Method for preparing rosuvastatin calcium midbody

A technology for rosuvastatin calcium and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of high price of raw material anhydride compounds, low yield of reaction products in the first step, unsuitability for large-scale production, etc., and achieve cheap raw materials , mild conditions, and the effect of three wastes treatment

Active Publication Date: 2010-06-16
JIANGXI DONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, the raw material acid anhydride compound used in this method is expensive, and the yield of the first step reaction product is low, and there is also the problem of high preparation cost, which is not suitable for industrialized large-scale production

Method used

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  • Method for preparing rosuvastatin calcium midbody
  • Method for preparing rosuvastatin calcium midbody
  • Method for preparing rosuvastatin calcium midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1, the preparation of compound I-1 (R is Me in general formula I, and Y is TBS)

[0040]

[0041] a. Reaction of vinyl chloride with metal magnesium to produce vinyl chloride Grignard reagent, and then carry out Grignard reaction with R-epichlorohydrin under the catalysis of cuprous chloride to obtain (2R)-1-chloro-2-hydroxyl -4-pentene;

[0042]

[0043] Add 2700ml of anhydrous-treated tetrahydrofuran and 216g of magnesium powder into the reaction flask, stir evenly, then add 4.5g of iodine, and add 100g of 1,2-dibromoethane in several times, after the addition, slowly heat up to 60-64 ℃, heat preservation and stirring for 3 to 4 hours, then feed vinyl chloride gas for reaction, react at a temperature of 60 to 64 ℃ and continue to feed vinyl chloride gas for 10 to 11 hours, then stop the reaction, cool down to 25 to 35 ℃, measure The concentration of the obtained vinyl chloride Grignard reagent is 3.34mol / L;

[0044] Continue to cool the reaction sol...

Embodiment 2

[0061] Embodiment 2, the preparation of compound I-1

[0062] a. Reaction of vinyl chloride with metal magnesium to produce vinyl chloride Grignard reagent, and then carry out Grignard reaction with R-epichlorohydrin under the catalysis of cuprous chloride to obtain (2R)-1-chloro-2-hydroxyl -4-pentene;

[0063] Add 300ml of anhydrous-treated tetrahydrofuran and 24g of magnesium powder into the reaction flask, stir evenly, then add 0.5g of iodine, and add 11g of 1,2-dibromoethane several times. ℃, heat preservation and stirring for 3 to 4 hours, then feed vinyl chloride gas for reaction, react at a temperature of 60 to 64 ℃ and continue to feed vinyl chloride gas for 10 to 11 hours, then stop the reaction, cool down to 25 to 35 ℃, measure The concentration of the obtained vinyl chloride Grignard reagent is 3.13mol / L;

[0064] Continue to cool the reaction solution to -35~-25°C, add 35g cuprous chloride, then slowly add 280g R-epichlorohydrin (the molar ratio of cuprous chlori...

Embodiment 3

[0076] Embodiment 3, the preparation of compound I-1

[0077] a. Reaction of vinyl chloride with metal magnesium to produce vinyl chloride Grignard reagent, and then carry out Grignard reaction with R-epichlorohydrin under the catalysis of cuprous chloride to obtain (2R)-1-chloro-2-hydroxyl -4-pentene;

[0078] Add 2700ml of anhydrous-treated tetrahydrofuran and 216g of magnesium powder into the reaction flask, stir evenly, then add 4.5g of iodine, and add 100g of 1,2-dibromoethane in several times, after the addition, slowly heat up to 60-64 ℃, heat preservation and stirring for 3 to 4 hours, then feed vinyl chloride gas for reaction, react at a temperature of 60 to 64 ℃ and continue to feed vinyl chloride gas for 10 to 11 hours, then stop the reaction, cool down to 25 to 35 ℃, measure The concentration of gained vinyl chloride Grignard reagent is 3.42mol / L;

[0079] Continue to cool the reaction solution to -35~-25°C, add 40g of cuprous chloride, then slowly add 370g of R-...

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Abstract

The invention discloses a method for preparing a rosuvastatin calcium midbody, namely a compound (R is C1-C10 alkyl, and Y is a hydroxyl protecting group) shown as the general formula I. Chloroethylene and R-epoxy chloropropane as initial raw materials are carried out seven steps of reaction, such as Grignard reaction, sodium cyanide nucleophilic substitution reaction, alcoholysis reaction, hydroxyl protection, oxidizing reaction, methylchloroformate acylation reaction and Wittig reaction to prepare the compound shown as the general formula I. The method has mild condition, simple and convenient operation, stable process, low cost and easy acquisition of raw materials, high product yield, easy disposal of the three wastes, less environmental pollution, low preparation cost and suitability for industrialized large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin calcium (Rosuvastatin calcium), the chemical name is (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl- Calcium N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoate (2:1), is a new generation of statins with a fully synthesized single enantiomer Drugs, which belong to HMG-GoA reductase inhibitors, can reduce the concentration of elevated low-density cholesterol, total cholesterol, triglyceride and apoprotein B, and increase the concentration of high-density cholesterol at the same time, which can be used for primary high Comprehensive treatment of cholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia. Because of its advantages of high efficiency, low toxicity, and small side effects, it is favored by pe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/535
CPCY02P20/55
Inventor 林文清郑宏杰刘小波
Owner JIANGXI DONGBANG PHARMA
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