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Preparation method of pitavastatin calcium

A technology of pitavastatin calcium and calcium salt, applied in the field of medicine, can solve the problems of rising cost and operation difficulty, and achieve the effects of reasonable design, high yield and concise process route

Inactive Publication Date: 2014-01-15
WEIHAI WEITAI PHARMA TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problems in the reaction process are the use of noble metals or boron compounds and the ultra-low temperature (-70°C) reaction system, which will undoubtedly greatly increase the cost and difficulty of operation

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Embodiment 1: Preparation of 3-cyclopropyl-3-oxo-propionic acid ethyl ester (compound II)

[0022] Start stirring, add 4.3L ether into the reaction kettle, lower the temperature, and add 355g of 80% (weight) sodium hydride. First add 2.8kg of diethyl carbonate into the reaction kettle, then slowly drop in the mixed solution of 455g of cyclopropylmethyl ketone and 1.1L of ether. After the dropwise addition, the ice-water bath was removed and stirred for 48 hours. Add 4.3 L of 3 mol / L hydrochloric acid dropwise to the reaction solution for acidification and hydrolysis. The organic phase was separated, and the aqueous phase was extracted 3 times with ether. Combine the organic phases, wash them with saturated saline for 3 times, dry them with anhydrous magnesium sulfate, recover diethyl ether under normal pressure, and then change to vacuum distillation to collect fractions at 69-72°C to obtain about 605 g of the product, with a yield ranging from 65% to 75%. .

Embodiment 2

[0023] Example 2: Preparation of ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate (compound IV)

[0024] Put 8L of toluene into the reaction kettle, add 760g of 2-amino-4'-fluoro-benzophenone, about 605g of compound II and 465g of p-toluenesulfonic acid, stir and heat to reflux for 30 hours, and remove the water formed in the reaction from time to time. Cooled to room temperature, the reaction solution was washed 3 times with saturated aqueous sodium bicarbonate solution, the organic layer was dried with anhydrous sodium sulfate, crystallized with petroleum ether after concentration, suction filtered, and dried to obtain about 1.06 kg of light yellow solid product, the yield range was 75% to 85%, melting point: 73.3-75.0°C.

Embodiment 3

[0025] Example 3: Preparation of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol (compound V)

[0026] Put 240g of lithium aluminum hydride and 5.4L of tetrahydrofuran into the reaction kettle, and start stirring. After stirring for 30 minutes, about 1.06 kg of the product from the previous step (compound IV) was dissolved in 2.6 L of anhydrous tetrahydrofuran and added dropwise to the reaction kettle. After the dropwise addition was completed, the reaction was continued at room temperature for 2 hours. Concentrate the reaction solution, add dropwise ice water solution to decompose unreacted lithium aluminum hydride, stir for 3 to 5 hours; filter, and dry the solid; dissolve the solid with ethanol, filter out the insoluble matter, and cool the filtrate to crystallize, filter and dry to obtain a white solid product of about 765g, the yield range is 78%-88%, melting point: 73.2-75.2°C.

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Abstract

The invention relates to a preparation method of pitavastatin calcium for treating hyperlipidemia. The preparation method comprises the following steps: performing cyclization on 2-amino-4'-fluorobenzophenone (III) and ethyl 3-cyclopropyl-3-oxo-propanoate (II), and then reducing with LiAlH4 to obtain 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methanol (V); bromizing the V to obtain 2-cyclopropyl-3-bromomethyl-4-(4-fluorophenyl) quinoline (VI); reacting the VI with triphenylphosphine to obtain (2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl) methyltriphenylphosphonium bromide (VII), performing alkali treatment on a phosphonium salt, then forming phosphonium ylide, performing condensation with (3R, 5S)-6-oxo-3, 5-isopropylidene-dioxo-6-heptenoic acid tert-butyl ester (VIII) to obtain a compound IX; and acidifying the compound IX with hydrochloric acid, performing hydrolysis deprotection with sodium hydroxide, performing salt formation and purification with chiral amine and forming a calcium slat to obtain a final product. The whole route has reasonable design, the process flow is simple, starting raw materials and reagents used by the preparation method can be purchased from the market, the reagents with severe toxicity and serious pollution are not used in a reaction process, the post-treatment of an intermediate is simple, and the preparation method has the advantages of high yield and is easy to purify.

Description

technology field; [0001] The invention relates to a preparation method of pitavastatin calcium (Pitavastatin Calcium) for treating hyperlipidemia, which belongs to the field of medicine. Background of the invention: [0002] Pitavastatin Calcium is the first fully synthetic HMG-CoA reductase inhibitor developed by Nissan Chemical Co., Ltd. and Kowa Co., Ltd. It was registered in Japan in November 1999 and was first released in Japan on July 17, 2003. Approved for listing. It 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. Pitavastatin calcium has the following structural formula: [0003] [0004] In the published literature at present, announced a variety of methods for preparing pitavastatin calcium, mainly divided into two categories: [0005] One is the achiral synthesis of pitavastatin calcium, suc...

Claims

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Application Information

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IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 刘春
Owner WEIHAI WEITAI PHARMA TECH DEV
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