Synthesis process of bemaprost intermediate

Abstract

The invention relates to the technical field of medicine synthesis, and particularly discloses a synthesis process of a bemaprost intermediate. According to the method, B is taken as a starting point of a reaction route, a carbon chain skeleton is constructed through a Grignard reaction, stereo enrichment is realized through enzymatic resolution, a byproduct configuration is converted in combination with a Mitsunobu reaction, finally, a target product is obtained through enzyme hydrolysis, the stereoselectivity of the whole process is good in control, and high enantiomer purity of the product is ensured through chiral recognition of an enzyme and overturning of the configuration through an SN2 reaction.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical synthesis technology, and more specifically, to a synthetic process for a bemexprost intermediate. Background Technology

[0002] Bimatoprost is a highly effective intraocular pressure-lowering drug developed and manufactured by Allergan in the United States. It is unique in its pharmacology, possessing a strong intraocular pressure-lowering effect. The chemical name of bimatoprost is (Z)-7-[(1R,2R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its chemical structure is as follows:

[0003] Compound A is a key intermediate in the preparation of bimetprost, and its chemical structure is as follows:

[0004] The method disclosed in patent WO2013186550 uses phenylpropionaldehyde B as a raw material, which undergoes a one-step esterification reaction to obtain methyl phenylpropionate C. Compound C is then amidated with dimethylhydroxylamine hydrochloride to obtain compound D, which is then combined with ethynyltriisopropylsilane at -78°C in the presence of n-butyllithium to form compound E. Compound E is then selectively reduced with [(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(ll)ruthenium(ll) as a catalyst to obtain compound F. Further removal of the triisopropylsilyl group yields the target product A. The entire process involves five steps and requires an ultra-low temperature environment and the participation of precious rare metals. This results in a lengthy process with poor operability, low efficiency, and high cost.

[0005] The literature *Journal of Organic Chemistry* (2009), 74(5), 1939-1951 discloses another synthetic method for compound A: using phenylpropanal B as a raw material, a Wittig-Honnar reaction is carried out to obtain an olefin ester H with extended valence bonds. Compound H is further reduced at -78°C with diisobutylaluminum hydride as a reducing agent to obtain an enol compound I. Compound I is reacted with tert-butyl hydroperoxide and Ti(Oi-Pr) at low temperatures of -20 to -40°C in the presence of diisopropyl isopropoxide titanium tartrate (L-(+)-DIPT) to obtain an olefin epoxide J. The hydroxyl group of epoxide J is replaced by chlorine in the presence of triphenylphosphine tetrachloride to obtain compound K. Compound K is reduced at -78°C with the participation of tert-butyllithium to obtain compound A. Research on this route has currently only reached the mg to g level, involving a total of five steps, many of which require ultra-low temperature environments and the participation of precious rare metals. The reaction conditions are harsh, and the materials are not readily available. This results in lengthy processes, poor operability, low efficiency, high costs, and is not conducive to large-scale production.

[0006] To address the issues of lengthy process steps, poor operability, low efficiency, and high cost mentioned above, a simple and efficient synthesis process for compound A is provided. This process shortens reaction steps, simplifies production operations, avoids process repetition, avoids ultra-low temperature reactions, avoids the use of expensive materials, improves production efficiency, and reduces production costs. This process is of great value for the production of bemexprost. Summary of the Invention

[0007] To address the issue of easily preparing bimeprost intermediates with high yields, this application provides a synthetic process for bimeprost intermediates.

