer excess of Formula I in the product 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] As a further improvement of the present invention, the acylation reaction of Method 1 is carried out in organic solvent A. Organic solvent A is one or any combination thereof selected from alkane, aromatic hydrocarbon, chloroalkane, nitrile, and ether solvents. For example, the alkane solvent is one or any combination thereof selected from n-hexane, cyclohexane, n-pentane, cyclopentane, and n-heptane. The aromatic hydrocarbon solvent is one or any combination thereof selected from toluene, xylene, and chlorobenzene. The chloroalkane solvent is selected from dichloromethane and chloroform. The nitrile solvent is one or any combination thereof selected from acetonitrile, propionitrile, and benzonitrile. The ether solvent is one or any combination thereof selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether (MTBE). Organic solvent A is preferably one or any combination thereof selected from petroleum ether, ethyl ether, methyl tert-butyl ether, dichloromethane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene, and acetonitrile, and more preferably one or a combination thereof selected from n-hexane and n-heptane.

[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 1g:1 to 15mL, and more preferably 1g:5 to 8mL.

[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 exhibits 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 biological enzyme A in Method 1 is 1:0.005 to 0.3, preferably 1:0.01 to 0.3, and more preferably 1:0.05 to 0.2.

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

[0024] As a further improvement of the present invention, the product obtained by the enantioselective acylation of the present invention comprises a mixture of the formula I compound with R configuration and the formula 4 compound with S configuration. Similarly, a mixture comprising the formula I compound with R configuration and the formula 4 compound with S configuration can be obtained by enantioselective enzymatic hydrolysis. The optical purity of the formula I compound 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] As a further improvement of the present invention, the hydrolysis reaction of Method 2 is carried out in water and organic solvent B. Organic solvent B includes one or any combination thereof selected from alkane, aromatic hydrocarbon, chloroalkane, nitrile, and ether solvents. For example, the alkanes are one or any combination thereof selected from n-hexane, cyclohexane, n-pentane, cyclopentane, and n-heptane. The aromatic hydrocarbons are one or any combination thereof selected from toluene, xylene, and chlorobenzene. The chloroalkanes are one or any combination thereof selected from dichloromethane and chloroform. The nitriles are one or any combination thereof selected from acetonitrile, propionitrile, and benzonitrile. The ethers are one or any combination thereof selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether (MTBE). Organic solvent B is preferably one or any combination thereof selected from toluene, xylene, methyl tert-butyl ether, and acetonitrile.

[0026] As a further improvement of the present invention, the base is selected from organic bases and inorganic bases. 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, and more preferably, the base is an alkali metal carbonate. Preferably, the base is one selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and potassium carbonate, or any combination thereof, and most preferably, one selected from sodium carbonate and potassium carbonate, or a combination thereof. The base of the present invention, when used in combination with biological enzyme B, selectively hydrolyzes the R configuration in racemic compound 3B to obtain compound I, resulting in a high reaction yield and good isomer purity.

[0027] As a further improvement of the present invention, the mass ratio of compound 3B to biological enzyme B in Method 2 is 1:0.005 to 0.3, preferably 1:0.01 to 0.3, and more preferably 1:0.05 to 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 to 10, preferably 1:1 to 8, and more preferably 1:1 to 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 1g:1 to 15mL, and more preferably 1g:3 to 8mL.

[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 exhibits high activity, a fast reaction rate, and high efficiency.

[0031] As a further improvement of the present invention, a method for selectively separating a mixture of compound 4 and compound I includes the following 1) or 2). 1) Separate 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, compound I in a mixture of compound 4 and compound I is selectively esterified with an acid anhydride and separated to obtain compound 4 and compound 5. Step b: Compound 5 is hydrolyzed to obtain compound I. The reaction equation is as follows. [ka] Here, R1 is a C1-C that is either substituted with Ra or unsubstituted. 12 The substituents are linear or branched acyl groups, benzoyl groups, or Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, and each group's substituent Ra can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group and C3-C 18 Selected from heterocyclic aromatic groups, the heteroatoms in the heterocyclic aromatic group are selected from O, N, and S, and R1 is preferably an acetyl group, propionyl group, butyryl group, isobutyryl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, 2-methylvaleryl group, 3-methylvaleryl group, 4-methylvaleryl group, hexanoyl group, lauroyl group, benzoyl group, or acryloyl group, and R2 is [ka] That is the case.

