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WO2024021261A1 - 一种艾日布林中间体的制备方法 - Google Patents

一种艾日布林中间体的制备方法 Download PDF

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WO2024021261A1
WO2024021261A1 PCT/CN2022/119607 CN2022119607W WO2024021261A1 WO 2024021261 A1 WO2024021261 A1 WO 2024021261A1 CN 2022119607 W CN2022119607 W CN 2022119607W WO 2024021261 A1 WO2024021261 A1 WO 2024021261A1
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compound
lipase
group
linear
branched
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PCT/CN2022/119607
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English (en)
French (fr)
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吴哲
孙敏
丁福斗
蔡伶俐
张宪恕
王子坤
高强
郑保富
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上海皓元医药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P9/00—Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/20—Purification, separation

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method of eribulin intermediate.
  • Eribulin Mesylate is a synthetic analog of halichondrin B and has the biologically active macrocyclic portion of halichondrin B.
  • Halichondrin B is a polyether macrolide that exhibits potent anticancer effects in both cell and animal models. Eribulin mesylate can inhibit the mitosis of cellular tubulin, leading to irreversible arrest in the G2/M phase of the cell cycle and mitotic spindle breakage. Cell apoptosis occurs after long-term mitosis arrest, and cell proliferation is inhibited. Eribulin mesylate injection was developed by Eisai Inc. and was approved by the US FDA for marketing in the United States in November 2010. The trade name is Halaven.
  • the approved indications are: suitable for patients who have received at least two previous treatments for metastatic cancer. of patients with metastatic breast cancer; results based on subset analysis show that eribulin mesylate can be actively and effectively used to treat triple-negative metastatic breast cancer, which is a malignant form of breast cancer. The prognosis is often poor. In many countries, eribulin mesylate was considered a third-line or even later drug therapy for the treatment of metastatic breast cancer. However, during the treatment, this drug was the only drug that could effectively improve the survival rate of patients. chemotherapy preparations. Eribulin mesylate is currently the only drug in this field with good clinical and market prospects.
  • TBDPS is tert-butyldiphenylsilyl.
  • Compound I has chirality to the tosyl-protected hydroxyl carbon.
  • a racemate is first obtained.
  • literature reports (Synlett (2013), 24(3), 327-332, WO2005118565, etc.), the compound of formula 3 is chiral.
  • a single configuration can be obtained through the preparation and separation of simulated moving bed (SMB), which has high preparation efficiency and low cost, and is not conducive to scale-up production.
  • SMB simulated moving bed
  • there are reports in the literature (Org. Lett., Vol. 10, No. 14, 2008) that a single-configuration product can be obtained under the catalysis of chiral ligands and metal chromium, but the cost is high.
  • the technical problem to be solved by the present invention is to provide a method for preparing the compound represented by formula I that is completely different from the existing technology.
  • the reaction conditions involved are mild and environmentally friendly, the route is novel, the post-processing and purification are simple, and the prepared
  • the compound represented by formula I has high purity, and the preparation method is simple to operate, has a high conversion rate, good selectivity and low cost, and is conducive to industrial scale-up production; the compound represented by formula I can be used in the preparation of eribulin drugs.
  • the present invention provides a method for enzymatically preparing chiral compound I, including the following methods:
  • the first method uses a compound as shown in formula 3A as a raw material, undergoes an acylation reaction with an acylating reagent under the action of biological enzyme A to obtain compound 4 and compound I, and selectively separates the mixture of compound 4 and compound I. ;
  • the second method is to use the compound shown in Formula 3B as raw material, undergo a hydrolysis reaction under the action of biological enzyme B and alkali to obtain compound 4 and compound I, and selectively separate the mixture of compound 4 and compound I;
  • R 1 is a C 1 -C 12 linear or branched acyl group substituted or unsubstituted by Ra, a benzoyl group, a C 3 -C 6 linear or branched enoyl group substituted or unsubstituted by Ra; each group
  • the substituents Ra of the group are each independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, cyano, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, C 1 -C 6 sulfanyl, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, phenyl or C 3 -C 18 Heterocyclic aromatic group, the heteroatom on the heterocyclic aromatic group is selected from O, N or S; R 1 is preferably acetyl, propionyl, butyryl, isobut
  • biological enzyme A is lipase or esterase
  • biological enzyme A is selected from lipase AK (Lipase AK "Amano"), lipase from pseudomonas fluorescens (Amano Lipase from pseudomonas fluorescens), CAL-B lipase immobilized on acrylic resin (Novozym 435), lipase AS (Lipase AS "Amano"), lipase PS (Lipase PS "Amano” SD) immobilized on acrylic resin , Lipase from Thermomyces lanuginosus, Lipase from Candida Rugosa, Lipase AYS (Lipase AYS "Amano"), Triacylglycerol lipase, from Either Lipase from Mucor miehei or Lipase from Rhizopus oryzae, Lipase B of Candida antarctica immobilized on Immobea
  • the biological enzyme B in method two is a lipase, esterase or 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, from Rhizopus sp.
  • lipase, esterase or 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, from Rhizopus sp.
  • lipase RS lipase PS from Pseudomonas cepacia, lipase AN from Aspergillus niger, lipase A from Achromobacter sp., lipase A from Alcaligenes
  • Lipase AS1 from Alcaligenes sp. lipase AS2 from Alcaligenes sp.
  • lipase C2 from Candida cylindracea
  • lipase C1 from Candida cylindracea lipase lipozym TL IM
  • 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.
  • the acylating reagent of method 1 is selected from vinyl ester or isopropylene ester, wherein the vinyl ester is selected from Rc-substituted or unsubstituted C 1 -C 12 linear or branched acid vinyl ester , vinyl benzoate, C 3 -C 6 linear or branched vinyl alkenoate substituted or unsubstituted by Rc; the isopropylene ester is selected from C 1 -C 12 linear or branched alkenoate substituted or unsubstituted by Rc Branched chain acid isopropyl ester, benzoic acid isopropyl ester, Rc-substituted or unsubstituted C 3 -C 6 linear or branched acrylic acid isopropyl ester.
  • the substituent Rc of each group is independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, cyano , C 1 -C 6 amide group, C 3 -C 6 cycloalkyl group, C 1 -C 6 sulfanyl group, C 1 -C 6 amide group, C 3 -C 6 cycloalkyl group, phenyl or C 3 - C 18 heterocyclic aromatic group, the heteroatom on the heterocyclic aromatic group is selected from O, N or S.
  • the acylating reagent of method one is preferably vinyl acetate, isopropylene acetate, vinyl propionate, isopropylene propionate, vinyl butyrate, isopropylene butyrate, or vinyl isobutyrate.
  • the biological enzyme A of method 1 provided by the invention can selectively acylate the alcohol of formula 3A with a biological enzyme A to generate the acylated compound of a single isomer of formula 4; subsequently, the compound of formula I can be easily combined with the formula 4 compounds were separated.
  • the acylation reaction can be carried out in organic solvents.
  • the enantiomeric excess of the product of formula I is preferably at least 96% ee, more preferably at least 99% ee.
  • the enzyme can be immobilized on a carrier to facilitate enzyme recovery and facilitate post-reaction treatment.
  • the enzyme has the characteristics of high selectivity, good stability, high enzyme activity and low cost.
  • the acylation reaction of method 1 is carried out in an organic solvent A.
  • the organic solvent A is selected from one or any of alkanes, aromatic hydrocarbons, chlorinated alkanes, nitriles or ether solvents. Combinations; for example, alkanes are selected from one or any combination of n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane; aromatic hydrocarbons are selected from one of toluene, xylene or chlorobenzene.
  • chlorinated alkanes are selected from dichloromethane and chloroform
  • nitriles are selected from one of acetonitrile, propionitrile or benzonitrile or any combination thereof
  • ethers are selected from petroleum ether, tetrahydrofuran, 1,4 -One or any combination of dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE);
  • the organic solvent A is preferably petroleum ether, diethyl ether, methyl tert-butyl ether or dichloro One or any combination of methane, n-hexane, cyclohexane, n-pentane, cyclopentane, n-heptane, toluene or acetonitrile; more preferably one or any combination of n-hexane or n-heptane .
  • the mass-volume ratio of compound 3A to organic solvent A in method 1 is 1g:1-15mL, more preferably 1g:5-8mL.
  • the acylation reaction temperature in method one is 30-80°C, preferably 55-60°C; in this temperature range, the enzyme has good activity, fast reaction rate and high efficiency.
  • the mass ratio of compound 3A to biological enzyme A in method one is 1:0.005-0.3, preferably 1:0.01-0.3, and more preferably 1:0.05-0.2.
