Method for realizing asymmetric efficient synthesis of latanoprost through enzyme catalysis

Abstract

The invention provides a method for realizing asymmetric efficient synthesis of latanoprost through enzyme catalysis, which specifically comprises the following steps: oxidizing and rearranging furfuryl alcohol to obtain a compound 1, carrying out Luche reduction and acetyl protection to obtain a compound 3, and splitting the compound 3 under the action of Candida antarctica lipase B to obtain a key intermediate 4; the preparation method comprises the following steps: carrying out a reaction with N-iodosuccinimide and vinyl ethyl ether to obtain a compound 5, carrying out Ni catalytic cyclization to obtain a Corey lactone derivative 6, carrying out a two-step continuous Grignard reaction to obtain a compound 8, carrying out a Corey-Bakshii-Shiba reaction, acetal oxidation, hydroxyl protection and lactone reduction to obtain a high-grade intermediate 12, carrying out a Wittig reaction to obtain a compound 13, carrying out carboxyl esterification to obtain a compound 14, and carrying out a reaction to obtain a compound 7. Removing alcoholic hydroxyl protection to obtain latanoprost; the synthesis method overcomes the defects of high cost, incomplete diversity, single technology, low comprehensive yield and the like of the existing process of prostaglandin molecules, and can realize mass production of latanoprostaglandin.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for realizing an asymmetric and efficient synthesis of latanoprost through enzyme catalysis. Background Art

[0002] The living system has a huge metabolic network, which provides abundant enzymes for various biochemical reactions to ensure the normal operation of the body. Natural biocatalysts (enzymes) are usually composed of 20 kinds of amino acids, which can catalyze specific reactions under mild conditions and have high selectivity. Enzymes include hydrolases, lyases, ketoreductases, alcohol dehydrogenases, etc. Due to their control over three-dimensional space, even substrates with fewer active sites can be converted to a large extent. A single enzymatic reaction can effectively reduce the reaction steps, increase yields, and reduce costs and environmental impacts, which are extremely valuable for industry. The combination of chemical and biocatalysis can use the methods and approaches of synthetic chemistry to obtain the unique structural characteristics of natural products, thereby producing a high hit rate, making drug discovery and production possible.

[0003] Since the separation of prostaglandins in the 1980s, the related chemical and biosynthetic work has attracted much attention, and it has excellent pharmacological and biological activities. This application has achieved the total synthesis of latanoprost for the first time through enzyme catalysis, and developed intermediate 8 with subsequent transformation potential, providing ideas for the divergent synthesis of prostaglandin family molecules. Summary of the invention

[0004] The present invention mainly overcomes the shortcomings of the prior art and proposes an asymmetric and efficient synthesis method of latanoprost by enzyme catalysis, specifically comprising: oxidative rearrangement of furfuryl alcohol to obtain compound 1, Luche reduction and acetyl protection to obtain compound 3, compound 3 is split under the action of Candida antarctica lipase B (CALB, Novozym 435) to obtain key intermediate 4; reacting with N-iodosuccinimide and vinyl ethyl ether to obtain compound 5, Ni-catalyzed cyclization to obtain Corey lactone derivative 6, and then two-step continuous Grignard reaction to obtain compound 8, compound 8 is subjected to Corey-Bakshi-Shibata (CBS) reaction, acetal oxidation, hydroxyl protection and lactone reduction to obtain advanced intermediate 12, and then Wittig reaction to obtain compound 13, esterification of carboxyl to obtain compound 14, and removal of alcohol hydroxyl protection to obtain latanoprost. The synthesis method overcomes the defects of the existing process of prostaglandin molecules, such as high cost, incomplete diversity, single technology and low comprehensive yield, and can realize the mass production of latanoprost. The key intermediate 6 can also be used to synthesize a variety of prostaglandin molecules.

[0005] In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

[0006] An asymmetric and efficient synthesis method of latanoprost by enzyme catalysis, the reaction process is as follows:

[0007]

[0008] The synthesis method comprises steps 1 to 15:

[0009] Specific:

[0010] Step 1: Using furfuryl alcohol as the starting material, oxidative rearrangement is carried out under acidic and high temperature conditions to obtain compound 1;

[0011] Step 2: Compound 1 is subjected to Luche reduction of the carbonyl group to obtain compound 2;

[0012] Step 3: Compound 2 undergoes esterification of two hydroxyl groups under alkaline conditions to obtain compound 3;

[0013] Step 4: Compound 3 removes one acetyl group in the presence of Novozym 435 to obtain compound 4 of specific configuration;

[0014] Step 5: Compound 4 is subjected to bromination reaction under the conditions of ethoxyethylene and N-bromosuccinimide and undergoes nucleophilic substitution reaction to obtain compound 5;

[0015] Step 6: Compound 5 is subjected to a tandem cyclization reaction with nickel chloride hexahydrate, zinc powder and methyl acrylate as ligands to obtain compound 6;

[0016] Step 7: Compound 6 reacts with N,O-dimethylhydroxylamine hydrochloride to obtain compound 7;

[0017] Step 8: Compound 7 undergoes a Grignard reaction with phenethylmagnesium bromide to obtain compound 8;

[0018] Step 9: Compound 8 undergoes reduction reaction with (R)-methyl-CBS-oxazaborolidine to obtain compound 9;

[0019] Step 10: Compound 9 reacts with m-chloroperbenzoic acid to obtain compound 10;

[0020] Step 11: Compound 10 is treated with tert-butyldimethylsilyl to protect the hydroxyl group to obtain compound 11;

[0021] Step 12: Compound 11 reacts with diisobutylaluminum hydride to obtain compound 12;

[0022] Step 13: Compound 12 reacts with 4-butylcarboxylic acid triphenylphosphonium bromide to obtain compound 13;

[0023] Step 14: Compound 13 reacts with 2-iodoisopropane to obtain compound 14;

[0024] Step 15: Compound 14 reacts with pyridine hydrofluoride to generate latanoprost.

