CN110305118B - Synthetic method suitable for industrial production of enggliflozin - Google Patents

Synthetic method suitable for industrial production of enggliflozin Download PDF

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CN110305118B
CN110305118B CN201910535608.7A CN201910535608A CN110305118B CN 110305118 B CN110305118 B CN 110305118B CN 201910535608 A CN201910535608 A CN 201910535608A CN 110305118 B CN110305118 B CN 110305118B
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reaction
compound
englitjing
synthesizing
formula
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CN110305118A (en
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骆伟
辜天彬
杨成喜
王晶翼
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Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a synthesis method suitable for industrial production of englitazone, which is prepared by reducing a compound of a formula (II) to obtain a compound of a formula (I) and removing a protecting group from the compound of the formula (I). The method for synthesizing the englitjing has simple process, only needs one-step reduction reaction, and effectively reduces the repeated use of high-toxicity and high-risk chemicals; in addition, the intermediate adopts a method of derivative protection and repurification, so that the process control can be effectively carried out, and the product quality is improved; has stronger practical application value and is suitable for industrial production.

Description

Synthetic method suitable for industrial production of enggliflozin
Technical Field
The invention relates to a drug synthesis method, in particular to a synthesis method suitable for industrialized production of englitazone.
Background
Engliflozin (Empagliflozin), molecular formula: c (C) 23 H 27 ClO 7 Chemical name: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl]Oxy group]Phenyl group]Methyl group]Phenyl group]-D-glucitol. Engliflozin was approved by the United states FDA for marketing in month 2014 and developed by Gift and Bolin Yinggahn, which belongs to the class of SGLT2 inhibitors, and is mainly used for treating adults with type 2 diabetes by inhibiting SGLT2 expressed in the kidney to reduce the glucose content in blood plasma, and has the structural formula:
the existing synthesis method of the englitjing comprises the following steps:
the synthesis method comprises the following steps: CN102574829B reports a method for synthesizing englitjing:
4- [ [ (3S) -tetrahydro-3-furan ] oxy ] phenyl ] - (5-iodo-2-chlorophenyl) methanone is reduced under the action of tetramethyl disiloxane to obtain (3S) -3- [4- [ (5-iodo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran, the (3S) -3- [4- [ (5-iodo-2-chlorophenyl) methyl ] phenoxy ] tetrahydrofuran is subjected to format reaction, then condensed with 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone to generate hemiketal, methanesulfonic acid is catalyzed to react with methanol to generate 1, 5-dehydrated-1-methoxy-C- [ 4-chloro-3- [ [4- [ [ [ (3S) -tetrahydro-3-furyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol, and the (3S) -tetrahydro-3-furyl ] oxy) phenyl ] -D-glucitol is reduced by aluminum trichloride/triethylsilane to obtain the enggliflozin.
The synthesis method II comprises the following steps: patent CN101193903B reports a method for synthesizing englitjing:
the preparation method comprises the steps of (5-bromo-2-chlorophenyl) (4-methoxyphenyl) methanone is subjected to carbonyl reduction, methoxy hydrolysis and hydroxyl protection to obtain an intermediate, n-butyllithium format reaction is carried out, then the intermediate is condensed with 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone to generate hemiketal, methanesulfonic acid is catalyzed to react with methanol to generate ether, boron trifluoride diethyl etherate/triethylsilane is reduced, and then the ether is substituted with (S) - (+) -3-p-toluenesulfonyl tetrahydrofuran to obtain the engagliflozin.
The prior art has the following defects:
the method comprises the following steps: the preparation method of the enggliflozin in the patent CN102574829B involves more reduction reactions, aluminum trichloride and a reducing agent are needed for two-step reaction, the operation is complex, a large amount of waste acid is generated, and the post-treatment is complex; in addition, the reduction reaction is carried out under a strict anhydrous condition, more byproduct impurities are generated under an acidic condition due to the existence of moisture, and the total yield of the englitazone is low; therefore, the preparation method is not suitable for industrial production.