  • 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; the acylation of the present invention
  • the combination of reagents and biological enzymes can selectively acylate the S-configuration compound in racemic compound 3A to obtain compound 4, with high reaction yield and good isomer purity.
  • the products obtained by the enantioselective acylation of the present invention include a mixture of R-form compounds of formula I and S-form compounds of formula 4.
  • enantioselective enzymatic hydrolysis can yield mixtures containing the R-form of a compound of formula I and the S-form of a compound of formula 4.
  • the optical purity of the compound of formula I obtained by the optical resolution method of the present invention is usually at least 96% ee, preferably at least 97% ee, more preferably at least 98% ee, and most preferably at least 99% ee.
  • the hydrolysis reaction of method two is carried out in water and organic solvent B.
  • Organic solvent B contains one selected from alkanes, aromatic hydrocarbons, chlorinated alkanes, nitrile solvents or ether solvents.
  • alkanes are selected from one or any combination of n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane; aromatic hydrocarbons are selected from toluene, xylene or chlorobenzene One or any combination thereof; chlorinated alkanes are selected from one or any combination of dichloromethane or chloroform; nitriles are selected from one or any combination of acetonitrile, propionitrile or benzonitrile; ethers
  • the solvent B is selected from one or any combination of petroleum ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE); the organic solvent B is preferably selected from toluene, One or any combination of xylene, methyl tert-butyl ether or acetonitrile
  • the base is selected from organic bases or inorganic bases, and the organic base is selected from diethylamine, triethylamine (TEA), diisopropylamine, morpholine, N-methylmorpholine, piperazine or One of N-methylpiperazine or any combination thereof;
  • the inorganic base includes, for example, one of alkali metal hydroxides, carbonates or bicarbonates or alkaline earth metal hydroxides or any combination thereof.
  • the base is one of alkali metal hydroxide, alkali metal carbonate or alkali metal bicarbonate or any combination thereof. More preferably, the base is an alkali metal carbonate.
  • the base is preferably selected from one or any combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, sodium bicarbonate or potassium carbonate; most preferably, it is one or any combination of sodium carbonate or potassium carbonate. random combination.
  • the base of the present invention is used in combination with biological enzyme B to selectively hydrolyze the R-configuration reaction in racemic compound 3B to obtain compound I, with high reaction yield and good isomer purity.
  • the mass ratio of compound 3B to biological enzyme B in method two is 1:0.005-0.3, preferably 1:0.01-0.3, and more preferably 1:0.05-0.2.
  • the molar ratio of compound 3B to the base in method two is 1:1-10, preferably 1:1-8, and more preferably 1:1-4.
  • the mass volume ratio of compound 3B and organic solvent B in method two is 1g:1-15mL, more preferably 1g:3-8mL.
  • the hydrolysis reaction temperature in method two is 30-80°C, preferably 35-40°C; in this temperature range, the enzyme has good activity, fast reaction rate and high efficiency.
  • the method for selectively separating a mixture of Compound 4 and Compound I includes:
  • Step a Under the action of a catalyst and an organic base, compound I in the mixture of compound 4 and compound I selectively undergoes an esterification reaction with an acid anhydride to separate compound 4 and compound 5.
  • Step b hydrolyze compound 5 to obtain compound I, the reaction formula is as follows:
  • R 1 is a C 1 -C 12 linear or branched acyl group substituted or unsubstituted by Ra, a benzoyl group, a C 3 -C 6 linear or branched enoyl group substituted or unsubstituted by Ra, each group
  • the substituents Ra of the group are each independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, cyano, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, C 1 -C 6 sulfanyl, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, phenyl or C 3 -C 18 Heterocyclic aromatic group, the heteroatom on the heterocyclic aromatic group is selected from O, N or S; R 1 is preferably acetyl, propionyl, butyryl, isobut
  • the column chromatography separation condition is to use petroleum ether:ethyl acetate in a volume ratio of 20:1 to 5:1 as the eluent for silica gel column chromatography separation.
  • the catalyst in step a is selected from 4-dimethylaminopyridine (DMAP).
  • the molar ratio of compound I to catalyst in step a is 1:0.1 ⁇ 0.5, preferably 1:0.2 ⁇ 0.3.
  • the organic base in step a is selected from diethylamine, triethylamine, diisopropylamine, pyridine, ⁇ -methylpyridine, 1,2-dimethylpyridine, 4-hydroxy-2-methyl One or any combination of pyridine, ⁇ -trimethylpyridine, quinoline or dimethylquinoline.
  • the organic base is preferably selected from triethylamine, diisopropylamine, pyridine or ⁇ -methylpyridine.
  • the molar ratio of compound I to organic base in step a is 1:1 ⁇ 10, preferably 1:1 ⁇ 5, more preferably 1:3 ⁇ 5; the esterification reaction
  • the temperature is 0 to 50°C, preferably 10 to 30°C.
  • the acid anhydride in step a is selected from 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.
  • the esterification reaction in step a is carried out in reaction solvent C.
  • the reaction solvent C includes one or any of aromatic hydrocarbons, chlorinated alkanes, nitrile solvents or ether solvents. Combinations; for example, aromatic hydrocarbons are selected from one or any combination of toluene, xylene or chlorobenzene; chlorinated alkanes are selected from one or any combination of dichloromethane or chloroform; nitriles are selected from acetonitrile , one of propionitrile or benzonitrile or any combination thereof; the ether is selected from one of petroleum ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether Or any combination thereof; the reaction solvent C is preferably selected from one of toluene, xylene, methyl tert-butyl ether or aceton
  • the separation in step a includes conventional separation steps, such as liquid separation, extraction, water washing or concentration.
  • the present invention has no special restrictions on the solvents for liquid separation or extraction. Alkanes and chlorinated alkanes can be used.
  • alkanes are selected from one or any combination of n-hexane, cyclohexane, n-pentane, cyclopentane or n-heptane; chlorinated alkanes
  • the ether is selected from petroleum ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, diisopropyl ether or methyl tert-butyl ether (MTBE) one or any combination thereof.
  • MTBE methyl tert-butyl ether
  • the hydrolysis in step b is carried out in water and organic solvent D.
  • Organic solvents that do not produce negative effects are suitable for the hydrolysis reaction.
  • Organic solvent D is selected from organic solvents that do not produce negative effects; organic solvent D
  • the reaction solvent C is preferably selected from the above step a.
  • the hydrolysis is carried out in water and acetonitrile; the reaction temperature is preferably room temperature.
  • the hydrolysis in step b is carried out in an inorganic base
  • the inorganic base is selected from one of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates or alkaline earth metal hydroxides or their combinations. random combination.
  • the base is selected from one of alkali metal hydroxides or alkaline earth metal hydroxides or any combination thereof. More preferably, the base is an alkali metal hydroxide.
  • the base is preferably selected from one of lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide or any combination thereof; more preferably, it is one of sodium hydroxide or potassium hydroxide or any combination thereof.
  • the molar ratio of compound 5 to inorganic base in step b is 1:1-20, preferably 1:1-4.
  • the present invention provides a method for preparing chiral compound I, which includes the step of separating a mixture of compound 4 and compound I.
  • the separation method includes:
  • Step a Under the action of a catalyst and an organic base, compound I in the mixture of compound 4 and compound I selectively undergoes an esterification reaction with an acid anhydride, and compound 4 and compound 5 are separated; step b: compound 5 is Hydrolysis gives compound I, the reaction formula is as follows:
  • R 1 is a C 1 -C 12 linear or branched acyl group substituted or unsubstituted by Ra, a benzoyl group, a substituted or unsubstituted C 3 -C 6 linear or branched enoyl group, and each group has The substituents Ra are each independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, cyano, C 1 - C 6 amide, C 3 -C 6 cycloalkyl, C 1 -C 6 sulfanyl, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, phenyl or C 3 -C 18 heterocycle
  • Aryl group, the heteroatom on the heterocyclic aromatic group is selected from O, N or S;
  • R 1 is preferably acetyl, propionyl, butyryl, isobutyryl, 2-
  • reaction conditions of each step of compound I in the second aspect can be referred to the reaction condition parameters of each step in the first aspect of the invention; during continuous feeding, whether it is through the acylation reaction of compound 3A in biological enzyme A Or compound 3B is hydrolyzed in biological enzyme B to obtain a mixture of compound I and compound 4.
  • the theoretical yields can be 50% each or the quantities can be accurately added according to the high-performance liquid chromatography (HPLC) detection, without affecting the next step and the acid anhydride step. a reaction.