[0025] Furthermore, the structural formulas of the compounds furfuryl alcohol, latanoprost and compounds 1 to 14 are:

[0026]

[0027] Furthermore, the specific synthesis method of step 1 is:

[0028] Furfuryl alcohol is used as the starting material, and oxidative rearrangement is carried out under acidic and high temperature conditions to obtain compound 1, which specifically includes:

[0029] Potassium dihydrogen phosphate was dissolved in distilled water, and then the pH was adjusted to 4.1 with phosphoric acid, and furfuryl alcohol was added and placed in an oil bath, and the temperature was slowly raised to 99°C to 115°C, and the mixture was refluxed for reaction for 39 to 45 hours at normal pressure. After the reaction, the mixture was cooled to room temperature, and the by-products were removed by extraction with 1,2-dichloromethane, leaving the aqueous phase, and the phase was concentrated under reduced pressure, and then separated and purified to obtain compound 1.

[0030] The molar ratio of the compound furfuryl alcohol to potassium dihydrogen phosphate is 203.87-210.00:10.19-15.00;

[0031] The specific synthesis method of step 2 is:

[0032] Compound 1 is subjected to Luche reduction of the carbonyl group to obtain compound 2, which specifically comprises:

[0033] Add cerium trichloride and compound 1 in a reaction bottle at room temperature, add sodium borohydride at -25°C to -20°C, react for 20 minutes to 30 minutes, and react at normal pressure; after the reaction, add 1N hydrochloric acid to quench, extract with ethyl acetate, add anhydrous sodium sulfate to dry, concentrate under reduced pressure, and separate and purify to obtain compound 2;

[0034] The molar ratio of the compound 1, cerium trichloride and sodium borohydride is 120.29-130.00: 240.57-245.00: 132.32-140.00.

[0035] Furthermore, the specific synthesis method of step 3 is:

[0036] Compound 2 is subjected to esterification of two hydroxyl groups under alkaline conditions to obtain compound 3, specifically comprising:

[0037] 4-dimethylaminopyridine, pyridine and compound 2 were added to the reaction bottle at 0°C to 5°C, and then acetic anhydride was added, and the reaction was carried out for 0.3 to 0.5 hours at normal pressure. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, washed with distilled water, extracted with 1,2-dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 3;

[0038] The molar ratio of the compound 2,4-dimethylaminopyridine, pyridine, and acetic anhydride is 93.85-100.00: 46.93-55.00: 119.19-125.00: 281.56-290.00;

[0039] The specific synthesis method of step 4 is:

[0040] Compound 3 removes one acetyl group in the presence of Novozym 435 to obtain a compound 4 of a specific configuration, specifically including:

[0041] Compound 3, Antarctic Candida lipase B, i.e. CALB, and Novozym 435 were added to a reaction bottle at room temperature, and reacted in a phosphate buffer of pH=8 for 5 to 6 hours at normal pressure; after the reaction was completed, Novozym 435 was removed by filtration, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 4;

[0042] The mass ratio of the compound 3 to Novozym 435 is 16.41-20.00:0.66-1.50.

[0043] Furthermore, the specific synthesis method of step 5 is:

[0044] Compound 4 is subjected to bromination reaction under the conditions of ethoxyethylene and N-bromosuccinimide and undergoes nucleophilic substitution reaction to obtain compound 5, which specifically includes:

[0045] N-bromosuccinimide and vinyl ethyl ether were added to a reaction flask at -25°C to -20°C, and after reacting for 5 to 10 minutes, compound 4 dissolved in 1,2-dichloromethane was added dropwise at normal pressure; after the reaction was completed, distilled water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 5;

[0046] The molar ratio of the compound 4, N-bromosuccinimide, and vinyl ethyl ether is 80.25-90.00: 264.82-270.00: 264.82-270.00;

[0047] The specific synthesis method of step 6 is:

[0048] Compound 5 is subjected to a tandem cyclization reaction with nickel chloride hexahydrate, zinc powder and methyl acrylate as ligands to obtain compound 6, specifically comprising:

[0049] Add nickel chloride hexahydrate, zinc powder, methyl acrylate and pyridine to a reaction bottle at 45°C to 50°C, and react for 0.8 to 1 hour at normal pressure; after cooling to room temperature, add compound 5 dissolved in pyridine dropwise, and react for 2.5 to 3 hours at normal pressure; after the reaction is completed, add water to quench; extract with ethyl acetate, wash with hydrochloric acid, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 6;

[0050] The molar ratio of the compound 5, nickel chloride hexahydrate, zinc powder, and methyl acrylate is 61.81-75.00: 24.72-30.00: 185.43-195.00: 185.43-195.00;

[0051] Furthermore, the specific synthesis method of step 7 is:

[0052] Compound 6 reacts with N,O-dimethylhydroxylamine hydrochloride to obtain compound 7, which specifically comprises:

[0053] Add N,O-dimethylhydroxylamine hydrochloride and compound 6 dissolved in anhydrous tetrahydrofuran into a reaction bottle at -78°C to -70°C, stir for 3 to 5 minutes, and place under normal pressure; add isopropylmagnesium chloride dropwise, and after the addition is complete, move to room temperature to react for 40 to 50 minutes. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 7;

[0054] The molar ratio of the compound 6, N,O-dimethylhydroxylamine hydrochloride, and isopropylmagnesium chloride is 24.73-30.00: 98.92-105.00: 247.28-260.00;

[0055] The specific synthesis method of step 8 is:

[0056] Compound 7 undergoes a Grignard reaction with phenethylmagnesium bromide to obtain compound 8, which specifically includes:

[0057] Add magnesium chips, iodine, and 2-phenylethyl bromide to a reaction flask at 70°C to 80°C, react for 5 to 10 minutes at normal pressure, and obtain the desired Grignard reagent phenethylmagnesium bromide after the reaction is completed; add compound 7 dissolved in anhydrous tetrahydrofuran to a reaction flask at 0°C to 5°C, dropwise add the prepared Grignard reagent phenethylmagnesium bromide, and react for 1.5 to 2 hours at normal pressure; after the reaction is completed, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 8;

[0058] The molar ratio of compound 7, magnesium chips, 2-phenylethyl bromide, and iodine is 23.51-30.00: 246.86-250.00: 117.53-125.00: 52.90×10 -3 ~62.00×10 -3 ;

