Preparation process of latanoprost, bemeprost and intermediates of latanoprost and bemeprost

Abstract

The invention discloses a preparation process of latanoprost, bemeprost and intermediates of the latanoprost and the bemeprost. Specifically, the invention provides a preparation method of a compound as shown in a formula IV, which comprises the following steps: in the presence of alkali and a solvent, carrying out wittig reaction on a compound as shown in a formula III and 4-carboxybutyl triphenylphosphonium bromide to generate the compound as shown in the formula IV, wherein the molar ratio of the compound shown in the formula III to the alkali is 1: (11-20); the reaction temperature of the wittig reaction is-40 DEG C to-5 DEG C. The preparation process provided by the invention has the advantages of high product purity, high yield and simple separation, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation process of latanoprost, bimatoprost and intermediates thereof. BACKGROUND

[0002] Prostaglandin (PG) is a kind of physiologically active unsaturated fatty acid, which is widely distributed in various tissues and body fluids, and can mediate a series of cell activities such as cell proliferation, differentiation and apoptosis after binding with specific receptors. Prostaglandin is mainly composed of one five alkyl and two side chains, and can be divided into various types according to the structure. Among them, PGF2α type prostaglandin drugs are widely used in clinical.

[0003] Representative drugs include bimatoprost and latanoprost, both of which can reduce intraocular pressure by increasing the aqueous humor outflow through the uveoscleral pathway, and are used for the treatment of open-angle glaucoma and high eye pressure. In addition, bimatoprost has been found to promote eyelash growth and has been approved for marketing in many countries and regions.

[0004] CN103288698A discloses a synthesis path of prostaglandin analogs, which is prepared by hydroxyl protection, reduction reaction, Wittig reaction, subsequent methyl esterification and isopropyl esterification, and ammonia solution and deprotection steps. The above route has many side reactions of the selected protecting groups, complex steps, which is not conducive to purification, and the final deprotection step will cause difficult separation of the product, many impurities and poor yield. SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the defects of difficult separation of the product, many impurities and poor yield in the prior art, and to provide a preparation process of bimatoprost and latanoprost with high product purity, high yield and simple separation.

[0006] The present application solves the above technical problems by the following technical scheme:

[0007] The present application provides a preparation method of a compound of formula IV, which comprises the following steps:

[0008] In the presence of a base and a solvent, a Wittig reaction occurs between a compound of formula III and 4-carboxybutyltriphenylphosphonium bromide to generate the compound of formula IV;

[0009] ;

[0010] The molar ratio of the compound of formula III to the base is 1: (11-20) ;

[0011] The reaction temperature of the Wittig reaction is -40~ -5℃.

[0012] In some embodiments, in the Wittig reaction, the base is one or more of potassium tert-butoxide, sodium tert-butoxide and sodium hydride; for example potassium tert-butoxide.

[0013] In some embodiments, in the Wittig reaction, the solvent is DMSO and / or THF; for example THF.

[0014] In some embodiments, in the Wittig reaction, when the base is potassium tert-butoxide, the potassium tert-butoxide is added in the form of a THF solution of potassium tert-butoxide, and the concentration of the THF solution of potassium tert-butoxide is (0.8-1.2) mol / L; for example 1 mol / L.

[0015] In some embodiments, in the Wittig reaction, when the base is sodium tert-butoxide or potassium tert-butoxide, the solvent is THF.

[0016] In some embodiments, in the Wittig reaction, when the base is sodium hydride, the solvent is DMSO.

[0017] In some embodiments, in the Wittig reaction, the molar ratio of the compound of formula III to 4-carboxybutyltriphenylphosphonium bromide is 1: (5-8); for example 1:6.

[0018] In some embodiments, in the Wittig reaction, the molar ratio of the compound of formula III to the base is 1: 11~14; for example 1: 11.5 or 1: 12.

[0019] In some embodiments, in the Wittig reaction, the compound of formula III is added in the form of a THF solution of the compound of formula III, and in the THF solution of the compound of formula III, the mass ratio of the compound of formula III to THF is 1: (2~5); for example 1:3.2.

[0020] In some embodiments, the reaction temperature of the Wittig reaction is -30~ -5℃; for example -30~ -20℃.

[0021] In some embodiments, in the Wittig reaction, the reaction material of the Wittig reaction consists of the compound of formula III, the base and the solvent.

[0022] In some embodiments, the Wittig reaction comprises the following specific steps: temperature control at -30 ~ -20℃; dropwise addition of the base to the mixture of the 4-carboxybutyltriphenylphosphonium bromide and the solvent, incubation and stirring, dropwise addition of the solution of the compound of formula III in the solvent at -30 ~ -20℃; incubation to generate the compound of formula IV.

[0023] The progress of the Wittig reaction can be monitored by conventional detection methods in the art (e.g. HPLC, TLC or NMR), and the reaction is generally terminated when the compound of formula III disappears, and the reaction time is generally 4-9 hours, for example 5 hours.

[0024] In some embodiments, the Wittig reaction further comprises the following post-treatment steps: after the reaction is completed, quenching with an aqueous ammonium chloride solution, extraction, and concentration.

[0025] In some embodiments, in the post-treatment step, the quenching is quenched at a temperature not exceeding 10℃.

[0026] In some embodiments, in the post-treatment step, the mass concentration of the aqueous ammonium chloride solution is 15-25%; for example, 20%.

[0027] In some embodiments, in the post-treatment step, the mass ratio of ammonium chloride in the aqueous ammonium chloride solution to the compound of formula III in the Wittig reaction is (10-20): 1; for example, 15: 1.

[0028] In some embodiments, the aqueous ammonium chloride solution adjusts the pH of the system to 5-8.

[0029] In some embodiments, in the post-treatment step, the extraction is extraction with ethyl acetate; the mass ratio of ethyl acetate to the compound of formula III in the Wittig reaction is (20-30): 1; for example, 25: 1; and the extraction times can be 1-3 times; for example, 2 times.

[0030] In some embodiments, the post-treatment step comprises the following specific steps: after the reaction is completed, slowly add 20% aqueous ammonium chloride solution to quench the reaction at a temperature not exceeding 10℃, adjust the pH of the system to 5-8, extract with ethyl acetate, and concentrate.

[0031] In some embodiments, the method for preparing the compound of formula IV further comprises the following step: in the presence of a solvent, the compound of formula II and DIBAL undergo a reduction reaction to generate the compound of formula III.

[0032] .

[0033] In some embodiments, in the reduction reaction, the solvent is one or more of toluene, dichloromethane, THF or methyl tert-butyl ether; for example, toluene.

[0034] In some embodiments, in the reduction reaction, the DIBAL is added in solution, for example, in toluene solution; for example, in 1.5M toluene solution; and the mass to volume ratio of the compound of formula II to the DIBAL solution is 1 kg / (3-6) L; for example, 1 kg / 5 L.

