Lisinopril impurity and preparation method thereof

A technology of lisinopril dihydrate and compound, which is applied in the field of medicinal chemistry, can solve problems such as difficult removal of impurities and difficulty in obtaining finished products of lisinopril, and achieve a strong practical effect

Pending Publication Date: 2018-12-07
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD +1
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when studying the above-mentioned process, it was found that an unknown impurity is easily produced under normal process conditions, and the impurity content in the crude lisinopril produced in some abnormal batches is...

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Lisinopril impurity and preparation method thereof
  • Lisinopril impurity and preparation method thereof
  • Lisinopril impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Add 1g of lisinopril anhydrous to 20mL of methanol, add 0.30g of sodium hydroxide and 0.30g of succinic anhydride, then add 20mL of water, heat up to 45°C and react for 18 hours, then adjust the reaction with 1N dilute hydrochloric acid solution Liquid pH is between 2.5-3.5, and rotary evaporator removes moisture and organic solvent, and the obtained solid is detected by HPLC, and the purity is 65.6%, and then column chromatography method [HP-Silica normal phase silica gel, eluent is Dichloromethane:methanol=(10:1, V / V)] the target product is separated to obtain N 6 -(3-carboxypropionyl)lisinopril 0.64g, HPLC purity 99.0%, yield 51%.

Embodiment 2

[0048] Add 1 g of lisinopril dihydrate into 30 mL of water, then add 0.42 g of potassium hydroxide and 0.32 g of succinic anhydride, heat up to 55°C and react for 12 hours, then adjust the pH of the reaction solution to 3-4 with 1N dilute hydrochloric acid solution In between, the obtained reaction solution was detected by HPLC, and the purity was 72.1%, and then freeze-dried to remove the moisture in the reaction system, and the obtained solid was subjected to column chromatography [HP-Silica normal phase silica gel, and the eluent was dichloro Methane:methanol=(12:1, V / V)] the target product is separated to obtain N 6 -(3-carboxypropionyl)lisinopril 0.70 g, HPLC purity 99.6%, yield 61%.

Embodiment 3

[0050] Add 1 g of lisinopril dihydrate into 30 mL of water, then add 0.86 g of potassium hydroxide and 0.35 g of succinimide, heat up to 55°C for 12 hours, and then adjust the pH of the reaction solution to 3 with 1N dilute hydrochloric acid solution Between -4, the obtained reaction solution is detected by HPLC, and the purity is 69.0%, and then freeze-dried to remove the moisture in the reaction system, and the obtained solid is used for column chromatography [HP-Silica normal phase silica gel, and the eluent is Dichloromethane:methanol=(12:1, V / V)] the target product is separated to obtain N 6 -(3-carboxypropionyl)lisinopril 0.66g, HPLC purity 99.4%, yield 58%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a lisinopril impurity N6-(3-carboxypropanoyl) lisinopril (I) and a preparation method thereof. The lisinopril impurity is prepared through reaction of lisinopril and succinic acid or succinic acid derivatives in a solvent, and the succinic acid derivatives are succinic anhydride, succinyl chloride, succinyl chloride and succinimide. The prepared N6-(3-carboxypropanoyl) lisinopril (I) can be used for supporting the development works for the quality research and an analytical method of the impurity and can be used for supporting the process improvement of lisinopril.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a new lisinopril impurity N 6 -(3-Carboxypropionyl)lisinopril (I) and a process for its preparation. [0002] Background technique [0003] Lisinopril (Lisinopril), is the third generation angiotensinase inhibitor developed by Merck, its chemical name is N-[N-[(S)-1-carboxy-3-phenylpropyl]- L-lysyl]-L-proline, the structural formula is as follows: [0004] [0005] Disclosed in the patents such as US 4786737, CN9511168 the method for lisinopril preparation (abbreviation DCC process), its step comprises: N 2 -(1-ethoxycarbonyl-3-phenylpropyl)-N 6 -Trifluoroacetyl-L-lysine is dissolved in tetrahydrofuran, and under the activation of N-hydroxysuccinimide (NHS for short) and dicyclohexylcarbodiimide, it undergoes a condensation reaction with L-proline and is hydrolyzed to remove Lisinopril is obtained after trifluoroacetyl protecting group and ethyl ester protec...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07K5/02C07K1/02
CPCC07K5/0222
Inventor 林金生肖潭王吉超王安宇郑扬胡佳兴朱文泉陈文斌李敏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap