Preparation method of simvastatin

A technology of simvastatin and lovastatin amide, which is applied in the field of preparation of simvastatin, can solve the problems of short process route, high price, long process route, etc., and achieve the effect of readily available raw materials and low cost

Active Publication Date: 2009-03-11
HEBEI GUOLONG PHARMA CO LTD
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  • Abstract
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Problems solved by technology

[0008] 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 a

Method used

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  • Preparation method of simvastatin
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  • Preparation method of simvastatin

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[0031] The preparation method of this simvastatin comprises the steps:

[0032] 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.

[0033] 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 trialky...

Embodiment 1

[0039] (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:

[0040] 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.

[0041] (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):

[0042] Add 100mL tetrahydrofuran and 50mL cyclohexane into the above viscous substance, after completely dissolving, add 225...

Embodiment 2

[0052] Except step (2), other is with embodiment 1, and the synthesis technique of step (2) is as follows:

[0053] 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.

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Abstract

The invention discloses a method for preparing simvastatin. The method is as follows: a. lovastatin and alkylamine are prepared into lovastatin amide; b. hydroxyl groups in lovastatin amide molecules are protected, and lovastatin amide di-(trimethyl) silyl ether is generated; c. the lovastatin amide dimethyl (trimethyl) silyl ether is subjected to methylation, so as to obtain simvastatin amide di-silyl ether; d. the simvastatin amide di-silyl ether is protected, and simvastatin amide is generated; e. the simvastatin amide is subjected to hydrolysis and is added with ammonia gas, and simvastatin ammonium salt is obtained; and f. the simvastatin ammonium salt is subjected to ring closure to generate the simvastatin. The method takes a composite solvent of tetrahydrofuran and cyclonexane as a solvent for the protective reaction; the lovastatin amide di-(trimethyl) silyl ether can directly perform methylation reaction without alkaline washing and water scrubbing; after water scrubbing of methylate, protective groups are automatically fallen off, thereby the reaction for removing the protective groups is saved and the products can directly perform ammonium salt reaction. The method simplifies the synthesis technique of the simvastatin.

Description

technical field [0001] The invention relates to a preparation method of simvastatin. Background technique [0002] 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: [0003] (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); [0004] (2), the method of directly methylating lovastatin amide without hydroxyl protection (US Patents USP6506929, USP4444784, USP6573385, USP6573392, USP6603022, British Patent EP0864596); [0005] (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,...

Claims

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Application Information

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IPC IPC(8): C07D309/30A61P3/06A61P9/00
CPCY02P20/55
Inventor 赵雄燕王明珠刘红杰
Owner HEBEI GUOLONG PHARMA CO LTD
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