Preparation method for rosuvastatin calcium intermediate

A technology for rosuvastatin calcium and intermediates, which is applied in the field of compound synthesis technology, can solve the problems of poor reaction selectivity, large amount of waste water, and high production cost, and achieve the effects of mild reaction conditions, environmental friendliness, and simple raw materials

Active Publication Date: 2016-03-16
ZHEJIANG LEPU PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lin Wenqing et al. (CN2011124050, WO2011124050, US20120310000) used vinyl chloride as raw material to prepare Grignard reagent and chiral epichlorohydrin reaction, and prepared 6-substituted (R)-(+)-3-(tert-butyldimethylsilyloxy)-5-oxo-hexanoic acid methyl ester, and then react with triphenylphosphine to prepare VI, the reaction also involves flammable and explosive Grignard reaction, and Grignard reagent and chiral epichlorohydrin reaction selectivity is poor, there are by-products of Markov addition in the addition of olefins, and the amount of waste water in the final oxidation reaction is large, etc.
Literature (J.Org.Chem, 59(25), 7849-7854 prepares VI through the resolution of acid anhydride compounds, the raw material acid anhydride compounds used in this method are expensive, and the other enantiomers left by the resolution cannot be used. high production cost

Method used

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  • Preparation method for rosuvastatin calcium intermediate
  • Preparation method for rosuvastatin calcium intermediate
  • Preparation method for rosuvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Add 0.275 g of SalenCo(III) (OAc) to 160 g of 30% sodium acetylene tetrahydrofuran solution, dropwise add 92.0 g of epichlorohydrin, react for 12 hours, concentrate and recover THF, add 200 ml of ethyl acetate, and wash with 100 ml of saturated saline , layered, concentrated and recovered ethyl acetate to obtain (2R)-1-chloro-2-hydroxyl-4-pentyne (I) 98.0 grams; 118.0 grams of (2R)-1-chloro-2-hydroxyl-4-pentyne Alkyne (I) was added dropwise in 245 grams of 20% sodium cyanide aqueous solution, and reacted for 4 hours at 30°C. After the reaction was completed, 500 ml of ethyl acetate was added, followed by washing with 100 ml of saturated brine, layering, concentration and recovery of ethyl acetate to obtain ( 2R)-1-cyano-2-hydroxy-4-pentyne (II) 98.0 g. 109.0 grams of (2R)-1-cyano-2-hydroxyl-4-pentyne (II) was added dropwise in 1000ml of methanol, followed by hydrogen chloride gas and gas chromatography to track the end of the reaction, and reacted at 0°C for 10 hours. A...

Embodiment 2

[0014] In 160 grams of 30% sodium acetylene tetrahydrofuran solution, add 0.542 grams of SalenCo(Ⅲ) Cl, dropwise add 101.2 grams of epichlorohydrin, react for 24 hours, concentrate and recover tetrahydrofuran, add 200 ml of ethyl acetate, add 100 ml of saturated saline to wash, divide layer, concentrated and recovered ethyl acetate to obtain (2R)-1-chloro-2-hydroxyl-4-pentyne (I) 100.2 grams; 118.0 grams of (2R)-1-chloro-2-hydroxyl-4-pentyne ( 1) Add dropwise to 257.3 grams of 20% sodium cyanide aqueous solution, and react at 30°C for 8 hours. After the reaction, add 500 ml of ethyl acetate, add 100 ml of saturated saline to wash, separate layers, concentrate and recover ethyl acetate to obtain (2R) - 98.9 g of 1-cyano-2-hydroxy-4-pentyne (II). 109.0 grams of (2R)-1-cyano-2-hydroxyl-4-pentyne (II) was added dropwise to 1000ml of methanol, followed by hydrogen chloride gas, followed by gas chromatography at the end of the reaction, and reacted at 5°C for 5 hours. After the reac...

Embodiment 3

[0016]Add 0.50 g of SalenCo(Ⅲ)Cl to 160 g of 30% sodium acetylene tetrahydrofuran solution, add dropwise 100.0 g of epichlorohydrin, react for 18 hours, concentrate and recover tetrahydrofuran, add 200 ml of ethyl acetate, add 100 ml of saturated saline to wash, divide layer, concentrated and recovered ethyl acetate to obtain (2R)-1-chloro-2-hydroxyl-4-pentyne (I) 112.2 grams; 118.0 grams of (2R)-1-chloro-2-hydroxyl-4-pentyne ( 1) Add dropwise to 250 grams of 20% sodium cyanide aqueous solution, and react at 30°C for 8 hours. After the reaction, add 500 ml of ethyl acetate, add 100 ml of saturated saline to wash, separate layers, concentrate and recover ethyl acetate to obtain (2R) - 100.1 g of 1-cyano-2-hydroxy-4-pentyne (II). 109.0 grams of (2R)-1-cyano-2-hydroxyl-4-pentyne (II) was added dropwise to 1000ml of methanol, followed by hydrogen chloride gas, followed by gas chromatography at the end of the reaction, and reacted at 0°C for 8 hours. After the reaction, Methanol w...

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Abstract

The invention discloses a preparation method for a rosuvastatin calcium intermediate. The preparation method comprises the following steps: adding Salen Co (III) in a sodium acetylide tetrahydrofuran solution, dropwise adding epichlorohydrin for reaction, dropwise adding a product into a sodium cyanide aqueous solution for reaction to obtain a product, and dropwise adding the obtained product into methanol and introducing hydrogen chloride to obtain (3R)-hydroxyl-methyl 5-octynoate (III); with dichloromethane as a solvent, adding the compound (III) and tert-butyldimethylsilyl chloride to obtain a compound (IV), dropwise adding the compound (IV) into a sodium hypochlorite aqueous solution to obtain 6-chloro-(R)-(+)-3-(tert-butyldimethylsilanyloxy)-5-oxo-methyl caproate (V); with 2-methyltetrahydrofuran as a solvent, adding 6-chloro-(R)-(+)-3-(tert-butyldimethylsilanyloxy)-5-oxo-methyl caproate and triphenylphosphine so as to obtain methyl (3R)-(tert-butyldimethylsilanyloxy)-5-oxo-6-triphenylphosphoranylidenehexanoate(VI). According to the preparation method provided by the invention, the raw materials are simple, the reaction conditions are mild, environment friendliness is realized and the preparation method can be used for industrial mass production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] (3R)-tert-butyldimethylsilyloxy-5-oxo-6-triphenylphosphine hexanoic acid methyl ester (VI) is a key intermediate for the synthesis of rosuvastatin (Current Organic Chemistry, 2010, 14, 816-845 ). Konoike et al. (JP06135975) synthesized VI through Witting reaction with methyl triphenylphosphine bromide as raw material, NaH as hydrogen extraction reagent and DMSO as solvent. Dangerous to use. Niddam-Hildesheim et al. (WO2006017357) synthesized VI by Witting reaction at -78°C by n-butyllithium hydrogen extraction in tetrahydrofuran as solvent. Lin Wenqing et al. (CN101735272) used vinyl chloride as raw material to prepare Grignard reagent, and synthesized VI through seven steps of ring opening, substitution, alcoholysis, hydroxyl protection, oxidation, acylation of methyl chloroformate, and W...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/535
CPCC07F9/5352
Inventor 蒋成君王永江韩小瑜
Owner ZHEJIANG LEPU PHARMA CO LTD
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