[0032] As a further improvement to the present invention, separation by column chromatography is performed using silica gel column chromatography with 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 the eluent.

[0033] As a further improvement 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 to 0.5, preferably 1:0.2 to 0.3.

[0035] As 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 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 to 10, preferably 1:1 to 5, and more preferably 1:3 to 5. The temperature of the esterification reaction is 0 to 50°C, preferably 10 to 30°C.

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

[0037] As a further improvement of the present invention, the esterification reaction in step a is carried out in reaction solvent C. Reaction solvent C includes one or any combination thereof selected from aromatic hydrocarbons, chloroalkanes, nitrile solvents, and ether solvents. For example, aromatic hydrocarbons include one or any combination thereof selected from toluene, xylene, and chlorobenzene. Chloroalkanes include one or any combination thereof selected from dichloromethane and chloroform. Nitrile solvents include one or any combination thereof selected from acetonitrile, propionitrile, and benzonitrile. Ether solvents include one or any combination thereof selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, ethyl ether, diisopropyl ether, and methyl tert-butyl ether. Reaction solvent C is preferably one or any combination thereof selected from toluene, xylene, methyl tert-butyl ether, and acetonitrile.

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

[0039] As a further improvement of the present invention, the hydrolysis in step b is carried out in water and organic solvent D. Any organic solvent that does not adversely affect the reaction is suitable for this hydrolysis reaction. Organic solvent D is selected from organic solvents that do not adversely affect the reaction. Organic solvent D is preferably selected from reaction solvent C in step a above. Preferably, the hydrolysis is carried out in water and acetonitrile. The reaction temperature is preferably room temperature.

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

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

[0042] In a second aspect, the present invention relates to a method for preparing a chiral compound I, the method comprising the step of separating a mixture of compound 4 and compound I, the separation step being 3) Separating the mixture of compound 4 and compound I by column chromatography to obtain compound I, or 4) The reaction comprises step a, in which, 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 separated to obtain compound 4 and compound 5; and step b, in which compound 5 is hydrolyzed to obtain compound I. The reaction formula is as follows: [ka] Here, R1 is a C1-C that is either substituted with Ra or unsubstituted. 12 The substituent Ra of each group is independently a C1-C6 linear or branched alkyl group, a benzoyl group, or a substituted or unsubstituted C3-C6 linear or branched alkenoyl group, and each substituent Ra is independently a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group, and C3-C 18 Selected from heterocyclic aromatic groups, the heteroatoms in the heterocyclic aromatic group are selected from O, N, and S, and R1 is preferably an acetyl group, propionyl group, butyryl group, isobutyryl group, 2-methylbutyryl group, 3-methylbutyryl group, pivaloyl group, 2-methylvaleryl group, 3-methylvaleryl group, 4-methylvaleryl group, hexanoyl group, lauroyl group, benzoyl group, or acryloyl group, and R2 is [ka] That is, To provide a method that includes doing so.

[0043] As 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 of the reaction conditions for each step of the first embodiment of the present invention described above. When added sequentially, whether a mixture of compound I and compound 4 is obtained by the acylation reaction of compound 3A with biological enzyme A, or by the hydrolysis reaction of compound 3B with biological enzyme B, the reaction with the acid anhydride in the next step a will not be affected, provided that the addition is accurate based on the theoretical yield of 50% in each case, or by referring to 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 (all of which are incorporated herein by reference).

[0045] As a further improvement of the present invention, the preparation of a mixture of compound 4 and compound I includes selectively acylating or hydrolyzing compound 3A or compound 3B under the action of biological enzyme A or biological enzyme B, respectively, to obtain a mixture of compound 4 and compound I. The reaction formula is as follows. [ka]

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

[0047] In a third embodiment, the present invention provides an important intermediate for preparing compound I. In some embodiments, the important intermediate compound C is represented as follows: [ka] * represents a chiral carbon, and R represents a C1-C substituted or unsubstituted with Ra. 12 Linear or branched acyl groups, Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, [ka] That is the case.

