CN101381356A - The preparation method of simvastatin - Google Patents

Abstract

The invention discloses a preparation method of simvastatin. The method comprises: a. lovastatin and alkylamine to prepare lovastatin amide; b. protecting the hydroxyl group in the lovastatin amide molecule to generate lovastatin amide di (trimethyl)silyl ether; c. Methylation of lovastatin amide di(trimethyl)silyl ether to obtain simvastatin amide disiloxane; d. deprotection of simvastatin amide disiloxane to generate octyl Vastatin amide; e. hydrolysis of simvastatin amide, ammonia gas to obtain simvastatin ammonium salt; f. cyclization of simvastatin ammonium salt to generate simvastatin. In the present invention, the composite solvent of tetrahydrofuran and cyclohexane is used as the solvent for the upper protection reaction, and the lovastatin amide bis(trimethyl)silyl ether can directly carry out the methylation reaction without alkali washing and water washing. After the methylated product is washed with water, the protective group falls off automatically, eliminating the need for deprotection group reaction, and the product can be directly subjected to ammonium salification reaction. The above method simplifies the synthesis process of simvastatin.

Description

The preparation method of simvastatin

technical field

The invention relates to a preparation method of simvastatin.

Background technique

Simvastatin, as an inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, is one of the most popular blood lipid-lowering drugs on the market. Cerebrovascular disease. The method for preparing simvastatin at present has:

(1), Lovastatin amide, using tert-butyldimethylsilyl chloride as a hydroxyl protection reagent, imidazole as a catalyst, methyl iodide as a methylation reagent, and methylating the side chain of 2-methylbutyrate Method (US Patent USP4820850);

(2), the method of directly methylating lovastatin amide without hydroxyl protection (US Patents USP6506929, USP4444784, USP6573385, USP6573392, USP6603022, British Patent EP0864596);

(3), hydrolyze lovastatin with potassium hydroxide, eliminate 2-methyl butyrate side chain, then carry out lactonization reaction to obtain glycol ester, protect with acetal, acylate, deprotect to obtain simvastatin (British patent EP0033538, EP0511867, US patent USP6384238);

(4), utilize lovastatin hydrolyzing enzyme to hydrolyze lovastatin, extract, separate and purify from the fermentation broth to obtain the hydrolyzate, then carry out selective silanization with tert-butyldimethylsilyl chloride, and 2,2- Acylation of dimethyl butyryl chloride, removal of tert-butyl dimethyl chloride silane protecting group to obtain simvastatin (US Patent USP4965200);

(5) A method for purifying lovastatin and simvastatin that can reduce the level of dimer impurities (US Patents USP6521762, USP6825362, USP6995277).

Among the above-mentioned methods, the reaction specificity of method (1) is better, but the reaction conditions are harsh, the technical difficulty is high, the used hydroxyl protection reagent tert-butyldimethylchlorosilane is expensive, and the deprotection reaction needs to be carried out under strongly acidic conditions. The process route is longer; the method (2) process route is short, but the temperature requirement of methylation is very harsh, and methylation may occur in other parts of the molecule, thereby introducing by-products, resulting in the yield and purity of the final product Neither is ideal; method (3) 2-methyl butyl ester has a large steric hindrance, and ester hydrolysis requires high temperature, strong alkali and long-term reaction (about 50h～60h), and under this condition, the six-membered lactone ring is easily Ring-opening, acyl group is difficult to remove completely, causes product yield not high (about 40%), and affects product quality; Method (4) utilizes the high specificity, high reactivity, low cost, low pollution characteristics of enzyme method, makes This semi-synthetic method using microorganisms and enzymes will become the trend of future drug production, but it is currently limited by the low level of fermentation and is difficult to achieve large-scale industrial production; method (5) purifies the dimer content of simvastatin products Most of the methods are more complicated and require more times of recrystallization.

Contents of the invention

The technical problem to be solved by the present invention is to provide a new synthetic method of simvastatin to reduce production cost and simplify the production process.

For solving the problems of the technologies described above, the preparation method of structural formula (I) simvastatin of the present invention is:

a, lovastatin (II) reacts with alkylamine to prepare lovastatin amide (III);

Wherein R is hydrogen, ethyl, butyl or cyclopropyl, _R is ethyl, butyl or cyclopropyl;

b. Using trialkylsilyl chloride to protect the hydroxyl group in the lovastatin amide molecule to generate lovastatin amide disiloxane (IV);

Wherein R ₂ , R ₃ , R ₄ are tert-butyl, methyl or phenyl;

c. Using a methylating agent to methylate the α-carbon of the side chain 2-methylbutyrate of the above lovastatin amide disiloxane to obtain simvastatin amide disiloxane (V);

d, adding water to terminate the reaction, deprotecting the above-mentioned simvastatin amide disiloxane to generate simvastatin amide (VI);

e, the above-mentioned simvastatin amide is hydrolyzed under alkaline conditions, and ammonia gas is passed to obtain simvastatin ammonium salt (VII);

f. The above simvastatin ammonium salt is cyclized under acidic conditions to generate simvastatin (I).