[0059] Furthermore, the specific synthesis method of step 9 is:

[0060] Compound 8 undergoes a reduction reaction with (R)-methyl-CBS-oxazaborolidine to obtain compound 9, which specifically comprises:

[0061] Add (R)-methyl-CBS-oxazolidinone to a reaction bottle at -40°C to -35°C, then drop borane tetrahydrofuran complex, stir for 2 minutes to 5 minutes, then slowly drop compound 8 at normal pressure; after the reaction is completed, quench the reaction with methanol, wash the organic phase with saturated sodium bicarbonate solution, saturated sodium chloride solution, and 2N hydrochloric acid, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 9;

[0062] The molar ratio of the compound 8, (R)-methyl-CBS-oxazolidinone, and borane tetrahydrofuran complex is 16.92-21.00: 25.38-31.00: 33.84-40.00;

[0063] The specific synthesis method of step 10 is:

[0064] Compound 9 reacts with m-chloroperbenzoic acid to obtain compound 10, which specifically comprises:

[0065] Add m-chloroperbenzoic acid and compound 9 to a reaction flask at room temperature, and slowly add boron trifluoride etherate dropwise at normal pressure; after the reaction is completed, quench with a saturated sodium sulfite solution, extract with ethyl acetate, and then wash the organic phase with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 10;

[0066] The molar ratio of the compound 9, m-chloroperbenzoic acid, and boron trifluoride ethyl ether is 14.72-20.00: 29.44-36.00: 29.44-36.00;

[0067] Furthermore, the specific synthesis method of step 11 is:

[0068] Compound 10 is protected with tert-butyldimethylsilyl to obtain compound 11, which specifically comprises:

[0069] 4-dimethylaminopyridine, compound 10 and triethylamine were added to a reaction bottle at room temperature, and then tert-butyldimethylsilyl chloride was added under ice bath, and the reaction was carried out for 22 to 24 hours at normal pressure; after the reaction was completed, saturated ammonium chloride aqueous solution was added to quench, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 11;

[0070] The molar ratio of the compound 10,4-dimethylaminopyridine, triethylamine, and tert-butyldimethylchlorosilane is 11.77-15.00: 11.77-15.00: 82.39-90.00: 70.62-80.00;

[0071] The specific synthesis method of step 12 is:

[0072] Compound 11 reacts with diisobutylaluminum hydride to obtain compound 12, which specifically comprises:

[0073] Compound 11 was added to a reaction bottle at -78°C to -70°C, and diisobutylaluminum hydride was slowly added dropwise, and the reaction was carried out for 2 to 3 hours at normal pressure. After the reaction, the mixture was quenched with saturated sodium potassium tartrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 12;

[0074] The molar ratio of the compound 11 to diisobutylaluminum hydride is 8.36-10.00:50.16-55.00;

[0075] Furthermore, the specific synthesis method of step 13 is:

[0076] Compound 12 reacts with 4-butylcarboxylic acid triphenylphosphonium bromide to obtain compound 13, which specifically includes:

[0077] Add 4-butylcarboxylic acid triphenylphosphonium bromide and lithium bis(trimethylsilyl)amide into a reaction bottle at 0°C to 5°C, stir for 40 to 60 minutes, then drop compound 12 and react for 1 to 1.5 hours at normal pressure. After the reaction, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 13.

[0078] The molar ratio of the compound 12,4-butylcarboxylic acid triphenylphosphonium bromide and bistrimethylsilylamide lithium is 4.34-6.00:34.73-40.00:78.12-85.00;

[0079] The specific synthesis method of step 14 is:

[0080] Compound 13 reacts with 2-iodoisopropane to obtain compound 14, which specifically comprises:

[0081] Cesium carbonate, 2-iodoisopropylane and compound 13 were added to a reaction bottle at room temperature and reacted for 22 to 24 hours under normal pressure. After the reaction, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 14.

[0082] The molar ratio of the compound 13, cesium carbonate, and 2-iodoisopropyl is 2.47-4.00: 6.18-9.00: 4.94-6.00;

[0083] Furthermore, the specific synthesis method of step 15 is:

[0084] Compound 14 reacts with hydrogen fluoride pyridine to generate latanoprost, specifically comprising:

[0085] Compound 14 was added to a reaction bottle at room temperature, and hydrogen fluoride pyridine was added dropwise, and the reaction was carried out for 30 to 40 minutes at normal pressure. After the reaction was completed, the mixture was directly concentrated under reduced pressure and then separated and purified to obtain the compound latanoprost;

[0086] The molar ratio of the compound 14 to hydrogen fluoride and pyridine is 1.98-2.50:0.02-0.03.

[0087] Beneficial Effects

[0088] Compared with the prior art, the present invention has the following advantages:

[0089] The invention provides an asymmetric and efficient synthesis method of latanoprost by enzyme catalysis, which specifically comprises: oxidative rearrangement of furfuryl alcohol to obtain compound 1, protection of hydroxyl group by tert-butyldimethylsilyl to obtain compound 2, reduction of carbonyl group to obtain compound 3, deprotection of hydroxyl group to obtain compound 4, reaction with acid anhydride to obtain compound 5, generation of compound 6 under the condition of Novozym 435, reaction with N-iodosuccinimide and vinyl ethyl ether to obtain compound 7, cyclization reaction catalyzed by nickel chloride hexahydrate and zinc powder to obtain compound 8, Grignard reaction to obtain compound 9, further Grignard reaction to obtain compound 10, reduction of keto carbonyl group to obtain compound 11, oxidation of hemiacetal to obtain compound 12, protection of hydroxyl group to obtain compound 13, reduction of lactone to obtain compound 14, Wittig reaction to obtain compound 15, esterification of carboxyl group to obtain compound 16, and removal of alcohol hydroxyl group protection to obtain compound 17. The synthesis method overcomes the defects of expensive reagents and low yield in the prior art, and can realize mass production of latanoprost. The synthesis of prostaglandin molecules can also be achieved through the key intermediate 8, which has excellent application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 The synthetic route diagram of latanoprost in the embodiment of the present invention;

[0091] Figure 2 are the structural formulas of the compounds furfuryl alcohol, latanoprost and compounds 1 to 14 in the examples. DETAILED DESCRIPTION

[0092] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0093] according to Figure 1 The synthetic route diagram shown in the figure is used to synthesize the compounds in the following examples, and the structural formulas of the compounds involved are Figure 2 shown.

