CN106986766B

CN106986766B - Preparation method of tafluprost

Info

Publication number: CN106986766B
Application number: CN201710316478.9A
Authority: CN
Inventors: 李鹏飞; 徐镜人; 阴启明; 周崴海; 吴川; 刘欢; 宋亚; 郝秀斌; 倪海华
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2017-05-08
Filing date: 2017-05-08
Publication date: 2021-01-12
Anticipated expiration: 2037-05-08
Also published as: CN106986766A

Abstract

The invention discloses a preparation method of tafluprost, which comprises the steps of taking a compound shown in a formula 1 as a raw material, and carrying out DIBAL-H reduction, Wittig reaction and esterification reaction; wherein, basic amino acid is adopted for refining after the wittig reaction. The total mass yield of the three-step reaction of the preparation method can reach 70 percent, the process is stable, the prepared tafluprost product is colorless to light yellow viscous oily liquid, and the purity is as high as more than 99 percent.

Description

Preparation method of tafluprost

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to a preparation method of tafluprost, namely (5Z) -7- [ (1R,2R,3R,5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-butene-1-yl ] -3, 5-dihydroxy cyclopentyl ] -5-heptenoic acid isopropyl ester.

Background

Tafluprost (Tafluprost) is a novel prostaglandin analogue, developed and produced by Japan ginseng, and is mainly used for treating open-angle glaucoma or ocular hypertension of patients with elevated intraocular pressure, and the main ocular hypotensive mechanism of the Tafluprost is to promote the outflow of aqueous humor through uveoscleral to lower the intraocular pressure. The 15 th hydroxyl group in the structure of the traditional prostaglandin analogue is an essential functional group for the prostaglandin receptor agonist to exert physiological activity, and the functional group is replaced by 2F atoms by the tafluprost which is taken as an isopropyl ester and can be rapidly hydrolyzed into a free acid form by corneal esterase, namely an active form of the drug. Tafluprost has approximately a 12-fold greater affinity for FP receptors of the iris ciliary body than the carboxylic acid product of latanoprost.

Compared with latanoprost which is used for treating primary open-angle glaucoma in the most extensive clinical application, the tafluprost can effectively reduce intraocular pressure, has good safety and eye tolerance and has wide market prospect.

The general synthesis method of tafluprost takes corolide as a starting material and synthesizes target compounds through reactions such as oxidation reaction, Hormer-Wadsworth-Emmons reaction, fluorination, hydrolysis, reduction, witting reaction, esterification and the like. However, these synthetic methods have problems of high content of over-reduction impurities, high content of trans-isomer impurities, and low yield (all between 38% and 47%).

Disclosure of Invention

The inventor develops a preparation method of tafluprost, and the method not only has the yield of more than 70 percent, but also can obtain the purity of the raw material medicine of more than 99 percent.

The invention aims to provide a preparation method of tafluprost, which adopts a hemiacetal analogue, namely a compound shown in a formula 1 as an initial raw material to prepare a raw material drug of the tafluprost through reduction reaction, wittig reaction, esterification reaction and the like, wherein the total mass yield of the three-step reaction of the process is up to more than 70%, and the purity of the obtained raw material drug is up to more than 99%.

In an embodiment of the present invention, there is provided a method for preparing tafluprost, i.e., (5Z) -7- [ (1R,2R,3R,5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -3, 5-dihydroxycyclopentyl ] -5-heptenylisopropyl ester (compound of formula 4), comprising the steps of:

(1) the compound of the formula 1 is subjected to reduction reaction to obtain a compound of a formula 2

(2) Subjecting the compound of formula 2 to wittig reaction with SM2 to obtain the compound of formula 3

(3) The compound of the formula 3 and iodoisopropane are subjected to esterification reaction to obtain the tafluprost, namely the compound of the formula 4

Wherein, the step (2) also comprises the operation of refining the compound of the formula 3 by salifying with basic amino acid after the reaction is finished.

In an embodiment of the present invention, the present invention provides the method for preparing tafluprost, wherein the basic amino acid in the step (2) is selected from L-lysine, L-histidine or L-arginine, preferably L-arginine.