[0035] In some embodiments, the reduction reaction is carried out under the protection of inert gas; for example, under the protection of nitrogen.

[0036] The progress of the reduction reaction can be monitored by conventional detection methods in the art (for example, HPLC, TLC or NMR), and the reaction is generally terminated when the compound of formula II disappears, and the reaction time is generally 1-4 hours, for example, 2-3 hours.

[0037] The reaction time of the reduction reaction is -30-0°C; for example, -25°C.

[0038] In some embodiments, the material of the reduction reaction consists of the compound of formula II, the DIBAL and the solvent.

[0039] In some embodiments, the reduction reaction comprises the following specific steps: under the protection of nitrogen, controlling the temperature at -30-0°C, adding 1.5M DIBAL toluene solution dropwise into the mixture of the solvent and the compound II, and reacting at -30-0°C to obtain the compound of formula III.

[0040] In some embodiments, the reduction reaction further comprises the following post-treatment steps: after the reaction is completed, adding an acid to adjust the pH to non-basic, extracting, washing and concentrating.

[0041] In some embodiments, in the post-treatment step, the acid is citric acid; preferably, the citric acid is added in the form of aqueous citric acid solution; for example, 10% citric acid monohydrate aqueous solution.

[0042] In some embodiments, in the post-treatment step, the addition of the acid to adjust the pH to non-basic is to adjust the pH to 4-7.

[0043] In some embodiments, in the post-treatment step, the extraction is extraction with ethyl acetate; and the mass ratio of the ethyl acetate to the compound of formula II in the reduction reaction can be (1.5-2.5): 1; for example, 2: 1.

[0044] In some embodiments, the washing is washing the organic phase with water; for example, washing with water until the organic phase is neutral.

[0045] In some embodiments, the post-treatment step comprises the following specific steps: after the reaction is completed, adding 10% aqueous citric acid solution to adjust the pH of the aqueous phase to 4-7; stirring at 20-30°C; separating, extracting the aqueous phase with ethyl acetate, washing the combined organic phase with water until neutral, and concentrating.

[0046] In some embodiments, the method for preparing the compound of formula IV further comprises the following step: substituting the compound of formula I with tert-butyldimethylsilyl chloride in the presence of a solvent and a base to generate the compound of formula II.

[0047] .

[0048] In some embodiments, in the substituting reaction, the solvent is one or more of dichloromethane, THF, DMF, and toluene; for example, dichloromethane.

[0049] In some embodiments, in the substituting reaction, the base is one or more of imidazole, triethylamine, and DEA; for example, imidazole.

[0050] In some embodiments, in the substituting reaction, the mass ratio of the compound of formula I to the solvent is 1: (4-8); for example, 1:5.

[0051] In some embodiments, in the substituting reaction, the molar ratio of the compound of formula I to the tert-butyldimethylsilyl chloride is 1: (1.5-3); for example, 1:2.

[0052] In some embodiments, in the substituting reaction, the molar ratio of the compound of formula I to the base is 1: (2.5-3.5); for example, 1:3.

[0053] In some embodiments, in the substituting reaction, the reaction temperature of the substituting reaction is 10-40°C; for example, 30-40°C; such as 32°C.

[0054] The progress of the substituting reaction can be monitored using conventional detection methods in the art (for example, HPLC, TLC, or NMR), and the reaction is generally terminated when the compound of formula III disappears, and the reaction time is generally 0.5-3 hours, for example, 0.5 hours.

[0055] In some embodiments, the reaction material of the substituting reaction consists of the compound of formula I, the solvent, the base, and the tert-butyldimethylsilyl chloride.

[0056] In some embodiments, the substituting reaction comprises the following specific steps: the compound of formula I and the tert-butyldimethylsilyl chloride react in the presence of the solvent and the base at 30-40 °C to generate the compound of formula II.

[0057] In some embodiments, the substituting reaction further comprises the following post-treatment steps: after the reaction is completed, an aqueous citric acid solution is added for quenching, and then liquid separation, concentration, and recrystallization are performed.

[0058] In some embodiments, in the substituting reaction, the recrystallization is cooling recrystallization using methyl tert-butyl ether as the solvent; for example, the product is dissolved at 55-65 °C, and then cooled to 30-40 °C for incubation and stirring, cooled to 0-10 °C for incubation and stirring, and then filtered and dried.

[0059] The present application provides a method for preparing a compound of formula V, which comprises the following steps:

[0060] (1) preparing a compound of formula IV by the method for preparing a compound of formula IV according to any one of the present application;

[0061] (2) the compound of formula IV undergoes a deprotection reaction in the presence of a solvent and an acid to generate the compound of formula V;

[0062] .

[0063] In some embodiments, the solvent is an alcohol solvent; preferably one or more of isopropyl alcohol, methanol, or ethanol; for example, methanol.

[0064] In some embodiments, the acid is hydrochloric acid or trifluoroacetic acid; preferably, hydrochloric acid.

[0065] In some embodiments, the acid is added in the form of an acid solution; for example, an aqueous acid solution.

[0066] In some embodiments, the concentration of the acid solution is 1-10 M; preferably, 2-3 M; for example, 2 M.

[0067] In some embodiments, the mass ratio of the compound of formula IV to the solvent is 1: (3-7); preferably, 1:5.

[0068] In some embodiments, the molar ratio of the compound of formula IV to the acid is 1: (1-2); for example, 1:1.1.

[0069] In some embodiments, the reaction temperature of the deprotection reaction is -30-10 °C; for example, 0-10 °C.

[0070] The progress of the reaction can be monitored by conventional detection methods in the art (e.g. HPLC, TLC or NMR), and the reaction is generally terminated when the compound of formula IV disappears, and the reaction time is generally 2-6 hours; for example, 4 hours.

[0071] In some embodiments, in the deprotection reaction, the material of the deprotection reaction consists of the compound of formula IV, the acid and the solvent.

[0072] In some embodiments, the deprotection reaction comprises the following specific steps: after mixing the compound of formula IV and the solvent, controlling the temperature at 0-30°C, and adding the acid solution dropwise; controlling the temperature at 0-10°C to generate the compound of formula V.

[0073] In some embodiments, the deprotection reaction comprises the following post-treatment steps: after the reaction is completed, adding a base to adjust the solution to be alkaline, extracting, adding an acid to adjust the pH to be acidic, extracting, and drying and concentrating the combined organic phase to obtain the compound of formula V.

[0074] In some embodiments, in the post-treatment step, the base is sodium hydroxide, and preferably, the sodium hydroxide is added in the form of a 5% sodium hydroxide aqueous solution.