The second method is as follows: the preparation method in the patent CN101193903B has long route, high process cost, more reduction reactions, the need of using Lewis acid and reducing agent for multiple times, and the difficulty of refining and purifying the intermediate is high, the quality control cannot be carried out in the preparation process, and the total yield of the engagliflozin is low, so that the method is not suitable for industrial production.
Therefore, there is a need for a simpler, efficient, environmentally friendly method for synthesizing englitjing suitable for industrial production.
Disclosure of Invention
The invention provides a novel method for synthesizing englitjing.
The invention provides a synthetic method of enggliflozin, which comprises the steps of firstly, carrying out reduction reaction on a compound shown in a formula (II) to obtain a compound shown in a formula (I), and then removing a protecting group from the compound shown in the formula (I);
wherein R is a hydroxy protecting group, preferably one of acetyl, benzyl, benzoyl, pivaloyl and t-butyryl;
R 1 is C 1-4 Alkyl, preferably methyl or ethyl.
In some embodiments, the reduction reaction is carried out with a reducing agent in the presence of a lewis acid and a reaction solvent; preferably, the reaction temperature of the reduction reaction is 20 ℃ to 45 ℃; preferably, the reduction reaction further comprises carrying out under nitrogen protection; preferably, the molar ratio of the compound of formula (II), lewis acid to reducing agent is 1:2-5:2-6, more preferably, the molar ratio is 1:2.5:3.
in some embodiments, the lewis acid is boron trifluoride diethyl etherate, anhydrous aluminum trichloride, ferric bromide, or tin tetrachloride, preferably anhydrous aluminum trichloride.
In some embodiments, the reaction solvent is selected from tetrahydrofuran, acetonitrile, toluene, xylene, or dichloromethane, preferably acetonitrile.
In some embodiments, the reducing agent is trimethylsilane, triethylsilane, triphenylsilane, triisopropylsilane, tris (trimethylsilyl) silane, dimethylphenylsilane, phenylsilane, diphenylsilane, or 1, 3-tetramethyldisiloxane; phenylsilane is preferred.
In some embodiments, the compound of formula (II) is prepared by acylating a compound of formula (III) with an acylating agent;
wherein R is 1 Is C 1-4 Alkyl, preferably methyl or ethyl.
In some embodiments, the acylation is carried out with an acylating agent in the presence of an acid-binding agent; preferably, the acid-binding agent is selected from one or more of triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate, N-methylmorpholine or sodium carbonate, more preferably the acid-binding agent is a mixture of 4-dimethylaminopyridine and N-methylmorpholine; preferably, the acylating reagent of the acylation reaction is selected from acetyl chloride or acetic anhydride.
In some embodiments, the compound (II) may be purified in an organic solvent, effective to control the impurity content of the intermediate; the organic solvent is selected from ethyl acetate, dichloromethane, n-heptane, n-hexane or methyl tertiary ether.
In some embodiments, the compound of formula (III) is prepared by:
step (1): reacting a compound of formula (IV) with an alkyl derivative of lithium;
step (2): adding the product obtained in the step (1) to a compound of a formula (V) and then to alcohol R 3 OH reacts under an acidic condition to obtain a compound of a formula (III);
wherein R is 1 Is C 1-4 An alkyl group;
R 2 is C 1-4 Alkyl silicon base;
R 3 represent C 1-4 An alkyl group;
x is halogen.
In some embodiments, the reaction of step (1) is performed at a reaction temperature of-100 ℃ to-60 ℃ with the reaction solvent being toluene or tetrahydrofuran; the alkyl derivative of lithium is n-butyllithium, isopropyl lithium or tert-butyllithium; preferably, the reaction temperature is from-80 ℃ to-70 ℃; preferably, the reaction is carried out under nitrogen protection; preferably, the reaction solvent is a mixed solvent of toluene and tetrahydrofuran, more preferably, the volume ratio of toluene to tetrahydrofuran in the reaction solvent is 1-5:1-2, more preferably a volume ratio of 2:1.