In an embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein the step (2) of refining the compound of formula 3 by salifying with a basic amino acid comprises:

after the reaction is completed, the reaction is quenched at a low temperature, e.g., 5 ± 10 ℃, using a reagent containing active hydrogen, preferably water, as a quenching reagent, using methods conventional in the art. The specific operation can be as follows: controlling the temperature of the reaction system to be 5 +/-10 ℃, slowly dripping the reaction liquid into water, and removing the incompletely reacted alkali and the wittig reagent. After quenching is finished: purification using flash column chromatography techniques yields the crude compound of formula 3. The crude product of the compound of the formula 3 is subjected to salifying pulping with basic amino acid to obtain the basic amino acid salt of the compound of the formula 3, which is white to light pink solid powder. The salifying and refining process is carried out by using a common large polar solvent, preferably methanol. During the salifying and pulping process, the volume of the methanol is 6-21mL/(1g of crude product), preferably 6-9mL/(1g of crude product); during the salt forming process, the temperature of beating is 20 ℃ to 65 ℃, preferably 65 ℃. Finally, adding the basic amino acid salt of the compound of the formula 3 into dichloromethane, and dropwise adding hydrochloric acid until no solid residue exists; the organic and aqueous phases are separated and the organic phase is concentrated to provide the compound of formula 3.

In an embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein the step (1) is: the compound of the formula 1 is subjected to reduction reaction with a reducing agent under the nitrogen protection low-temperature condition, wherein the reducing agent is DIBAL-H reagent (toluene solution of diisobutylaluminum hydride); the reduction reaction is carried out in a dry aprotic solvent, preferably tetrahydrofuran.

In a preferred embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein the reducing agent selected in step (1) is DIBAL-H reagent, the molar ratio of the compound of formula 1 to DIBAL-H reagent is 1:2.2 to 1:3.5, the low temperature condition means-75 ℃ to-30 ℃ and the reaction time is 1 to 10 hours. Further preferably, the molar ratio of the compound of formula 1 to DIBAL-H reagent is 1:2.8, the temperature of the reduction reaction is-60. + -. 10 ℃ and the reaction time is 2H.

In an embodiment of the present invention, there is provided a method for preparing tafluprost, wherein the step (1) comprises, after completion of the reaction: quenching the reaction at low temperature, which is-60 + -10 deg.C, using conventional methods in the art, e.g., using an active proton-containing reagent, such as aqueous sodium bisulfate or methanol, preferably methanol. The specific operation can be as follows: the temperature was controlled at-60. + -. 10 ℃ and methanol was carefully added dropwise to the reaction, with care taken to vent the gas to remove unreacted DIBAL-H reagent.

In an embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein, after quenching is completed, the step (1): purifying by column chromatography to obtain crude product of formula 2. Pulping the crude product of the formula 2 at room temperature to obtain a fine product of the formula 2, which is white solid powder; the pulping solvents chosen are n-heptane and ethyl acetate, and an organic base, preferably triethylamine, is added as an auxiliary reagent. The volume ratio of the beating solvent ethyl acetate to n-heptane is 0:10 to 4:10, the volume ratio of ethyl acetate to triethylamine is 0 to 0.2, preferably the volume ratio of ethyl acetate to n-heptane to triethylamine is 1:10: 0.1.

In an embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein the step (2) is: the compound of the formula 2 and the SM2 compound are subjected to wittig reaction under the protection of nitrogen and the alkaline condition to obtain the compound of the formula 3. Wherein the base is an organic strong base, preferably NaHMDS reagent (sodium hexamethyldisilazide in tetrahydrofuran), and the wittig reaction is carried out in an aprotic solvent, preferably tetrahydrofuran. The mixing of the SM2 compound and the NaHMDS is carried out by dropwise adding a NaHMDS solution into the SM2 compound, wherein the temperature is controlled to be 5 +/-5 ℃ in the dropwise adding process; the compound of formula 2 was added by dropwise addition of a solution of the compound of formula 2 in anhydrous tetrahydrofuran to a mixture of the compound of SM2 and NaHMDS, with the temperature being controlled to-20 ± 5 ℃.

