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Method for preparing simvastatin intermediate - simva-acylamide second silicon ether

A technology of simvastatin and simvastatin, which is applied in the directions of silicon organic compounds, organic chemistry, drug combination, etc., can solve the problems of increased preparation cost of simvastatin, difficult control of the production process, etc., so as to improve product purity and simplify production. Process, cost reduction effect

Active Publication Date: 2010-06-23
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the above-mentioned reaction process of preparing simvastatin with lovastatin, the key intermediate is simvastatin disiloxane; the methylating reagents used in the current common preparation methods all use expensive methyl iodide, so that simvastatin The preparation cost is greatly increased, and the production process is not easy to control

Method used

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  • Method for preparing simvastatin intermediate - simva-acylamide second silicon ether
  • Method for preparing simvastatin intermediate - simva-acylamide second silicon ether

Examples

Experimental program
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Effect test

Embodiment 1

[0014] At room temperature, add 100g of lovastatin (II), add 80ml of n-butylamine, heat to 80°C under stirring, reflux for 1-1.5 hours, cool down to 50°C, evaporate excess n-butylamine under reduced pressure, and obtain lovastatin (III ) 118g, purity 98%. used directly in the next reaction.

[0015] The above-mentioned lovaamide (III) was dissolved in 250ml of DMF, 38g of imidazole and 88g of tert-butyldimethylsilyl chloride (TBSCl) were added, heated to 50°C, reacted for 3.5 hours, the mixture was cooled to room temperature, 1500ml of water was added, and 1800ml of cyclohexane Extract and separate the organic layer. After drying over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure to obtain lovaamide disiloxane (IV) with a purity of over 97%, which was directly used in the next reaction.

[0016] Under the protection of nitrogen, cool the mixture of 50ml of pyrrolidine and 300ml of tetrahydrofuran dried through molecular sieves to -25°C, add ...

Embodiment 2

[0020] According to Example 1, lovaamide, lovaamide disiloxane and lithium pyrrolidinyl were prepared.

[0021] Compound (IV), add 650ml of tetrahydrofuran, stir to dissolve, cool to -45°C, under the protection of nitrogen, add pyrrolidinyl lithium solution dropwise at -40°C ~ -45°C, after dropping, keep warm for 2.5 hours, then drop Dimethyl sulfate was added, and the end point was controlled by HPLC. Water was added to terminate the reaction, and after treatment, the organic layer was concentrated to dryness under reduced pressure to obtain the product (V). Unreacted raw material (IV) 0.48%.

Embodiment 3

[0023] According to Example 1, lovaamide, lovaamide disiloxane and lithium pyrrolidinyl were prepared.

[0024] Compound (IV), add 350ml tetrahydrofuran and 350ml cyclohexane, dissolve under stirring, cool to -35°C, under vigorous stirring, add the prepared pyrrolidinyl lithium solution at -35°C ~ -30°C, and complete the addition. Heat preservation reaction for 2 hours, then add 60ml of methyl p-toluenesulfonate, the temperature rises, then cool to -30°C, stir for 1 hour, add 500ml of water, stir for 10 minutes, let stand, separate the organic layer, wash and concentrate under reduced pressure to After drying, simvaxamide disiloxane (V) and 0.51% of unreacted raw material lovaamide disiloxane (IV) were obtained.

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Abstract

The invention relates to a preparation method of the intermediate of medicine simvastatin. The method comprises the following steps: 1) lovastatin and amine react to prepare lova-acylamide; 2) hydroxyl in lova-acylamide molecules is protected; and 3) sulfonic acid single-ester and sulfuric acid ester compounds are used to methylate the pha-carbon of lova-acylamide second silicon ether side chain 2 - methyl butyric ester to obtain the simva-acylamide second silicon ether. The simva-acylamide second silicon ether can be used for preparing simvastatin. The method greatly reduces the cost for preparing the key intermediate of the simvastatin - simva-acylamide second silicon ether, simplifies the production technology and improves product purity.

Description

technical field [0001] The invention relates to a preparation method of simvastatin, a key intermediate of the hypolipidemic drug simvastatin, simvastatin disiloxane. Background technique [0002] Lovastatin (US4231938) is a well-known blood lipid-lowering drug, which is methylated on the 2-methylbutyrate side chain at the 8-position of its hexahydronaphthalene ring system to obtain 2,2-dimethyl derivatives that are octyl Vastatin has a stronger lipid-lowering effect. [0003] Simvastatin is developed by Merck Company of the United States and is currently one of the most commonly used statin blood lipid-lowering drugs. Its production mostly uses lovastatin as the raw material. After opening the ring with n-butylamine, the hydroxyl group is protected with tert-butyldimethylsilyl chloride (TBSCl), and then methylated to obtain the key intermediate - simvastatin disiloxane. Deprotection of simvaxamide disiloxane generates simvastatin; then hydrolyzes with lye to generate simv...

Claims

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Application Information

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IPC IPC(8): C07F7/08C07D309/30A61P9/12
Inventor 马德银谢伟彬
Owner NEW FOUNDER HLDG DEV LLC
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