[0008] The synthetic process for the bemexprost intermediate provided in this application adopts the following technical solution: S1: Synthesis of compound L: B was dissolved in tetrahydrofuran, and a solution of ethynyl magnesium bromide in diethyl ether was slowly added. The reaction was stirred at low temperature, and then a saturated ammonium chloride solution was added. The precipitate was dissolved in water, the organic layer was separated, the aqueous layer was extracted with methyl tert-butyl ether, the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to obtain L. S2: Synthesis of compounds M and N: L and lipase PS "Amano" were added to a mixed solution of vinyl acetate and n-heptane, the mixture was heated and stirred, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N. S3: Synthesis of compounds M and O: A mixture of M and N, triphenylphosphine, and formic acid were dissolved in THF. After cooling, a tetrahydrofuran solution of diethyl azodicarbonate was added dropwise. The mixture was heated and stirred, concentrated under reduced pressure, and a mixture of ethyl acetate and n-heptane was added. The mixture was filtered and concentrated, and column chromatography was used to obtain a mixture of M and O. S4: Synthesis of intermediate A: A mixture of M and O was dissolved in a mixed solvent including a nonpolar solvent, lipase was added, the mixture was reacted, washed, and dried to obtain A.

[0009] By adopting the above technical solution, using B as the starting material and ethynyl magnesium bromide as a nucleophile to attack B from both sides, a Grignard reaction is carried out to generate racemic L. Lipase PS "Amano" selectively catalyzes the reaction of the hydroxyl group of L with vinyl acetate to generate M, while the (R)-configured N is difficult to react due to steric hindrance and exists in the form of free alcohol. Enantiomer separation is achieved by recognizing the chiral active site of the enzyme. Diethyl azodicarbonate reacts with triphenylphosphine to form a phosphate intermediate, which activates the carboxyl group of formic acid, making it an electrophile. Formic acid attacks the chiral carbon of nitrogen to form a formate, while triphenylphosphine captures a proton, causing the hydroxyl group to invert and convert nitrogen to oxygen. The mixture of M and O was selectively alcoholyzed into compound A in a mixed solvent system using lipase PS "Amano" as a catalyst. The unreacted S-chiral isomers of M and O were separated by column chromatography, thereby achieving a high ee value for compound A.

[0010] In one specific feasible implementation, the molar ratio of B to ethynyl magnesium bromide in S1 is 1:(1-1.1), the low temperature is 0-10℃, and nitrogen gas is used for protection during the reaction.

[0011] Preferably, the ammonium chloride solution is added slowly during quenching.

[0012] By adopting the above technical solutions, the attack effect of acetylated magnesium bromide is better, and it also prevents violent exothermic reactions. The reaction process is relatively mild, the reaction effect is better, and the purity is higher.

[0013] In one specific feasible implementation, the mass ratio of lipase PS "Amano" and L in S2 is 0.5:(0.9-1), and the reaction temperature is 38-42℃.

[0014] By adopting the above technical solutions, the reaction temperature and concentration are suitable for the lipase of this application, the reaction rate is fast, the yield is high, the lipase has high activity, and the catalytic effect is good.

[0015] In one specific feasible implementation, the cooling temperature in S3 is 0-10°C, the stirring time is 1-2 hours, and the tetrahydrofuran is anhydrous tetrahydrofuran.

[0016] By adopting the above technical solutions, diethyl azodicarbonate does not decompose, has few side reactions, and does not produce double bond isomerization.

[0017] In one specific feasible implementation, the mass ratio of M+N, triphenylphosphine and diethyl azodicarbonate in S3 is 1:3:(2.2-2.7).

[0018] By adopting the above technical solutions, the activation effect is better, the hydroxyl configuration is better flipped, and the configuration control effect is better.

[0019] In one specific implementation, the enzyme in S4 includes powdered lipase or immobilized lipase.

[0020] In one specific implementation, the enzyme in S4 includes one or more of immobilized BCA lipase and immobilized BL-IM lipase supplied by Shanghai Banglin Biotechnology.

[0021] By adopting the above technical solutions, the reaction effect is better, the enzyme stability is stronger, it is not easily deformed by stirring, etc., it has strong recognition of the stereoconfiguration of the reactants, and preferentially catalyzes the alcoholysis of the target ester bond.