  • Compound 4 can be directly transformed to Compound I by following hydrolysis with reference to the method in Synlett (2013), 24(3), 327-332 (the entire text of which is incorporated into this application by reference).
  • the preparation of the mixture of compound 4 and compound I includes: selective acylation or hydrolysis of compound 3A or compound 3B under the action of biological enzyme A and biological enzyme B to obtain compound 4 and compound 3B, respectively.
  • the reaction formula is as follows:
  • reaction conditions in the preparation of the mixture of compound 4 and compound I in the second aspect can refer to the reaction conditions of each step in the first aspect of the present invention.
  • the present invention provides a key intermediate for preparing compound I.
  • key intermediate compound C is represented by:
  • R is selected from C 1 -C 12 linear or branched acyl group substituted or unsubstituted by Ra, C 3 -C 6 linear or branched enoyl group substituted or unsubstituted by Ra,
  • each group is independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, Cyano, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, C 1 -C 6 sulfanyl, C 1 -C 6 amide, C 3 -C 6 cycloalkyl, phenyl or C 3 -C 18 heterocyclic aromatic group, the heteroatom on the heterocyclic aromatic group is selected from O, N or S.
  • the structure is:
  • R 1 is a C 1 -C 12 linear or branched acyl group substituted or unsubstituted by Ra, a C 3 -C 6 linear or branched enoyl group substituted or unsubstituted by Ra, and the substituents of each group Ra is each independently selected from C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched alkoxy, hydroxyl, amino, halogen, nitro, cyano, C 1 -C 6 Amide group, C 3 -C 6 cycloalkyl group, C 1 -C 6 sulfanyl group, C 1 -C 6 amide group, C 3 -C 6 cycloalkyl group, phenyl group or C 3 -C 18 heterocyclic aromatic group , the heteroatom on the heterocyclic aromatic group is selected from O, N or S; R 1 is preferably propionyl, butyryl, isobutyryl, 2-methylbutyryl, 3-
  • the key intermediate compound is selected from the following compounds without limitation:
  • R 2 is selected from
  • the key intermediate compound is selected from the following compounds without limitation:
  • this application provides a method for preparing eribulin medicine, which includes the method provided in the first aspect of this application or the method provided in the second aspect of this application.
  • the present invention provides a new method for preparing the compound represented by formula I.
  • the reaction conditions involved are mild and environmentally friendly, the route is novel, and the post-processing and purification are simple.
  • the prepared compound represented by formula I is The compound has high purity, the preparation method is simple, the conversion rate is high, the selectivity is good, the cost is low, and it is conducive to industrial scale-up production; the compound represented by formula I can be used in the preparation of eribulin drugs; the method for preparing compound I is The advantages are:
  • the racemic compound 3 of the present invention (including 3A or 3B) does not need to be operated through high-cost SMB or the catalytic effect of chiral ligands and metal chromium. It only needs to be purified through column chromatography, and the compound 3 of the present invention is screened.
  • the biological enzyme (A or B) can be selectively separated by conventional filtration operations. Compared with SMB chromatography preparation, it is simple to operate, easy to scale up, reduces the production cycle, and increases production capacity.
  • the biological enzymes screened in the present invention have the characteristics of high selectivity, good stability, high enzyme activity, recyclability and low cost.
  • the present invention selectively acylates biological enzymes and finds that the difference in polarity is used to achieve the resolution of racemic compounds.
  • the yield of compound I is >93% and the ee value is >99%.
  • the present invention more specifically adopts a biological enzyme resolution method to selectively protect the unwanted configuration with acyl groups to reduce the polarity of the intermediate product, and uses acid anhydride to combine the desired configuration with hydroxyl groups under the action of organic bases and catalysts.
  • Acid anhydride reaction increases the water solubility of the intermediate product, and a small polar solvent is used to extract the unwanted configuration (using acyl protected product).
  • the two configurations can be separated without purification by column chromatography, ee Values can reach over 99%.
  • yield refers to the molar percentage between the actual yield and the theoretical yield of a certain product.
  • w is the mass ratio.
  • a 0.2w biological enzyme means that the mass ratio of the biological enzyme to the raw material (Compound 3A/Compound 3B) is 0.2.
  • the crude product was dissolved in 40 mL acetonitrile, and (7.92g, 78.23mmol) triethylamine (TEA), (0.55g, 4.47mmol) DMAP, (3.35g, 33.53mmol) were added. ) Succinic anhydride, react at room temperature until the raw material spots disappear according to TLC. After the reaction is completed, add n-heptane and water to the reaction solution, collect the n-heptane phase, and extract the acetonitrile water phase with n-heptane, and combine the n-heptane phases. The n-heptane phase was concentrated to dryness under reduced pressure at 35-40°C to obtain 10.4 g of compound 4-1, with a yield of 47.6%.
