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Method for preparing cilazapril intermediate

A technology of intermediates and compounds, which is applied in the field of cilazapril synthesis technology, can solve the problems of reducing the yield of the final product cilazapril, difficulty in separation and purification, and instability, so as to achieve economical and practical production methods and avoid separation and purification , the effect of increasing productivity

Active Publication Date: 2011-08-03
苏州亚培克生物科技有限公司
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0007] Since the compound (1S)-hexahydropyridazine-3-tert-butylcarboxylate (8) is extremely unstable in the air, its separation and purification become very difficult
During the filtration process, (1S)-hexahydropyridazine-3-tert-butyl carboxylate is partially oxidized to azo compound (AZO), and it is also easy to produce a large amount of by-products during hydrogenation, which greatly reduces the Yield of final product Cilazapril

Method used

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  • Method for preparing cilazapril intermediate
  • Method for preparing cilazapril intermediate
  • Method for preparing cilazapril intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add (1S)-1,2-dibenzyloxycarbonyl-3-tert-butylhexahydropyridazine-1,2,3-tricarboxylate 90g (0.198mol), L-tartaric acid 35.6 (0.237mol), tetrahydrofuran (THF) solvent 0.75L, Pd / C (5% Pd) 9.0g, control reaction temperature is 70 ℃, hydrogen pressure is 4atm, react until the hydrogen pressure no longer drops, the reaction material is cooled to 0°C, filter, wash the filter cake with ethyl acetate, and then wash the filter cake three times with a mixture of methanol and water with a volume ratio of 3:1, collect the filtrate, and rotary evaporate to obtain a white solid. The obtained white solid was dissolved in n-butanol, and crystallized slowly to obtain 54 g of cilazapril intermediate (1S)-hexahydropyridazine-3-tert-butylcarboxylate L-tartrate in (S) configuration. The calculated yield of the cilazapril intermediate was 81%.

Embodiment 2

[0023] Add (1S)-1,2-dibenzyloxycarbonyl-3-tert-butylhexahydropyridazine-1,2,3-tricarboxylate 90g (0.198mol), L-tartaric acid 35.6 g (0.237mol), tetrahydrofuran (THF) solvent 0.75L, Pd / C (5%Pd) 9.0g, the control reaction temperature is 65 ℃, and the hydrogen pressure is 5atm, reacts until the hydrogen pressure no longer drops, and the reaction mass is cooled to 0°C, filtered, washed the filter cake with ethyl acetate, and washed the filter cake three times with a mixture of methanol and water at a volume ratio of 3:1, collected the filtrate, and rotovapped to obtain a white solid. The resulting white solid was dissolved in n-butanol and crystallized slowly to obtain the (S) configuration of Cilazapril intermediate (1S)-hexahydropyridazine-3-tert-butylcarboxylate L-tartrate (51g) . The calculated yield of cilazapril intermediate was 76.7%.

Embodiment 3

[0025] Add (1S)-1,2-dibenzyloxycarbonyl-3-tert-butylhexahydropyridazine-1,2,3-tricarboxylate 120g (0.264mol), L-tartaric acid 39.6 g (0.264mol), tetrahydrofuran (THF) solvent 1L, Pd / C (5% Pd) 12g, control the reaction temperature to 70°C, the hydrogen pressure to 4atm, react until the hydrogen pressure no longer drops, and cool the reaction materials to 0°C , filtered, washed the filter cake with ethyl acetate, and washed the filter cake three times with a mixture of methanol and water with a volume ratio of 3:1, collected the filtrate, and rotovapped to obtain a white solid. The resulting white solid was dissolved in n-butanol and slowly crystallized to obtain the (S) configuration of Cilazapril intermediate (1S)-hexahydropyridazine-3-tert-butylcarboxylate L-tartrate (70g) . The calculated yield of cilazapril intermediate was 78.9%.

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Abstract

The invention discloses a method for preparing a cilazapril intermediate, which comprises the following steps: taking tetrahydrofuran, ethanol, methanol or water as a solvent, taking Pd / C, iron, zinc or nickel as a catalyst, adding (1S)-1,2-di-benzoyloxycarbonyl group-3-tert-butyl hexahydro pyridazine-1,2,3-tricarboxylic ester shown in a formula (II) and an L-tartaric acid into a hydrogenation reactor, controlling the reaction temperature to between 65 and 75 DEG C and hydrogen pressure to between 4 and 5 atm for reaction until the hydrogen pressure is not decreased any longer; and cooling and filtering reaction materials, washing a filter cake with ethyl acetate, washing the filter cake with aqueous solution of methanol, collecting a filtrate, rotating and evaporating the filtrate to obtain a white solid, dissolving the white solid in normal butanol and crystallizing the solution to obtain the cilazapril intermediate of (S) configuration, namely (1S)-hexahydro-pyridazine-3-tert-butylcarboxylic ether L-tartrate. The method has the advantages of improving key production technology, improving the yield of a key intermediate under a stable condition so as to make the method for producing cilazapril more economic and practicable, and greatly improving the yield of the cilazapril.

Description

technical field [0001] The invention relates to a synthesis process of Cilazapril, in particular to a preparation method of a Cilazapril intermediate. Background technique [0002] Cilazapril (cilazapril), the chemical name is (1S, 9S)-9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]octahydro-10-oxo-6H-da Azino[1,2-α][1,2]diazepine-1-carboxylic acid, its structural formula is: [0003] [0004] Cilazapril is a specific long-acting angiotensin-converting enzyme inhibitor (ACEI), which is an important variety of antihypertensive drugs. It was developed by the Swiss pharmaceutical company Roche and first listed in Switzerland in 1990. Since its inception, it has been active in the arena of cardiovascular drugs, relieving the crisis for hundreds of millions of patients with primary and secondary hypertension. [0005] The difficulty in the synthesis process of Cilazapril lies in the synthesis of the two chiral centers of the main ring. [0006] figure 1 Shown is a kind of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D237/04
Inventor 陈韩魏东初
Owner 苏州亚培克生物科技有限公司
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