In a preferred embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein, in the step (2): the wittig reaction has a reaction temperature of-20 ℃ to 20 ℃, a molar ratio of the compound of formula 2 to the SM2 compound of 1:2.4 to 1:4.8, a molar ratio of the compound of formula 2 to NaHMDS of 1:6.5 to 1:13, and a reaction time of 1h to 21 h. Further preferably, the wittig reaction has a reaction temperature of 0 ± 5 ℃, a molar ratio of the compound of formula 2 to the SM2 compound of 1:3.2, a molar ratio of the compound of formula 2 to NaHMDS of 1:8.0, and a reaction time of 2 h.

In an embodiment of the present invention, the present invention provides a method for preparing tafluprost, wherein the step (3) is: the compound of formula 3 and 2-iodopropane undergo nucleophilic substitution reaction under the action of alkali and catalyst to produce ester, i.e. the compound of formula 4. Wherein the base is a common organic or inorganic base, preferably DBU (1, 8-diazabicycloundecen-7-ene). The reaction is carried out in an aprotic solvent, such as N, N-dimethylformamide, acetonitrile, dimethylsulfoxide, acetone, etc., preferably acetone.

In a preferred embodiment of the present invention, there is provided a method for preparing tafluprost, wherein DBU is used as the base and the catalyst in the step (3), the reaction temperature is 20 to 65 ℃, and the molar ratio of the compound of formula 3 to 2-iodopropane is 1:1.2 to 1:4.0, the molar ratio of the compound of formula 2 to DBU is 1:1.2 to 1:6.0, and the reaction time is 6h to 40 h. Further preferably, the reaction temperature is 55 ℃ and the molar ratio of the compound of formula 3 to 2-iodopropane is 1:2.0, the molar ratio of the compound of formula 2 to DBU is 1:2.0 and the reaction time is 20 h.

Compared with the prior art, the invention has the following advantages: the preparation method of the tafluprost raw material medicine provided by the invention adopts the compound shown in the formula 1 as the raw material, and the quality of the starting material is controllable. In the subsequent reaction, the reaction condition is accurately controlled, and the content of over-reduction impurities of the compound shown in the formula 1 is low, generally not more than 5 percent. The content of trans-isomer impurities generated in the Wittig reaction process of the compound of the formula 2 is below 1.5 percent, the trans-isomer impurities are removed by a special L-arginine salt-forming refining method, and the trans-isomer impurities in the final product can be reduced to below 0.35 percent (the impurity is 0.6 percent of the limit in the original ground manufacturer standard). The overall process has three steps, the reaction quality yield is up to more than 70 percent (equivalent to the molar yield of more than 50 percent), and the purity of the obtained raw material medicine is up to more than 99 percent. (the yields reported in the prior art patents are all between 38-47%)

Detailed Description

The technical solutions of the present invention are further described below by examples, which are illustrative and do not limit the scope of the present invention. The technical features of the invention are equally replaced by the prior art according to the teaching of the invention and the technical scope of the invention is also covered by the technical personnel in the technical field.

The compound of formula 1 in the following examples was purchased from Shanghai Kaihuy pharmaceuticals, Inc., and other materials and reagents, unless otherwise specified, were all commonly available.

The meanings of english abbreviations in the examples of the present invention are:

DIBAL-H reagent: diisobutylaluminum hydride in tetrahydrofuran, Shanghai Fuxing pharmaceutical science and technology, Inc., technical grade.

NaHMDS reagent: bis (trimethylsilyl) amide sodium in toluene, found in Duyun science and technology development Inc., with a label concentration of 40%, technical grade.

DBU: 1, 8-diazabicycloundecen-7-ene, domestic, technical grade.