[0048] Here, the substituent Ra of each group can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group, and C3-C 18 A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S.

[0049] Preferably, when the chiral carbon represented by * is in an S configuration, the structure is [ka] And, Here, R1 is a C1-C that is either substituted with Ra or unsubstituted. 12 The substituents are linear or branched acyl groups, or Ra-substituted or unsubstituted C3-C6 linear or branched alkenoyl groups, and each group's substituent Ra can independently be a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched alkoxy group, a hydroxyl group, an amino group, a halogen, a nitro group, a cyano group, a C1-C6 amide group, a C3-C6 cycloalkyl group, or a C1-C6 thioalkyl group. ,centre henyl group, and C3-C 18 A heterocyclic aromatic group is selected from heterocyclic aromatic groups, the heteroatom in the heterocyclic aromatic group is selected from O, N, and S, and 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 to the present invention, the important intermediate compounds are: [ka] Selected from, but not limited to, these.

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

[0052] As a further improvement to the present invention, the important intermediate compounds are: [ka] Selected from, but not limited to, these.

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

[0054] Compared to prior art, the present invention provides a novel preparation method for compound represented by formula I, which has mild reaction conditions, is environmentally friendly, has a novel pathway, is easy to work with and purify, has high purity, is simple to operate, has a high conversion rate, good selectivity, is low cost, and is advantageous for large-scale industrial production. Compound represented by formula I can be used in the preparation of eribulin drugs. The advantages of the preparation method for compound I are as follows: 1) The racemic compound 3 of the present invention (including compound 3A or compound 3B) does not require costly SMB operations or the use of chiral ligands and metallic chromium catalysis. Instead, compound 3 of the present invention can be selectively separated by a screened biological enzyme (biological enzyme A or biological enzyme B) using column chromatography purification methods, and separation can be achieved through a normal filtration procedure. Compared to preparation by SMB chromatography, the preparation method of the present invention is easier to operate, easier to scale up, shortens the production cycle, and improves production capacity. 2) The biological enzymes screened in the present invention have the characteristics of high selectivity, excellent stability, high enzyme activity, recovery and reuseability, and low cost. 3) The present invention involves selective acylation by biological enzymes, and by utilizing the difference in polarity, it has been discovered that it is possible to achieve the resolution of racemic compounds with a yield of compound I of over 93% and an ee value of over 99%. 4) More specifically, the present invention uses a biological enzyme resolution method to selectively protect unwanted configurations with acyl groups in order to reduce the polarity of the intermediate product, and then uses an acid anhydride to react the hydroxyl group of the desired configuration with the acid anhydride under the action of an organic base and a catalyst to increase the water solubility of the intermediate product, and then extracts with a low-polarity solvent to remove unwanted configurations (products protected by acyl groups). This method achieves separation of two configurations without the need for purification by column chromatography, and can achieve an ee value of 99% or higher. [Examples]

[0055] The following description further illustrates the technical solutions of the present invention with reference to specific examples, in order to facilitate understanding of the invention by those skilled in the art. However, the following description is not intended to limit the scope or intent of the claims of the present invention. Unless otherwise specified, the raw materials, reagents, or solvents used in the present invention are purchased from commercial sources, and experimental methods under specific conditions not specifically described are carried out under the normal operating conditions of the art.

[0056] In this invention, yield refers to the molar percentage of the actual yield relative to the theoretical yield of a certain product. "w" is a mass ratio; for example, a 0.2w bioenzyme means that the ratio of the mass of the bioenzyme to the mass of the starting 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 biological enzyme Lipase AK "Amano" (4.0 g, 0.2 w) were added, and under the protection of nitrogen gas, the internal temperature was raised to 55-60°C and maintained at 55-60°C until the reaction was completed when the ee value of compound I detected by HPLC was ≥ 99%. The reaction mixture was filtered directly, 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, concentrated and dried 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 following synthesis route was followed, and the parameters were adjusted according to Table 1, in the same manner as in Example 1. The nuclear magnetic resonance of the obtained product was as follows. [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 following synthesis route was followed, and the parameters were adjusted according to Table 1, in the same manner as in Example 1. The nuclear magnetic resonance of the obtained product was as follows. [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 following synthesis route was followed, and the parameters were adjusted according to Table 1, in the same manner as in Example 1. The nuclear magnetic resonance of the obtained product was as follows. [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 at room temperature under the protection of nitrogen gas until the spots of the starting materials disappeared as observed by thin-layer chromatography (TLC), and the reaction was completed. The reaction mixture was concentrated to obtain a pale yellow oily substance, which was separated by silica gel column chromatography, distilled under reduced pressure, and concentrated to dryness to obtain 2.35 g of a pale yellow oily substance, compound 5-1, with a yield of 96.0%.