  • TAA triethylamine
  • Example 12 Except for following the following synthesis route and adjusting parameters according to Table 4, the rest is the same as Example 12, and the obtained product NMR is as follows.
  • Example 12 Except for following the following synthesis route and adjusting parameters according to Table 4, the rest is the same as Example 12, and the obtained product NMR is as follows.
  • Example 12 Except for following the following synthesis route and adjusting parameters according to Table 4, the rest is the same as Example 12, and the obtained product NMR is as follows.
  • the crude product was dissolved in 20 mL acetonitrile, and (3.62 g, 35.75 mmol) TEA, (0.25 g, 2.043 mmol) DMAP, ( 1.50g, 15.32mmol) maleic anhydride, react at room temperature until the spots of the raw material disappear as observed by TLC. After the reaction is completed, add 20mL n-heptane and 25mL water to the reaction solution, collect the n-heptane phase, and use the acetonitrile water phase with n-heptane. Extract with alkane, combine the n-heptane phases, and concentrate the n-heptane phase to dryness under reduced pressure at 35-40°C to obtain 4.79 g of compound 4-1, with a yield of 47.9%.

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  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

提供了一种式Ⅰ化合物的制备方法，包括以下步骤：从化合物3A或化合物3B出发，经生物酶A选择性酰化或者生物酶B选择性水解后，用酸酐在有机碱和催化剂作用下将需要的构型的羟基与酸酐反应得到化合物5，增加该中间产物水溶性，通过萃取分离，实现两个构型分离，ee值可以达到99％以上，制备方法操作简单、转化率高、选择性好、成本低，利于工业放大生产。

Description

一种艾日布林中间体的制备方法
本申请要求于2022年7月29日提交中国专利局、申请号为202210904052.6、发明名称为“一种艾日布林中间体的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物化学领域，具体涉及一种艾日布林中间体的制备方法。
背景技术
甲磺酸艾日布林(Eribulin Mesylate)是软海绵素B的一种合成类似物，具有软海绵素B的生物活性大环部分。软海绵素B是一种聚醚大环内酯，在细胞和动物模型中均表现有强效的抗癌作用。甲磺酸艾日布林能够抑制细胞微管蛋白有丝分裂，从而导致不可逆的细胞周期G2/M期阻滞和有丝分裂纺锤体断裂，细胞有丝分裂长期阻滞后发生凋亡，细胞增殖受抑。甲磺酸艾日布林注射液由Eisai Inc.研制开发，于2010年11月经美国FDA批准在美国上市，商品名为Halaven，批准适应症为：适用于先前接受过至少两次转移癌治疗方案的转移性乳腺癌患者；基于子集分析的结果显示，甲磺酸艾日布林可以积极有效地用于治疗三阴性转移性乳腺癌，三阴性转移性乳腺癌是一种恶性的乳腺癌，其预后往往较差。曾经在很多国家，甲磺酸艾日布林被认为是治疗转移性乳腺癌的三线甚至是更靠后的药物疗法，然而在治疗过程中该药物却是唯一一种可以有效提高患者生存率的化疗制剂。甲磺酸艾日布林是目前该领域内唯一的一个具有良好临床、市场前景的药物。
艾日布林早期中间体结构如下式Ⅰ所示：
Figure PCTCN2022119607-appb-000001
现有技术中合成式Ⅰ所示的化合物为以下方法：
原研厂家卫材合成艾日布林原料药的早期中间体Ⅰ的工艺路线如下：
Figure PCTCN2022119607-appb-000002
其中，TBDPS为叔丁基二苯基硅基。
化合物Ⅰ对甲苯磺酰基保护的羟基碳具有手性，在合成过程中先是得到消旋体，文献报道(Synlett(2013),24(3),327-332，WO2005118565等)在式3化合物通过手性模拟移动床(SMB)制备分离得到单一构型，制备效率低成本高，不利于放大生产。另外，有文献(Org.Lett.,Vol.10,No.14,2008)报道，在手性配体与金属铬的催化下得到单一构型的产品，但 是成本高。
发明内容
本发明要解决的技术问题是提供一种与现有技术完全不相同的制备式Ⅰ所示的化合物的方法，所涉及的反应条件温和、环保，路线新颖、后处理和纯化简单，制备得到的式Ⅰ所示的化合物纯度高，制备方法操作简单、转化率高、选择性好、成本低，利于工业放大生产；式Ⅰ所示的化合物可用于在制备艾日布林药物中的应用。
第一方面，本发明提供一种酶法制备手性化合物I的方法，包括如下方法：
方法一：
Figure PCTCN2022119607-appb-000003
所述方法一以如式3A所示的化合物为原料，在生物酶A的作用下与酰化试剂发生酰化反应得到化合物4和化合物I，选择性地将化合物4和化合物I的混合物进行分离；
方法二：
Figure PCTCN2022119607-appb-000004
所述方法二为以如式3B所示的化合物为原料，在生物酶B和碱的作用下水解反应得到化合物4和化合物I，选择性地将化合物4和化合物I的混合物进行分离；
其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基；各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基，更优选为乙酰基、丙酰基、丁酰基、苯甲酰基或丙烯酰基。
作为本发明的进一步改进，生物酶A为脂肪酶或酯酶，生物酶A选自脂肪酶AK(Lipase AK“Amano”)，来自荧光假单胞菌的脂肪酶(Amano Lipase from pseudomonas fluorescens)，固定在丙烯酸树脂上的南极假丝酵母脂肪酶B(CAL-B lipase immobilized on acrylic resin(Novozym 435))，脂肪酶AS(Lipase AS“Amano”)，脂肪酶PS(Lipase PS“Amano”SD)，来自嗜热霉菌的脂肪酶(Lipase from Thermomyces lanuginosus)，来自念珠菌的脂肪酶(Lipase from Candide Rugosa)，脂肪酶AYS(Lipase AYS“Amano”)，三酰基甘油脂肪酶(Triacylglycerol lipase)，来自米赫毛霉菌的脂肪酶(Lipase from Mucor miehei)或来自米根霉菌的脂肪酶(Lipase from Rhizopus oryzae)中的任一种，固定化于Immobead 150的 南极洲假丝酵母的脂肪酶B，重组来源于米曲霉(Lipase B Candida antarctica immobilized on Immobead 150，recombinant from Aspergillus oryzae)；生物酶A优选为脂肪酶AK(Lipase AK“Amano”)，来自荧光假单胞菌的脂肪酶(Amano Lipase from pseudomonas fluorescens)或固定在丙烯酸树脂上的南极假丝酵母脂肪酶B Novozym 435(CAL-B lipase(Novozym 435)immobilized on acrylic resin)。
作为本发明的进一步改进，方法二的生物酶B为脂肪酶、酯酶或者水解酶，例如脂肪酶TL，来自洋葱假单胞菌的脂酶PS-30，脂肪酶QLM，来自疏棉状嗜热丝孢菌(Thermomyceslanuginosus)的脂肪酶，来自洋葱假单胞菌(Pseudomonas cepacia)的脂肪酶P2，来自施氏假单胞菌(Pseudomonas stutzeri)的脂肪酶PS，来自酒曲酶属(Rhizopus sp.)的脂肪酶RS，来自洋葱假单胞菌的脂肪酶PS，来自黑曲霉(Aspergillus niger)的脂肪酶AN，来自无色菌属(Achromobacter sp.)的脂肪酶A，来自产碱杆菌属(Alcaligenes sp.)的脂肪酶AS1，来自产碱杆菌属的脂肪酶AS2，来自圆柱假丝酵母(Candida cylindracea)的脂肪酶C2，来自圆柱假丝酵母的脂肪酶C1，脂肪酶lipozym TL IM，脂肪酶lipozym TL 100L，南极假丝酵母(Candida antarctica)脂肪酶B(CALB)，CHIRAZYME E-1猪肝酯酶，来自假单胞菌属L-6的脂肪酶，南极假丝酵母脂肪酶A(CALA)，皱褶假丝酵母(Candida rugosa)脂肪酶(L-3)或胰脂肪酶USP Grade。
作为本发明的进一步改进，方法一的酰化试剂选自乙烯酯或异丙烯酯，其中，所述乙烯酯选自被Rc取代或未取代的C 1-C 12直链或支链酸乙烯酯、苯甲酸乙烯酯、被Rc取代或未取代的C 3-C 6直链或支链烯酸乙烯酯；所述异丙烯酯选自被Rc取代或未取代的C 1-C 12直链或支链酸异丙烯酯、苯甲酸异丙烯酯、被Rc取代或未取代的C 3-C 6直链或支链烯酸异丙烯酯。各个基团的取代基Rc自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S。
作为本发明的进一步改进，方法一的酰化试剂优选为乙酸乙烯酯、乙酸异丙烯酯、丙酸乙烯酯、丙酸异丙烯酯、丁酸乙烯酯、丁酸异丙烯酯、异丁酸乙烯酯、异丁酸异丙烯酯、2-甲基丁酸乙烯酯、2-甲基丁酸异丙烯酯、3-甲基丁酸乙烯酯、3-甲基丁酸异丙烯酯、新戊酸乙烯酯、新戊酸异丙烯酯、2-甲基戊酸乙烯酯、2-甲基戊酸异丙烯酯、3-甲基戊酸乙烯酯、3-甲基戊酸异丙烯酯、4-甲基戊乙烯酯、4-甲基戊异丙烯酯、己酸乙烯酯、己酸异丙烯酯、月桂酸乙烯酯、月桂酸异丙烯酯、苯甲酸乙烯酯、苯甲酸异丙烯酯、丙烯酸乙烯酯或丙烯酸异丙烯酯，更优选为乙酸乙烯酯、乙酸异丙烯酯、丙酸乙烯酯、丙酸异丙烯酯、丁酸乙烯酯、丁酸异丙烯酯、苯甲酸乙烯酯、苯甲酸异丙烯酯、丙烯酸乙烯酯或丙烯酸异丙烯酯。
本发明提供的方法一的生物酶A可将式3A的醇用一种生物酶A选择性酰化，生成式4的单一异构体的酰化化合物；后续能方便地将式I化合物与式4化合物进行分离。酰化 反应可以在有机溶剂中进行。该产物式I对映体过量优选至少为96％ee，更优选至少为99％ee。该酶可被固定在载体上，以有助于酶的回收和使反应后处理变容易，所述的酶具有选择性高、稳定性好、酶活性高和成本低的特点。