Example 1

Preparation of the Compound of formula 2

50.0g of the compound of formula 1 is added to a four-necked reaction flask containing 500mL of anhydrous tetrahydrofuran, and the temperature is reduced to-70 ℃. + -. 10 ℃. DIBAL-H solution (245.6g, 2.8eq) was slowly added dropwise under nitrogen. After the dripping is finished, the temperature is kept, the stirring reaction is continued for 1h, the temperature is kept at minus 70 +/-10 ℃, methanol (9.45g, 8.0eq) is slowly dripped, the stirring is carried out for 0.5h, and the reaction is quenched. The mixture was added to 1000mL of water, 1000mL of ethyl acetate was added, and the mixture was stirred overnight until the organic phase was clear. Extracting, separating liquid and combining organic phases; washing the organic phase with saturated salt solution, standing and separating; adding silica gel into the organic phase for sample mixing, and performing column chromatography chromatographic separation: preparing n-heptane/triethylamine (17.0kg/36.5g) for column washing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (9.5kg/6.3kg) column flushing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (8.2kg/7.2kg) column flushing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (6.8kg/9.0kg) column flushing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (5.4kg/10.8kg) column flushing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (4.8kg/12.6kg) column flushing; the receiving bucket collects 4L each time. Preparing n-heptane/ethyl acetate (3.4kg/13.5kg) column flushing; collecting qualified column liquid, combining and concentrating until no liquid is discharged; adding ethyl acetate 45g and triethylamine 4.5g into the mixture, slowly dripping n-heptane 450g into the mixture, crystallizing, pulping, filtering, and collecting solids to obtain white solid powder, namely the compound of the formula 2 46.0g, with the purity of 97.9 percent and the yield of 90.0 percent.

Example 2

Preparation of the Compound of formula 3

33.0g of the compound of the formula 2 is added into a four-mouth reaction flask filled with 500mL of anhydrous tetrahydrofuran, the temperature is reduced to 5 +/-5 ℃, and NaHMDS solution (359.7g, 8.0eq) is added dropwise under the protection of nitrogen. After the dripping is finished, the temperature is kept at 5 +/-5 ℃, and the stirring reaction is continued for 1 h. The temperature was reduced to-20. + -. 5 ℃ and 160mL of a solution of 33.0g of the compound of formula SM2 in tetrahydrofuran was added dropwise to the system. After the dripping is finished, the temperature of the reaction solution is raised to 0 +/-5 ℃, and the reaction solution is stirred for 1 hour. The reaction solution was poured into 495g of an ice-water mixture, and the reaction was quenched with stirring, 330mL of ethyl acetate was added, and the mixture was separated with stirring. Extracting the organic phase once with water, and combining the water phases; the aqueous phase was extracted twice with ethyl acetate and the organic phase was discarded. And adding 330mL of ethyl acetate into the water phase, cooling the mixed solution to 5 +/-5 ℃, and slowly adding concentrated hydrochloric acid while stirring. Separating liquid, extracting the water phase twice with ethyl acetate, and combining the organic phases; washing the organic phase with saturated saline water, standing for 0.5h, separating the liquid, retaining the organic phase, fully stirring until solid impurities are separated out, and filtering. Adding silica gel into the filtrate, mixing the sample with the filtrate, and performing column chromatography and chromatographic separation: preparing normal heptane (34.0kg/kg) column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (38.0kg/kg)/(12.75kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (35.75kg/kg)/(15.75kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (63.5kg/kg)/(42.25kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (47.5kg/kg)/(63.25kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (31.75kg/kg)/(84.0kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. The eluent ratio was maintained until the column was run through. Collecting qualified column separating liquid, combining and concentrating to obtain light yellow oily liquid, dissolving with 300mL methanol, adding 18g L-arginine until solid is separated out, heating reflux and pulping. Cooling to room temperature, stirring for 10h, and filtering to obtain arginine salt solid powder. Arginine salt solid was added to 450mL of dichloromethane, and about 0.5N hydrochloric acid solution was added dropwise until no solid remained. The organic phase was concentrated by rotary evaporation to give 33.0g of a pale yellow oily liquid having a purity of 99.69%, a trans-isomer content of 0.30% and a yield of 79.5%.

