Preparation method of atorvastatin calcium intermediate

A technology of atorvastatin calcium and its intermediates, which is applied in the field of medicine and chemical industry, can solve the problems of harm to human body, difficulty in purchasing, increasing the cost of atorvastatin calcium preparation, etc., and achieve the effect of reagent safety

Active Publication Date: 2018-09-28
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These substances are not only extremely harmful to the human body, but also seriously pollute the environment.
The use of hydrocyanic acid and hydrogen salt as reaction raw materials not only does not conform to the current

Method used

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  • Preparation method of atorvastatin calcium intermediate
  • Preparation method of atorvastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] At 0°C, metal lithium (0.18g) was dissolved in 40mL of anhydrous ether, and 10ml of ether solution of compound II (2.79g, 0.01mol) was slowly added dropwise to it, and stirred at 0°C. During the reaction, a white precipitate was produced. After reacting until the lithium reaction is complete, let it stand still, and take the supernatant containing compound III for the next reaction.

[0046] Methyl chloroformate (1.09g, 0.012mol) was dissolved in 10ml of anhydrous ether, and the supernatant containing compound III obtained in the previous step (diethyl ether solution of compound III) was added dropwise thereto at -20°C , After the dropwise addition is completed, warm up to room temperature (15~25°C), and stir until the reaction is completed. Then lower the temperature to 0°C, and add 6.5mL saturated ammonium chloride solution to the reacted solution, then add 2.2ml hydrochloric acid with a mass percentage of 10%, keep the organic layer, wash with 5% sodium bicarbonate, ...

Embodiment 2

[0051] At 0°C, metal lithium (0.18g) was dissolved in 40mL of anhydrous tetrahydrofuran, and 10ml of compound II (2.79g, 0.01mol) in tetrahydrofuran was slowly added dropwise, and stirred at 0°C. During the reaction, a white precipitate was produced. After reacting until the lithium reaction is complete, let it stand still, and take the supernatant containing compound III for the next reaction.

[0052] Methyl chloroformate (1.09 g, 0.012 mol) was dissolved in 10 mL of anhydrous tetrahydrofuran. At -20°C, add dropwise the supernatant containing compound III obtained in the previous step (the tetrahydrofuran solution of compound III), rise to room temperature (15~25°C), stir, and after the reaction is completed, Add 6.5mL of saturated ammonium chloride solution, then add 2.2ml of 10% hydrochloric acid, retain the organic layer, wash with 5% sodium bicarbonate, remove THF by rotary evaporation, and obtain 2.05g of compound IV (purity: 92%, yield: 68%) .

[0053] Compound IV (6...

Embodiment 3

[0057] At 0°C, metal lithium (0.18g) was dissolved in 40mL of anhydrous ether, and 10ml of ether solution of compound II (2.79g, 0.01mol) was slowly added dropwise to it, and stirred at 0°C. During the reaction, a white precipitate was produced. After reacting until the lithium reaction is complete, let it stand still, and take the supernatant containing compound III for the next reaction.

[0058] Methyl chloroformate (1.09 g, 0.012 mol) was dissolved in 10 mL of anhydrous ether. Add the supernatant containing compound III (diethyl ether solution of compound III) obtained in the previous step dropwise to it at -20°C, rise to room temperature (15~25°C), stir, and after the reaction is completed, Saturated ammonium chloride solution was added, followed by 2.2ml of 10% hydrochloric acid, the organic layer was retained, washed with 5% sodium bicarbonate, and ether was removed by rotary evaporation to obtain 2.11g of compound IV (93% purity, 70% yield).

[0059] In compound IV (6...

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Abstract

The invention belongs to the field of medicines and chemical industry, and particularly relates to the field of pharmacy, in particular to a preparation method of an atorvastatin calcium intermediate.The preparation method comprises the following steps: firstly preparing a compound II into a lithium reagent, then reacting with methyl chloroformate, introducing an ester group, aminolyzing the ester group into amine, dehydrating the amide, and finally reducing a cyano group to obtain a target compound. By the brand-new preparation method of the atorvastatin calcium intermediate, a compound VI can be synthesized under the premise that highly toxic substances such as hydrocyanic acid, hydrobromide and the like are not used, and the compound VI is used for preparing a compound I; reagents usedin the whole preparation process are safe and environment-friendly, and the preparation method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to the field of pharmacy, in particular to a preparation method of an atorvastatin calcium intermediate. Background technique [0002] Atorvastatin Calcium (Atorvastatin Calcium) was developed by Warner-Lambert (now incorporated into Pfizer), and was approved by the FDA in 1996 for marketing in the United States. Its main purpose is to treat hypercholesterolemia and mixed hyperlipidemia. [0003] (4R-Cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxolane-hexanoic acid tert-butyl ester (125995-13-3) (compound Ⅰ) is atorvastatin Key intermediate compounds in calcium synthesis. [0004] At present, the synthetic route that the preparation method of compound I follows basically is: [0005] [0006] Therefore, compound VI, as a key intermediate compound in the synthesis of compound I, has important research significance in the research and development of the preparation process ...

Claims

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Application Information

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IPC IPC(8): C07D319/06
CPCC07D319/06
Inventor 陈本顺周长岳石利平成洪业徐春涛万新强何义毛玲妙李娜
Owner JIANGSU ALPHA PHARM CO LTD
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