[0094] Embodiment 1:

[0095] Step 1:

[0096] Take a two-necked round-bottom flask and set up a reflux device, weigh potassium dihydrogen phosphate (1.39 g, 10.19 mmol. 0.05 equiv) and add it to 400 ml of distilled water, and adjust the pH to 4.1 with phosphoric acid, then add it to the two-necked flask, measure furfuryl alcohol (20 g, 203.87 mmol, 1.0 equiv) and add it to the two-necked flask, place it in an oil bath and slowly heat it to 110 ° C and reflux for 45 hours. After the reaction is completed, wait for the system to cool, and use 1,2-dichloromethane to extract (50 mL × 3) to remove the black polymer. After the aqueous phase is concentrated under reduced pressure, it is separated and purified by column chromatography. The eluent volume ratio is petroleum ether: ethyl acetate = 2:1 to obtain a yellow oily compound 1 (11.80 g, 59%). f =0.4 (petroleum ether:ethyl acetate=1:1).

[0097] Step 2:

[0098] Take a double-mouth round-bottom flask to remove water, add cerium trichloride (59.30g, 240.57mmol, 2.0equiv) and replace argon three times, add compound 1 (11.80g, 120.29mmol, 1.0equiv) dissolved in methanol (120ml), and then slowly add sodium borohydride (5.01g, 132.32mmol, 1.1equiv) at -20°C, react for 30 minutes, after the reaction is completed, quench the reaction with 1N hydrochloric acid (50ml), extract with ethyl acetate (100mL×3), dry with anhydrous sodium sulfate, separate and purify by column chromatography, the eluent volume ratio is ethyl acetate: methanol = 16:1, and a colorless solid substance is obtained as compound 2 (9.39g, 78%). f =0.5 (ethyl acetate:methanol=16:1).

[0099] Step 3:

[0100] Take a two-necked flask, add a stirrer, heat to remove water, add 4-dimethylaminopyridine (5.73 g, 46.93 mmol, 0.5 equiv) and replace argon three times, add compound 2 (9.39 g, 93.85 mmol, 1.0 equiv) and pyridine (9.59 mL, 119.19 mmol, 1.27 equiv) dissolved in anhydrous dichloromethane (100 ml) at 0°C, then add acetic anhydride (26.62 mL, 281.56 mmol, 3.0 equiv) dropwise, react for 20 minutes, quench the reaction with saturated ammonium chloride solution (30 mL), wash with distilled water, extract with 1,2-dichloromethane (120 mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 5:1, and a colorless oily substance is obtained as compound 3 (16.41 g, 95%). f =0.5 (petroleum ether:ethyl acetate=4:1).

[0101] Step 4:

[0102] Take a two-necked flask and add pH=8 phosphate buffer (160 mL) and compound 3 (16.41 g, 89.15 mmol, 1.0 equiv), add Novozym 435 (0.66 g) at room temperature, react for 5 hours, and after the reaction is completed, remove Novozym435 by suction filtration, extract with ethyl acetate (150 mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The eluent volume ratio is petroleum ether: ethyl acetate = 1:1, and a colorless solid substance is obtained, which is compound 4 (11.40 g, 90%). f =0.5 (petroleum ether:ethyl acetate=1:1). [α] 2 D 0 = +66.4 (c = 1.3, CHCl3); 1 H NMR (400MHz, CDCl3) δ = 6.09 (ddd, J = 5.6, 2.0, 1.2Hz, 1H), 5.96 (ddd, J = 5.6, 2.0, 1.2Hz, 1H), 5.54–5.38 (m ,1H),4.70(s,1H),2.78(dt,J=14.8,7.2Hz,1H),2.13(s,1H),2.03(s,3H),1.63(dt,J=14.4,4.0Hz,1H).

[0103] Step 5:

[0104] Heat the two-necked flask to remove water, add N-bromosuccinimide (47.13 g, 264.82 mmol, 3.3 equiv) and replace argon three times, add anhydrous dichloromethane (100 ml) at -20 ° C and drop vinyl ethyl ether (27.28 mL, 264.82 mmol, 3.3 equiv), stir for 5 minutes, slowly drop compound 4 (11.40 g, 80.25 mmol, 1.0 equiv) dissolved in anhydrous dichloromethane (50 ml), react for 2 hours and move to room temperature to react for another 5 hours. After the reaction is completed, add distilled water (50 ml) to quench, extract with ethyl acetate (120 mL × 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The eluent volume ratio is petroleum ether: ethyl acetate = 15:1 to obtain a colorless oily substance, which is compound 5 (18.05 g, 77%). f =0.5 (petroleum ether:ethyl acetate=6:1).

[0105] Step 6:

[0106] Heat a two-necked flask to remove water, weigh zinc powder (12.12 g, 185.43 mmol, 3.0 equiv) and nickel chloride hexahydrate (5.88 g, 24.72 mmol, 0.4 equiv) and add them to the reaction flask and replace the argon three times, add pyridine (90 mL), place at 50 ° C, add methyl acrylate (16.90 mL, 185.43 mmol, 3.0 equiv), react for 40 minutes, cool to room temperature, slowly add 2-nitropropene dissolved in pyridine ( 50mL) of compound 5 (18.05g, 61.81mmol, 1.0equiv) was reacted for 3 hours. After the reaction was completed, distilled water (50ml) was added to quench, extracted with ethyl acetate (130mL×3), 2N hydrochloric acid (870mL) was used to remove pyridine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The eluent volume ratio was petroleum ether: ethyl acetate = 5:1, and a colorless oily substance was obtained, which was compound 6 (8.14g, 40%). f =0.5 (petroleum ether:ethyl acetate=3:1). 1H NMR (400MHz, CDCl3) δ = 5.21 (d, J = 6.4Hz, 1H), 5.15 (d, J = 4.4Hz, 1H), 4.80 (q, J = 6.4Hz, 1H), 4.61 (td, J =10.0,6.8Hz,1H),4.55–4.46(m,2H),3.803.66(m,2H),3.66(s,6H),3.44–3.40(m,2H),2.60(dt,J=1 2.8,7.2Hz,1H),2.47–2.32(m,6H),2.34–2.22(m,1H),2.21–2.04(m,3H),2.03(s,2H),2.01(s,3H),1 .96–1.85(m,2H),1.86–1.73(m,3H),1.76–1.57(m,6H),1.18(t,J=4.4Hz,1H),1.16(t,J=7.2Hz,1H).