Example 3

Preparation of the Compound of formula 4

16.99g of 1, 8-diazabicycloundecen-7-ene and 18.99g of 2-iodopropane were added successively to a solution of the compound of the formula 2 in 33.0g of acetone, and the mixture was stirred under reflux at 55. + -. 5 ℃ under heating. The reaction mixture was cooled to room temperature, and 460mL of methylene chloride and 138mL of water were added thereto and the mixture was stirred to dissolve. Extracting and separating liquid, and keeping an organic phase. Concentrating the organic phase under reduced pressure to small volume, adding silica gel, mixing with the sample, making sand, and separating by column chromatography. The sample was collected, fractionated on a column, combined and concentrated to give a crude product as a pale yellow oily liquid 35.0g, 99.4% in purity, 0.34% in trans isomer and 93.2% in yield.

Example 4

Preparation of the Compound of formula 2

100.0g of the compound of formula 1 was charged into a four-necked reaction flask containing 1000mL of anhydrous dichloromethane, and the temperature was reduced to-30 ℃. DIBAL-H solution (491.2g, 2.8eq) was slowly added dropwise under nitrogen. After the addition, the temperature was maintained, the reaction was continued for 1h with stirring, the reaction was maintained at-30 ℃ and methanol (18.9g, 8.0eq) was slowly added dropwise, the reaction was stirred for 0.5h and quenched. The mixture was added to 1000mL of water, 1000mL of dichloromethane was added, and the mixture was stirred overnight until the organic phase was clear. Extracting, separating liquid and combining organic phases; washing the organic phase with saturated salt solution, standing and separating; adding silica gel into the organic phase, stirring, and separating by column chromatography. Collecting qualified column liquid, combining and concentrating until no liquid is discharged; adding ethyl acetate 90g and triethylamine 9.0g into the solution, slowly dripping n-heptane 900g, crystallizing, pulping, filtering, and collecting solid to obtain white solid powder, namely the compound of the formula 2 90.0g, with the purity of 97.6% and the yield of 88.0%.

Example 5

Preparation of the Compound of formula 3

33.0g of the compound of the formula 2 is added into a four-mouth reaction bottle filled with 500mL of anhydrous dichloromethane, the temperature is reduced to 5 +/-5 ℃, and NaHMDS solution (359.7g, 8.0eq) is added dropwise under the protection of nitrogen. After the dripping is finished, the temperature is kept at 5 +/-5 ℃, and the stirring reaction is continued for 1 h. The temperature was reduced to-20. + -. 5 ℃ and 160mL of a solution of 33.0g of the compound of formula SM2 in methylene chloride was added dropwise to the system. After the dripping is finished, the temperature of the reaction solution is raised to 0 +/-5 ℃, and the reaction solution is stirred for 1 hour. The reaction solution was poured into 495g of an ice-water mixture, and the reaction was quenched with stirring, 330mL of dichloromethane was added, and the mixture was separated with stirring. Extracting the organic phase once with water, and combining the water phases; the aqueous phase was extracted twice with dichloromethane and the organic phase was discarded. And adding 330mL of ethyl acetate into the water phase, cooling the mixed solution to 5 +/-5 ℃, and slowly adding concentrated hydrochloric acid while stirring. Separating liquid, extracting the water phase twice with ethyl acetate, and combining the organic phases; washing the organic phase with saturated saline water, standing for 0.5h, separating the liquid, retaining the organic phase, fully stirring until solid impurities are separated out, and filtering. Adding silica gel into the filtrate, mixing the sample with the filtrate, and performing column chromatography and chromatographic separation: preparing 68.0kg/kg of n-heptane for column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (54.0kg/kg)/(18.0kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (50.9kg/kg)/(22.6kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (49.1kg/kg)/(30.3kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (154.3kg/kg)/(36.0kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (154.3kg/kg)/(36.0kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. Preparing n-heptane/ethyl acetate [ (154.3kg/kg)/(36.0kg/kg) ] column flushing; the receiving bucket collects 4.0L each time. The eluent ratio was maintained until the column was run through. Collecting qualified column liquid, combining and concentrating to obtain light yellow oily liquid, dissolving with 300mL methanol, adding L-arginine until solid is separated out, heating reflux and pulping. Cooling to room temperature, continuing stirring for 10h, and filtering to obtain L-arginine salt solid powder. The L-arginine salt solid was added to 450mL of dichloromethane, and about 0.5N hydrochloric acid solution was added dropwise until no solid remained. Separating, and concentrating the organic phase by rotary evaporation to obtain 30.0g of light yellow oily liquid with the purity of 99.01 percent, the trans-isomer content of 0.35 percent and the yield of 72.3 percent.

