A method for preparing atorvastatin key intermediate l1 by a solvent-free method

An atorvastatin, solvent-free technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of complex post-processing, difficult solvent recovery, long reaction time, etc., and achieve the effect of shortening reaction time, short reaction time and high conversion rate

Inactive Publication Date: 2021-01-05
ZHEJIANG HAISEN PHARMACY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to provide a method for preparing atorvastatin key intermediate L1 by a solvent-free method, so as to solve the problems of long reaction time of the above-mentioned existing process, complicated aftertreatment, large energy consumption and difficult solvent recovery

Method used

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  • A method for preparing atorvastatin key intermediate l1 by a solvent-free method
  • A method for preparing atorvastatin key intermediate l1 by a solvent-free method
  • A method for preparing atorvastatin key intermediate l1 by a solvent-free method

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Effect test

Embodiment 1

[0038] A method for preparing atorvastatin key intermediate L1 by a solvent-free method, comprising the following steps: adding M4 25g (59.88mmol) to the three-necked reaction flask successively, tetrabutylammonium bisulfate 6.25g (18.41mmol), neopentyl ammonium bisulfate Acid 3.15g (30.84mmol), A9 32.86g (119.76mmol), stirring, heating and melting reaction (external temperature 120°C), using a water separator to separate water, the reaction system is yellowish-brown thick;

[0039] The reaction progress was monitored by HPLC detection method, and the mobile phase conditions were: 75% acetonitrile, and the reaction was complete within 5.5 hours. The raw material M4HPLC content is less than 1%, and the L1 content is greater than 90%;

[0040] After the reaction was complete, the reaction system was cooled to 95°C, ethanol was added to dissolve until clarified, water was added dropwise until turbid, and the temperature was lowered to crystallize to obtain 28.55 g of a light yell...

Embodiment 2

[0046] A method for preparing atorvastatin key intermediate L1 by a solvent-free method, comprising the following steps: adding M4 25g (59.88mmol) to the three-necked reaction flask successively, tetrabutylammonium bisulfate 6.25g (18.41mmol), neopentyl ammonium bisulfate Acid 3.15g (30.84mmol), A9 32.86g (119.76mmol), stirred and heated for melting reaction (external temperature 130°C), water was separated with a water separator, and the reaction system was brown and thick;

[0047] Use HPLC detection method to monitor the reaction process, mobile phase conditions: 75% acetonitrile, 6.5h reaction is complete, raw material M4HPLC content is less than 3%, L1 content is greater than 87%, the reaction is complete;

[0048] After the reaction was complete, the reaction system was cooled to 95°C, 95% ethanol was added to dissolve it, water was added dropwise until cloudy, and the temperature dropped to crystallize to obtain 32 g of a light yellow powdery solid crude product. After t...

Embodiment 3

[0050] A method for preparing atorvastatin key intermediate L1 by a solvent-free method, comprising the following steps: adding M4 25g (59.88mmol) to the three-necked reaction flask successively, tetrabutylammonium bisulfate 6.25g (18.41mmol), neopentyl ammonium bisulfate Acid 3.15g (30.84mmol), A9 19.72g (71.87mmol), stirred and heated for melting reaction (external temperature 120°C), water was separated with a water separator, and the reaction system was brown and thick;

[0051] Adopt HPLC detection method to monitor reaction progress, mobile phase condition: 75% acetonitrile, 7h reaction is complete;

[0052] After the reaction is complete, cool the reaction system to 95°C, add ethanol to dissolve it, add water dropwise until cloudy, cool down and crystallize to obtain 26.67g of a light yellow powder solid crude product, after drying the crude product, recrystallize twice to obtain a white powder Solid 24.59g. The content of the product detected by HPLC was 99.84%; the y...

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Abstract

The invention discloses a novel method for preparing an atorvastatin key intermediate L1 through a solvent-free method and belongs to the technical field of drug chemical synthesis. The novel method comprises the following steps that M4 and A9 are taken as raw materials, under the effects of a phase transfer catalyst and an acid catalyst, constant-temperature stirring melting reaction is directlyconducted for 5-7 hours under the solvent-free condition, the reaction temperature is 80-140 DEG C, water distribution is conducted in the reaction process, after reaction is completed, cooling is conducted, then recrystallization is conducted, and thus the atorvastatin key intermediate L1 is obtained. According to the novel method, the phase transfer catalyst and the acid catalyst are adopted, aparent nucleus M4 and a chiral side chain A9 are subjected to stirring melting reaction under the solvent-free condition, after reaction, recrystallization is conducted directly through ethyl alcohol / water, and thus L1 is obtained; and as for the process, the reaction time can be shortened to be 5 h, the conversion rate can reach up to 90%, operation and aftertreatment are easy, no mixed solvent is recovered, pollution is reduced remarkably, and the method is suitable for amplification production.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis of medicines, in particular to a method for preparing atorvastatin key intermediate L1 by a solvent-free method. Background technique [0002] Atorvastatin is a statin hypolipidemic drug jointly developed by WarnerLambert Company and Pfizer Company of the United States. It can strongly inhibit the activity of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. It is a potent HMG-CoA reductase inhibitor, which can significantly reduce the content of total cholesterol and low-density lipoprotein cholesterol. It has the characteristics of strong lipid-lowering effect, high safety, and less toxic and side effects. Because atorvastatin is the world's first drug with a sales volume exceeding 10 billion U.S. dollars, it has a very broad application prospect, so it is favored by people, and the huge economic benefits stimulate researchers to continuously improve and enhance its technological ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 陈宇瑛曾其炀艾林李腾阳
Owner ZHEJIANG HAISEN PHARMACY CO LTD
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