Process for the preparation of simvastatin

A technology of simvastatin and separation method, which is applied in the field of preparation of simvastatin, can solve the problems of many reaction steps, high energy consumption, low output rate, etc., and achieve the effect of simplifying the production process

Inactive Publication Date: 2006-04-05
PFICKER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this production process is that there are too many reaction steps, the reagents are expensive, and the first step of the methylation reaction is carried out at a temperature below -50°C, which requires special equipment, consumes too much energy, and has a low output rate.

Method used

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  • Process for the preparation of simvastatin
  • Process for the preparation of simvastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The hydrolysis of embodiment one lovastatin and the generation of trihydroxy acid molecular intermediate (reaction 4)

[0070] Under nitrogen protection, 20.0 g of lovastatin was dissolved in 200 ml of hot ethanol. At room temperature, 100 ml of cold potassium hydroxide (36 g) aqueous solution was slowly added to the above reaction solution. The reaction mixture was stirred at room temperature under nitrogen protection for 0.5 to 1 hour, and then refluxed for 12 to 16 hours. Then add 300 ml of water, evaporate 500 ml of solvent, and cool to 5-10°C. Then add 80 ml of diethyl ether, slowly add concentrated hydrochloric acid to adjust the pH value to 5.0 and control the temperature between 5-10°C during the process of adding concentrated hydrochloric acid. Stirring was kept for another hour, and the trihydroxy acid molecular intermediate was crystallized and precipitated in ether, and the obtained solid product was washed with water and dried under vacuum.

Embodiment 2

[0071] The synthesis (reaction 5) of the simvastatin derivative of embodiment two formula (4)

[0072] Under nitrogen protection, 16.0 g of the dried trihydroxy acid molecular intermediate was suspended in 300 ml of dichloromethane. After adding 0.4 g of p-toluenesulfonic acid, heat back distillation and distill off about 100 ml of dichloromethane. The white solid disappeared quickly and dissolved to give a clear solution. After cooling to a temperature of 5-10° C., 0.5 molar equivalents of lithium bromide, 2.1 molar equivalents of triethylammonia, and 2.4 molar equivalents of 2,2-dimethyl-butyryl chloride were added. After the reaction mixture was stirred under nitrogen for 0.5 to 1 hour, the reaction was stirred at room temperature. After the reaction was completed, 100 ml of water was added, and the organic layer was separated after stirring for 30 minutes. The organic layer was washed once with saturated brine (100 ml), washed four times with saturated aqueous sodium bi...

Embodiment 3

[0073] The synthesis (reaction 5) of the simvastatin derivative of embodiment three formula (4)

[0074] Under nitrogen protection, 16.0 g of the dried trihydroxy acid molecular intermediate was suspended in 300 ml of dichloromethane. After adding 0.4 g of p-toluenesulfonic acid, heat back distillation and distill off about 100 ml of dichloromethane. The white solid disappeared quickly and dissolved to give a clear solution. Then cool to a temperature of 5-10° C., and then add 0.5 molar equivalents of lithium bromide, 2.1 molar equivalents of triethylammonia, and 2.4 molar equivalents of 2,2-dimethyl-butyryl anhydride. After the reaction mixture was stirred under nitrogen for 0.5 to 1 hour, the reaction was stirred at room temperature. After the reaction was completed, 100 ml of water was added, and the organic layer was separated after stirring for 30 minutes. The organic layer was washed once with saturated brine (100 ml), washed four times with saturated aqueous sodium b...

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Abstract

The invention discloses a preparation method for simvastatin. Wherein, using inorganic base to hydrolyze lovastatin and obtain trioxyacidic intermediate with formulate (3); then, etherifying directly the intermediate to prepare simvastatin derivative with formulate (4), taking ring-opening reaction with catalyst to obtain open-loop ester with formulate (6), catalyzing, acidifying, and obtaining the product; or, improving existing technique with this invention, such as, converting the intermediate into ketal intermediate with six membered ring, catalyzing, etherifying to obtain the simvastatin derivative with formulate (8), using acid-catalysis de-preserving reaction to obtain product. This invention simplifies greatly existing technique.

Description

Field of invention: [0001] The invention relates to a preparation method of simvastatin. Background of the invention: [0002] Simvastatin, namely 2,2-dimethylbutyric acid-8-{(4R,6R)-6-{2-[(1S,2S,6R,8S,8αR)-1,2,6 , 7,8,8α-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl}}tetrahydro-4-hydroxy-2H-pyran-2-one ester, its molecular structure As shown in the following formula (1): [0003] Formula 1) Formula (2) [0004] Simvastatin is generally well tolerated, and most of the adverse reactions are mild, and less than 2% of patients in controlled clinical trials discontinued the drug due to adverse reactions. In 2002, the sales of simvastatin in North America reached more than 5.7 billion US dollars. [0005] Simvastatin is an HMG-CoA reductase inhibitor semi-synthesized from lovastatin of formula (2), as shown in Reaction 1. The difference between the two is only the functional group at the 8-position: lovastatin is 2-methylbutyryl at the 8-position, while simvastatin ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/46C07C51/42C07D309/30
CPCC07C69/732C07C67/03C07C59/46C07D317/30C07D309/30C07C2102/28C07C2602/28
Inventor 叶红平孙盟
Owner PFICKER PHARMA
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