作为本发明的进一步改进，方法一的酰化反应在有机溶剂A中进行，有机溶剂A选自烷烃类、芳香烃类、氯代烷烃类、腈类或醚类溶剂中的一种或其任意组合；例如，烷烃类选自正己烷、环己烷、正戊烷、环戊烷或正庚烷中的一种或其任意组合；芳香烃类选自甲苯、二甲苯或氯苯中的一种或其任意组合；氯代烷烃类选自二氯甲烷、氯仿；腈类选自乙腈、丙腈或苯腈中的一种或其任意组合；醚类选自石油醚、四氢呋喃、1,4-二氧六环、乙醚、二异丙醚或甲基叔丁基醚(MTBE)中的一种或其任意组合；有机溶剂A优选为石油醚、乙醚、甲基叔丁基醚、二氯甲烷、正己烷、环己烷、正戊烷、环戊烷、正庚烷、甲苯或乙腈中的一种或其任意组合；更优选为正己烷或正庚烷中的一种或其任意组合。
作为本发明的进一步改进，方法一中化合物3A与有机溶剂A的质量体积比为1g:1～15mL，更优选为1g:5～8mL。
作为本发明的进一步改进，方法一中酰化反应温度为30～80℃，优选为55～60℃；在此温度区间该酶的活性好，反应速率快，效率高。
作为本发明的进一步改进，方法一中化合物3A与生物酶A的质量比为1:0.005～0.3，优选为1:0.01～0.3，更优选为1:0.05～0.2。
作为本发明的进一步改进，方法一中化合物3A与酰化试剂的摩尔比为1:1～20，优选为1:2～10，更优选为1:3～6；本发明的所述酰化试剂与生物酶组合使用，能够选择性地将外消旋化合物3A中的S构型化合物通过酰化反应得到化合物4，反应收率高，异构体纯度好。
作为本发明的进一步改进，本发明的对映选择性的酰化得到的产物包括R-形式的式I化合物以及S-形式的式4化合物的混合物。同样地，对映选择性的酶水解可以得到包含R-形式的式I化合物以及S-形式的式4化合物的混合物。通过本发明的光学拆分法得到的式I化合物的光学纯度通常至少为96％ee，优选至少为97％ee，更优选至少为98％ee，且最优选至少为99％ee。
作为本发明的进一步改进，方法二的水解反应在水和有机溶剂B中进行，有机溶剂B包含选自烷烃类、芳香烃类、氯代烷烃类、腈类溶剂或醚类溶剂中的一种或其任意组合；例如，烷烃类选自正己烷、环己烷、正戊烷、环戊烷或正庚烷中的一种或其任意组合；芳香烃类选自甲苯或二甲苯或氯苯中的一种或其任意组合；氯代烷烃类选自二氯甲烷或氯仿中的一种或其任意组合；腈类选自乙腈、丙腈或苯腈中的一种或其任意组合；醚类选自石油醚、四氢呋喃、1,4-二氧六环、乙醚、二异丙醚或甲基叔丁基醚(MTBE)中的一种或其任意组合；有机溶剂B优选选自甲苯、二甲苯、甲基叔丁基醚或乙腈中的一种或其任意组合。
作为本发明的进一步改进，所述碱选自有机碱或无机碱，有机碱选自二乙胺、三乙胺 (TEA)、二异丙胺、吗啉、N-甲基吗啉、哌嗪或N-甲基哌嗪中的一种或其任意组合；无机碱包含例如碱金属氢氧化物、碳酸盐或碳酸氢盐或碱土金属氢氧化物中的一种或其任意组合。优选地，所述碱是碱金属的氢氧化物，碱金属的碳酸盐或碱金属的碳酸氢盐中的一种或其任意组合，更优选地，所述碱是碱金属碳酸盐。所述碱优选选自氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钾、碳酸氢钠或碳酸钾中的一种或其任意组合；最优选为碳酸钠或碳酸钾中的一种或其任意组合。本发明的所述碱与生物酶B组合使用，能够选择性地水解外消旋化合物3B中的R构型反应得到化合物I，反应收率高，异构体纯度好。
作为本发明的进一步改进，方法二中化合物3B与生物酶B的质量比为1:0.005～0.3，优选为1:0.01～0.3，更优选为1:0.05～0.2。
作为本发明的进一步改进，方法二中化合物3B与碱的摩尔比为1:1～10，优选为1:1～8，更优选为1:1～4。
作为本发明的进一步改进，方法二中化合物3B与有机溶剂B的质量体积比为1g:1～15mL，更优选为1g:3～8mL。
作为本发明的进一步改进，方法二中水解反应温度为30～80℃，优选为35～40℃；在此温度区间该酶的活性好，反应速率快，效率高。
作为本发明的进一步改进，所述选择性地将化合物4和化合物I的混合物进行分离的方法，包括：
1)通过柱层析方法分离化合物4和化合物I的混合物，得到化合物I；或
2)步骤a：在催化剂和有机碱作用下，化合物4和化合物I混合物中的化合物I选择性地与酸酐发生酯化反应，分离得到化合物4和化合物5，步骤b：将化合物5水解得到化合物I，反应式如下：
Figure PCTCN2022119607-appb-000005
其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基；R 2选自
Figure PCTCN2022119607-appb-000006
作为本发明的进一步改进，柱层析方法分离条件是以体积比为20:1～5:1的石油醚∶乙酸乙酯为洗脱剂进行硅胶柱层析分离。
作为本发明的进一步改进，步骤a中催化剂选自4-二甲氨基吡啶(DMAP)。
作为本发明的进一步改进，步骤a中化合物I与催化剂的摩尔比为1:0.1～0.5，优选为1:0.2～0.3。
作为本发明的进一步改进，步骤a中有机碱选自二乙胺、三乙胺、二异丙胺、吡啶、α-甲基吡啶、1，2-二甲基吡啶、4-羟基-2-甲基吡啶、γ-三甲基吡啶、喹啉或二甲基喹啉中的一种或其任意组合，步骤a中有机碱优选选自三乙胺、二异丙胺、吡啶或α-甲基吡啶中的一种或其任意组合；步骤a中化合物I与有机碱的摩尔比为1:1～10，优选为1:1～5，更优选为1:3～5；所述酯化反应的温度为0～50℃，优选为10～30℃。
作为本发明的进一步改进，步骤a中的酸酐选自
Figure PCTCN2022119607-appb-000007
所述化合物I与酸酐的摩尔比为1:1～10，优选为1:1～5，更优选为1:1.1～1.8。
作为本发明的进一步改进，步骤a中的酯化反应在反应溶剂C中进行，反应溶剂C包选自芳香烃类、氯代烷烃类、腈类溶剂或醚类溶剂中的一种或其任意组合；例如，芳香烃类选自甲苯、二甲苯或氯苯中的一种或其任意组合；氯代烷烃类选自二氯甲烷或氯仿中的一种或其任意组合；腈类选自乙腈、丙腈或苯腈中的一种或其任意组合；醚类选自石油醚、四氢呋喃、1,4-二氧六环、乙醚、二异丙醚或甲基叔丁基醚中的一种或其任意组合；反应溶剂C优选选自甲苯、二甲苯、甲基叔丁基醚或乙腈中的一种或其任意组合。
作为本发明的进一步改进，步骤a分离包括常规的分离步骤，例如分液、萃取、水洗或浓缩等，本发明对分液或萃取的溶剂没有特别的限制，可使用烷烃类、氯代烷烃类或醚类溶剂中的一种或其任意组合；例如，烷烃类选自正己烷、环己烷、正戊烷、环戊烷或正庚烷中的一种或其任意组合；氯代烷烃类选自二氯甲烷或氯仿中的一种或其任意组合；醚类选自石油醚、四氢呋喃、1,4-二氧六环、乙醚、二异丙醚或甲基叔丁基醚(MTBE)中的一种或其任意组合。
作为本发明的进一步改进，步骤b中的水解在水和有机溶剂D中进行，不产生负面作用的有机溶剂均适合该水解反应，有机溶剂D选自不产生负面作用的有机溶剂；有机溶剂D优选选自上述步骤a中的反应溶剂C，优选地，水解在水和乙腈中进行；反应温度优选为室温。
作为本发明的进一步改进，步骤b的水解在无机碱中进行，无机碱选自碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐或碱土金属氢氧化物中的一种或其任意组合。优选地，所述碱选自碱金属的氢氧化物或碱土金属氢氧化物中的一种或其任意组合，更优选地，所述碱是碱金属的氢氧化物。所述碱优选选自氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡中的一种或其任意组合；更优选为氢氧化钠或氢氧化钾中的一种或其任意组合。
作为本发明的进一步改进，步骤b中化合物5与无机碱的摩尔比为1:1～20，优选1:1～4。
第二方面，本发明提供一种制备手性化合物I的方法，包含将化合物4和化合物I的混合物进行分离的步骤，所述分离的方法包括：
3)通过柱层析方法分离化合物4和化合物I的混合物，得到化合物I；或
4)步骤a：在催化剂和有机碱作用下，化合物4和化合物I的混合物中的化合物I选择性地与酸酐发生酯化反应，分离得到化合物4和化合物5；步骤b：将所述化合物5水解得到化合物I，反应式如下：
Figure PCTCN2022119607-appb-000008
其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基；R 2选自
Figure PCTCN2022119607-appb-000009
作为本发明的进一步改进，第二方面化合物I的各步反应条件，可参考上述本发明第一方面中各步反应条件参数；连续投料时候，无论是通过化合物3A在生物酶A中酰化反应或者化合物3B在生物酶B中水解反应，得到化合物I和化合物4混合物，可按照理论收率各50％或者参考高效液相色谱法(HPLC)检测数量精准投料，均不影响下步与酸酐步骤a的反应。
作为本发明的进一步改进，化合物4可通过水解后，参考Synlett(2013),24(3),327-332(其全文通过引用结合至本申请中)中的方法直接转化得到化合物I。
作为本发明的进一步改进，所述化合物4和化合物I的混合物的制备包括：将化合物3A或化合物3B分别通过在生物酶A、生物酶B作用下选择性酰化或水解反应得到化合物4和化合物I的混合物。反应式如下：
Figure PCTCN2022119607-appb-000010
作为本发明的进一步改进，第二方面化合物4和化合物I的混合物的制备中的反应条件可参考上述本发明第一方面中各步反应条件。
第三方面，本发明提供制备化合物Ⅰ的一种关键中间体。在某些实施方案中，关键中间体化合物C如下表示：
Figure PCTCN2022119607-appb-000011
*表示手性碳；R选自被Ra取代或未取代的C 1-C 12直链或支链酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基、
Figure PCTCN2022119607-appb-000012
Figure PCTCN2022119607-appb-000013
，其中各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S。
优选地，当*表示的手性碳为S构型时，结构为：
Figure PCTCN2022119607-appb-000014
其中：R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基或丙烯酰基。
作为本发明的进一步改进，关键中间体化合物非限制性地选自以下化合物：
Figure PCTCN2022119607-appb-000015
当*表示手性碳为R构型时，结构为：
Figure PCTCN2022119607-appb-000016
其中：R 2选自
Figure PCTCN2022119607-appb-000017
作为本发明的进一步改进，关键中间体化合物非限制性地选自以下化合物：
Figure PCTCN2022119607-appb-000018
第三方面，本申请提供了一种制备艾日布林药物的方法，其包括本申请第一方面提供的方法或本申请第二方面提供的方法。
与现有技术相比，本发明提供了一种新的制备式Ⅰ所示的化合物的方法，所涉及的反应条件温和、环保，路线新颖、后处理和纯化简单，制备得到的式Ⅰ所示的化合物纯度高，制备方法操作简单、转化率高、选择性好、成本低、利于工业放大生产；式Ⅰ所示的化合物可用于在制备艾日布林药物中的应用；制备化合物Ⅰ方法的优点在于：
1)本发明外消旋化合物3(包括3A或3B)无需通过高成本SMB操作或利用手性配体与金属铬的催化作用，只需通过柱层析纯化手段，将本发明化合物3通过筛选的生物酶(A或B)选择性拆分，经常规过滤操作即可实现分离，相较于SMB色谱法制备，操作简便，便于放大，且降低生产周期，提高产能。
2)本发明筛选的生物酶具有选择性高，稳定性好，酶活性高和可回收重复利用，成本低的特点。
3)本发明通过生物酶选择性酰化，并发现利用极性差异实现外消旋化合物拆分，化合物Ⅰ收率＞93％，ee值＞99％。
4)本发明更具体地采用生物酶拆分法选择性将不需要的构型采用酰基进行保护，减小该中间产物极性，用酸酐在有机碱和催化剂作用下将需要的构型羟基与酸酐反应，增加该中间产物的水溶性，采用小极性溶剂萃取除去不需要的构型(采用酰基保护的产物)，在不通过柱层析纯化手段下也可以实现两个构型分离，ee值可以达到99％以上。
