Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

Antihypertensive drug cilazapril intermediate and preparation method thereof

A cilazapril and antihypertensive technology, which is applied in the field of preparing antihypertensive drug cilazapril intermediates, can solve the problems of unsuitability for industrialized production, complicated column-passing process, and high three-waste discharge, and avoids the need for column-passing. Split, simplify the synthesis process, reduce the effect of the three wastes

Active Publication Date: 2013-11-13
ZHEJIANG HUAHAI PHARMA CO LTD +1
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned route method has a complicated column passing process, is not suitable for industrial production, and discharges a lot of three wastes, polluting the environment

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
  • Antihypertensive drug cilazapril intermediate and preparation method thereof
  • Antihypertensive drug cilazapril intermediate and preparation method thereof
  • Antihypertensive drug cilazapril intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of the compound N-phthaloylamino-L-glutamic anhydride of structural formula 4, concrete reaction formula is as follows:

[0019]

[0020] 20 g of L-glutamic acid and 31.9 g of N-ethoxycarbonylphthalic imide were sequentially added to 360 ml of an aqueous solution containing 28.8 g of sodium carbonate. Stir at room temperature, then extract with ethyl acetate. After the water layer was cooled, the water phase was adjusted to pH=2 with hydrochloric acid, then extracted with ethyl acetate, washed with saturated sodium chloride solution, dried, filtered, and concentrated under reduced pressure to obtain an oily product, which was recrystallized from water to obtain a white solid product N - Phthalylamino-L-glutamic acid 19.0g Melting point: 153-154°C

[0021] 18.5 g of N-phthaloylamino-L-glutamic acid was dissolved in 53.1 g of acetic anhydride, and heated to 110° C. for 5 minutes. Concentrate and add ether. After filtration, 16.5 g of white solid prod...

Embodiment 2

[0023] The compound of structural formula 1 (2S)-5-[(S)-3-(tetrahydro-3-tert-butoxycarbonyl)pyridazinyl-1-yl]-2-(1,3-dioxo-2H- Preparation of isoindol-2-yl)-5-oxopentanoic acid

[0024] Example 2

[0025] Add 9.2g of the compound of structural formula 2 to 40ml of tetrahydrofuran, stir to form a suspension solution, slowly drop into 140ml of 5% sodium bicarbonate solution to alkalinize and remove L-type tartaric acid, then drop into 30ml of tetrahydrofuran solution of 7.1g of the compound of structural formula 4, at room temperature After stirring for half an hour, after the reaction was complete, the aqueous layer was extracted with 30ml of ethyl acetate. The extracted aqueous layer was cooled to 0-5°C, and the pH value was adjusted to 3 with concentrated hydrochloric acid. A white solid was precipitated, and 10.8g of compound 1 was obtained after filtration. MS: (M+Na) + =468 +

Embodiment 3

[0027] Dissolve 33.5g of sodium bicarbonate in 350ml of water, drop into 150ml of tetrahydrofuran solution of 44.8g of compound of structural formula 2, then add 50ml of tetrahydrofuran solution of 34.5g of compound of structural formula 4, stir at room temperature for one hour, extract water with 60ml of ethyl acetate layer, the extracted water layer was cooled to 0-5°C, and the pH value was adjusted to 3.5 with concentrated hydrochloric acid, a large amount of white solid was precipitated, and 55.5 g of compound 1 was obtained after filtration. MS: (M+Na) + =468 +

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

An antihypertensive drug cilazapril intermediate is the compound of the structural formula 1, which is obtained by the steps of alkalising the compound of structural formula 2 to remove L-tartaric acid and obtaining the compound of structural formula 3, subjecting the compound of structural formula 3 and the compound of structural formula 4 to a reaction to obtain a single SS-configuration compound 1 of structural formula 1. The compound of structural formula 1 in the invention is cyclized to obtain the compound of structural formula 8. The compound of structural formula 8 is processed by reduction through borane, protective group removal and suprafacial chain condensation, and is processed by tertiary butyl protective group removal under the action of hydrochloric acid gas so as to obtain the antihypertensive drug cilazapril 13. The invention uses front split, obtains a single SS-configuration new compound of structural formula 1, avoids column-passing spit in subsequent procedures, simplifies synthesis technology, decreases cost, and reduces three wastes. Thus, the invention is more suitable for commercial production.

Description

technical field [0001] The invention relates to the preparation of an antihypertensive drug cilazapril intermediate and a preparation method. Background technique [0002] Cilazapril is a specific long-acting angiotensin-converting enzyme inhibitor that can inhibit the renin-angiotensin-aldosterone system (RAAS), thereby inhibiting the conversion of angiotensin I (AngI) into a strong vasoconstrictor Angiotensin II (AngII). Reduce peripheral vascular resistance and blood pressure. For the treatment of various degrees of essential hypertension and renal hypertension. It can also be used in combination with digitalis or diuretics to treat chronic heart failure. [0003] The method for preparing Cilazapril has following several at present: [0004] In the patent US6201118 or US6512111, the preparation method of the compound of the racemic structure formula 6 is prepared from the compound of the structure formula 5 and the compound of the structure formula 4, and then the com...

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
Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06C07B57/00
CPCY02P20/55
Inventor 唐超钟静芬时惠麟
Owner ZHEJIANG HUAHAI PHARMA 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
Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com