The preparation method of Pisicani hydrochloride intermediate

A technology of piricanib hydrochloride and an intermediate, applied in the field of medicine, can solve the problems of low yield of 8-acetonitrile-based bicyclopyrrolidine, unsuitable for quantitative production, instability of bicyclopyrrolidine and the like, and achieve stable product quality and cost. Low, easy-to-use effect

Active Publication Date: 2021-11-30
HANCHEM BIOPHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The raw material of this method, bicyclic pyrrolidine, is unstable and easily polymerized into diploids, and there is currently no manufacturer to produce and supply it. The yield of 8-acetonitrile-based bicyclic pyrrolidine prepared with cyanoacetic acid is low, and it is not suitable for quantitative production.

Method used

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  • The preparation method of Pisicani hydrochloride intermediate
  • The preparation method of Pisicani hydrochloride intermediate
  • The preparation method of Pisicani hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of N-(3-carboxypropyl)butyrolactam (Ⅲ)

[0045] Add 18.4g (0.8mol) of sodium metal and 86.0g (1.0mol) of γ-butyrolactone (II) sequentially into a 250mL four-necked bottle equipped with mechanical stirring, a condenser, and a thermometer, heat up to 100°C, stir and Add 85.0 g (1.0 mol) of butyrolactam (I) dropwise while keeping warm, keep warm for 2 hours, slowly pour into ice water when the temperature drops to 70°C, adjust to PH=2~3 with concentrated hydrochloric acid, filter, wash with water, and dry 103.1 g of white solid was obtained, the target compound N-(3-carboxypropyl)butyrolactam (III), with a melting point of 78-80° C., yield: 60.3%.

Embodiment 2

[0047] Preparation of N-(3-carboxypropyl)butyrolactam (Ⅲ)

[0048] Add 23.0 g (1.0 mol) of sodium metal and 86.0 g (1.0 mol) of γ-butyrolactone (II) sequentially into a 250 mL four-necked bottle equipped with mechanical stirring, a condenser, and a thermometer, raise the temperature to 130 ° C, and stir for 0.5 Hours, add 85.0g (1.0mol) of butyrolactam (I) dropwise while keeping warm, keep warm for 4 hours, slowly pour into ice water when the temperature is lowered to 70°C, adjust to PH=2~3 with concentrated hydrochloric acid, filter, wash with water, Drying gave 145.7g of white solid, melting point 78-80°C, which was the target compound N-(3-carboxypropyl)butyrolactam (Ⅲ), yield: 85.2%.

Embodiment 3

[0050] Preparation of N-(3-carboxypropyl)butyrolactam (Ⅲ)

[0051] Add 27.6g (1.2mol) of sodium metal and 86.0g (1.0mol) of γ-butyrolactone (II) sequentially into a 250mL four-necked bottle equipped with mechanical stirring, a condenser, and a thermometer, raise the temperature to 250°C, and stir for 1 Hours, add 85.0g (1.0mol) of butyrolactam (I) dropwise while keeping warm, keep warm for 8 hours, slowly pour into ice water when the temperature is lowered to 70°C, adjust to PH=2~3 with concentrated hydrochloric acid, filter, wash with water, Drying gave 150.0 g of a white solid with a melting point of 78-80° C., which was the target compound N-(3-carboxypropyl)butyrolactam (Ⅲ), yield: 87.7%.

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Abstract

The present invention provides a preparation method of Piscicanide hydrochloride intermediate, which is characterized in that it comprises: Step 1, butyrolactam (I) and γ-butyrolactone (II) undergo polymerization reaction under strong base and predetermined conditions Generate N-(3-carboxypropyl) butyrolactam (Ⅲ); Step 2, N-(3-carboxypropyl) butyrolactam (Ⅲ) is cyclized at high temperature in monoisopropyl malonate solvent and Condensation with malonate monoester salt to generate 7α-double condensed pyrrolidine-acetate; a better choice is to generate 7α-double condensed pyrrolidine-acetate isopropyl ester (Ⅴ). Step 3, 7α-biscondensed pyrrolidine-acetate is hydrolyzed in acid to generate the corresponding pharmaceutically acceptable salt. The preparation method of the invention avoids expensive or difficult-to-obtain raw materials, avoids the use of liquid ammonia in the synthesis process, reduces reaction steps, is simple to operate, has few wastes and high yield.

Description

technical field [0001] The invention relates to a preparation method of an intermediate of Piscicarbide Hydrochloride, which belongs to the field of medicine. Background technique [0002] The chemical name of Pisicani hydrochloride is N-(2,6-dimethylphenyl)-2-(1,2,3,5,6,7-hexahydropyrrolidazin-8-yl)acetamide salt Salt (Ⅶ), is a class Ic antiarrhythmic drug for the treatment of supraventricular arrhythmias. Clinical trials have shown that Pisicarib hydrochloride can significantly improve supraventricular premature beats, ventricular premature beats, paroxysmal atrial fibrillation, and atrial flutter. [0003] [0004] According to reports in the literature (EP0089061, EP0153855, J.MED.CHEM 1985 (28) 714, etc.), compound (VII) is composed of 7α-biscondensed pyrrolidine-acetic acid hydrochloride (VI), 2,6-dimethyl Aniline (Ⅷ) and so on are synthesized as raw materials. [0005] [0006] Among them, intermediate VII is a large chemical product, which is cheap and easy ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 熊轶
Owner HANCHEM BIOPHARM TECH
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