[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, and the parameters were adjusted according to Table 2, in the same manner as in Example 5. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 2, in the same manner as in Example 5. The nuclear magnetic resonance 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 w), and water (1.5 g, 0.1 w) were added. The reaction was carried out under the protection of nitrogen gas at 35-40°C with stirring until the ee value of compound I detected by HPLC was ≥ 99%, and the reaction was completed. The reaction mixture was filtered directly, the filter cake was collected, the filtrate was washed with saturated brine, and the organic phase was concentrated to obtain the crude product. This was separated by silica gel column chromatography to obtain 4.81 g of compound 4-1 with a yield of 48.1%, and 4.37 g of compound I with a yield of 47.8% and an ee value of 99.8%.

[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, and the parameters were adjusted according to Table 3, in the same manner as in Example 8. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 3, in the same manner as in Example 8. The nuclear magnetic resonance of the obtained product was as follows. [ka]

[0085] For Compound 4-3 1 H-NMR (400 MHz, CDCl3): δ = 8.07 (d, 2H, J = 9.2 Hz), 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] For Compound I 1 H-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.

[0087] <Example 11> Following the synthesis route below, the procedure was performed in the same manner as in Example 8, except that parameters were adjusted according to Table 3. The nuclear magnetic resonance data of the obtained product was as follows.

Chemical Formula

[0088] For Compound 4-4 1H-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] of Compound I 1 H-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 Formula

[0091] Compound 3A (20.0 g, 44.70 mmol) was dissolved in 100 mL of n-hexane, vinyl acetate (19.24 g, 223.48 mmol) and the biological enzyme Lipase AK "Amano" (4.0 g, 0.2 w) were added, and under the protection of nitrogen gas, the internal temperature was raised to 55-60°C and maintained at 55-60°C until the reaction was completed when the ee value of compound I detected by HPLC was ≥ 99%. The reaction mixture was filtered directly, the filter cake was collected, and 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 allowed to react at room temperature until the spots of the starting materials disappeared as observed by TLC. After the reaction was complete, n-heptane and water were added to the reaction mixture, and the n-heptane phase was collected. The acetonitrile / aqueous phase was extracted again with n-heptane, and the n-heptane phases were combined. The n-heptane phase was concentrated under reduced pressure at 35-40°C and dried to obtain 10.4 g of compound 4-1, with a yield of 47.6%.

[0092] Sodium hydroxide solid (3.58 g, 89.40 mmol) was added to the acetonitrile / aqueous phase, and the reaction was allowed to proceed at room temperature until the spots of the starting materials disappeared as observed by TLC. The reaction was then separated, the acetonitrile phase was collected, and the acetonitrile phase was concentrated under reduced pressure at 35-40°C and dried to obtain 9.26 g of compound I. The yield was 46.3%, and the ee value was 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, and the parameters were adjusted according to Table 4, in the same manner as in Example 12. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 4, in the same manner as in Example 12. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 4, in the same manner as in Example 12. The nuclear magnetic resonance 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 anhydride acetate (6.84 g, 67.035 mmol) were added. The reaction was carried out at room temperature under the protection of nitrogen gas until the spots of the starting materials, as observed by TLC, disappeared, and the reaction was completed. 50 mL of saturated saline solution was added to the reaction mixture, stirred, and separated. The organic phase was concentrated to obtain a pale yellow oily crude product. This was slurryed with 100 mL of n-heptane, filtered, and the filtrate was concentrated to obtain 21.34 g of pale yellow oily compound 3B-1, with a yield of 97.53%.