[0107] Step 7:

[0108] Take a two-necked flask and heat it to remove water and replace argon three times, add N, O-dimethylhydroxylamine hydrochloride (9.65g, 98.92mmol, 4.0equiv) and compound 6 (8.14g, 24.73mmol, 1.0equiv) dissolved in anhydrous tetrahydrofuran (80mL), place it at -78°C and stir for 3 to 5 minutes, then slowly drop isopropylmagnesium chloride (247.28mL, 247.28mmol, 10.0equiv), after the dropwise addition is completed, move to room temperature to react for 50 minutes, after the reaction is completed, quench the reaction with saturated ammonium chloride solution (40mL), extract with ethyl acetate (150mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 1:1, and a colorless oily substance is obtained, which is compound 7 (6.75g, 95%). f =0.2 (petroleum ether:ethyl acetate=1:1).

[0109] Step 8:

[0110] Take a double-necked round-bottom flask and set up a reflux device. After removing water, add magnesium chips (6.00 g, 246.86 mmol, 10.5 equiv) and replace argon three times. Add anhydrous tetrahydrofuran (80 ml) and iodine (0.01 g, 52.90 × 10 -3 mmol,2.25×10 -3equiv) was placed at 80°C and 2-phenylbromoethane (16.05mL, 117.53mmol, 5.0equiv) was slowly added dropwise. After slightly heating, the mixture was placed at room temperature to react for 35 minutes. After the reaction, the system was placed at 0°C and compound 7 (6.75g, 23.51mmol, 1.0equiv) dissolved in anhydrous tetrahydrofuran (60ml) was added dropwise. After the addition was completed, the mixture was placed at room temperature to react for 2 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (40mL), extracted with ethyl acetate (150mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The eluent volume ratio was petroleum ether: ethyl acetate = 1:1, and a colorless oily substance was obtained, which was compound 8 (5.62g, 72%). f =0.6 (petroleum ether:ethyl acetate=1:1).

[0111] Step 9:

[0112] Heat a two-necked flask to remove water, add (R)-methyl-CBS-oxazaborolidine (7.03 g, 25.38 mmol, 1.5 equiv) and replace argon three times, add anhydrous tetrahydrofuran (80 mL), slowly drop borane tetrahydrofuran complex (33.84 mL, 33.84 mmol, 2.0 equiv) at -40 ° C, stir for 2 to 5 minutes, and then slowly drop compound 8 ( 5.62g, 16.92mmol, 1.0equiv). After the reaction was completed, the reaction was quenched with methanol (30mL), and the organic phase was washed with saturated sodium bicarbonate solution (30mL), saturated sodium chloride solution (30mL), and 2N hydrochloric acid (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The eluent volume ratio was petroleum ether: ethyl acetate = 1:1, and a colorless oily substance was obtained, which was compound 9 (4.92g, 87%). f =0.3 (petroleum ether:ethyl acetate=1:1).

[0113] Step 10:

[0114] Take a two-necked flask and heat it to remove water and replace argon three times, add m-chloroperbenzoic acid (5.08g, 29.44mmol, 2.0equiv) and compound 9 (4.92g, 14.72mmol, 1.0equiv) dissolved in anhydrous dichloromethane (70mL), slowly add boron trifluoride ether (3.71mL, 29.44mmol, 2.0equiv) dropwise at room temperature, react for 2 minutes, after the reaction is completed, quench with saturated sodium sulfite solution (20mL), extract with ethyl acetate (120mL×3), and then wash the organic phase with saturated sodium bicarbonate solution (30mL) and saturated sodium chloride solution (30mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 1:1, and a colorless oily substance is obtained as compound 10 (3.58g, 80%). f =0.3 (petroleum ether:ethyl acetate=1:2).

[0115] Step 11:

[0116] Take a two-necked flask and heat it to remove water and replace argon three times, add 4-dimethylaminopyridine (1.44 g, 11.77 mmol, 1.0 equiv), triethylamine (11.45 mL, 82.39 mmol, 7.0 equiv) and compound 10 (3.58 g, 11.77 mmol, 1.0 equiv) dissolved in anhydrous dichloromethane (60 mL), then add tert-butyldimethylsilyl chloride ( 10.64g, 70.62mmol, 6.0equiv), react at room temperature for 22 hours, the reaction is completed, quenched with saturated aqueous ammonium chloride solution (30mL), extracted with ethyl acetate (120mL×3), and then washed with saturated brine (50mL) for the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 10:1, and a colorless oily substance is obtained as compound 11 (4.45g, 71%). f =0.7 (petroleum ether:ethyl acetate=4:1).

[0117] Step 12:

[0118] Take a two-necked flask and heat it to remove water and replace argon three times, add compound 11 (4.45 g, 8.36 mmol, 1.0 equiv) dissolved in anhydrous dichloromethane (100 mL), slowly add diisobutylaluminum hydride (50.16 mL, 50.16 mmol, 6.0 equiv) at -78 ° C, react for 2.5 hours, and after the reaction is completed, quench with saturated potassium sodium tartrate (20 mL), extract with ethyl acetate (120 mL × 3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. The eluent volume ratio is petroleum ether: ethyl acetate = 5:1, and a colorless oily substance is obtained, which is compound 12 (2.32 g, 52%). f =0.6 (petroleum ether:ethyl acetate=4:1). 1 H NMR(400MHz, CD3OD-d4)δ=7.29–7.20(m,2H),7.16–7.19(m,3H),5.55–5.39(m ,1H),4.61–4.35(m,1H),3.87–3.65(m,2H),2.72–2.55(m,2H),2.38–2.13(m,2 H),2.09–1.99(m,1H),1.99–1.85(m,1H),1.76(dtd,J=8.8,5.6,2.0Hz,2H),1 .68–1.45(m,4H),1.34–1.13(m,2H),0.97–0.81(m,18H),0.17–-0.04(m,12H).