具体实施方式
为便于本领域技术人员理解本发明内容，下面将结合具体实施例进一步描述本发明的技术方案，但以下内容不是针对本发明权利要求书请求保护的范围和精神做出限制。本发明所用原料、试剂或溶剂无特殊说明均由商业化渠道购得，未特别说明的具体条件的实验方法以本领域常规操作条件进行。
本发明中，收率是指某生成物的实际产率与理论产率的摩尔百分比。“w”是质量比，例如，0.2w的生物酶就是指生物酶的质量与原料(化合物3A/化合物3B)的质量比为0.2。
实施例1
Figure PCTCN2022119607-appb-000019
将(20.0g，44.70mmol)化合物3A溶于120mL正庚烷中，加入(15.4g，223.48mmol)乙酸乙烯酯、(4.0g，0.2w)生物酶(enzyme)Lipase AK“Amano”，在氮气保护下，升内温至55-60℃，保持内温55-60℃反应至HPLC检测化合物I的ee值≥99％，反应完毕。反应液直接过滤，滤饼回收，滤液浓缩得粗品，过硅胶柱层析分离，减压蒸馏、浓缩至干得到10.5g化合物4-1，收率为48.0％；以及9.44g化合物Ⅰ，收率47.2％，ee值为99.8％。
化合物4-1的 1H-NMR(400MHz,CDCl 3):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 33BrO 3Si] +490.3,found 490.3.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例2
除了按照下述合成路线和按照表1调整参数以外，其余与实施例1相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000020
化合物4-2的 1H-NMR(400MHz,CDCl 3):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),1.05(s,9H).LC-MS(ESI):m/z calcd for[C 26H 35BrO 3Si] +504.5,found 504.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例3
除了按照下述合成路线和按照表1调整参数以外，其余与实施例1相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000021
化合物4-3的 1H-NMR(400MHz,CDCl 3):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 30H 35BrO 3Si] +552.4,found 552.4.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例4
除了按照下述合成路线和按照表1调整参数以外，其余与实施例1相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000022
化合物4-4的 1H-NMR(400MHz,CDCl 3):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)2.61-2.56(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 26H 33BrO 3Si] +504.5,found 504.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例5
Figure PCTCN2022119607-appb-000023
将(2.0g，4.47mmol)化合物Ⅰ溶于20mL乙腈中，加入(1.06g，13.41mmol)吡啶、(0.11g，0.894mmol)4-二甲氨基吡啶(DMAP)、(0.67g，6.705mmol)丁二酸酐，在氮气保护下，室温反应至薄层色谱(TLC)观测原料斑点消失，反应完毕。反应液浓缩得浅黄色油状物，过硅胶柱层析分离，减压蒸馏、浓缩至干得2.35g浅黄色油状物的化合物5-1，收率为96.0％。
1H-NMR(400MHz,CDCl 3):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),5.24-5.18(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 27H 35BrO5Si] +548.3,found 548.3.
实施例6
除了按照下述合成路线和按照表2调整参数以外，其余与实施例5相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000024
1H-NMR(400MHz,CDCl 3):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 27H 33BrO 5Si] +546.4,found 546.4.
实施例7
除了按照下述合成路线和按照表2调整参数以外，其余与实施例5相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000025
1H-NMR(400MHz,CDCl 3):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),5.49(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 31H 35BrO 5Si] +596.2,found 596.2.
实施例8
Figure PCTCN2022119607-appb-000026
将(10.0g，20.43mmol)化合物3B-1溶于50mL甲苯，加入(2.17g，20.43mmol)碳酸钠、(1.0g，0.1w)脂肪酶TL，水(1.5g，0.1w)，在氮气保护下，在35-40℃下搅拌反应至HPLC检测化合物I ee值≥99％，反应完毕。反应液直接过滤，滤饼回收，滤液用饱和食盐水洗涤，有机相浓缩得到粗品，过硅胶柱层析分离，得到4.81g化合物4-1，收率为48.1％；以及4.37g化合物Ⅰ，收率47.8％，ee值为99.8％。
化合物4-1的 1H-NMR(400MHz,CDCl 3):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 33BrO 3Si] +490.3,found 490.3.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例9
除了按照下述合成路线和按照表3调整参数以外，其余与实施例8相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000027
化合物4-2的 1H-NMR(400MHz,CDCl 3):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 26H 35BrO 3Si] +504.5,found 504.5
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例10
除了按照下述合成路线和按照表3调整参数以外，其余与实施例8相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000028
化合物4-3的 1H-NMR(400MHz,CDCl 3):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 30H 35BrO 3Si] +552.4,found 552.4；
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例11
除了按照下述合成路线和按照表3调整参数以外，其余与实施例8相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000029
化合物4-4的 1H-NMR(400MHz,CDCl 3):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)2.61-2.56(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 26H 33BrO 3Si] +502.5,found 502.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例12
Figure PCTCN2022119607-appb-000030
将(20.0g，44.70mmol)化合物3A溶于100mL正己烷中，加入(19.24g，223.48mmol)乙酸乙烯酯、(4.0g，0.2w)生物酶Lipase AK“Amano”，在氮气保护下，升内温至55-60℃，保持内温55-60℃反应至HPLC检测化合物I ee值≥99％，反应完毕。反应液直接过滤，滤饼回收，滤液浓缩得粗品，粗品用40mL乙腈溶解，加入(7.92g，78.23mmol)三乙胺(TEA)、(0.55g，4.47mmol)DMAP、(3.35g，33.53mmol)丁二酸酐，室温反应至TLC观测原料斑点消失，反应完毕，向反应液中加入正庚烷、水，收集正庚烷相，乙腈水相再用正庚烷萃取，合并正庚烷相，正庚烷相35～40℃减压浓缩干得到10.4g化合物4-1，收率为47.6％。
乙腈水相加(3.58g，89.40mmol)氢氧化钠固体，室温反应至TLC观测原料斑点消失，分液，收集乙腈相，乙腈相35～40℃减压浓缩干得到9.26g化合物Ⅰ，收率46.3％，ee值为99.7％。
化合物4-1的 1H-NMR(400MHz,CDCl 3):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 33BrO 3Si] +490.3, found 490.3.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例13
除了按照下述合成路线和按照表4调整参数以外，其余与实施例12相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000031
化合物4-2的 1H-NMR(400MHz,CDCl 3):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),1.05(s,9H).LC-MS(ESI):m/z calcd for[C 26H 35BrO 3Si] +504.5,found 504.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例14
除了按照下述合成路线和按照表4调整参数以外，其余与实施例12相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000032
化合物4-3的 1H-NMR(400MHz,CDCl 3):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 30H 35BrO 3Si] +552.4,found 552.4.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例15
除了按照下述合成路线和按照表4调整参数以外，其余与实施例12相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000033
化合物4-4的 1H-NMR(400MHz,CDCl 3):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)2.61-2.56(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 26H 33BrO 3Si] +504.5,found 504.5.