[0022] In one specific feasible implementation, the mass ratio of enzyme to M+O in S4 is (1-50):100.

[0023] In one specific feasible implementation, the enzyme in S4 is an immobilized BL-IM lipase, with a mass ratio of (10-20):100 to M+O.

[0024] By adopting the above technical solutions, the enzyme is more stable and the reaction effect is better, without causing substrate mass transfer restriction or aggregation effect that leads to a decrease in enzyme activity.

[0025] Preferably, the nonpolar organic solvent in the mixed solvent includes one or more of n-pentane, n-hexane, n-heptane, and n-octane, and the amount used is 2-50 times the volume weight ratio of the M and O mixture.

[0026] Preferably, the nonpolar organic solvent is n-heptane, and the amount used is 3-10 times the volume of the mixture of M and O.

[0027] In one specific feasible implementation, the reaction temperature in S4 is 10-70°C.

[0028] By adopting the above technical solutions, the active center of lipase is moderately flexible at this temperature, resulting in the highest catalytic efficiency. This temperature also maintains the stability of the substrate configuration and avoids racemization.

[0029] Preferably, S4 also includes column chromatography.

[0030] In summary, this application has the following beneficial effects: This application uses B as the starting point of the reaction route, constructs the carbon chain backbone through Grignard reaction, achieves stereoenrichment through enzyme-catalyzed resolution, transforms the configuration of by-products through Mitsunobu reaction, and finally obtains the target product through enzymatic hydrolysis. The stereoselectivity of the entire process is well controlled, and the high enantiomeric purity of the product is ensured by using the chiral recognition of enzymes and the SN2 reaction to flip the configuration.

[0031] This application presents a mild and easy-to-operate reaction with high safety. The reaction process exhibits excellent stability and strong tolerance, with no significant impurity generation or growth even after prolonged reaction time. The enzymatic resolution and esterification process, a one-step reaction, replaces the original three-step reaction, simplifying the process and improving economic efficiency. This one-step reaction achieves a conversion rate of over 90% and a separation yield of over 85%, approximately 10% higher than the original three-step reaction's total yield of 75%, making it highly valuable for the production of bemeprost. Attached Figure Description

[0032] Figure 1 , Figure 2 The NMR spectrum of the bemeprost intermediate obtained in the embodiments of this application. Detailed Implementation Example

[0033] To further aid in understanding the technical solution of this invention, several specific implementation examples are provided below to describe the technical solution of this invention in more detail. All of these described embodiments are only some embodiments of this invention, and not all of them. The following specific embodiments can be combined with each other, and the same or similar concepts or processes may not be described again in some embodiments; and the reaction devices, monomer compounds, etc. involved in the following embodiments are all commercially available.

[0034] The following specific embodiments can be combined with each other, and the same or similar concepts or processes may not be described again in some embodiments.

[0035] The following examples are further illustrations of the present invention, but the present invention is not limited thereto.

[0036] Example 1 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through methyl tert-butyl ether silica gel, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.2 g of a mixture of compounds M and O, 0.1 g of immobilized BCA lipase and 2 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 29 hours. Compound A was generated in 88.0% of the sample with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 85%.

[0037] Example 2: S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 200 mL of 0.5 M ethynyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 78.4%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.1%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.2 g of a mixture of compounds M and O, 0.1 g of immobilized BCA lipase and 2 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 29 hours. Compound A was generated in 88.0% of the sample with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 85%.

[0038] Example 3 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 10g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 59.1%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.2 g of a mixture of compounds M and O, 0.1 g of immobilized BCA lipase and 2 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 29 hours. Compound A was generated at 88.1% with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 84%.

[0039] Example 4 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 75 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 92.6%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.2 g of a mixture of compounds M and O, 0.1 g of immobilized BCA lipase and 2 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 29 hours. Compound A was generated in 88.0% of the sample with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 86%.