[0119] Step 13:

[0120] Take a two-necked flask and heat to remove water, add 4-butylcarboxylic acid triphenylphosphonium bromide (15.40 g, 34.73 mmol, 8.0 equiv) and replace argon three times, add anhydrous tetrahydrofuran (80 mL) and lithium bistrimethylsilylamide (78.12 mL, 78.12 mmol, 18.0 equiv) at 0°C, stir for 50 minutes, then drop compound 12 (2.32 g, 4.34 mmol, 1.0 equiv) dissolved in anhydrous tetrahydrofuran (30 mL), react for 1 hour, after the reaction is completed, quench with saturated aqueous ammonium chloride solution (40 mL), extract with ethyl acetate (120 mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 1:1, and a colorless oily substance is obtained as compound 13 (1.53 g, 57%). f =0.8 (petroleum ether:ethyl acetate=1:1). 1H NMR (400MHz, CDCl3) δ = 7.29 (d, J = 8.0Hz, 2H), 7.18 (dd, J = 7.6, 5.2Hz, 3H), 5.52 (dd, J = 12.4, 5.6Hz, 1H), 5.37 (qd, J = 8.8, 8.0, 4.0Hz,1H),4.18–4.06(m,1H),3.99(d,J=4.4Hz,1H),3.72(td,J=5.6,2.4Hz,1H),2.74–2.62(m,1H),2.60(dt,J=14.0,7.6Hz ,1H),2.35(t,J=7.2Hz,3H),2.23(t,J=6.8Hz,1H),2.21–2.11(m,2H),1.86(d,J=14.0Hz,1H),1.82–1.66(m,5H),1.63(q,J=7 .2Hz,1H),1.55(ddt,J=14.8,10.4,5.2Hz,2H),1.46–1.35(m,2H),1.36–1.27(m,2H),0.98–0.84(m,18H),0.16–0.03(m,1H).

[0121] Step 14:

[0122] Heat the double-necked flask to remove water, add cesium carbonate (2.01 g, 6.18 mmol, 2.5 equiv) and replace argon three times, add compound 13 (1.53 g, 2.47 mmol, 1.0 equiv) and 2-iodoisopropane (0.49 mL, 4.94 mmol, 2.0 equiv) dissolved in N, N-dimethylformamide (40 mL), react at room temperature for 22 hours, after the reaction is completed, quench the reaction with water (20 mL), extract with ethyl acetate (100 mL × 3), wash the organic phase with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 10:1, and a colorless oily substance is obtained, which is compound 14 (1.31 g, 80%). f =0.7 (petroleum ether:ethyl acetate=6:1). 1H NMR (400MHz, CDCl3) δ=7.36–7.22(m,1H),7.18(td,J=5.8,5.3,2.7Hz,1H),5.51(q,J=8.3Hz,1H),5.37(dd,J=17.5,7.7Hz,0H),5.00(p,J=6.3H z,0H),4.08(p,J=4.1Hz,1H),3.98(s,0H),3.71(p,J=5.5Hz,0H),2.95( d,J=10.3Hz,0H),2.75–2.64(m,0H),2.64–2.52(m,0H),2.37(dt,J=15. 4,8.2Hz,0H),2.30–2.24(m,1H),2.24–2.18(m,0H),2.13(q,J=7.4Hz,1 H),1.85(d,J=13.9Hz,1H),1.79–1.73(m,1H),1.73–1.66(m,0H),1.61( t,J=8.3Hz,0H),1.57–1.49(m,0H),1.43–1.33(m,1H),1.30(d,J=12.0H z,0H),1.22(d,J=6.2Hz,3H),0.90(d,J=11.1Hz,8H),0.12–0.03(m,5H).

[0123] Step 15:

[0124] Take a centrifuge tube and add a stirrer, add compound 14 (1.31 g, 1.98 mmol, 1.0 equiv) dissolved in dichloromethane (20 mL), then add hydrofluoric acid pyridine (1.87 mL, 0.02 mmol, 0.01 equiv) dropwise, react at room temperature for 30 minutes, and after the reaction is completed, directly reduce pressure and concentrate, and then separate and purify by column chromatography, the eluent volume ratio is petroleum ether: ethyl acetate = 1:2, and a colorless oily substance is obtained, which is latanoprost (0.79 g, 92%). f =0.1 (petroleum ether:ethyl acetate=1:1). 1H NMR (400MHz, CDCl3) δ = 7.29 (dd, J = 8.0, 2.0 Hz, 2H), 7.24–7.14 (m, 3H), 5.53–5.42 (m, 1H), 5.41 (d, J = 8. 4Hz,1H),5.00(p,J=6.4Hz,1H),4.17(s,1H),3.95(s,1H),3.72–3.60(m,1H),2.86–2.74(m,1H),2.74– 2.62(m,1H),2.34(s,1H),2.32–2.18(m,4H),2.12(d,J=6.8Hz,2H),1.88(d,J=3.2Hz,2H),1.84–1.73( m,2H),1.68(p,J=6.8Hz,4H),1.61(s,3H),1.59–1.45(m,1H),1.43–1.30(m,1H),1.23(d,J=6.4Hz,6H).

[0125] In summary, the present invention discloses an asymmetric and efficient synthesis method of latanoprost by enzyme catalysis. With latanoprost as the target, a series of key stereocenter constructions catalyzed by Novozym 435 and key cyclization reactions constructed by nickel chloride hexahydrate and zinc powder are designed by chemical synthesis. The method is simple to operate and has cheap raw materials, which lays a foundation for the subsequent synthesis of other prostaglandins, reflects the superiority of the method, and has high practical value.