[0075] In some embodiments, in the post-treatment step, the molar ratio of the base to the acid in the deprotection reaction is (1.1-2):1; for example, 1.3:1.

[0076] In some embodiments, in the post-treatment step, the acid is citric acid monohydrate.

[0077] In some embodiments, in the post-treatment step, the addition of the acid to adjust the pH to be acidic is the addition of an acid to adjust the pH to be 5-7.

[0078] In some embodiments, in the post-treatment step, the drying is drying with anhydrous sodium sulfate.

[0079] In some embodiments, in the post-treatment step, the concentration is suction filtration.

[0080] In some embodiments, the post-treatment step comprises the following specific steps: after the reaction is completed, controlling the internal temperature to be not more than 20-30°C, slowly adding the base, extracting with ethyl acetate, adjusting the pH of the aqueous phase to 5-7 and then extracting with ethyl acetate, combining the organic phases, drying, suction filtering, and concentrating to obtain the compound of formula V.

[0081] The present application also provides a method for preparing a compound of formula VII, which comprises the following steps:

[0082] (1) preparing a compound of formula V: prepared by any of the methods for preparing a compound of formula V described in the present application;

[0083] (2) the compound of formula V and a methylating agent undergo a methylation reaction to obtain a compound of formula VI;

[0084] ;

[0085] (3) the compound of formula VI and an aqueous ethylamine solution undergo an amination reaction to obtain a compound of formula VII;

[0086] .

[0087] In some embodiments, the amination reaction further comprises a post-treatment step: after the reaction is completed, an acid is added to adjust the pH to 5-7, extraction is performed, and the organic phase is concentrated to obtain a crude product of the compound of formula VII a;

[0088] In some embodiments, the post-treatment step in the amination reaction further comprises recrystallization of the crude product of the compound of formula VII a: the crude product of the compound of formula VII a is dissolved in ethyl acetate, n-heptane or methyl tert-butyl ether is added, stirring is performed at -10-10°C, and concentration is performed to obtain a solid of the compound of formula VII.

[0089] In some embodiments, the aqueous ethylamine solution in the amination reaction is a 50-80% aqueous ethylamine solution; for example, a 70% aqueous ethylamine solution. The percentage of the aqueous ethylamine solution refers to the mass percentage of ethylamine in the aqueous ethylamine solution.

[0090] In some embodiments, the molar ratio of the compound of formula VI to the ethylamine in the amination reaction is 1: (40-100); for example, 1:62.

[0091] The reaction temperature of the amination reaction is a conventional reaction temperature for such reactions in the art; for example, 20-30°C; for example, 25°C.

[0092] The progress of the amination reaction can be monitored by using conventional detection methods in the art (for example, HPLC, TLC or NMR), and the reaction is generally terminated when the compound of formula VI disappears or no longer converts. The reaction time is generally 20-60 hours; for example, 30 hours.

[0093] In some embodiments, the acid in the post-treatment step in the amination reaction is citric acid.

[0094] In some embodiments, the extraction in the post-treatment step in the amination reaction is extraction with ethyl acetate and water.

[0095] In some embodiments, the mass ratio of ethyl acetate to water added in the extraction in the post-treatment step in the amination reaction is 10: (5-15); for example, 10:9.

[0096] In some embodiments, in the ammonolysis reaction, in the post-treatment step, the mass ratio of the compound of formula VI to the water added in the extraction is 1: (5-15); for example, 1:10.

[0097] In some embodiments, in the ammonolysis reaction, in the post-treatment step, the extraction further comprises using ethyl acetate to extract the aqueous phase after the layering, and the number of times of using ethyl acetate to extract the aqueous phase can be 2-6 times; for example, 4 times; and the mass ratio of ethyl acetate added in the extraction using ethyl acetate to water in the aqueous phase can be 1: (1-3); for example, 1:2.

[0098] In some embodiments, in the ammonolysis reaction, the post-treatment step comprises the following steps: after the reaction is completed, ethyl acetate and water are added, the layers are separated, an acid is added to adjust the pH to 5-7, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined and concentrated to obtain the crude compound of formula VII a.

[0099] In some embodiments, in the recrystallization of the crude compound of formula VII a, when the crude compound of formula VII a is dissolved in ethyl acetate and n-heptane is added, the mass ratio of the ethyl acetate to the n-heptane is 1000: (1-10); for example, 1000:2.3.

[0100] In some embodiments, in the recrystallization of the crude compound of formula VII a, when the crude compound of formula VII a is dissolved in ethyl acetate and methyl tert-butyl ether is added, the mass ratio of the ethyl acetate to the methyl tert-butyl ether is 1: (1.5-4); for example, 3:7.

[0101] In some embodiments, in the recrystallization of the crude compound of formula VII a, the mass ratio of the crude compound of formula VII a to the ethyl acetate is 1: (7-11); for example, 1:9.

[0102] In some embodiments, in the recrystallization of the crude compound of formula VII a, the stirring time is 1-2 h.

[0103] In some embodiments, the recrystallization of the crude compound of formula VII a comprises the following specific steps: the crude compound of formula VII a is dissolved in ethyl acetate, n-heptane is added, stirring is performed at -10-10°C, suction filtration is performed, and vacuum drying is performed at 30°C to obtain the solid compound of formula VII.

[0104] In some embodiments, the post-treatment further comprises a purification step: dissolving the solid compound of formula VII in a solvent at 55-65 °C, incubating with stirring, stirring at 35-45 °C (e.g. 40 °C), stirring at -10-10 °C (e.g. 5 °C), filtering, and drying to obtain the pure compound of formula VII; the solvent is a mixture of ethyl acetate and n-heptane or a mixture of ethyl acetate and methyl tert-butyl ether.

[0105] In some embodiments, in the purification step, the mass ratio of the solid compound of formula VII to the solvent is 1: (25-35); for example, 1:30.

[0106] In some embodiments, in the purification step, the solvent is a mixture of ethyl acetate and n-heptane, and the mass ratio of the ethyl acetate to the n-heptane is 1: (1.5-4); for example, 3:7.

[0107] In some embodiments, in the purification step, the solvent is a mixture of ethyl acetate and methyl tert-butyl ether, and the mass ratio of the ethyl acetate to the methyl tert-butyl ether is 1: (1.5-4); for example, 3:7.

[0108] In some embodiments, in the purification step, the filtering is suction filtration.

[0109] In some embodiments, in the purification step, the drying is vacuum drying at 30 °C.

[0110] In some embodiments, in the purification step, the incubation with stirring is for 0.5-1 hour; for example, 0.5 hour.

[0111] In some embodiments, in the purification step, the stirring at 35-45 °C is for 0.5-1 hour; for example, 0.5 hour.

[0112] In some embodiments, in the purification step, the stirring at -10-10 °C is for 1-2 hours; for example, 2 hours.