化合物I的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例16
Figure PCTCN2022119607-appb-000034
(20.0g，44.69mmol)化合物3A溶于100mL二氯甲烷(DCM)中，加入(13.57g，134.07mmol)三乙胺、(2.73g，22.34mmol)DMAP、(6.84g，67.035mmol)乙酸酐，在氮气保护下，室温反应至TLC观测原料斑点消失，反应完毕。反应液加50mL饱和食盐水，搅拌，分液，有机相浓缩得浅黄色油状物的粗品，用100mL正庚烷打浆，过滤，滤液浓缩 得21.34g浅黄色油状物化合物3B-1，收率为97.53％。
化合物3B-1的H-NMR(400MHz,CDCl 3):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 33BrO 3Si] +490.3,found 490.3.
实施例17
Figure PCTCN2022119607-appb-000035
将(10.0g，20.43mmol)化合物3B-1溶于50mL甲苯，加入(2.17g，20.43mmol)碳酸钠、(1.0g，0.1w)来自洋葱假单胞菌的脂酶PS-30、(1.0g，0.1w)水，在氮气保护下，35-40℃下搅拌反应至HPLC检测化合物5ee值≥99％，反应完毕。反应液直接过滤，滤饼回收，滤液用10mL饱和食盐水洗1次，有机相浓缩得粗品，粗品用20mL乙腈溶解，加入(3.62g，35.75mmol)TEA、(0.25g，2.043mmol)DMAP、(1.50g，15.32mmol)顺丁烯二酸酐，室温反应至TLC观测原料斑点消失，反应完毕，向反应液中加入20mL正庚烷、25mL水，收集正庚烷相，乙腈水相再用正庚烷萃取，合并正庚烷相，正庚烷相35～40℃减压浓缩干得到4.79g化合物4-1，收率为47.9％。
乙腈水相加(1.63g，40.86mmol)氢氧化钠固体，室温反应至TLC观测原料斑点消失，分液，收集乙腈相，乙腈相35～40℃减压浓缩干得到4.39g化合物Ⅰ，收率48.1％，ee值为99.8％。
化合物4-1的 1H-NMR(400MHz,CDCl 3):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 33BrO 3Si] +490.3,found 490.3.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例18
除了按照下述合成路线和按照表5调整参数以外，其余与实施例16相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000036
化合物3B-2的 1H-NMR(400MHz,CDCl 3):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 26H 35BrO 3Si] +504.5,found 504.5.
实施例19
除了按照下述合成路线和按照表6调整参数以外，其余与实施例17相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000037
化合物4-2的 1H-NMR(400MHz,CDCl 3):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 26H 35BrO 3Si] +504.5,found 504.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
实施例20
除了按照下述合成路线和按照表5调整参数以外，其余与实施例16相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000038
化合物3B-3的 1H-NMR(400MHz,CDCl 3):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 30H 35BrO 3Si] +552.4,found 552.4.
实施例21
除了按照下述合成路线和按照表6调整参数以外，其余与实施例17相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000039
化合物4-3的 1H-NMR(400MHz,CDCl 3):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 30H 35BrO 3Si] +552.4,found 552.4.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2
实施例22
除了按照下述合成路线和按照表5调整参数以外，其余与实施例16相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000040
化合物3B-4的 1H-NMR(400MHz,CDCl 3):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)2.61-2.56(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 26H 33BrO 3Si] +502.5,found 502.5.
实施例23
除了按照下述合成路线和按照表6调整参数以外，其余与实施例17相同，得到的产物核磁如下。
Figure PCTCN2022119607-appb-000041
化合物4-4的 1H-NMR(400MHz,CDCl 3):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)2.61-2.56(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 26H 33BrO 3Si] +502.5,found 502.5.
化合物Ⅰ的 1H-NMR(400MHz,CDCl 3):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 23H 31BrO 2Si] +448.2,found 448.2.
上述实施例1至实施例23中的相关参数如表1至表6所示。
表1
Figure PCTCN2022119607-appb-000042
表2
Figure PCTCN2022119607-appb-000043
表3
Figure PCTCN2022119607-appb-000044
Figure PCTCN2022119607-appb-000045
表4
Figure PCTCN2022119607-appb-000046
表5
Figure PCTCN2022119607-appb-000047
Figure PCTCN2022119607-appb-000048
表6
Figure PCTCN2022119607-appb-000049

Claims (10)

  1. 一种酶法制备手性化合物I的方法，包括如下方法：
    方法一：
    Figure PCTCN2022119607-appb-100001
    所述方法一以如式3A所示的化合物为原料，在生物酶A的作用下与酰化试剂发生酰化反应得到化合物4和化合物I，选择性地将所述化合物4和所述化合物I的混合物进行分离；
    方法二：
    Figure PCTCN2022119607-appb-100002
    所述方法二以如式3B所示的化合物为原料，在生物酶B和碱的作用下水解反应得到所述化合物4和所述化合物I，选择性地将所述化合物4和所述化合物I的混合物进行分离；
    其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基，更优选为乙酰基、丙酰基、丁酰基、苯甲酰基或丙烯酰基；
    所述生物酶A为脂肪酶或酯酶，所述生物酶A选自脂肪酶AK，来自荧光假单胞菌的脂肪酶，来自南极假丝酵母的脂肪酶B，固定在丙烯酸树脂上的南极假丝酵母脂肪酶B，脂肪酶AS，脂肪酶PS，来自嗜热霉菌的脂肪酶，来自念珠菌的脂肪酶，脂肪酶AYS，三酰基甘油脂肪酶，来自米赫毛霉菌的脂肪酶或来自米根霉菌的脂肪酶中的任一种，固定化于Immobead 150的南极洲假丝酵母脂肪酶B，重组来源于米曲霉；所述生物酶A优选为脂肪酶AK，来自荧光假单胞菌的脂肪酶或固定在丙烯酸树脂上的南极假丝酵母脂肪酶B Novozym 435；
    所述生物酶B为脂肪酶、酯酶或者水解酶，所述生物酶B选自脂肪酶TL，来自洋葱假单胞菌的脂酶PS-30，脂肪酶QLM，来自疏棉状嗜热丝孢菌的脂肪酶，来自洋葱假单胞菌的脂肪酶P2，来自施氏假单胞菌的脂肪酶PS，来自酒曲酶属的脂肪酶RS，来自洋葱假单胞菌的脂肪酶PS，来自黑曲霉的脂肪酶AN，来自无色菌属的脂肪酶A，来自产碱杆菌属的脂肪酶AS1，来自产碱杆菌属的脂肪酶AS2，来自圆柱假丝酵母的脂肪酶C2，来自圆 柱假丝酵母的脂肪酶C1，脂肪酶TL IM，脂肪酶TL 100L，南极假丝酵母脂肪酶B，CHIRAZYME E-1猪肝酯酶，来自假单胞菌属L-6的脂肪酶，南极假丝酵母脂肪酶A，皱褶假丝酵母脂肪酶L-3或胰脂肪酶，所述生物酶B优选为脂肪酶TL或来自洋葱假单胞菌的脂酶PS-30。