[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), lipase PS-30 derived from Pseudomonas cepacia (1.0 g, 0.1 w), and water (1.0 g, 0.1 w) were added. The mixture was stirred and allowed to react under the protection of nitrogen gas at 35-40°C until the ee value of compound 5 detected by HPLC was ≥ 99%, at which point the reaction was completed. The reaction mixture was filtered directly, the filter cake was collected, the filtrate was washed once with 10 mL of saturated brine, and the organic phase was concentrated to obtain 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 was allowed to proceed at room temperature until the spots of the starting materials, as observed by TLC, disappeared. 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, the acetonitrile / aqueous phase was extracted again with n-heptane, and the n-heptane phases were combined. The n-heptane phase was concentrated under reduced pressure at 35-40°C and dried to obtain 4.79 g of compound 4-1, with a yield of 47.9%.

[0109] (1.63 g, 40.86 mmol) of sodium hydroxide solid was added to the acetonitrile / aqueous phase, and the reaction was allowed to proceed at room temperature until the spots of the starting materials disappeared as observed by TLC. The reaction was then separated, the acetonitrile phase was collected, and the acetonitrile phase was concentrated under reduced pressure at 35-40°C and dried to obtain 4.39 g of compound I. The yield was 48.1%, and the ee value was 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, and the parameters were adjusted according to Table 5, in the same manner as in Example 16. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 6, in the same manner as in Example 17. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 5, in the same manner as in Example 16. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 6, in the same manner as in Example 17. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 5, in the same manner as in Example 16. The nuclear magnetic resonance 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, and the parameters were adjusted according to Table 6, in the same manner as in Example 17. The nuclear magnetic resonance 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 (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.

[0127] Relevant parameters in the above Examples 1 to 23 are shown in Tables 1 to 6.

[0128]

Table 1

[0129]

Table 2

[0130]

Table 3

[0131]

Table 4

[0132]

Table 5

[0133]

Table 6

Claims

1. A method for preparing chiral compound I by an enzymatic method, The above method includes method 1 or method 2, In the above method 1, a compound represented by formula 3A is used as a raw material and is subjected to an acylation reaction with an acylation reagent under the action of biological enzyme A to obtain compound 4 and compound I, and a mixture of compound 4 and compound I is selectively separated. 【Chemistry 1】 In the above method 2, a compound represented by formula 3B is used as a raw material and subjected to a hydrolysis reaction under the action of biological enzyme B and a base to obtain compound 4 and compound I, and a mixture of compound 4 and compound I is selectively separated, 【Chemistry 2】 Here, R １ is a C which is substituted or unsubstituted with Ra １ -C １２ linear or branched acyl group, a benzoyl group, or a C which is substituted or unsubstituted with Ra ３ -C ６ linear or branched alkenoyl group, and the substituent Ra on each group is each independently C １ -C ６ linear or branched alkyl group, C １ -C ６ linear or branched alkoxy group, hydroxy group, amino group, halogen, nitro group, cyano group, C １ -C ６ amido group, C ３ -C ６ cycloalkyl group, C １ -C ６ thioalkyl group, a phenyl group, and C ３ -C １８ selected from heterocyclic aromatic groups, the heteroatoms in said heterocyclic aromatic group are selected from O, N and S, The aforementioned biological enzyme A is lipase AK, lipase derived from Pseudomonas fluorescein, Novozym 435, which is Candida antarcticalipase B immobilized on acrylic resin, or lipase AS. The method wherein the biological enzyme B is lipase TL or lipase PS-30 derived from Pseudomonas cepacia.

2. The acylation reagent in Method 1 is selected from vinyl esters and isopropenyl esters. The vinyl ester is either substituted with Rc or unsubstituted with C １ -C １２ Vinyl esters of linear or branched acids, vinyl benzoate, and Rc-substituted or unsubstituted C ３ -C ６ Selected from vinyl esters of linear or branched olefinic acids, The isopropenyl ester is Rc-substituted or unsubstituted C １ -C １２ Isopropenyl esters of linear or branched acids, isopropenyl benzoate, and Rc-substituted or unsubstituted C ３ -C ６ Selected from isopropenyl esters of linear or branched olefinic acids, Each substituent Rc of each group is independently C １ -C ６ Linear or branched alkyl groups, C １ -C ６ Linear or branched alkoxy groups, hydroxyl groups, amino groups, halogens, nitro groups, cyano groups, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, C １ -C ６ Thioalkyl groups, phenyl groups and C ３ -C １８ The method according to claim 1, characterized in that a heteroatom in the heterocyclic aromatic group is selected from O, N, and S.