In some embodiments, the addition reaction of step (2) is performed in an inert solvent; the acid is selected from methane sulfonic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrogen chloride or hydrogen chloride solution; the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; preferably, the inert solvent is selected from toluene, tetrahydrofuran or n-hexane.
The synthesis method of the engagliflozin is simple in process, only needs one-step reduction reaction, and effectively reduces the repeated use of high-toxicity and high-risk chemicals; the intermediate adopts a method of derivative protection and repurification, can effectively control the process, and improves the product quality (the purity of the Engliflozin is more than 99.9 percent and the single impurity is less than 0.10 percent); has stronger practical application value and is suitable for industrial production.
Detailed Description
In order to make the technical problems and control schemes to be solved by the invention more clear, the invention is described in detail with reference to examples.
The invention takes 2,3,4, 6-tetra-O-trimethylsilyl-D-glucolactone (compound V-1) and 4- [ [ (3S) -tetrahydro-3-furan ] oxy ] phenyl ] - (5-bromo-2-chlorophenyl) methanone (compound IV-1) as raw materials to prepare the engagliflozin product.
Example 1:
step (1): preparation of Compound (III-1)
117g of the compound (IV-1) and a toluene/tetrahydrofuran mixed solvent (volume ratio: 2:1, total volume: 700 mL) were added to a four-necked flask, and stirred and mixed well. The internal temperature of the system was reduced to-80℃under nitrogen protection, and 93g of a 2.5M n-butyllithium in n-hexane were then added dropwise. After the addition, 300g of a toluene solution of the compound (V-1) (150 g of the compound (V-1) was diluted with an equal amount of toluene) was added dropwise after stirring for 20 minutes. After the addition, the mixture is stirred for 2 hours at a constant temperature. The methanesulfonic acid/methanol mixed solution (59 g/230 g) was continuously added dropwise. After the addition, the system was heated to 30℃and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is added into 500ml of saturated sodium bicarbonate aqueous solution to quench, 1000ml of ethyl acetate is added to stir and extract for two times, then 500ml of saturated sodium chloride aqueous solution is used for washing, the solvent is removed by decompression concentration, the obtained concentrate is heated and dissolved by methanol, then is dripped into n-hexane to solidify and separate out solid, and the compound (III-1) is obtained by filtration to directly carry out the next feeding.
Step (2): preparation of Compound (II-1)
The compound (III-1) was dissolved in 800ml of ethyl acetate, and 5g of 4-dimethylaminopyridine and 140-g N-methylmorpholine were added. Under the protection of nitrogen, the internal temperature of the system is reduced to 5 ℃, and 105g of acetyl chloride is added dropwise. After the addition, the reaction was stirred at 30℃for 4 hours. After the reaction, the reaction mixture was quenched in 1000ml of purified water, 500ml of ethyl acetate was added thereto, and the extracted organic layer was dissolved by stirring, and then the organic phase was washed with 500ml of saturated aqueous sodium chloride solution, and the solvent was removed by concentration under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane to obtain 116g of compound (II-1) with a purity of 98.8%.
Step (3): preparation of Compound (I-1)
The compound (II-1) was dissolved in 600g of acetonitrile, 57g of phenylsilane was added under nitrogen protection, 58g of anhydrous aluminum trichloride was added in portions after stirring and mixing uniformly, and the mixture was reacted at 45℃for 6 hours with stirring. After the reaction, adding the reaction solution into 300ml of purified water for quenching, and adding 500ml of ethyl acetate for extracting an organic phase; further, the mixture was washed with 200ml of a saturated aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure to remove the solvent, 500ml of purified water was added to the residue, and the mixture was heated to 50℃and stirred to precipitate a white solid. Cooling, centrifuging, and drying to obtain 95g of compound (I-1) with purity of 98.2%.