In step b of the method of the present invention, the hydroxyl protection reagent trialkylsilyl chloride used is trimethylchlorosilane, the reaction solvent is a composite solvent formed by tetrahydrofuran and cyclohexane, and the obtained product is lovastatin amide bis(trimethyl) Silyl ethers (VIII). After the reaction of generating lovastatin amide bis(trimethyl)silyl ether (VIII) is complete, the insoluble matter can be removed by filtration, and the methylation reaction can be directly carried out. In the pickling and water washing process after methylation, the protecting group Agglomerates fall off automatically, and can directly form simvastatin amide (VI), which simplifies the production process and reduces the production cost;

In the step c of the method of the present invention, after the methylated product (simvastatin amide disiloxane) is washed with water, the protecting group falls off automatically, and can directly form simvastatin amide; in step f, under acidic conditions (strong acid and organic Alkali buffer solution) to carry out cyclization esterification reaction, can obtain the simvastatin crude product of higher purity.

The alkylamine described in step a of the method of the present invention is n-butylamine, cyclopropylamine, ethylenediamine; the methylating reagent described in step c refers to n-butyllithium, pyrrolidine, methyl iodide; the alkaline described in step e The solution is 2-4M sodium hydroxide solution.

The inventive principle of the present invention is to be raw material with lovastatin, on the 2-methylbutyrate side chain on the 8-position of the hexahydronaphthalene ring system of lovastatin, increase a methyl group, form the - Compounds with dimethylbutyrate side chains. 1. Using lovastatin (II) as the starting material, open the ring under the action of primary or secondary amines to form lovastatin amide (III); 2. Protect the lovastatin amide molecule with a hydroxyl protecting group The hydroxyl group is protected to generate lovastatin amide disiloxane (IV), and trialkylchlorosilane is used instead of tert-butyldimethylchlorosilane in the original process as the protective reagent, which has the characteristics of easy-to-obtain raw materials and low cost. The reaction is carried out according to the traditional process. After the upper protection reaction is completed, alkali washing and water washing operations are required. At this time, the trialkyl silicon group will fall off, which will affect the progress of the methylation reaction; The composite solvent is the solvent for the upprotection reaction, and when imidazole is used as the catalyst for the upprotection reaction, after the reaction is completed, cool until the insoluble matter is completely precipitated out, and filter to remove the insoluble matter, and the solution can be directly used in the methylation reaction after drying. 3. Use alkyllithium, secondary amine, and methyl iodide to methylate it to form simvastatin amide disiloxane (V); 4. After methylation, use methanesulfonic acid, tetrabutylammonium fluoride, acetic acid, Acidic catalysts such as hydrochloric acid are deprotected to generate simvastatin amide (VI); 5, simvastatin amide is hydrolyzed under alkaline conditions, and ammonia gas generates simvastatin ammonium salt (VII); 6, simvastatin ammonium salt Dissolved in an aprotic organic solvent, catalyzed cyclization under acidic conditions (buffer solution of strong acid and a small amount of organic base) to obtain crude simvastatin, then dissolve crude simvastatin in polar solvents such as methanol or ethanol, and undergo After activated carbon decolorization, add water to recrystallize to obtain pharmaceutical grade simvastatin. Among them, the aprotic solvent can be acetonitrile, dichloromethane, ethyl acetate and toluene, etc.; the strong acid can be methanesulfonic acid, tetrabutylammonium fluoride, acetic acid, hydrochloric acid, etc.; the organic base can be pyridine, imidazole and alkylamine wait.

The beneficial effects produced by adopting the above-mentioned technical scheme are: using trialkylchlorosilane as the protecting group of the hydroxyl group in the lovastatin amide molecule, using the composite solvent formed by tetrahydrofuran and cyclohexane as the solvent for the upper protection reaction, and using imidazole Carry out the protection reaction for the catalyst. After the reaction, cool until the insoluble matter is completely precipitated. After the insoluble matter is removed, the methylation reaction is carried out directly, which solves the problem of the protective group falling off; after the methylation reaction, the product is washed in water In , the protecting group falls off automatically, which saves the deprotection reaction and simplifies the synthesis process.