[0113] In some embodiments, the methyl esterification reaction is carried out in the presence of a solvent and a base.

[0114] In the methyl esterification reaction, the solvent is a conventional solvent for such reactions in the art, such as a ketone solvent; for example, acetone.

[0115] In some embodiments, in the methyl esterification reaction, the base is DBU, triethylamine, or pyridine; for example, DBU.

[0116] In some embodiments, in the methyl esterification reaction, the methyl esterification reagent is iodomethane or dimethyl sulfate; for example, iodomethane.

[0117] In some embodiments, the molar ratio of the compound of Formula V to the base in the methyl esterification reaction is 1: (3-5); for example, 1:4.

[0118] In some embodiments, the molar ratio of the compound of Formula V to the methyl esterification reagent in the methyl esterification reaction is 1: (5-9); for example, 1:6.

[0119] In some embodiments, the mass ratio of the compound of Formula V to the solvent in the methyl esterification reaction is 1: (5-10); for example, 1:6.

[0120] In some embodiments, the reaction temperature of the methyl esterification reaction is -30-30°C; for example, 0-10°C.

[0121] The progress of the methyl esterification reaction can be monitored by using conventional detection methods in the art (e.g., HPLC, TLC or NMR), and the reaction is generally terminated when the compound of Formula V disappears or no longer converts. The reaction time is generally 4-10 hours; for example, 4 hours.

[0122] In some embodiments, the methyl esterification reaction further comprises the following post-treatment steps: after the reaction is completed, extraction, concentration, and column chromatography.

[0123] In some embodiments, the post-treatment steps remove triphenylphosphine oxide and 5-(diphenylphosphinyl)pentanoic acid in the methyl esterification reaction.

[0124] In some embodiments, the extraction in the post-treatment steps in the methyl esterification reaction is extraction with ethyl acetate and water.

[0125] In some embodiments, the column chromatography in the post-treatment steps in the methyl esterification reaction is silica gel column chromatography; the eluent of the silica gel column chromatography can be dichloromethane / methanol or chloroform / methanol; for example, dichloromethane / methanol; the volume ratio of the dichloromethane / methanol can be (20-100):1.

[0126] The present application also provides a preparation method of a compound of Formula VIII, which comprises the following steps:

[0127] (1) preparing a compound of Formula V: prepared by any of the preparation methods of the compound of Formula V described in the present application;

[0128] (2) preparing a compound of Formula VIII: the compound of Formula V and isopropyl alcohol undergo isopropylization to generate the compound of Formula VIII;

[0129] .

[0130] In some embodiments, the isopropylation reaction is carried out in the presence of a base and a solvent.

[0131] In some embodiments, in the isopropylation reaction, the base is an organic strong base; for example, DBU.

[0132] In the isopropylation reaction, the solvent is a conventional solvent for such reactions in the art, such as a ketone solvent; for example, acetone.

[0133] The reaction temperature of the isopropylation reaction is a conventional reaction temperature for such reactions in the art; for example, 10-30°C; for example, 20°C.

[0134] In some embodiments, in the isopropylation reaction, the molar ratio of the compound of formula V to the base is 1: (3-5); for example, 1:4.

[0135] In some embodiments, in the isopropylation reaction, the molar ratio of the compound of formula V to the isopropanol is 1: (5-18); for example, 1:14.

[0136] In some embodiments, in the isopropylation reaction, the mass ratio of the compound of formula V to the solvent is 1: (6-14); for example, 1:10.

[0137] In some embodiments, the reaction material of the isopropylation reaction is the solvent, the base, the compound of formula V, and the isopropanol.

[0138] In some embodiments, the reaction time of the isopropylation reaction is 4-7 hours; for example, 5 hours.

[0139] In some embodiments, the isopropylation reaction further comprises the following post-treatment steps: after the reaction is completed, filtering, concentrating, adding ethyl acetate and water to extract, washing, concentrating, and column chromatography.

[0140] In some embodiments, in the isopropylation reaction, in the post-treatment step, in the extraction, the mass ratio of the compound of formula V to the ethyl acetate is 1: (10-20); for example, 1:15; and the mass ratio of the compound of formula V to the water can be 1: (5-15); for example, 1:10.

[0141] In some embodiments, the column chromatography is silica gel column chromatography; the eluent of the silica gel column chromatography can be a mixture of dichloromethane and methanol; and the volume ratio of the dichloromethane to the methanol can be (20-100):1.

[0142] The positive progress effect of the present application is that the preparation process of the present application has high product purity, high yield, and simple separation, and is more suitable for industrial production. DETAILED DESCRIPTION

[0143] The application will be further illustrated by the following examples without limiting the application to the examples.

[0144] Synthesis of compound II of example 1 (hydroxyl protection)

[0145] ;

[0146] The reactor was charged with 47.5 kg of compound I, 237.5 kg of dichloromethane was added to dissolve and 29 kg of tert-butyl dimethyl chlorosilane and 20 kg of imidazole were added, the solution was turbid, the temperature was raised, the internal temperature was kept at 30-40℃, and the stirring was carried out at reflux for 1-2 h.

[0147] Work-up:

[0148] The reactor was charged with 141 kg of 10% citric acid aqueous solution, the phases were separated, the organic phase was washed once with 100 kg of water, the phases were separated, and the organic phase was concentrated to obtain an oily substance. The oily substance was added with 100 kg of methyl tert-butyl ether, the temperature was raised to 55-65℃ to dissolve, the heating was turned off, and the natural cooling was carried out to 32℃, the solid was precipitated, the temperature was kept and the stirring was carried out for 30 min, the temperature was lowered, the internal temperature was kept at 0-10℃, and the stirring was carried out for 0.5 h, the filtration was carried out, and the filter cake was dried to obtain 51.3 kg of yellow solid. The yield was 87.6%.

[0149] Example 2 reduction reaction

[0150] ;

[0151] The reactor was charged with 51 kg of compound II and 255 kg of toluene, the temperature was lowered under nitrogen protection, the internal temperature was kept at -30~0℃, and 200 L of 1.5 mol / L DIBAL solution was added dropwise. After the dropwise addition was completed, the temperature was kept at -25℃ and the stirring was carried out for 2-3 h.

[0152] Work-up:

[0153] After the reaction was completed, 550 kg of 10% citric acid monohydrate aqueous solution was added to adjust the pH of the aqueous phase to 4~7, the stirring was carried out at 20-30℃ for 1-2 h, the phases were separated, the aqueous phase was extracted once with 100 kg of ethyl acetate, the phases were separated, the combined organic phase was washed with 300 kg of water until it was neutral, and the organic phase was concentrated to obtain 52 kg of solid. The column was passed to obtain 29 g of white solid. The yield was 81.1%.

