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Refining method for lisinopril hydride

A refining method and hydride technology, which is applied in the field of refining lisinopril hydride, can solve the problems of a large amount of hydride remaining, low refining yield, and poor refining effect, so as to improve the refining yield and refining efficiency, improve Refining efficiency, effect of reducing impurities

Active Publication Date: 2016-03-30
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention provides a method for separating and refining crude lisinopril hydride through solvent crystallization to solve the problems of high energy consumption, poor refining effect, low refining yield, For problems such as a large amount of hydride remaining in the mother liquor, the method provided by the invention can efficiently separate lisinopril hydride from the crude product, with a yield greater than 80%, and the purity of the hydride is as high as 97%, and even more than 98%.

Method used

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  • Refining method for lisinopril hydride
  • Refining method for lisinopril hydride
  • Refining method for lisinopril hydride

Examples

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Effect test

Embodiment 1

[0021] Embodiment 1: the refining of lisinopril crude product

[0022] Get lisinopril hydride crude product (lisinopril hydride isomer (II) content is 18.0%, lisinopril hydrogenation transition state (III) 0.15%, lisinopril hydrogenation hydrolyzate (IV) content 1.50%,) 200g, liquid chromatography shows that the content of lisinopril hydride in the crude product is 77.0%, add methyl isobutyl ketone 1500mL, heat to 66°C and stir to dissolve, stir and cool down at 5°C / h to 25°C, grow crystals for 7 hours, continue to cool down to 2°C with stirring at 5-10°C / h, stir and crystallize, suction filter and dry to obtain 128g of solid white product, the purity of lisinopril hydride (HPLC) is 97.5 %.

[0023] The source of the seed crystal of the present invention is disclosed. The seed crystal is a refined product obtained by repeated recrystallization using 65% ethanol aqueous solution, and the purity is above 98%.

Embodiment 2

[0024] Embodiment 2: the refining of lisinopril crude product

[0025] Get lisinopril hydride crude product (lisinopril hydride isomer (II) content is 18.2%, lisinopril hydrogenation transition state (III) 0.16%, lisinopril hydrogenation hydrolyzate (IV) content 1.40%,) 200g, liquid chromatography shows that the content of lisinopril hydride in the crude product is 76.2%, add acetone 1600mL, heat to 60 ℃ and stir to dissolve, stir and drop to 35 ℃ with the cooling rate of 8 ℃ / h , add 2g of seed crystals, continue to cool down to 25°C with stirring at 5-10°C / h, grow crystals for 8 hours, continue to cool down to 5°C with stirring at 5-10°C / h, stir and crystallize, filter with suction, and dry to obtain 127 g of solid white product, lisinopril hydride purity (HPLC) 98.1%.

Embodiment 3

[0026] Embodiment 3: the refining of lisinopril crude product

[0027] Take 200g of lisinopril hydride crude product, liquid chromatography shows that the content of lisinopril hydride in the crude product is 76.4%, add 1600mL of butanone, heat to 60°C and stir to dissolve, stir and cool down at a rate of 5°C / h Lower to 28°C, add 2g of seed crystals, continue to stir at 5-10°C / h to cool down to 15°C, grow crystals for 10 hours, continue to stir at 5-10°C / h to cool down to 2°C, stir to crystallize, and filter with suction , and dried to obtain 134 g of a solid white product with a purity (HPLC) of 98.2%.

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Abstract

The invention provides a method for refining a crude lisinopril hydride product through solvent crystallization. The method comprises the following concrete steps: adding a ketone solvent into a crude product containing lisinopril hydride (I), lisinopril isomer (II) and other impurities (such as impurities III and IV); carrying out heating to dissolve the crude product; then carrying out cooling and crystallization for the first time; selectively adding a seed crystal and continuing cooling and crystallization; carrying out crystal growing and continuing cooling and crystallization; and then carrying out pumping filtration so as to obtain lisinopril hydride, wherein yield of lisinopril hydride reaches 80%, and purity of lisinopril hydride is more than 97%, or even more than 98%. The method can separate and refine hydride in the crude lisinopril hydride product, improves the refining yield of lisinopril hydride and has obvious utilization value in industrial application. The lisinopril hydride (I), the lisinopril isomer (II), a lisinopril hydrogenation transition state (III) and a lisinopril hydrogenation transition state (IV) are as described in the specification.

Description

technical field [0001] The invention relates to a method for purifying lisinopril hydride, an important intermediate of lisinopril. Background technique [0002] Lisinopril is a new generation of angiotensin-converting enzyme inhibitors, which mainly lowers blood pressure by inhibiting the renin-angiotensin-aldosterone system, and lisinopril also has antihypertensive effects on low-renin hypertension. Lisinopril hydride is the main intermediate in the synthesis process of lisinopril, and its structural formula is as shown in formula I: [0003] [0004] At present, the synthesis of lisinopril hydride mainly uses trifluoroacetyl lysine and phenyl esters as raw materials, and is obtained through the addition-hydrogenation process. The crude lisinopril hydride synthesized by this route contains A large number of impurities such as lisinopril hydride isomer (II), lisinopril hydrogenation transition state (III), lisinopril hydrogenation hydrolyzate (IV), etc., the specific st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/47C07C231/24C07K5/068A61P9/12
CPCC07C231/24C07K5/06086C07C233/47
Inventor 胡佳兴黄文锋涂国良林恩敏王安宇方玉玲
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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