Detailed ways

The preparation method of this simvastatin comprises the steps:

Synthesis of lovastatin amide (III): ring-opening lovastatin (II) with primary or secondary amines to form lovastatin amide, the reaction temperature is 50-90°C, the reaction time is 2-8 hours, and then the Pressure distillation to remove excess amine to obtain viscous lovastatin amide; or after extraction with an aprotic organic solvent, pickling to remove excess amine, distilling off the solvent to obtain viscous lovastatin amide.

The synthesis of lovastatin amide bis(trimethylsilyl) ether (VIII): lovastatin amide is dissolved in the composite solvent of tetrahydrofuran and cyclohexane, wherein the volume ratio of tetrahydrofuran and cyclohexane in the composite solvent is (1.0～ 4.2):1, the preferred volume ratio is (2.5～3.5):1. Then, add 1-8 moles of trialkylchlorosilane and 1-6 moles of imidazole, and react at 40-90° C. for 2-10 hours. A better process formula is 4-8 moles of trialkylchlorosilane, 2-5 moles of imidazole, react at 40-80°C for 1-6 hours, then put the product in the refrigerator until the insoluble matter is completely precipitated, remove After removing the insoluble matter, the solution was directly used for the methylation reaction.

Synthesis of simvastatin amide (VI): secondary amines (pyrrolidine, diisopropylamine, etc.) and alkyllithium (such as n-butyllithium, hexyllithium, etc.) are formed at -40 to -10°C to form lithium amides , add 2 to 10 moles of lithium amide to the solution of lovastatin amide bis(trimethylsilyl) ether at one time, keep it warm at -50 to -10°C for 1 to 5 hours, and add iodine at one time 3~10 moles of methane, react at -40~-10°C for another 2~3 hours, the methylation reaction produces simvastatin amide disiloxane (V), and add water to terminate the reaction. During this process, the protective group falls off automatically, directly Generated simvastatin amide, which simplifies the synthesis process.

Synthesis of simvastatin ammonium salt (VII): in methanol or ethanol solution of simvastatin amide (VI), slowly add 2-4M sodium oxide solution, hydrolyze reaction at 60-90°C for 2-8 hours, Preferably, the reaction is carried out at 70-80° C. for 2-5 hours, and then extraction is carried out step by step with an aprotic solvent such as ethyl acetate, and ammonia gas is passed to obtain simvastatin ammonium salt (VII).

The synthesis of simvastatin (I): the prepared simvastatin ammonium salt (VII) is dissolved in ethyl acetate or dichloromethane and other aprotic solvents or mixed solvents, in acidic (strong acid and a small amount of organic base buffer Under the catalysis of liquid), preferably the buffer solution of methanesulfonic acid and pyridine, the cyclization lactonization can obtain the crude product of simvastatin with high purity. After dissolving the crude product of simvastatin with ethanol, add activated carbon for decolorization, and add Water with twice the volume of ethanol, preferably 1-2 times the volume of ethanol, crystallized, filtered, and vacuum-dried at 20-50°C to obtain a pharmaceutical-grade simvastatin product.

The following is the embodiment of the preparation method of the simvastatin.

Example 1:

(1), N-butyl-7-[1,2,6,7,8α(R)-hexahydro-2(S), 6(R)-dimethyl-8-[[2-(S )-methylbutyryl]oxyl]-1-(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid amide (lovastatin n-butyramide, III) synthesis:

At room temperature, 24 g (59.6 mmol) of lovastatin and 50 mL of n-butylamine were added into a dry reactor filled with nitrogen, heated to 80° C. and refluxed for 3 to 4 hours. Then cool to room temperature, place in a water bath at 60°C, distill under reduced pressure to remove n-butylamine, or extract with an aprotic organic solvent, then pickle to remove excess amine to obtain viscous lovastatin n-butyramide.

(2), N-butyl-7-[1,2,6,7,8α(R)-hexahydro-2(S), 6(R)-dimethyl-8-[[2-(S )-methylbutyryl]oxy]-1-(S)-naphthyl]-3(R),5(R)-bis(trimethylsilyloxy)heptanoic acid amide (lovastatin n-butyramide Synthesis of bis(trimethylsilyl) ether, VIII):

Add 100mL tetrahydrofuran and 50mL cyclohexane into the above viscous substance, after completely dissolving, add 225g (3.3 moles) of imidazole and 432g (4.0 moles) of trimethylchlorosilane, heat to 65°C for 3 hours, cool to At room temperature, refrigerate in the refrigerator until the insoluble matter is completely precipitated, then filter, and the filtrate is directly used in the next reaction.