  2. 根据权利要求1所述的方法，其特征在于：所述方法一的酰化试剂选自乙烯酯或异丙烯酯，其中，所述乙烯酯选自被Rc取代或未取代的C 1-C 12直链或支链酸乙烯酯、苯甲酸乙烯酯、被Rc取代或未取代的C 3-C 6直链或支链烯酸乙烯酯；所述异丙烯酯选自被Rc取代或未取代的C 1-C 12直链或支链酸异丙烯酯、苯甲酸异丙烯酯、被Rc取代或未取代的C 3-C 6直链或支链烯酸异丙烯酯；各个基团的取代基Rc自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；
    所述酰化试剂优选为乙酸乙烯酯、乙酸异丙烯酯、丙酸乙烯酯、丙酸异丙烯酯、丁酸乙烯酯、丁酸异丙烯酯、异丁酸乙烯酯、异丁酸异丙烯酯、2-甲基丁酸乙烯酯、2-甲基丁酸异丙烯酯、3-甲基丁酸乙烯酯、3-甲基丁酸异丙烯酯、新戊酸乙烯酯、新戊酸异丙烯酯、2-甲基戊酸乙烯酯、2-甲基戊酸异丙烯酯、3-甲基戊酸乙烯酯、3-甲基戊酸异丙烯酯、4-甲基戊乙烯酯、4-甲基戊异丙烯酯、己酸乙烯酯、己酸异丙烯酯、月桂酸乙烯酯、月桂酸异丙烯酯、苯甲酸乙烯酯、苯甲酸异丙烯酯、丙烯酸乙烯酯或丙烯酸异丙烯酯，更优选为乙酸乙烯酯、乙酸异丙烯酯、丙酸乙烯酯、丙酸异丙烯酯、丁酸乙烯酯、丁酸异丙烯酯、苯甲酸乙烯酯、苯甲酸异丙烯酯、丙烯酸乙烯酯或丙烯酸异丙烯酯。
  3. 根据权利要求1所述的方法，其特征在于：所述方法一的酰化反应在有机溶剂A中进行，所述有机溶剂A选自烷烃类、芳香烃类、氯代烷烃类、腈类或醚类溶剂中的一种或其任意组合；所述有机溶剂A优选为石油醚、乙醚、甲基叔丁基醚、二氯甲烷、正己烷、环己烷、正戊烷、环戊烷、正庚烷、甲苯或乙腈中的一种或其任意组合；更优选为正己烷或正庚烷中的一种或其任意组合；
    和/或所述方法一中化合物3A与所述有机溶剂A的质量体积比为1g:1～15mL，更优选为1g:5～8mL；
    和/或所述方法一中酰化反应温度为30～80℃，优选为55～60℃；
    和/或所述方法一中化合物3A与所述生物酶A的质量比为1:0.005～0.3，优选为1:0.01～0.3，更优选为1:0.05～0.2；
    和/或所述方法一中化合物3A与所述酰化试剂的摩尔比为1:1～20，优选为1:2～10，更优选为1:3～6。
  4. 根据权利要求1所述的方法，其特征在于：所述方法二的水解反应在水和有机溶剂B中进行，所述有机溶剂B选自烷烃类、芳香烃类、氯代烷烃类、腈类溶剂或醚类溶剂中的一种或其任意组合；所述有机溶剂B优选选自甲苯、二甲苯、甲基叔丁基醚或乙腈中的 一种或其任意组合；
    和/或所述碱选自有机碱或无机碱，所述有机碱选自二乙胺、三乙胺、二异丙胺、吗啉、N-甲基吗啉、哌嗪或N-甲基哌嗪中的一种或其任意组合；所述无机碱选自碱金属氢氧化物、碳酸盐或碳酸氢盐或碱土金属氢氧化物中的一种或其任意组合；所述碱优选为氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钾、碳酸氢钠或碳酸钾中的一种或其任意组合；最优选为碳酸钠或碳酸钾中的一种或其任意组合；
    和/或方法二中化合物3B与所述生物酶B的质量比为1:0.005～0.3，优选为1:0.01～0.3，更优选为1:0.05～0.2；
    和/或方法二中化合物3B与所述碱的摩尔比为1:1～10，优选为1:1～8，更优选为1:1～4；
    和/或方法二中化合物3B与所述有机溶剂B的质量体积比为1g:1～15mL，更优选为1g:3～8mL。
    和/或方法二中水解反应温度为30～80℃，优选为35～40℃。
  5. 根据权利要求1所述的方法，其特征在于，所述选择性地将化合物4和化合物I的混合物进行分离的方法，包括：
    1)通过柱层析方法分离化合物4和化合物I的混合物，得到化合物I；或
    2)步骤a：在催化剂和有机碱作用下，化合物4和化合物I的混合物中的化合物I选择性地与酸酐发生酯化反应，分离得到化合物4和化合物5；步骤b：将所述化合物5水解得到化合物I，反应式如下：
    Figure PCTCN2022119607-appb-100003
    其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基；R 2选自
    Figure PCTCN2022119607-appb-100004
  6. 一种制备手性化合物I的方法，包含将化合物4和化合物I的混合物进行分离的步骤， 所述分离的方法包括：
    3)通过柱层析方法分离化合物4和化合物I的混合物，得到化合物I；或
    4)步骤a：在催化剂和有机碱作用下，化合物4和化合物I的混合物中的化合物I选择性地与酸酐发生酯化反应，分离得到化合物4和化合物5；步骤b：将所述化合物5水解得到化合物I，反应式如下：
    Figure PCTCN2022119607-appb-100005
    其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、苯甲酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为乙酰基、丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基、苯甲酰基或丙烯酰基；R 2选自
    Figure PCTCN2022119607-appb-100006
  7. 根据权利要求5或6所述的方法，其特征在于：所述柱层析方法分离是以体积比为20:1～5:1的石油醚∶乙酸乙酯为洗脱剂进行硅胶柱层析分离。
  8. 根据权利要求5或6所述的方法，其特征在于：所述步骤a中催化剂选自4-二甲氨基吡啶；
    和/或所述步骤a中化合物I与所述催化剂的摩尔比为1:0.1～0.5，优选为1:0.2～0.3；
    和/或所述步骤a中有机碱选自二乙胺、三乙胺、二异丙胺、吡啶、α-甲基吡啶、1，2-二甲基吡啶、4-羟基-2-甲基吡啶、γ-三甲基吡啶、喹啉或二甲基喹啉中的一种或其任意组合，优选选自三乙胺、二异丙胺、吡啶或α-甲基吡啶中的一种或其任意组合；
    和/或所述步骤a中化合物I与所述有机碱的摩尔比为1:1～10，优选为1:1～5，更优选为1:3～5；所述酯化反应的温度为0～50℃，优选为10～30℃；
    和/或所述步骤a中的酸酐选自
    Figure PCTCN2022119607-appb-100007
    所述化合物I与所述酸酐的摩尔比为1:1～10，优选为1:1～5，更优选为1:1.1～1.8；
    和/或所述步骤a中的酯化反应在反应溶剂C中进行，所述反应溶剂C选自芳香烃类、 氯代烷烃类、腈类溶剂或醚类溶剂中的一种或其任意组合；所述反应溶剂C优选选自甲苯、二甲苯、甲基叔丁基醚或乙腈中的一种或其任意组合；
    和/或所述步骤b中的水解在水和有机溶剂D中进行，所述有机溶剂D选自步骤a中的反应溶剂C，优选地，水解在水和乙腈中进行；反应温度优选为室温；
    和/或所述步骤b中的水解在无机碱中进行，所述无机碱选自碱金属氢氧化物、碱金属碳酸盐、碱金属碳酸氢盐或碱土金属氢氧化物中的一种或其任意组合；优选选自氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡中的一种或其任意组合；更优选选自氢氧化钠或氢氧化钾中的一种或其任意组合。
  9. 一种中间体化合物，结构如下：
    Figure PCTCN2022119607-appb-100008
    *表示手性碳；R为被Ra取代或未取代的C 1-C 12直链或支链酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基、
    Figure PCTCN2022119607-appb-100009
    Figure PCTCN2022119607-appb-100010
    其中各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；
    优选地，当*表示的手性碳为S构型时，结构为：
    Figure PCTCN2022119607-appb-100011
    其中，R 1为被Ra取代或未取代的C 1-C 12直链或支链酰基、被Ra取代或未取代的C 3-C 6直链或支链烯酰基，各个基团的取代基Ra各自独立地选自C 1-C 6直链或支链烷基、C 1-C 6直链或支链烷氧基、羟基、氨基、卤素、硝基、氰基、C 1-C 6酰胺基、C 3-C 6环烷基、C 1-C 6硫烷基、C 1-C 6酰胺基、C 3-C 6环烷基、苯基或C 3-C 18杂环芳香基，所述杂环芳香基上的杂原子选自O、N或S；R 1优选为丙酰基、丁酰基、异丁酰基、2-甲基丁酰基、3-甲基丁酰基、新戊酰基、2-甲基戊酰基、3-甲基戊酰基、4-甲基戊酰基、己酰基、月桂酰基或丙烯酰基；
    所述中间体化合物优选为以下化合物：
    Figure PCTCN2022119607-appb-100012
    当*表示的手性碳为R构型时，结构为：
    Figure PCTCN2022119607-appb-100013
    其中，R 2选自
    Figure PCTCN2022119607-appb-100014
    所述中间体化合物优选为以下化合物：
    Figure PCTCN2022119607-appb-100015
  10. 一种制备艾日布林药物的方法，其特征在于：包括权利要求1-5中任一项所述的方法或权利要求6-8中任一项所述的方法。
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