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Preparation method of pitavastatin calcium

A technology of pitavastatin calcium and cyclopropyl, which is applied in the field of preparation of cholesterol-lowering drugs, can solve problems such as unfavorable industrial production, unfriendly environment, complicated operation, etc., and achieves improved safety, friendliness, environment friendliness, and yield. high effect

Active Publication Date: 2016-06-29
XUZHOU WANBANG JINQIAO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The present invention aims at the problems of long steps, complicated operation and unfriendly environment caused by the use of highly corrosive reagents in the existing pitavastatin calcium synthesis technology, which seriously corrodes equipment and is unfavorable for industrialized production.

Method used

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  • Preparation method of pitavastatin calcium
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  • Preparation method of pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 compound II

[0044]Reaction formula:

[0045]

Embodiment 1-1

[0047] Steps:

[0048] Add 29.1g of compound I, 17.2g of methyldichlorosilane, 8g of ferric chloride, 40.2g of halogenation reagent phosphorus tribromide, and 60ml of acetonitrile into a 100ml three-necked flask, stir and reflux at 75~85°C under nitrogen protection, until TLC Detect that the reaction is complete, add dilute hydrochloric acid to the reaction system to terminate the reaction, let stand for stratification, separate the organic layer, and wash with sodium bicarbonate and saturated brine, separate the washing liquid from the organic layer, add anhydrous magnesium sulfate to the organic layer, After drying, filtering, and concentrating the filtrate under reduced pressure, 30.5 g of compound was obtained, which was confirmed to be compound II by comparison with the melting point data of standard compound II. The melting point of compound II was 138-140°C, and the yield of compound II was 86%.

Embodiment 1-2

[0050] Add 29.1g of compound I, 17.2g of methyldichlorosilane, 8g of ferric chloride, 40.2g of phosphorus tribromide, and 60ml of acetonitrile into a 100ml three-necked flask, stir at 65~75°C under nitrogen protection, and TLC detects that the reaction is complete. Add dilute hydrochloric acid to the reaction system to terminate the reaction, let stand to separate the layers, separate the organic layer, and wash with sodium bicarbonate and saturated brine, separate the washing liquid from the organic layer, add anhydrous magnesium sulfate to the organic layer, dry, filter, The filtrate was concentrated under reduced pressure to obtain 28.4 g of compound, which was confirmed to be compound II by comparison with the melting point data of standard compound II. The melting point of compound II was 138-140 °C, and the yield of compound II was 80%.

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Abstract

The invention relates to a preparation method of a cholesterol reduction drug, particularly relates to a preparation method of pitavastatin calcium as a crude drug of the cholesterol reduction drug, and aims at the problems that the pitavastatin calcium synthetic technology in the prior art is long in steps and complicated in operation, and uses strongly corrosive reagents which is environmentally unfriendly, causes serious corrosion to equipment, and may not facilitate industrial production. The invention provides the new preparation method of the pitavastatin calcium, the new preparation method is as follows: 3-bromomethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline is prepared from 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde by a one step reaction, and then reacts with an organophosphorus reagent to obtain pitavastatin calcium intermediate phosphorus ylide, on the basis of improving of the yield to 80%, the reaction steps are reduced, and the reaction difficulty is reduced, and hydroxylamine hydrochloride is selected as a deprotection reagent, so that the new preparation method is mild in reaction conditions, environmentally friendly, high in yield, and beneficial to industrial production.

Description

technical field [0001] The invention relates to a preparation method of cholesterol-lowering medicine, in particular to a preparation method of pitavastatin calcium, a raw material drug of cholesterol-lowering medicine. Background technique [0002] Pitavastatin was jointly developed and marketed by Nissan Chemical Industry, Kowa and Sankyo (now DaiichiSankyoCo). [0003] Pitavastatin calcium is another potential super statin. Low doses (0.1mg, 0.3mg, 1mg / kg) have similar efficacy in lowering LDL-C as ten times the dose of atorvastatin. patients more effectively. Compared with simvastatin, lovastatin and atorvastatin, although they can reduce TC in a dose-dependent manner, this product has the best effect. [0004] Pitavastatin calcium is regarded as a "super statin" product by the pharmaceutical industry because of its small dosage but excellent curative effect. It has been listed as the 18 new drugs with the greatest sales potential in the world. Therefore, pitavastatin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/14C07F9/60
CPCC07D215/14C07F9/60
Inventor 王鹏李孝成陆沛传陆海波
Owner XUZHOU WANBANG JINQIAO PHARMA
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