Step (4): preparation of Engliflozin
The compound (I-1) was dissolved in 200ml of tetrahydrofuran, followed by addition of 20ml of purified water and 32g of lithium hydroxide monohydrate, and the reaction was stirred at 30℃for 2 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, and the residue was dissolved by heating to 50℃with ethyl acetate/water (volume ratio: 5:3), and washed with extraction. Concentrating the organic phase under reduced pressure to obtain crude product of the Engliflozin. And refluxing and dissolving the crude product of the enggliflozin by using isopropanol/isopropyl acetate, and cooling and crystallizing in a gradient way. After crystallization, the solution is centrifugally dried to obtain 55g of Engliflozin with the purity of 99.91 percent.
Example 2:
step (1): preparation of Compound (III-1)
8.0Kg of compound (IV-1) and a toluene/tetrahydrofuran mixed solvent (volume ratio is 2:1, total volume is 48.0L) are added into a 200L ultralow temperature reaction kettle, and the mixture is stirred and mixed uniformly. The internal temperature of the system was reduced to-80℃under nitrogen protection, and then 6.4Kg of a 2.5M n-hexane solution of n-butyllithium was added dropwise. After the addition, stirring was carried out for 30 minutes, 20.6Kg of a toluene solution of the compound (V-1) (10.3 Kg of the compound (V-1) was diluted with an equal amount of toluene) was added dropwise. After the addition, the mixture is stirred for 2 hours at a constant temperature. The methanesulfonic acid/methanol mixed solution (4.0 Kg/15.7 Kg) was further added dropwise. After the addition, the system was heated to 30℃and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is added into 34.2Kg of saturated sodium bicarbonate aqueous solution to quench, 54.5Kg of ethyl acetate is added to stir and extract twice, then 34.2Kg of saturated sodium chloride aqueous solution is used for washing, the solvent is removed by decompression concentration, the obtained concentrate is heated and dissolved by methanol, then is dripped into n-hexane to solidify and separate out solid, and the compound (III-1) is obtained by filtration to directly carry out the next feeding.
Step (2): preparation of Compound (II-1)
Compound (III-1) was dissolved in 43.5Kg of ethyl acetate, and 340g of 4-dimethylaminopyridine and 9.6Kg of triethylamine were added. Under the protection of nitrogen, the internal temperature of the system is reduced to 5 ℃, and 9.3Kg of acetic anhydride is added dropwise. After the addition, the reaction was stirred at 30℃for 4 hours. After the reaction, the reaction mixture was quenched by adding 68.4Kg of purified water, 27.5Kg of ethyl acetate was added thereto, and the organic layer was extracted by stirring, and then the organic phase was washed with 34.2Kg of saturated aqueous sodium chloride solution and concentrated under reduced pressure to remove the solvent. The obtained residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane to obtain 8.14Kg of compound (II-1) with a purity of 98.10%.
Step (3): preparation of Compound (I-1)
Under the protection of nitrogen, the compound (II-1) is added into 41.0Kg of acetonitrile, 4.1Kg of anhydrous aluminum trichloride is added in batches, 4.0Kg of phenylsilane is added dropwise after stirring and dissolving, and the reaction is carried out at 45 ℃ for 6 hours under stirring. After the reaction, the reaction solution was quenched by adding 20.5Kg of purified water, and the organic phase was extracted by adding 27.5Kg of ethyl acetate; then, the mixture was washed with 13.7Kg of saturated aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure to remove the solvent, 32.4Kg of purified water was added to the residue, and the temperature was raised to 50℃and stirred to precipitate a white solid. Cooling, centrifuging, and drying to obtain 6.38Kg of compound (I-1) with purity of 98.9%.
Step (4): preparation of Engliflozin
The compound (I-1) was dissolved by adding 13.7L of tetrahydrofuran and 6.8L of methanol, and then 1.4L of purified water and 2.1Kg of lithium hydroxide monohydrate were added thereto, followed by stirring at 30℃for 2 hours. After the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was dissolved by heating to 50℃with 45L of ethyl acetate/water (volume ratio: 5:3), and washed with extraction. Concentrating the organic phase under reduced pressure to obtain crude product of the Engliflozin. And refluxing and dissolving the crude product of the enggliflozin by using isopropanol/isopropyl acetate, and cooling and crystallizing in a gradient way. After crystallization, centrifugal drying is carried out, thus obtaining 3.22Kg of Engliflozin with the purity of 99.95 percent.