Example 6

Preparation of the Compound of formula 4

10g of triethylamine and 18.99g of 2-iodopropane are added successively to a solution of the compound of formula 2 in 33.0g of acetonitrile, and the mixture is heated under reflux at 55. + -. 5 ℃ with stirring. The reaction mixture was cooled to room temperature, and 460mL of methylene chloride and 138mL of water were added thereto and the mixture was stirred to dissolve. Extracting and separating liquid, and keeping an organic phase. Concentrating the organic phase under reduced pressure to small volume, adding silica gel, mixing with the sample, making sand, and separating by column chromatography. The sample was collected, fractionated, combined and concentrated to give a crude product as a pale yellow oily liquid 30.0g, 98.9% pure, 0.35% trans isomer content and 84.7% yield.

Claims

1. A preparation method of tafluprost comprises the following steps:

(3) The compound of formula 3 and 2-iodopropane are subjected to esterification reaction to obtain the compound of formula 4

Wherein, the step (2) also comprises the operation of refining the compound of the formula 3 by salifying with basic amino acid after the reaction is finished; the basic amino acid is L-arginine;

wherein, the step (2) of refining the compound of formula 3 with basic amino acid through salifying comprises the following steps: after the reaction is finished, quenching the reaction; purifying by using a flash column chromatography technology to obtain a crude product of the compound shown in the formula 3; pulping and refining the crude product of the compound of the formula 3 and basic amino acid to obtain basic amino acid salt of the compound of the formula 3; finally, adding the basic amino acid salt of the compound shown in the formula 3 into dichloromethane, and dropwise adding hydrochloric acid until no solid residue exists; the organic and aqueous phases are separated and the organic phase is concentrated to provide the compound of formula 3.

2. The preparation method according to claim 1, wherein the reduction reaction in step (1) is carried out in a dry aprotic solvent using a DIBAL-H reagent.

3. The production method according to claim 2, wherein the aprotic solvent in the step (1) is tetrahydrofuran.

4. The preparation method of claim 2, wherein the reduction reaction in step (1) is performed under nitrogen protection at a low temperature, wherein the molar ratio of the compound of formula 1 to the DIBAL-H reagent is 1:2.2 to 1:3.5, the low temperature is-80 ℃ to-30 ℃ and the reaction time is 1 to 10 hours.

5. The preparation method according to claim 4, wherein the molar ratio of the compound of formula 1 to DIBAL-H reagent in step (1) is 1:2.8, the temperature of the reduction reaction is-60 ± 10 ℃, and the reaction time is 2H.

6. The method according to claim 1, wherein the wittig reaction in step (2) is carried out under basic conditions using a SM2 compound as a reagent; here, the base is an organic strong base; furthermore, the wittig reaction is carried out in an aprotic solvent.

7. The process according to claim 6, wherein the base in the step (2) is NaHMDS; the aprotic solvent is tetrahydrofuran.

8. The preparation method according to claim 7, wherein the wittig reaction in the step (2) has a reaction temperature of-20 ℃ to 20 ℃, a molar ratio of the compound of formula 2 to the compound of SM2 of 1:2.4 to 1:4.8, a molar ratio of the compound of formula 2 to NaHMDS of 1:6.5 to 1:13, and a reaction time of 1h to 21 h.

9. The method of claim 8, wherein the mixing of the SM2 compound with NaHMDS is performed by dropwise adding a solution of NaHMDS to the SM2 compound; the addition of the compound of formula 2 is carried out by dropwise addition of a solution of the compound of formula 2 to a mixture of the compound of SM2 and NaHMDS.