[0126] Finally, it should be noted that the terms "comprises," "includes," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements that are inherent to such process, method, article, or apparatus.

[0127] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0128] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A method for the asymmetric and efficient synthesis of latanoprost by enzyme catalysis, characterized in that: The reaction process of the preparation method is as follows: The synthesis method comprises steps 1 to 15: Specific: Step 1: Using furfuryl alcohol as the starting material, oxidative rearrangement is carried out under acidic and high temperature conditions to obtain compound 1; Step 2: Compound 1 is subjected to Luche reduction of the carbonyl group to obtain compound 2; Step 3: Compound 2 undergoes esterification of two hydroxyl groups under alkaline conditions to obtain compound 3; Step 4: Compound 3 removes one acetyl group in the presence of Novozym 435 to obtain compound 4 of specific configuration; Step 5: Compound 4 is subjected to bromination reaction under the conditions of ethoxyethylene and N-bromosuccinimide and undergoes nucleophilic substitution reaction to obtain compound 5; Step 6: Compound 5 is subjected to a tandem cyclization reaction with nickel chloride hexahydrate, zinc powder and methyl acrylate as ligands to obtain compound 6; Step 7: Compound 6 reacts with N,O-dimethylhydroxylamine hydrochloride to obtain compound 7; Step 8: Compound 7 undergoes a Grignard reaction with phenethylmagnesium bromide to obtain compound 8; Step 9: Compound 8 undergoes reduction reaction with (R)-methyl-CBS-oxazaborolidine to obtain compound 9; Step 10: Compound 9 reacts with m-chloroperbenzoic acid to obtain compound 10; Step 11: Compound 10 is treated with tert-butyldimethylsilyl to protect the hydroxyl group to obtain compound 11; Step 12: Compound 11 reacts with diisobutylaluminum hydride to obtain compound 12; Step 13: Compound 12 reacts with 4-butylcarboxylic acid triphenylphosphonium bromide to obtain compound 13; Step 14: Compound 13 reacts with 2-iodoisopropane to obtain compound 14; Step 15: Compound 14 reacts with pyridine hydrofluoride to generate latanoprost.

2. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The structural formulas of the compounds furfuryl alcohol, latanoprost and compounds 1 to 14 are:

3. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 1 is: Furfuryl alcohol is used as the starting material, and oxidative rearrangement is carried out under acidic and high temperature conditions to obtain compound 1, which specifically includes: Potassium dihydrogen phosphate was dissolved in distilled water, and then the pH was adjusted to 4.1 with phosphoric acid, and furfuryl alcohol was added and placed in an oil bath, and the temperature was slowly raised to 99°C to 115°C, and the mixture was refluxed for reaction for 39 to 45 hours at normal pressure. After the reaction, the mixture was cooled to room temperature, and the by-products were removed by extraction with 1,2-dichloromethane, leaving the aqueous phase, and the phase was concentrated under reduced pressure, and then separated and purified to obtain compound 1. The molar ratio of the compound furfuryl alcohol to potassium dihydrogen phosphate is 203.87-210.00:10.19-15.00; The specific synthesis method of step 2 is: Compound 1 is subjected to Luche reduction of the carbonyl group to obtain compound 2, which specifically comprises: Add cerium trichloride and compound 1 in a reaction bottle at room temperature, add sodium borohydride at -25°C to -20°C, react for 20 minutes to 30 minutes, and react at normal pressure; after the reaction, add 1N hydrochloric acid to quench, extract with ethyl acetate, add anhydrous sodium sulfate to dry, concentrate under reduced pressure, and separate and purify to obtain compound 2; The molar ratio of the compound 1, cerium trichloride and sodium borohydride is 120.29-130.00: 240.57-245.00: 132.32-140.

00.

4. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 3 is: Compound 2 is subjected to esterification of two hydroxyl groups under alkaline conditions to obtain compound 3, specifically comprising: 4-dimethylaminopyridine, pyridine and compound 2 were added to the reaction bottle at 0°C to 5°C, and then acetic anhydride was added, and the reaction was carried out for 0.3 to 0.5 hours at normal pressure. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, washed with distilled water, extracted with 1,2-dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 3; The molar ratio of the compound 2,4-dimethylaminopyridine, pyridine, and acetic anhydride is 93.85-100.00: 46.93-55.00: 119.19-125.00: 281.56-290.00; The specific synthesis method of step 4 is: Compound 3 removes one acetyl group in the presence of Novozym 435 to obtain a compound 4 of a specific configuration, specifically including: Compound 3, Antarctic Candida lipase B, i.e. CALB, and Novozym 435 were added to a reaction bottle at room temperature, and reacted in a phosphate buffer of pH=8 for 5 to 6 hours at normal pressure; after the reaction was completed, Novozym 435 was removed by filtration, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 4; The mass ratio of the compound 3 to Novozym 435 is 16.41-20.00:0.66-1.

50.

5. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 5 is: Compound 4 is subjected to bromination reaction under the conditions of ethoxyethylene and N-bromosuccinimide and undergoes nucleophilic substitution reaction to obtain compound 5, which specifically includes: N-bromosuccinimide and vinyl ethyl ether were added to a reaction flask at -25°C to -20°C, and after reacting for 5 to 10 minutes, compound 4 dissolved in 1,2-dichloromethane was added dropwise at normal pressure; after the reaction was completed, distilled water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 5; The molar ratio of the compound 4, N-bromosuccinimide, and vinyl ethyl ether is 80.25-90.00: 264.82-270.00: 264.82-270.00; The specific synthesis method of step 6 is: Compound 5 is subjected to a tandem cyclization reaction with nickel chloride hexahydrate, zinc powder and methyl acrylate as ligands to obtain compound 6, specifically comprising: Add nickel chloride hexahydrate, zinc powder, methyl acrylate and pyridine to a reaction bottle at 45°C to 50°C, and react for 0.8 to 1 hour at normal pressure; after cooling to room temperature, add compound 5 dissolved in pyridine dropwise, and react for 2.5 to 3 hours at normal pressure; after the reaction is completed, add water to quench; extract with ethyl acetate, wash with hydrochloric acid, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 6; The molar ratio of the compound 5, nickel chloride hexahydrate, zinc powder and methyl acrylate is 61.81-75.00: 24.72-30.00: 185.43-195.00: 185.43-195.