(3), N-butyl-7-[1,2,6,7,8α(R)-hexahydro-2(S), 6(R)-dimethyl-8-[[2-(S )-methylbutyryl]oxyl]-1-(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid amide (simvastatin amide, VI) synthesis:

Under nitrogen protection, cool 45ml of molecular sieve-dried THF and 20ml of pyrrolidine to -20°C, control the temperature between -25 and -20°C, slowly add 1.6M n-butyllithium solution, react for 1.5 hours, and keep warm After 30 minutes, a lithium pyrrolidine solution was obtained.

Cool the lovastatin n-butyramide bis(trimethylsilyl) ether solution obtained in the previous step to -80～-70°C, quickly add the prepared lithium pyrrolidine under nitrogen protection, and react at -35°C for 1.5 hours, Add 150 mL (2.4 moles) of methyl iodide, and when the natural temperature rise is not obvious, lower the temperature to -35～-30°C, keep the reaction for 1 hour, raise the temperature to -10°C, and keep the reaction for 30 minutes. Add a mixture of 150mL cyclohexane and 150mL water, stir for 5 minutes, stand still for 15 minutes, and separate the water layer; distill the oil layer under reduced pressure to remove the solvent to obtain a brown viscous simvastatin amide, add 150mL methanol to dissolve and set aside.

(4), 7-[1,2,6,7,8α(R)-hexahydro-2(S), 6(R)-dimethyl-8-[[2-(S)-methylbutyl Acyl]oxyl]-1-(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid ammonium (simvastatin ammonium salt, VII) synthesis:

At room temperature, add 150 mL of 3M sodium hydroxide solution to the methanol solution of simvastatin amide prepared in step (3) under stirring conditions, heat to 70-80 ° C, reflux for 3 hours, and distill under reduced pressure until the solution becomes viscous thicken, cool to 5-10°C, add 1.5M hydrochloric acid to adjust the pH to 7.0, add 450mL ethyl acetate, stir, continue to adjust the pH to 5, stir for 5 minutes, stand still for 30 minutes, separate the water layer, and pass through the oil layer with ammonia gas When the pH is 8.5, simvastatin ammonium salt is obtained, and dried under reduced pressure at 40°C to obtain white crystal simvastatin ammonium salt.

(5), 7-[1,2,6,7,8α(R)-hexahydro-2(S), 6(R)-dimethyl-8-[[2-(S)-methylbutyl Acyl]oxyl]-1-(S)-naphthyl]-3(R),5(R)-dihydroxy-2-pyrone (simvastatin, I) synthesis:

The simvastatin ammonium salt 7g (14.9 mmol) obtained in step (4) was dissolved in 70mL of dichloromethane, and slowly added solution A (1.25mL methanesulfonic acid, 0.05mL pyridine and 30mL of dichloromethane) 25mL, React for 30 minutes, add 25 mL of water, stir for 15 minutes, stand still for 30 minutes, separate the water layer, add 2M sodium hydroxide solution to the oil layer, stir to stand still, separate the water layer, add 0.5 g of activated carbon to the oil layer, stir for 1 hour to decolorize , filtered, and the oil layer was distilled and concentrated under reduced pressure, added 50mL of ethanol, heated to 60°C, and after it was completely dissolved, added 50mL of purified water at 50°C, cooled in a water bath, crystallized, after the crystallization was complete, dried under reduced pressure at 40°C to obtain Simvastatin crude.

Add 12 g (28.7 mmol) of crude simvastatin into 50 ml of ethanol, stir and heat, fully dissolve at 50-60° C., stop stirring; filter. At 50-60°C, slowly and uniformly drop 45ml of purified water at about 55°C into the feed liquid, stir and crystallize the feed liquid, and place it overnight at room temperature. The crystallization liquid was filtered, and the filter cake was fully washed with 50 ml of purified water, filtered and weighed; vacuum-dried at 30-45° C. for 24 hours to obtain pharmaceutical grade simvastatin (yield 80%) with a content of 99.5%.

Example 2:

Except step (2), other is with embodiment 1, and the synthesis technique of step (2) is as follows:

Add 107mL tetrahydrofuran and 43mL cyclohexane to the above-mentioned viscous substance, after completely dissolving, add 238g (3.5 moles) of imidazole and 432g (4.0 moles) of trimethylchlorosilane, heat to 60°C for 3 hours, cool to At room temperature, put it in the refrigerator to refrigerate until the insoluble matter is completely precipitated, then filter, and the filtrate is directly used in the next step of the synthesis reaction.