[0154] Example 3 wittig reaction

[0155] ;

[0156] 240 kg 4-carboxybutyltriphenylphosphonium bromide and 270.0 kg anhydrous THF were added into a reaction kettle, under nitrogen protection, cooling, and the internal temperature was kept at -30 ~ -20 °C, 900 kg potassium tert-butoxide tetrahydrofuran solution (1 mol / L) was added dropwise, and after the dropwise addition was completed, the internal temperature was kept at -30 ~ -20 °C for 1 h; cooling, the internal temperature was kept at -30 ~ -20 °C, 36 kg of the compound of formula III was added into anhydrous THF (115 kg), and after the addition was completed, the internal temperature was kept at 25 °C for 5 h.

[0157] Post-processing:

[0158] The internal temperature was controlled not to exceed 10 °C, about 2700.0 kg of 20% ammonium chloride aqueous solution was slowly added dropwise, the pH was adjusted to 5 ~ 8, 900.0 kg of ethyl acetate was added for extraction twice, and the organic phase was concentrated to obtain 90.0 kg of oil.

[0159] Example 4: deprotection

[0160] ;

[0161] 90 kg of compound IV and 450 kg of methanol were added into a reaction kettle and dissolved; cooling, the internal temperature was kept at 0-10 °C, 120 kg of 2M hydrochloric acid was slowly added dropwise, after the dropwise addition was completed, the internal temperature was kept at 5 °C for 4 h.

[0162] Post-processing:

[0163] The internal temperature was controlled not to exceed 20 ~ 30 °C, 520 kg of 5% sodium hydroxide was slowly added dropwise, after the dropwise addition was completed, the water phase was extracted with ethyl acetate for several times; the water phase was adjusted to pH 5 ~ 7 with 20% citric acid monohydrate, and extracted with 900.0 kg of ethyl acetate three times; the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 33.0 g of oil, with a yield of 97.0% (two-step yield of examples 3, 4). HPLC results showed that the content of 5-trans isomer (5-trans isomer) impurity was 0.69%.

[0164] Example 5: methyl esterification

[0165] ;

[0166] 30.0 kg of compound V and 180.0 kg of acetone were added into a reaction kettle, and cooled under nitrogen protection; the internal temperature was kept at 0-10 °C, 48 kg of DBU was added dropwise, after the dropwise addition of DBU was completed, the internal temperature was kept at 0-10 °C, 66 kg of iodomethane was added dropwise, after the dropwise addition was completed, the internal temperature was kept at 25 °C for 4 h;

[0167] Post-processing:

[0168] ​The filtrate was concentrated to give 90.0 kg of oil. 450.0 kg of ethyl acetate and 300.0 kg of water were added, and the phases were separated. The aqueous phase was extracted once more with 150.0 kg of ethyl acetate, the phases were separated, and the organic phases were combined. The organic phase was washed with 300.0 kg of water, and the phases were separated. The organic phase was concentrated (40-50 °C) to give 25.0 g of oil.

[0169] Column chromatography:

[0170] The oil was subjected to column chromatography on silica gel (dichloromethane / methanol = 100:1 to 20:1). The eluate was concentrated to give about 22.8 g of product, with a yield of 73.4%.

[0171] Example 6: Ammonolysis reaction

[0172] ;

[0173] 18.0 kg of compound VI and 180 kg of 70% aqueous ethylamine were added to a reaction kettle, and the internal temperature was maintained at 25 °C. The mixture was stirred for 30 h, and the reaction was completed.

[0174] Work-up:

[0175] The reaction liquid was concentrated to give 17.9 kg of oil. 200 kg of ethyl acetate and 180 kg of water were added, and the phases were separated. The pH was adjusted to 5-7 using 10% aqueous citric acid. The aqueous phase was extracted four times with 90.0 kg of ethyl acetate, and the organic phases were combined. The organic phase was washed with 180 kg of water. Anhydrous sodium sulfate (anhydrous sodium sulfate was agglomerated) was added to the organic phase, and the mixture was suction filtered. The filtrate was concentrated to give 17.9 kg of oil.

[0176] The above oil was dissolved in 162.0 kg of ethyl acetate. 380.0 g of n-heptane was added, and the temperature was lowered to -10-10 °C. The mixture was stirred for 1-2 h, and the mixture was suction filtered. The filter cake was dried at 30 °C under vacuum to give 14.5 g of white solid. The yield was 78.0%.

[0177] Example 7: Refining

[0178] ;

[0179] 12.7 g of solid (dry product) was added to 381 g of an ethyl acetate / n-heptane solution. The temperature was raised to 55-65 °C, and the mixture was dissolved. The mixture was stirred for 0.5 h while maintaining the temperature. The heating was turned off, and the temperature was slowly lowered. At 40 °C, the solid precipitated. The mixture was stirred for 0.5 h while maintaining the temperature. The temperature was lowered using an ice water bath, and the internal temperature was maintained at 5 °C. The mixture was stirred for 2 h, and the mixture was suction filtered. The filter cake was dried at 30 °C under vacuum to give 12.1 g of white solid. The purity of the product was 99.8%, and the yield was 95.3%.

[0180] Example 8: Isopropyl esterification

[0181] ;

[0182] Into a reaction kettle, 30.0 kg of compound V and 300 kg of acetone were added, and the temperature was lowered under nitrogen protection; the internal temperature was kept at 0-10 °C, 48 kg of DBU was added dropwise, after the dropwise addition of DBU was completed, the internal temperature was kept at 0-10 °C, 66 kg of isopropanol was added dropwise, after the dropwise addition was completed, the internal temperature was kept at 20 °C and stirred for 5 h;

[0183] Post-treatment:

[0184] The filtrate was concentrated to obtain 90.0 kg of an oil, 450.0 kg of ethyl acetate and 300.0 kg of water were added, and the phases were separated; the aqueous phase was extracted once more with 150.0 kg of ethyl acetate, the phases were separated, and the organic phases were combined, the organic phase was washed with 300.0 kg of water, and the phases were separated; the organic phase was concentrated (40-50 °C) to obtain 25.0 g of an oil.

[0185] Column chromatography:

[0186] The oil was subjected to silica gel column chromatography (dichloromethane / methanol = 100:1-20:1), and the eluent was concentrated to obtain about 24.7 kg of product, with a yield of 73.9%.

[0187] Example 9

[0188] ;

[0189] ;

[0190] The same method as in Examples 3-4 was used, except that the reaction temperature in Example 3 was replaced by -10-0 °C; the deprotected product was detected, and the HPLC results showed that the content of 5-trans isomer impurities was 1.24%.

[0191] Comparative Example 1

[0192] ;

[0193] ;

[0194] The same method as in Examples 3-4 was used, except that the equivalent of tert-butyl alcohol in Example 3 was changed to 8 equivalents, and the reaction time was changed to 10 hours; the product was detected, and the HPLC results showed that the content of 5-trans isomer impurities was 2.79%.