Example 3:
step (1): preparation of Compound (III-1)
20.0Kg of compound (IV-1) and a toluene/tetrahydrofuran mixed solvent (volume ratio is 2:1, total volume is about 120L) are added into a 500L ultralow temperature reaction kettle, and the mixture is stirred and mixed uniformly. The internal temperature of the system was reduced to-80℃under nitrogen protection, and then 15.9kg of a 2.5M n-hexane solution of n-butyllithium was added dropwise. After the addition, 51.2Kg of a toluene solution of the compound (V-1) (25.6 Kg of the compound (V-1) was diluted with an equal amount of toluene) was added dropwise after stirring for 30 minutes. After the addition, the mixture is stirred for 2 hours at a constant temperature. The methanesulfonic acid/methanol mixed solution (10.0 Kg/39.3 Kg) was continuously added dropwise. After the addition, the system was heated to 30℃and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is added into 85.5Kg of saturated sodium bicarbonate aqueous solution to quench, 140Kg of ethyl acetate is added to stir and extract for two times, then 85.5Kg of saturated sodium chloride aqueous solution is used for washing, the solvent is removed by decompression concentration, the obtained concentrate is heated and dissolved by methanol, then is dripped into n-hexane to solidify and separate out solid, and the compound (III-1) is obtained by filtering to directly carry out the next feeding.
Step (2): preparation of Compound (II-1)
Compound (III-1) was dissolved in 110Kg of ethyl acetate, and 850g of 4-dimethylaminopyridine and 23.9Kg of N-methylmorpholine were added. Under the protection of nitrogen, the internal temperature of the system is reduced to 5 ℃, and 17.9g of acetyl chloride is added dropwise. After the addition, the reaction was stirred at 30℃for 4 hours. After the reaction, the reaction mixture was quenched in 170.0Kg of purified water, 70.0Kg of ethyl acetate was added thereto, and the organic layer was extracted by stirring, washed with 85.0Kg of saturated aqueous sodium chloride solution, and concentrated under reduced pressure to remove the solvent. The obtained residue was recrystallized from a mixed solvent of ethyl acetate/n-hexane to obtain 19.20Kg of compound (II-1) with a purity of 98.01%.
Step (3): preparation of Compound (I-1)
The compound (II-1) was dissolved in 100Kg of acetonitrile, 9.4Kg of phenylsilane was added under nitrogen protection, 9.7Kg of anhydrous aluminum trichloride was added in portions after stirring and mixing uniformly, and the mixture was reacted at 45℃for 6 hours under stirring. After the reaction, adding the reaction solution into 51.0Kg of purified water for quenching, adding 70.0Kg of ethyl acetate for extracting an organic phase; then washed with 35.0Kg of saturated aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure to remove the solvent, 85.0Kg of purified water was added to the residue, and the temperature was raised to 50℃and stirred to precipitate a white solid. Cooling, centrifuging, and drying to obtain 15.96Kg of compound (I-1) with purity of 98.30%.
Step (4): preparation of Engliflozin
The compound (I-1) was dissolved by adding 30.0Kg of tetrahydrofuran and 13.0Kg of methanol, and then 2.7Kg of purified water and 5.5Kg of lithium hydroxide monohydrate were added thereto, followed by stirring at 30℃for 2 hours. After the reaction, the residue was concentrated to dryness under reduced pressure at 50℃and dissolved by heating to 50℃with ethyl acetate/water (volume ratio 5:3), and washed with extraction. Concentrating the organic phase under reduced pressure to obtain crude product of the Engliflozin. And refluxing and dissolving the crude product of the enggliflozin by using isopropanol/isopropyl acetate, and cooling and crystallizing in a gradient way. After crystallization, centrifugal drying is carried out, and 8.60Kg of Engliflozin is obtained, and the purity is 99.88%.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above embodiments of the present invention will be described in further detail. It should not be understood that the scope of the above subject matter of the present invention is limited to the above examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Claims (17)

1. A synthetic method of Engliflozin is characterized in that: the compound of the formula (I) is obtained by the reduction reaction of the compound of the formula (II); removing the protecting group from the compound of formula (I) to obtain the englitazone;
wherein R is a hydroxyl protecting group;
R 1 is C 1-4 An alkyl group;
the reduction reaction is carried out with a reducing agent in the presence of Lewis acid and a reaction solvent; the Lewis acid is anhydrous aluminum trichloride; the reducing agent is phenylsilane;
the reaction temperature of the reduction reaction is 20 ℃ to 45 ℃.