[0040] Example 5 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.2 g of a mixture of compounds M and O, 0.1 g of immobilized BL-IM lipase and 2 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 29 hours. Compound A was generated at 88.8% with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 85%.

[0041] Example 6 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.5 g of a mixture of compounds M and O, 0.25 g of immobilized BL-IM lipase and 5 mL of ethanol were added to a reaction flask. The mixture was stirred at 50 °C for 22 hours. 90.8% of compound A was generated, with an ee value of 99.1%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 85%.

[0042] Example 7 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.5 g of a mixture of compounds M and O, 0.1 g of immobilized BL-IM lipase and 5 mL of n-propanol were added to a reaction flask. The mixture was stirred at 45 °C for 25.5 hours. 94.8% of compound A was generated with an ee value of 98.9%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 90%.

[0043] Example 8 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 1.0 g of a mixture of compounds M and O, 0.2 g of immobilized BL-IM lipase and 10 mL of n-propanol were added to a reaction flask. The mixture was stirred at 25 °C for 24 hours. Compound A was generated in 95.5% of the solution with an ee value of 99.1%. The solution was filtered and the mother liquor was concentrated to dryness to obtain compound A with a yield of 91%.

[0044] Example 9 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 1.0 g of a mixture of compounds M and O, 0.2 g of immobilized BL-IM lipase and 10 mL of n-propanol were added to a reaction flask. The mixture was stirred at 45 °C for 24 hours. 93.7% of compound A was generated with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 91%.

[0045] Example 10 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.5 g of a mixture of compounds M and O, 0.05 g of immobilized BL-IM lipase, and 5 ml of n-propanol and n-heptane in a 1:1 volume ratio were added to a reaction flask. The mixture was stirred at 45 °C for 28 hours. 96.2% of compound A was generated, with an ee value of 99.1%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 93%.

[0046] Example 11 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.5 g of a mixture of compounds M and O, 0.05 g of immobilized BL-IM lipase, and 5 ml of n-propanol and n-heptane in a volume ratio of 1:2 were added to a reaction flask. The mixture was stirred at 45 °C for 20 hours. 96.0% of compound A was generated, with an ee value of 99.0%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 93%.

[0047] Example 12 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 10g of a mixture of compounds M and O, 1g of immobilized BL-IM lipase, and 100ml of n-propanol and n-heptane in a volume ratio of 1:2 were added to a reaction flask. The mixture was stirred at 45°C for 24 hours, and 97.2% of compound A was generated. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A. The compound A was then purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 5) to obtain compound A with a purity of 99.2%, an ee value of 99.2%, and a yield of 85%.

[0048] Example 13 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of Intermediate A Under nitrogen protection, 10 g of a mixture of compounds M and O, 1 g of immobilized BL-IM lipase, and 100 ml of n-propanol and n-heptane (volume ratio 1:2) were added to a reaction flask. The mixture was stirred at 45°C for 20 hours. Compound A was generated at 96.4% purity with an ee value of 99.3%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A. Compound A was then purified by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 7) to obtain compound A with a GC purity of 99.8%, an ee value of 99.3%, and a yield of 88%.