[0195] Although the specific embodiments of the present application are described above, those skilled in the art should understand that this is only an illustration, and the protection scope of the present application is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present application, and such changes and modifications all fall within the protection scope of the present application.

Claims

1. A method for preparing a compound of formula IV, characterized in that, It includes the following steps: In the presence of a base and a solvent, the compound of formula III and 4-carboxybutyltriphenylphosphine bromide undergo a Wittig reaction to generate the compound of formula IV; ； Wherein, the molar ratio of the compound of formula III to the base is 1:(11~20). The reaction temperature of the Wittig reaction is -40 to -5℃.

2. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In the Wittig reaction, the base is one or more of potassium tert-butoxide, sodium tert-butoxide, and sodium hydride; for example, potassium tert-butoxide; Preferably, when the base is sodium tert-butoxide or potassium tert-butoxide, the solvent is THF; Preferably, when the base is sodium hydride, the solvent is DMSO; (2) In the Wittig reaction, the solvent is DMSO and / or THF; for example, THF; (3) In the Wittig reaction, when the base is potassium tert-butoxide, the potassium tert-butoxide is added in the form of a potassium tert-butoxide THF solution, and the concentration of the potassium tert-butoxide THF solution is (0.8-1.2) mol / L; for example, 1 mol / L; (4) In the Wittig reaction, the molar ratio of the compound of formula III to the 4-carboxybutyltriphenylphosphine bromide is 1:(5-8); for example, 1:6; (5) In the Wittig reaction, the molar ratio of the compound of formula III to the base is 1:11 to 13; for example, 1:11.5 or 1:12; (6) In the Wittig reaction, the compound of formula III is added as a THF solution of the compound of formula III, wherein the mass ratio of the compound of formula III to the THF in the THF solution is 1:(2~5); for example, 1:3.2; (7) The reaction temperature of the Wittig reaction is -30 to -5℃; for example, -30 to -20℃; (8) In the Wittig reaction, the reactants of the Wittig reaction consist of the following: the compound of formula III, the base, and the solvent; Preferably, the Wittig reaction includes the following specific steps: controlling the temperature to -30~-20℃; adding the base dropwise to the mixture of the 4-carboxybutyltriphenylphosphine bromide and the solvent, stirring while maintaining the temperature, and adding a solution of the solvent of the compound of formula III dropwise while maintaining the temperature to -30~-20℃; and reacting at this temperature to generate the compound of formula IV. (9) The reaction time of the Wittig reaction is 4-9 hours, for example 5-8 hours; such as 5 hours; (10) The Wittig reaction further includes the following post-processing steps: after the reaction is completed, the reaction is quenched with an ammonium chloride aqueous solution, and then extracted and concentrated. Preferably, in the Wittig reaction, in the post-processing step, the quenching is performed at a temperature not exceeding 10°C; Preferably, in the Wittig reaction, in the post-treatment step, the mass concentration of the ammonium chloride aqueous solution is 15-25%; for example, 20%. Preferably, in the Wittig reaction, in the post-treatment step, the mass ratio of ammonium chloride in the ammonium chloride aqueous solution to the compound of formula III in the Wittig reaction is (10~20):1; for example, 15:1; Preferably, in the Wittig reaction, in the post-treatment step, the pH of the ammonium chloride aqueous solution is adjusted to 5-8; Preferably, in the Wittig reaction, in the post-treatment step, the extraction is performed using ethyl acetate; the mass ratio of ethyl acetate to the compound of formula III in the Wittig reaction is (20~30):1; for example, 25:1; Preferably, in the Wittig reaction, the post-processing step includes the following specific steps: after the reaction is completed, quench the reaction by slowly adding 20% ​​ammonium chloride aqueous solution while controlling the temperature to no more than 10°C, adjust the pH of the system to 5-8, extract with ethyl acetate, and concentrate.

3. The preparation method according to claim 1, characterized in that, The preparation method of the compound of formula IV further includes the following steps: in the presence of a solvent, the compound of formula II and DIBAL undergo a reduction reaction to generate the compound of formula III; 。 4. The preparation method according to claim 3, characterized in that, It meets one or more of the following conditions: (1) In the reduction reaction, the solvent is one or more of toluene, dichloromethane, THF, and methyl tert-butyl ether; for example, toluene; (2) In the reduction reaction, the DIBAL is added in solution form, such as in toluene solution; for example, in 1.5M toluene solution; the mass-to-volume ratio of the compound of formula II and the DIBAL solution is 1 kg / (3-6) L; for example, 1 kg / 5 L; (3) The reduction reaction is carried out under a protective atmosphere; for example, under nitrogen protection. (4) The reaction time of the reduction reaction is 1-4 hours, for example 2-3 hours; (5) The reaction temperature of the reduction reaction is -30~0℃; for example, -25℃; (6) The materials for the reduction reaction consist of the following: the compound of formula II, the DIBAL and the solvent; (7) The reduction reaction includes the following specific steps: under nitrogen protection, the temperature is controlled at -30~0℃, 1.5M DIBAL toluene solution is added dropwise to the mixture of the solvent and the compound II, and the reaction is carried out at -30~0℃ to obtain the compound of formula III; (8) The reduction reaction also includes the following post-processing steps: after the reaction is completed, acid is added to adjust the pH to non-alkaline, then extraction, washing and concentration are performed. Preferably, in the reduction reaction, in the post-treatment step, the acid is citric acid; preferably, the citric acid is added in the form of an aqueous solution of citric acid, for example, a 10% aqueous solution of citric acid monohydrate. Preferably, in the reduction reaction, in the post-treatment step, the addition of acid to adjust the pH to non-alkaline means adding acid to adjust the pH to 4-7; Preferably, in the reduction reaction, in the post-treatment step, the extraction is performed with ethyl acetate; the mass ratio of ethyl acetate to the compound of formula II in the reduction reaction can be (1.5~2.5):1; for example, 2:1; Preferably, in the reduction reaction, the washing is the washing of the organic phase with water; for example, washing with water until the organic phase is neutral; Preferably, in the reduction reaction, the post-processing step includes the following specific steps: after the reaction is completed, add 10% citric acid monohydrate aqueous solution to adjust the pH of the aqueous phase to 4-7; stir at 20-30℃; separate the liquid and extract the aqueous phase with ethyl acetate, combine the organic phases, wash with water until neutral, and concentrate.