3. The acylation reaction of Method 1 is carried out in an organic solvent A, and the organic solvent A is one or any combination thereof selected from alkane, aromatic hydrocarbon, chloroalkane, nitrile, and ether solvents, and / or In method 1, the ratio of the mass of compound 3A to the volume of the organic solvent A is 1 g: 1 to 15 mL, and / or The acylation reaction temperature in method 1 is 30 to 80°C, and / or The mass ratio of compound 3A to the biological enzyme A in method 1 is 1:0.005 to 0.3, and / or The method according to claim 1, characterized in that the molar ratio of compound 3A to the acylation reagent in method 1 is 1:1 to 20.

4. The hydrolysis reaction of method 2 is carried out in water and organic solvent B, wherein organic solvent B is one or any combination thereof selected from alkane, aromatic hydrocarbon, chloroalkane, nitrile, and ether solvents, and / or The base is selected from organic bases and inorganic bases, the organic base being one or any combination thereof selected from diethylamine, triethylamine, diisopropylamine, morpholine, N-methylmorpholine, piperazine, and N-methylpiperazine, the inorganic base being one or any combination thereof selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, and alkaline earth metal hydroxides, and / or The mass ratio of compound 3B to the biological enzyme B in method 2 is 1:0.005 to 0.3, and / or The molar ratio of compound 3B to the base in method 2 is 1:1 to 10, and / or In Method 2, the ratio of the mass of compound 3B to the volume of the organic solvent B is 1 g: 1 to 15 mL, and / or The method according to claim 1, characterized in that the hydrolysis reaction temperature in method 2 is 30 to 80°C.

5. A method for selectively separating a mixture of compound 4 and compound I includes either 1) or 2) below: 1) Separate 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, compound I in the mixture of compound 4 and compound I is selectively esterified with an acid anhydride and separated to obtain compound 4 and compound 5. Step b: Compound 5 is hydrolyzed to obtain compound I, and the reaction formula is as follows: 【Transformation 3】 Here, R １ C is either substituted or unsubstituted with Ra. １ -C １２ Linear or branched acyl groups, benzoyl groups, or Ra-substituted or unsubstituted C ３ -C ６ The linear or branched alkenoyl group, and each substituent Ra of the group is independently C １ -C ６ Linear or branched alkyl groups, C １ -C ６ Linear or branched alkoxy groups, hydroxyl groups, amino groups, halogens, nitro groups, cyano groups, C １ -C ６ Amide group, C ３ -C ６ Cycloalkyl groups, C １ -C ６ Thioalkyl groups, phenyl groups, and C ３ -C １８ A heterocyclic aromatic group is selected, and the heteroatom in the heterocyclic aromatic group is selected from O, N, and S. R ２ teeth, 【Chemistry 4】 That is, The method according to claim 1, characterized in that

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

7. 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 to 0.5, 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, and / or The molar ratio of compound I to the organic base in step a is 1:1 to 10, the temperature of the esterification reaction is 0 to 50°C, and / or The acid anhydride in step a is 【Transformation 5】 Selected from the above, the molar ratio of compound I to the acid anhydride is 1:1 to 10, and / or The esterification reaction in step a is carried out in reaction solvent C, and the reaction solvent C is one or any combination thereof selected from aromatic hydrocarbons, chloroalkanes, nitrile solvents and ether solvents, and / or The hydrolysis in step b is carried out in water and organic solvent D, the organic solvent D is selected from the reaction solvent C in step a, the reaction temperature is room temperature, and / or The method according to claim 5, characterized in that the hydrolysis in step b is carried out in an inorganic base, and 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.

8. A method for preparing an eribulin drug, characterized by comprising the method described in any one of claims 1 to 7.

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