[0049] Example 14 S1: Synthesis of compound L: 16 g B was dissolved in 30 mL tetrahydrofuran under nitrogen protection, and 250 mL of 0.5 M acetylenyl magnesium bromide in diethyl ether solution was slowly added. The mixture was stirred at 0 °C, and then 70 mL of saturated ammonium chloride solution was slowly added. 70 mL of water was added to dissolve the white precipitate. The organic layer was separated, and the aqueous layer was extracted twice with 70 mL of methyl tert-butyl ether. The organic layers were combined, dried over magnesium sulfate, filtered through a silica gel column of methyl tert-butyl ether, and concentrated under reduced pressure to obtain L, with a yield of 98.1%. S2: Synthesis of compounds M and N: 40g of L and 20g of lipase PS "Amano" were added to a mixed solution of 50g of vinyl acetate and 130ml of n-heptane. The mixture was heated to 40°C and stirred for 24 hours. The mixture was filtered through a diatomaceous earth layer, and the filtrate was concentrated under reduced pressure to obtain a mixture of M and N with a yield of 89.4%. S3: Synthesis of compounds M and O: 30 g of the mixture of M and N obtained in S2, 90 g of triphenylphosphine, and 16 ml of formic acid were dissolved in 157 ml of tetrahydrofuran. A mixture of 60 ml of diethyl azodicarbonate and 68 ml of tetrahydrofuran was added dropwise at 0 °C. The mixture was stirred for 2 hours, concentrated under reduced pressure, and 400 ml of a mixture of ethyl acetate and n-heptane in a volume ratio of 1:2 was added. The precipitate was filtered and purified by column chromatography to obtain a mixture of M and O with a yield of 87.4%. S4: Synthesis of intermediate A: Under nitrogen protection, 0.5 g of a mixture of compounds M and O, 0.10 g of immobilized BL-IM lipase, and 5 ml of n-propanol and n-heptane in a 1:1 volume ratio were added to a reaction flask. The mixture was stirred at 45 °C for 28 hours. Compound A was generated at a yield of 96.1% and an ee value of 99.3%. The mixture was filtered, and the mother liquor was concentrated to dryness to obtain compound A with a yield of 93%.

[0050] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A synthetic process for a bemexprost intermediate, characterized in that: The synthesis process includes the following steps: S1: Synthesis of compound L: B was dissolved in tetrahydrofuran, and a solution of ethynyl magnesium bromide in diethyl ether was slowly added. The reaction was stirred at low temperature, and then a saturated ammonium chloride solution was added. The precipitate was dissolved in water, the organic layer was separated, the aqueous layer was extracted with methyl tert-butyl ether, the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to obtain L. S2: Synthesis of compounds M and N: L and lipase PS "Amano" were added to a mixture of vinyl acetate and n-heptane, the mixture was heated and stirred, and then filtered and concentrated to obtain a mixture of M and N. S3: Synthesis of compounds M and O: A mixture of M and N, triphenylphosphine, and formic acid were dissolved in tetrahydrofuran. After cooling, a tetrahydrofuran solution of diethyl azodicarbonate was added dropwise. The mixture was heated and stirred, concentrated under reduced pressure, and then a mixture of ethyl acetate and n-heptane was added. After filtration and concentration, column chromatography was used to obtain a mixture of M and O. S4: Synthesis of intermediate A: Dissolve a mixture of M and O in an alcohol or a mixture of alcohol and a nonpolar solvent, add lipase, react, cool, filter, dry and concentrate to obtain A:

2. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The molar ratio of B to acetylated magnesium bromide in S1 is 1:(1-1.1), the low temperature is 0-10℃, and nitrogen gas is used for protection during the reaction.

3. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The mass ratio of lipase PS "Amano" to L in S2 is 0.5:(0.9-1), and the reaction temperature is 38-42℃.

4. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The cooling temperature in S3 is 0-10℃, and the stirring time is 1-2 hours.

5. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The mass ratio of M+N, triphenylphosphine and diethyl azodicarbonate in S3 is 1:3:(2.2-2.7).

6. The synthesis process of the bemexprost intermediate according to claim 1, characterized in that... The enzyme in S4 includes powdered lipase or immobilized lipase.

7. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The enzyme in S4 includes one or more of the immobilized BCA lipase and immobilized BL-IM lipase supplied by Shanghai Banglin Biotechnology.

8. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The mass ratio of enzyme to M+O in S4 is (1-50):

100.

9. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The enzyme in S4 is an immobilized BL-IM lipase with a mass ratio of (1-2):

10.

10. The synthesis process of the bemeprost intermediate according to claim 1, characterized in that... The reaction temperature in S4 is 10-70℃.

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