Example 3:

Except step (2), other is with embodiment 1, and the synthesis technique of step (2) is as follows:

Add 120mL tetrahydrofuran and 30mL cyclohexane to the above-mentioned viscous substance. After completely dissolving, add 136g (2.0 moles) of imidazole and 432g (4.0 moles) of trimethylchlorosilane, heat to 75°C for 2 hours, and cool to At room temperature, put it in the refrigerator to refrigerate until the insoluble matter is completely precipitated, then filter, and the filtrate is directly used in the next step of the synthesis reaction.

Example 4:

Except step (3), other is with embodiment 1, and the synthetic technique of step (3) is as follows:

Under the protection of nitrogen, cool 40ml of tetrahydrofuran and 25ml of pyrrolidine dried on molecular sieves to -20°C, control the temperature between -25 and -20°C, slowly add 1.6M n-butyllithium solution, react for 1.5 hours, and keep warm for 30 Minutes to obtain lithium pyrrolidine solution.

Cool the lovastatin n-butyramide bis(trimethylsilyl)ether solution obtained in the previous step to -80～-70°C, quickly add the prepared lithium pyrrolidine under nitrogen protection, and react at -25°C for 1.0 hour, Add 188mL (3.0 moles) of methyl iodide, and when the natural temperature rise is not obvious, lower the temperature to -25～-20°C, keep the reaction for 2 hours, raise the temperature to -10°C, and keep the reaction for 30 minutes. Add a mixture of 150mL cyclohexane and 150mL water, stir for 5 minutes, stand still for 15 minutes, and separate the water layer; distill the oil layer under reduced pressure to remove the solvent to obtain a brown viscous simvastatin amide, add 150mL methanol to dissolve and set aside.

Claims (9)

1, the preparation method of a kind of structural formula (I) Simvastatin,

It comprises:

A, lovastatin (II) prepare lovastatin acid amides (III) with alkylamine;

Wherein R is hydrogen, ethyl, butyl or cyclopropyl, R ₁Be ethyl, butyl or cyclopropyl;

B, use trialkyl silica chlorine are protected the hydroxyl in the above-mentioned lovastatin amide molecule, generate lovastatin acid amides two silicon ethers (IV);

R wherein ₂, R ₃, R ₄Be the tertiary butyl, methyl or phenyl;

C, use methylating reagent methylate to the alpha-carbon of the side chain 2-Methyl Butyric Acid ester of above-mentioned lovastatin acid amides two silicon ethers, obtain Simvastatin acid amides two silicon ethers (V);

D, add the water termination reaction, make above-mentioned Simvastatin acid amides two silicon ether deprotections generate Simvastatin acid amides (VI);

E, the hydrolysis under alkaline condition of above-mentioned Simvastatin acid amides, logical ammonia obtains simvastatin ammonium salt (VII);

F, the cyclization under acidic conditions of above-mentioned simvastatin ammonium salt generate Simvastatin (I).

2, the preparation method of Simvastatin according to claim 1; it is characterized in that among the described step b; used hydroxyl protection reagent trialkyl silica chlorine is trimethylchlorosilane; reaction solvent is tetrahydrofuran (THF) and the formed double solvents of hexanaphthene, and products therefrom is lovastatin acid amides two (trimethylammonium) silicon ether (VIII).

3, the preparation method of Simvastatin according to claim 1 is characterized in that described steps d is: the methylate Simvastatin acid amides two silicon ethers among the step c are after washing, and blocking group comes off automatically, directly forms the Simvastatin acid amides.

4, the preparation method of Simvastatin according to claim 1 is characterized in that among the described step f, carries out the cyclization esterification under acidic conditions, obtains the Simvastatin crude product of higher degree.

5, the preparation method of Simvastatin according to claim 4 is characterized in that the acidic conditions among the described step f is to carry out the cyclization esterification in the damping fluid of strong acid and organic bases.

6, the preparation method of Simvastatin according to claim 1 is characterized in that the described alkylamine of described step a is n-Butyl Amine 99, cyclopropylamine, quadrol.

7, the preparation method of Simvastatin according to claim 1 is characterized in that the described methylating reagent of described step c is meant n-Butyl Lithium, tetramethyleneimine, methyl iodide.

8, the preparation method of Simvastatin according to claim 1 is characterized in that the described basic solution of described step e is the sodium hydroxide solution of 2～4M.

9, the preparation method of Simvastatin according to claim 1 is characterized in that Simvastatin (I) that described step f obtains after the proper amount of active carbon decolouring, carries out recrystallization with the second alcohol and water.