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Preparation process of atorvastatin calcium

A technology for the preparation of atorvastatin calcium, which is applied in the field of chemical synthesis, can solve the problems of reduced yield of condensate and generation of impurities, and achieve the effects of reducing impurities, increasing yield, and improving quality

Active Publication Date: 2013-01-02
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since one end of the structure of the reactant ATS-9 is -NH 2 , the other end is -COO-C-, the two are prone to self-reaction under this condition to form amides, resulting in impurities, and at the same time lead to a decrease in the yield of the condensate, which is basically 55-60% at present

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] In a 2L reaction flask, add 600ml of n-heptane, 200ml of tetrahydrofuran, and 200ml of toluene, add 14.6g of pivalic acid while stirring, raise the temperature to 40°C, then add 60.1g of ATS-9, and react at 40°C for 1 hour. Then add 83.5g M-4, raise the temperature to 85°C, and react for 24 hours. After completion of the reaction, concentrate under reduced pressure until no distillate evaporates, add 500ml of ethyl acetate to dissolve, wash with 100ml of saturated sodium bicarbonate solution and 100ml of saturated saline solution, add 50g of anhydrous sodium sulfate and dry for 2 hours, recover ethyl acetate under reduced pressure , concentrated until no distillate was evaporated. Add 500ml of isopropanol to dissolve, concentrate under reduced pressure until no distillate evaporates; repeat the operation 2 times. Add 550ml of isopropanol to dissolve, add dropwise 400ml of water, drop to 25-30°C, filter with suction, wash the filter cake with 300ml of isopropanol-water ...

Embodiment 2

[0014] In a 2L reaction flask, add 600ml of n-heptane, 200ml of tetrahydrofuran, and 200ml of toluene, add 14.6g of pivalic acid while stirring, raise the temperature to 40°C, then add 60.1g of ATS-9, and react at 55°C for 2 hours. Then add 83.5g M-4, raise the temperature to 90°C, and react for 24 hours. After completion of the reaction, concentrate under reduced pressure until no distillate evaporates, add 500ml of ethyl acetate to dissolve, wash with 100ml of saturated sodium bicarbonate solution and 100ml of saturated saline solution, add 50g of anhydrous sodium sulfate and dry for 2 hours, recover ethyl acetate under reduced pressure , concentrated until no distillate was evaporated. Add 500ml of isopropanol to dissolve, concentrate under reduced pressure until no distillate evaporates; repeat the operation 2 times. Add 550ml of isopropanol to dissolve, add dropwise 400ml of water, drop to 25-30°C, filter with suction, wash the filter cake with 300ml of isopropanol-water...

Embodiment 3

[0016] In a 2L reaction flask, add 600ml of n-heptane, 200ml of tetrahydrofuran, and 200ml of toluene, add 14.6g of pivalic acid while stirring, raise the temperature to 40°C, then add 60.1g of ATS-9, and react at 75°C for 0.5 hours. Then add 83.5g M-4, raise the temperature to 92°C, and react for 20 hours. After completion of the reaction, concentrate under reduced pressure until no distillate evaporates, add 500ml of ethyl acetate to dissolve, wash with 100ml of saturated sodium bicarbonate solution and 100ml of saturated saline solution, add 50g of anhydrous sodium sulfate and dry for 2 hours, recover ethyl acetate under reduced pressure , concentrated until no distillate was evaporated. Add 500ml of isopropanol to dissolve, concentrate under reduced pressure until no distillate evaporates; repeat the operation 2 times. Add 550ml of isopropanol to dissolve, add dropwise 400ml of water, drop to 25-30°C, filter with suction, wash the filter cake with 300ml of isopropanol-wat...

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PUM

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Abstract

The invention provides a preparation process of atorvastatin calcium, which is characterized by being divided into two steps when preparing a condensation compound (4R-cis)-1,1-dimethyl ethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methyl ethyl)-3-phenyl-4-[(phenyl amino)-carbonyl]-1H-pyrrole-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate: 1), adding (4R-cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tertbutyl acetate (called ATS-9 for short) into a mixed solvent of n-heptane, tetrahydrofuran and toluene to react with pivalic acid; and 2), adding 4-fluorine-alpha-[2-methyl-1-oxygen-propyl]-gamma-oxo-N,beta-diphenyl phenyl butyramide (called M-4 for short) and rising the temperature for reaction. The invention has the advantage of capability of greatly improving the yield of the intermediate condensation compound and is more in favor of industrialized production.

Description

technical field [0001] The invention belongs to chemical synthesis, in particular to a preparation process of atorvastatin calcium. Background technique [0002] Atorvastatin is a selective and competitive inhibitor of HMG-CoA reductase, which can reduce plasma cholesterol and lipoprotein levels by inhibiting the synthesis of HMG-CoA reductase and cholesterol in the liver, and increase the liver LDL expressed by cells receptors to enhance LDL uptake and metabolism. Where (4R-cis)-1,1-dimethylethyl-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4 -[(phenylamino)-carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate (hereinafter referred to as condensate ) is an important intermediate, and the current common preparation process for the condensate is to add (4R-cis) 6-aminoethyl-2,2-dimethyl-1 to a mixed solvent composed of n-heptane, tetrahydrofuran and toluene ,3-Dioxane-4-tert-butyl acetate (hereinafter referred to as ATS-9), pivalic acid, 4-fluo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/34
Inventor 贺新恒刘怀林蒋涛
Owner SHANDONG XINHUA PHARMA CO LTD
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