00.

6. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 7 is: Compound 6 reacts with N,O-dimethylhydroxylamine hydrochloride to obtain compound 7, which specifically comprises: Add N,O-dimethylhydroxylamine hydrochloride and compound 6 dissolved in anhydrous tetrahydrofuran into a reaction bottle at -78°C to -70°C, stir for 3 to 5 minutes, and place under normal pressure; add isopropylmagnesium chloride dropwise, and after the addition is complete, move to room temperature to react for 40 to 50 minutes. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 7; The molar ratio of the compound 6, N,O-dimethylhydroxylamine hydrochloride, and isopropylmagnesium chloride is 24.73-30.00: 98.92-105.00: 247.28-260.00; The specific synthesis method of step 8 is: Compound 7 undergoes a Grignard reaction with phenethylmagnesium bromide to obtain compound 8, which specifically includes: Add magnesium chips, iodine, and 2-phenylethyl bromide to a reaction flask at 70°C to 80°C, react for 5 to 10 minutes at normal pressure, and obtain the desired Grignard reagent phenethylmagnesium bromide after the reaction is completed; add compound 7 dissolved in anhydrous tetrahydrofuran to a reaction flask at 0°C to 5°C, dropwise add the prepared Grignard reagent phenethylmagnesium bromide, and react for 1.5 to 2 hours at normal pressure; after the reaction is completed, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 8; The molar ratio of compound 7, magnesium chips, 2-phenylethyl bromide, and iodine is 23.51-30.00: 246.86-250.00: 117.53-125.00: 52.90×10 -3 ~62.00×10 -3。 7. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 9 is: Compound 8 undergoes a reduction reaction with (R)-methyl-CBS-oxazaborolidine to obtain compound 9, which specifically comprises: Add (R)-methyl-CBS-oxazolidinone to a reaction bottle at -40°C to -35°C, then drop borane tetrahydrofuran complex, stir for 2 minutes to 5 minutes, then slowly drop compound 8 at normal pressure; after the reaction is completed, quench the reaction with methanol, wash the organic phase with saturated sodium bicarbonate solution, saturated sodium chloride solution, and 2N hydrochloric acid, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 9; The molar ratio of the compound 8, (R)-methyl-CBS-oxazolidinone, and borane tetrahydrofuran complex is 16.92-21.00: 25.38-31.00: 33.84-40.00; The specific synthesis method of step 10 is: Compound 9 reacts with m-chloroperbenzoic acid to obtain compound 10, which specifically comprises: Add m-chloroperbenzoic acid and compound 9 to a reaction flask at room temperature, and slowly add boron trifluoride etherate dropwise at normal pressure; after the reaction is completed, quench with a saturated sodium sulfite solution, extract with ethyl acetate, and then wash the organic phase with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 10; The molar ratio of the compound 9, m-chloroperbenzoic acid and boron trifluoride ether is 14.72-20.00: 29.44-36.00: 29.44-36.

00.

8. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 11 is: Compound 10 is protected with tert-butyldimethylsilyl to obtain compound 11, which specifically comprises: 4-dimethylaminopyridine, compound 10 and triethylamine were added to a reaction bottle at room temperature, and then tert-butyldimethylsilyl chloride was added under ice bath, and the reaction was carried out for 22 to 24 hours at normal pressure; after the reaction was completed, saturated ammonium chloride aqueous solution was added to quench, and the organic phase was extracted with ethyl acetate, and then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 11; The molar ratio of the compound 10,4-dimethylaminopyridine, triethylamine, and tert-butyldimethylchlorosilane is 11.77-15.00: 11.77-15.00: 82.39-90.00: 70.62-80.00; The specific synthesis method of step 12 is: Compound 11 reacts with diisobutylaluminum hydride to obtain compound 12, which specifically comprises: Compound 11 was added to a reaction bottle at -78°C to -70°C, and diisobutylaluminum hydride was slowly added dropwise, and the reaction was carried out for 2 to 3 hours at normal pressure. After the reaction, the mixture was quenched with saturated sodium potassium tartrate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 12; The molar ratio of the compound 11 to diisobutylaluminum hydride is 8.36-10.00:50.16-55.

00.

9. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 13 is: Compound 12 reacts with 4-butylcarboxylic acid triphenylphosphonium bromide to obtain compound 13, which specifically includes: Add 4-butylcarboxylic acid triphenylphosphonium bromide and lithium bis(trimethylsilyl)amide into a reaction bottle at 0°C to 5°C, stir for 40 to 60 minutes, then drop compound 12 and react for 1 to 1.5 hours at normal pressure. After the reaction, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify to obtain compound 13. The molar ratio of the compound 12,4-butylcarboxylic acid triphenylphosphonium bromide and bistrimethylsilylamide lithium is 4.34-6.00:34.73-40.00:78.12-85.00; The specific synthesis method of step 14 is: Compound 13 reacts with 2-iodoisopropane to obtain compound 14, which specifically comprises: Cesium carbonate, 2-iodoisopropylane and compound 13 were added to a reaction bottle at room temperature and reacted for 22 to 24 hours at normal pressure. After the reaction, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified to obtain compound 14. The molar ratio of the compound 13, cesium carbonate and 2-iodoisopropyl is 2.47-4.00: 6.18-9.00: 4.94-6.

00.

10. A method for asymmetric and efficient synthesis of latanoprost by enzyme catalysis as claimed in claim 1, characterized in that: The specific synthesis method of step 15 is: Compound 14 reacts with hydrogen fluoride pyridine to generate latanoprost, specifically comprising: Add compound 14 to a reaction bottle at room temperature, add hydrogen fluoride pyridine dropwise, and react for 30 to 40 minutes at normal pressure; after the reaction, directly reduce pressure and concentrate, and then separate and purify to obtain compound latanoprost; The molar ratio of the compound 14 to hydrogen fluoride and pyridine is 1.98-2.50:0.02-0.03.

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