5. The preparation method according to claim 3, characterized in that, The preparation method of the compound of formula IV further includes the following steps: in the presence of a solvent and a base, the compound of formula I and tert-butyldimethylchlorosilane undergo a substitution reaction to generate the compound of formula II; 。 6. The preparation method according to claim 5, characterized in that, It meets one or more of the following conditions: (1) In the substitution reaction, the solvent is one or more of dichloromethane, THF, DMF and toluene; for example, dichloromethane; (2) In the substitution reaction, the base is one or more of imidazole, triethylamine, and DEA; for example, imidazole; (3) In the substitution reaction, the mass ratio of the compound of formula I to the solvent is 1:(4-8); for example, 1:5; (4) In the substitution reaction, the molar ratio of the compound of formula I and the tert-butyldimethylchlorosilane is 1:(1.5-3); for example, 1:2; (5) In the substitution reaction, the molar ratio of the compound of formula I to the base is 1:(2.5-3.5); for example, 1:3; (6) In the substitution reaction, the reaction temperature is 10-40℃; for example, 30-40℃; such as 32℃; (7) The reaction time of the substitution reaction is 0.5-3 hours, for example 0.5 hours; (8) The reactants for the substitution reaction consist of the following: the compound of formula I, the solvent, the base, and the tert-butyldimethylchlorosilane; Preferably, the substitution reaction includes the following specific steps: in the presence of the solvent and the base, the compound of formula I and the tert-butyldimethylchlorosilane are refluxed at 30-40°C to generate the compound of formula II; (9) The substitution reaction further includes the following post-processing steps: after the reaction is completed, citric acid aqueous solution is added to quench the reaction, followed by separation, concentration, and recrystallization; Preferably, in the substitution reaction, in the post-processing step, the recrystallization is carried out by using methyl tert-ether as a solvent for cooling recrystallization; for example, the product is dissolved at 55-65°C, cooled to 30-40°C and stirred, cooled to 0-10°C and stirred, and then filtered and dried.

7. A method for preparing a compound of formula V, comprising the following steps: (1) Preparation of Formula IV compound: prepared by the method for preparing Formula IV compound according to any one of claims 1-6; (2) In the presence of solvent and acid, compound IV undergoes a deprotection reaction to generate compound V; 。 8. The preparation method according to claim 7, characterized in that, It meets one or more of the following conditions: (1) In the deprotection reaction, the solvent is an alcohol solvent; preferably one or more of isopropanol, methanol or ethanol; for example, methanol; (2) In the deprotection reaction, the acid is trifluoroacetic acid; preferably hydrochloric acid; (3) In the deprotection reaction, the acid is added in the form of an acid solution; the acid solution is, for example, an aqueous solution of an acid; (4) In the deprotection reaction, the concentration of the acid solution is 1-10M; preferably 2-3M; for example, 2M; (5) In the deprotection reaction, the mass ratio of the compound of formula IV to the solvent is 1:(3-7); preferably 1:5; (6) In the deprotection reaction, the molar ratio of the compound of formula IV to the acid is 1:(1-2); for example, 1:1.1; (7) The reaction temperature of the deprotection reaction is -30~10℃; for example, 0~10℃; (8) The reaction time for the deprotection reaction is 2 to 6 hours; for example, 4 hours; (9) In the deprotection reaction, the materials for the deprotection reaction consist of the following: the compound of formula IV, the acid, and the solvent; Preferably, the deprotection reaction includes the following specific steps: the compound of formula IV is mixed with a solvent and the temperature is controlled at 0-30°C, and the acid solution is added dropwise; the reaction is controlled at 0-10°C to generate compound of formula V; (10) The deprotection reaction includes the following post-processing steps: after the reaction is completed, add alkali to adjust the solution to alkaline, extract, add acid to adjust the pH of the aqueous phase to acidic, extract, combine the organic phases, dry and concentrate. Preferably, in the deprotection reaction and in the post-treatment step, the base is sodium hydroxide, and preferably, the sodium hydroxide is added in the form of a 5% sodium hydroxide aqueous solution; Preferably, in the deprotection reaction, in the post-treatment step, the molar ratio of the base to the acid in the deprotection reaction is (1.1~2):1; for example, 1.3:1; Preferably, in the deprotection reaction, in the post-treatment step, the acid is citric acid monohydrate; Preferably, in the deprotection reaction, in the post-treatment step, the addition of acid to adjust the pH of the aqueous phase to acidity is to adjust the pH to 5-7. Preferably, in the deprotection reaction, in the post-treatment step, the drying is performed using anhydrous sodium sulfate; Preferably, in the deprotection reaction, in the post-processing step, the concentration is performed by vacuum filtration; Preferably, in the deprotection reaction, the post-processing step includes the following specific steps: after the reaction is completed, the internal temperature is controlled not to exceed 20~30℃, the base is slowly added, and the mixture is extracted with ethyl acetate. The pH of the aqueous phase is adjusted to 5~7 and then extracted with ethyl acetate. The organic phases are combined, dried, filtered, and concentrated.

9. A method for preparing a compound of formula VII, comprising the following steps: (1) Preparation of compound V: prepared by the method for preparing compound V according to any one of claims 7-8; (2) Compound V and a methylating agent undergo a methylation reaction to yield compound VI; Preferably, the methyl esterification reaction is carried out in the presence of a solvent and a base; ； (3) Compound VI reacts with aqueous ethylamine to produce compound VII via ammonolysis. ； Preferably, the ammonolysis reaction further includes the following post-processing steps: after the reaction is complete, acid is added to adjust the pH to 5-7, extraction is performed, and the organic phase is concentrated to obtain crude product a of compound VII; Preferably, the post-processing step further includes recrystallization of crude compound a of formula VII: dissolving crude compound a of formula VII in ethyl acetate, adding n-heptane or methyl tert-butyl ether, stirring at -10 to 10°C, and concentrating to obtain solid compound VII.

10. The preparation method according to claim 9, characterized in that, It meets one or more of the following conditions: (1) In the ammonolysis reaction, the aqueous ethylamine solution is a 50-80% aqueous ethylamine solution; for example, a 70% aqueous ethylamine solution; the percentage of the aqueous ethylamine solution refers to the mass percentage of ethylamine in the aqueous ethylamine solution; (2) In the ammonolysis reaction, the molar ratio of the compound of formula VI to the ethylamine is 1:(40~100); for example, 1:62; (3) The reaction temperature of the ammonolysis reaction is 20-30℃; for example, 25℃; (4) The reaction time for the ammonolysis reaction is 20 to 60 hours; for example, 30 hours; (5) In the ammonolysis reaction, in the post-treatment step, the acid is citric acid; (6) In the ammonolysis reaction, in the post-treatment step, the extraction is performed by adding ethyl acetate and water for extraction; (7) In the ammonolysis reaction, in the post-treatment step, the mass ratio of ethyl acetate and water added during extraction is 10:(5~15); for example, 10:9; (8) In the ammonolysis reaction, in the post-treatment step, the mass ratio of the compound of formula VI to the water added during extraction is 1:(5~15); for example, 1:10; (9) In the ammonolysis reaction, in the post-processing step, the extraction further includes extraction of the aqueous phase with ethyl acetate after separation, and the number of times the aqueous phase is extracted with ethyl acetate can be 2-6 times; for example, 4 times; the mass ratio of ethyl acetate added to water in the aqueous phase during the extraction of the aqueous phase can be 1:(1~3); for example, 1:

2. Preferably, in the ammonolysis reaction, the post-processing step includes the following steps: after the reaction is complete, ethyl acetate and water are added, the layers are separated, acid is added to adjust the pH to 5-7, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined and concentrated to obtain crude product a of compound VII; (10) In the recrystallization of crude compound a of formula VII, when crude compound a of formula VII is dissolved in ethyl acetate and n-heptane is added, the mass ratio of ethyl acetate to n-heptane is 1000:(1~10); for example, 1000:2.3; (11) In the recrystallization of crude compound a of formula VII, when crude compound a of formula VII is dissolved in ethyl acetate and methyl tert-butyl ether is added, the mass ratio of ethyl acetate to methyl tert-butyl ether is 1:(1.5~4); for example, 3:7; (12) In the recrystallization of the crude compound a of formula VII, the mass ratio of the crude compound a of formula VII to the ethyl acetate is 1:(7~11); for example, 1:9; (13) In the recrystallization of the crude product a of compound of formula VII, the stirring time is 1-2 h; (14) The recrystallization of crude compound a of formula VII includes the following specific steps: dissolve crude compound a of formula VII in ethyl acetate, add n-heptane or methyl tert-butyl ether, stir at -10~10℃, filter, and dry under vacuum at 30℃ to obtain solid compound VII; (15) The post-processing further includes a purification step: dissolving the solid of the compound of formula VII in a solvent at 55~65°C, stirring at a constant temperature, stirring at 35~45°C (e.g. 40°C), stirring at -10~10°C (e.g. 5°C), filtering, and drying to obtain the pure product of the compound of formula VII; the solvent is a mixed solvent of ethyl acetate and n-heptane or a mixed solvent of ethyl acetate and methyl tert-butyl ether; Preferably, in the purification step, the mass ratio of the solid compound of formula VII to the solvent is 1:(25~35); for example, 1:30; Preferably, in the purification step, the solvent is a mixture of ethyl acetate and n-heptane, wherein the mass ratio of ethyl acetate to n-heptane is 1:(1.5~4); for example, 3:

7. Preferably, in the purification step, the solvent is a mixture of ethyl acetate and methyl tert-butyl ether, and the mass ratio of ethyl acetate to methyl tert-butyl ether is 1:(1.5~4); for example, 3:

7. Preferably, in the refining step, the filtration is vacuum filtration; Preferably, in the refining step, the drying is vacuum drying at 30°C; Preferably, in the refining step, the stirring time for the heat-preserving stirring is 0.5 to 1 hour; for example, 0.5 hours. Preferably, in the refining step, the stirring time at 35~45°C is 0.5~1 hour; for example, 0.5 hours. Preferably, in the refining step, the stirring time at -10~10℃ is 1~2 hours; for example, 2 hours.

11. The preparation method according to claim 9, characterized in that, It meets one or more of the following conditions: (1) In the methyl esterification reaction, the solvent is a ketone solvent, such as acetone; (2) In the methyl esterification reaction, the base is DBU, triethylamine, or pyridine; for example, DBU; (3) In the methyl esterification reaction, the methyl esterification reagent is iodomethane or dimethyl sulfate; for example, iodomethane; (4) In the methyl esterification reaction, the molar ratio of the compound of formula V to the base is 1:(3~5); for example, 1:4; (5) In the methyl esterification reaction, the molar ratio of the compound of formula V to the methyl esterification reagent is 1:(5~9); for example, 1:6; (6) In the methyl esterification reaction, the mass ratio of the compound of formula V to the solvent is 1:(5~10); for example, 1:6; (7) The reaction temperature of the methyl esterification reaction is -30~30℃; for example, 0~10℃; (8) The reaction time for the methyl esterification reaction is 4 to 10 hours; for example, 4 hours; (9) The methyl esterification reaction also includes the following post-processing steps: after the reaction is completed, extraction, concentration, and column chromatography are performed. Preferably, in the methyl esterification reaction, the post-treatment step removes triphenylphosphine oxide and 5-(diphenylphosphino)valerate. Preferably, in the methyl esterification reaction, in the post-treatment step, the extraction is performed by adding ethyl acetate and water for extraction; Preferably, in the methyl esterification reaction, in the post-treatment step, the column chromatography is silica gel column chromatography; the eluent for the silica gel column chromatography can be dichloromethane / methanol or chloroform / methanol; for example, dichloromethane / methanol; the volume ratio of dichloromethane / methanol can be (20~100):

1.

12. A method for preparing a compound of formula VIII, comprising the following steps: (1) Preparation of compound V: prepared by the method for preparing compound V according to any one of claims 7-8; (2) Preparation of compound VIII: Compound V and isopropanol undergo an isopropylation reaction to generate compound VIII; ； Preferably, the isopropylation reaction is carried out in the presence of a base and a solvent.

13. The preparation method according to claim 12, characterized in that, It meets one or more of the following conditions: (1) In the isopropylation reaction, the base is a strong organic base; for example, DBU; (2) In the isopropylation reaction, the solvent is a ketone solvent; for example, acetone; (3) The reaction temperature of the isopropylation reaction is 10~30℃; for example, 20℃; (4) In the isopropylation reaction, the molar ratio of the compound of formula V to the base is 1:(3~5); for example, 1:4; (5) In the isopropylation reaction, the molar ratio of the compound of formula V to the isopropanol is 1:(5~18); for example, 1:14; (6) In the isopropylation reaction, the mass ratio of the compound of formula V to the solvent is 1:(6~14); for example, 1:10; (7) The reactants for the isopropylation reaction are the solvent, the base, the compound of formula V, and the isopropanol; (8) The reaction time for the isopropylation reaction is 4-7 hours; for example, 5 hours; (9) The isopropylation reaction further includes the following post-processing steps: after the reaction is completed, filter, concentrate, add ethyl acetate and water for extraction, wash, concentrate, and column chromatography. Preferably, in the isopropylation reaction, in the post-treatment step, in the extraction, the mass ratio of the compound of formula V to the ethyl acetate is 1:(10~20); for example, 1:15; the mass ratio of the compound of formula V to the water can be 1:(5~15); for example, 1:10; Preferably, in the isopropylation reaction, in the post-processing step, the column chromatography is silica gel column chromatography; the eluent for the silica gel column chromatography can be a mixture of dichloromethane and methanol; the volume ratio of dichloromethane to methanol can be (20~100):1.

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