2. The method for synthesizing englitjing according to claim 1, characterized in that: the reduction reaction also comprises the step of carrying out under the protection of nitrogen.
3. The method for synthesizing englitjing according to claim 1, characterized in that: the reaction mole ratio of the compound of the formula (II), the Lewis acid and the reducing agent is 1:2-5:2-6.
4. The method for synthesizing englitjing according to claim 1, characterized in that: the reaction solvent is selected from tetrahydrofuran, acetonitrile, toluene, xylene or dichloromethane.
5. The method for synthesizing englitjing according to claim 1, characterized in that:
r is selected from one of acetyl, benzyl, benzoyl, pivaloyl and tert-butyryl;
R 1 is methyl or ethyl.
6. The method for synthesizing englitjing according to any one of claims 1 to 5, characterized in that: the compound of the formula (II) is prepared by carrying out an acylation reaction on a compound of the formula (III) and an acylating agent;
wherein R is 1 Is C 1-4 An alkyl group.
7. The method for synthesizing englitjing according to claim 6, characterized in that: r is R 1 Is methyl or ethyl.
8. The method for synthesizing englitjing according to claim 6, wherein the acylation reaction is an acylation reaction with an acylating agent in the presence of an acid-binding agent; the acid binding agent is one or more selected from triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, triethanolamine, tetrabutylammonium bromide, potassium carbonate, ammonium carbonate, N-methylmorpholine or sodium carbonate.
9. The method for synthesizing englitjing according to claim 8, characterized in that the acylating agent of the acylation reaction is selected from acetyl chloride or acetic anhydride.
10. The method of claim 6, wherein the compound of formula (III) is prepared by:
step (1): reacting a compound of formula (IV) with an alkyl derivative of lithium;
step (2): adding the product obtained in the step (1) to a compound of a formula (V) and then to alcohol R 3 OH reacts under an acidic condition to obtain a compound of a formula (III);
wherein R is 1 Is C 1-4 An alkyl group;
R 2 is C 1-4 Alkyl groupSilicon-based;
R 3 represent C 1-4 An alkyl group;
x is halogen.
11. The method for synthesizing englitjing according to claim 10, wherein the reaction of step (1) is carried out at a reaction temperature of-100 ℃ to-60 ℃ and a reaction solvent of toluene or tetrahydrofuran; the alkyl derivative of lithium is selected from n-butyl lithium, isopropyl lithium or tert-butyl lithium.
12. The method for synthesizing englitjing according to claim 11, characterized in that said reaction temperature is between-80 ℃ and-70 ℃.
13. The method for synthesizing englitjing according to claim 11, characterized in that the reaction of step (1) is carried out under nitrogen protection.
14. The method of claim 10, wherein the reaction solvent in step (1) is a mixed solvent of toluene and tetrahydrofuran.
15. The method for synthesizing englitjing according to claim 14, characterized in that the volume ratio of toluene to tetrahydrofuran in the reaction solvent is 1-5:1-2.
16. The method for synthesizing englitjing according to claim 10, characterized in that the addition reaction of step (2) is carried out in an inert solvent; the acid is selected from methane sulfonic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrogen chloride or a solution thereof; the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
17. The method for synthesizing englitjing according to claim 16, characterized in that said inert solvent is selected from toluene, tetrahydrofuran or n-hexane.
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