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Method for preparing rosuvastatin calcium intermediate

A technology for rosuvastatin calcium and its intermediates, which is applied in the field of drug synthesis, can solve problems that are not conducive to large-scale production, and achieve the effects of reducing side reactions, improving process methods, and improving reaction efficiency

Active Publication Date: 2014-09-03
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction is catalyzed by metal zinc. Since a large amount of heat is generated after the reaction is initiated, it is easy to produce flushing materials, which is not conducive to large-scale production.

Method used

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  • Method for preparing rosuvastatin calcium intermediate
  • Method for preparing rosuvastatin calcium intermediate
  • Method for preparing rosuvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of intermediate Ⅰ: Dissolve 30g of ethyl S(-)-4-chloro-3-hydroxybutyrate in 300mL of tetrahydrofuran, cool down to 5°C, add 36.5g of triethylamine dropwise; after dropping, stir for 15 minutes ; Add 40.5g of tert-butyldimethylsilyl chloride dropwise at 5°C. After the drop is complete, heat up to 30°C for reaction, and monitor the reaction by TLC; The organic phase and the aqueous phase were extracted with toluene (500mL×3); the organic phases were combined, washed with saturated aqueous sodium chloride solution (500mL×2), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 49.1g of an oily product. Yield: 97%.

[0031] Preparation of intermediate II: under anhydrous and oxygen-free conditions, put 125mL of butyllithium (2M) solution in 250mL of tetrahydrofuran at -78°C, stir, and slowly add 29.1g of tert-butyl bromoacetate dropwise; Stir the reaction for 30 minutes; dissolve 35g of intermediate I in 100mL of tetrahydr...

Embodiment 2

[0035] Preparation of Intermediate I: Dissolve 20g of S(-)-4-chloro-3-hydroxybutyric acid ethyl ester in 300mL of toluene, cool down to 5°C, add 42.2g of HMDS dropwise; after dropping, stir the reaction for 15 minutes; Add 36g of tert-butyldimethylsilyl chloride dropwise at 5°C. After the drop is complete, heat up to 30°C for reaction, and monitor the reaction by TLC; The aqueous phase was extracted with toluene (300mL×3); the organic phases were combined, washed with saturated aqueous sodium chloride solution (300mL×2), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 33.3g of an oily product. Yield: 95%.

[0036] Preparation of Intermediate II: Under anhydrous and oxygen-free conditions, put 107mL of sodium hexamethyldisilazide (2M) solution in 200mL of toluene at -78°C, stir, and slowly add 27g of tert-butyl bromoacetate dropwise; After dropping, stir and react for 30 minutes; dissolve 30g of intermediate I in 90mL of toluene and add d...

Embodiment 3

[0040] Preparation of intermediate Ⅰ: Dissolve 35g of S(-)-4-chloro-3-hydroxybutyric acid ethyl ester in 500mL of dichloromethane, cool down to 5°C, add 54.4g of DIPEA dropwise; after dropping, stir for 15 minutes ; Add 79.1g of tert-butyldimethylsilyl chloride dropwise at 5°C, after dropping, heat up to 30°C for reaction, and monitor the reaction by TLC; after the reaction is completed, pour the reaction solution into 1200mL ice-water solution, stir and separate The organic phase and the aqueous phase were extracted with dichloromethane (500mL×3); the organic phases were combined, and the organic phase was washed with saturated aqueous sodium chloride solution (500mL×2), dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 56.1g of an oily product . Yield: 95%.

[0041] Preparation of intermediate II: under anhydrous and oxygen-free conditions, put 492mL lithium hexamethyldisilazide (2M) solution in 600mL tetrahydrofuran at -78°C, stir, ...

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Abstract

The invention discloses a method for preparing a rosuvastatin calcium intermediate. The name of the intermediate is 2-[(4R, 6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl]-tert-butyl acetate. The preparation method comprises the following steps: (1) preparing an intermediate I; (2) preparing an intermediate II; (3) preparing an intermediate III; and (4) preparing the 2-[(4R, 6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl]-tert-butyl acetate. The method has the beneficial effects that active hydroxyl in an initial material is protected in the reaction process disclosed by the invention, side reaction is reduced, the technique is improved, the reaction efficiency is improved, and the method is applicable to large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium) is the latest statin drug approved by AstraZeneca in Europe in 2002, and it is a "super statin" evaluated by the media. For the treatment of primary, familial hypercholesterolemia and mixed dyslipidemia. It was approved in the United States in August 2003, making it the seventh statin to hit the market. Its chemical name is: (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonamido)-5- Calcium pyrimidine]-3,5-dihydroxy-6-heptenoate. The structure is shown in Formula 1. [0003] [0004] Formula 1. [0005] Rosuvastatin calcium is a new statin drug discovered after the synthesis and screening of a series of pyrimidine substituted compounds. Except for the typical pharmacophore of statins that can bind to the activ...

Claims

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Application Information

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IPC IPC(8): C07D319/06
CPCC07D319/06
Inventor 严军李泽标邹林林燕峰吕连岭
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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