Synthesis method for chiral intermediate of atorvastatin calcium

A technology of atorvastatin calcium and chiral intermediates, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of difficult preservation of enzymes, difficulty in industrial production, and easy inactivation

Active Publication Date: 2015-12-16
北京华素制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the DERA enzyme reported in the literature is mainly extracted from wild bacteria, the extraction procedure is complicat

Method used

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  • Synthesis method for chiral intermediate of atorvastatin calcium
  • Synthesis method for chiral intermediate of atorvastatin calcium
  • Synthesis method for chiral intermediate of atorvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033]In a 2000mL reaction flask equipped with mechanical stirring and a thermometer, add 50g (0.735mol) of furan and 1000mL of methanol, place it at -50°C, replace the air with nitrogen protection, and slowly add 240g (1.5mol) of liquid bromine dropwise. After the dropwise addition, react for 3 hours, raise the temperature to 0°C and continue the reaction for 2 hours. After the reaction is completed, rise to room temperature, adjust the pH of the reaction solution to 7-8 with 1000mL saturated sodium bicarbonate solution, distill off the remaining methanol under reduced pressure, and then use ethyl acetate Extract the reaction solution three times with 1000 mL of ester, combine the organic phases and wash with saturated sodium chloride solution, separate the organic phase, and distill off the ethyl acetate to obtain 75 g of compound 1,1,4,4-tetramethoxy-2-butene .

Embodiment 2

[0035]

[0036] Add 70g of compound 1,1,4,4-tetramethoxy-2-butene and 500mL of dimethyl sulfide into a 1000mL reaction bottle with mechanical stirring and a thermometer, place it at -10°C, and replace it in the bottle Nitrogen was introduced after the air, and 30g of ozone was slowly injected into the closed reaction system, and the reaction temperature was controlled to maintain at -10°C. After 10 hours of reaction, the raw materials were completely reacted, raised to room temperature, and the compound 1,1-dimethoxy was obtained after distilling off the solvent. Acetaldehyde 32g.

Embodiment 3

[0038]

[0039] In a 1000mL reaction flask with mechanical stirring and a thermometer, add 30g (0.3mol) of 1,1-dimethoxyacetaldehyde, 19g (0.3mol) of nitromethane and 3g (0.03mol) of anhydrous aluminum oxide into 500mL of DMF , under nitrogen protection, heated to 130 ° C, after the reaction was completed, lowered to room temperature, filtered the reaction liquid, added 500 mL of saturated sodium chloride solution to the filtrate after concentration, then extracted the reaction liquid twice with 600 mL of dichloromethane, combined organic 43 g of 1,1-dimethoxy-2-hydroxy-3-nitropropane was obtained after distilling off the solvent.

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Abstract

The invention discloses a synthesis method for a chiral intermediate of atorvastatin calcium, and belongs to the technical field of medical intermediate synthesis. The synthesis method is characterized in that according to the process route, not only are dangerous, highly toxic and expensive chemicals such as butyl lithium, editpotassium cyanide and periodic acid in chemical synthesis prevented from being used, but also an ee value of the chiral intermediate is effectively improved due to usage of a mixed chiral catalysts of titanium iso-propylate and S-xenol. According to the synthesis method, the raw materials are low in cost and easy to obtain, the route operation is easy, the repeatability is good, the yield is very high, and the synthesis method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of atorvastatin calcium chiral intermediates. Background technique [0002] Atorvastatin calcium is a powerful lipid-lowering drug launched by Pfizer in 1997. Atorvastatin calcium is a drug that can lower total cholesterol and triglycerides at the same time, and belongs to the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Since atorvastatin calcium is suitable for the simultaneous treatment of both elevated total cholesterol and triglycerides, in 2008 the American Heart Association and the Stroke Society emphasized in the "Guidelines for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack" The use of statins to strengthen lipid-lowering and the emphasis on recommending atorvastatin calcium have further established its status as a major drug with a large variety and a lo...

Claims

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Application Information

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IPC IPC(8): C07D319/06
CPCC07B2200/07C07D319/06
Inventor 毛伸毛龙飞李伟徐桂清姜玉钦蒋涛
Owner 北京华素制药股份有限公司
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