Ibutilide fumarate synthetic process

A synthesis process, a maleate technology, which is applied in the directions of drug combination, sulfonic acid amide preparation, cardiovascular system diseases, etc., can solve the problems of low yield, no industrial production of methanesulfonanilide, low total yield, etc.

Inactive Publication Date: 2009-03-11
重庆医科大学医药研究所
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0011] The comparison of the three methods, the first method is an older preparation method, but there is no industrial production of methanesulfonanilide in China, and the yield is low
In method two, pyridine, which is more toxic and difficult to handle, is used as a binding agent for the acid. In the third step of method two, 1-hydroxybenzotriazole, which is more toxic and difficult to handle, is used as a catalyst. Imine is a shrinking agent, and the obtained product amide is not easy to handle, and the overall yield is not high
Generally speaking method three is better, and raw material is easy to get, and overall yield is higher, is suitable for industrialized production, but the diisopropylcarbodiimide (DIC), N-ethylheptylamine and The reductant lithium aluminum tetrahydrohydride (2,000,000.00 yuan / ton) for the final hydrogenation reduction is relatively expensive, and the hydrogenation reduction of N-ethyl-N-heptyl 4-oxo-4-(4-methanesulfonamidophenyl)butyramide For Ibutilide, two carbonyl groups need to be reduced, that is, it takes twice as much Lithium Aluminum Hydride, resulting in high synthesis cost

Method used

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  • Ibutilide fumarate synthetic process
  • Ibutilide fumarate synthetic process
  • Ibutilide fumarate synthetic process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 1. Preparation of N-ethyl-butyrolactam (product 2)

[0032]

[0033] Add 320ml of N,N-dimethylformamide (DMF) into a dry 1000ml three-necked flask, slowly add 28.8g (0.6mol) of 50% sodium hydride under ice water cooling, then slowly drop into 34.0g (0.4mol) ) a mixture of butyrolactam-80ml DMF. After the dropping, 43.6 g (0.4 mol) of ethyl bromide was slowly added dropwise. After the dropping, the mixture was stirred at room temperature for 2 hours. Slowly add 600ml of ice water dropwise under ice water cooling, extract with 200ml of dichloromethane x 2, wash with 200ml of water to obtain an organic layer, add 60g of sodium sulfate to dry. After filtering, the filter cake was washed with dichloromethane, and the filtrate was recovered under reduced pressure to exhaust the solvent, and 36.94 g of a light yellow residual liquid was obtained, which was the product (2), with a yield of 81.6%.

[0034] 2. Preparation of 4-ethylamino-n-butyric acid (product 3)

[0035] ...

Embodiment 2

[0066] 1, the preparation of N-ethyl-butyrolactam (product 2)

[0067] Add 80ml of DMF to a dry three-necked flask, slowly add 7.2g (0.15mol) of 50% sodium hydride under ice water cooling, and then slowly drop in a mixture of 8.5g (0.1mol) of butyrolactam-20ml of DMF. After the dropping, 9.68 g (0.15 mol) of ethyl chloride was slowly added dropwise. After the dropping, the mixture was stirred at room temperature for 2 hours. Slowly add 150ml of ice water dropwise under ice water cooling, extract with 50ml of dichloromethane x 2, wash with 50ml of water to obtain an organic layer, add 15g of sodium sulfate to dry. After filtration, the filtrate was recovered under reduced pressure to exhaust the solvent, and 13.81 g of the residual liquid was obtained, which was the product (2) N-ethyl-butyrolactam, with a yield of 81.3%.

[0068] 2, Preparation of 4-ethylamino-n-butyric acid (product 3)

[0069] Add 11.3 g (0.1 mol) of N-heptyl-butyrolactin prepared into a three-necked flask...

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Abstract

The invention relates to a process for synthesizing ibutilide fumarate. 2-pyrrolidone is taken as an initial raw material, DMF is taken as a solvent, and the 2-pyrrolidone and the DMF are N-alkylated with halogen ethane to obtain N-ethyl-butyrolactam under the catalysis; then 4-ethylamino-ethyl acetic acid is obtained through acid hydrolysis; the 4-ethylamino-ethyl acetic acid reacts with chloroheptane under the catalysis to obtain 4-ethylheptylamino-ethyl acetic acid; 4-ethylheptylamino-n-butyryl chloride is obtained through the acidylation; and the 4-ethylheptylamino-n-butyryl chloride is subjected to friedel-crafts reaction with N-phenylmethanesulfonamide to obtain (+/-)-N-[4-[4-(ethylheptylamino)-1-ketonebutyl]phenyl] methanesulfonamide, (+/-)-N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl] methanesulfonamide is obtained by reducing sodium borohydride and/or tetrahydro-aluminate lithium, and then a target compound, namely the tetrahydro-aluminate lithium is obtained by salifying with fumaric acid. The process is more reasonable and is more convenient for industrialized production.

Description

Technical field: [0001] The invention relates to a new synthesis process of ibutilide fumarate Background technique: [0002] The new antiarrhythmic drug ibutilide fumarate (Ibutilide fumarate) is a fast-acting and safe class III antiarrhythmic drug, especially for the rapid termination of atrial flutter and atrial fibrillation. The chemical name of ibutilide fumarate is (±)-N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl]methanesulfonamide fumarate, which is A new type of ion antagonist antiarrhythmic drug developed by Upjohn Company of the United States, which was first launched in the United States in 1996. Ibutilide fumarate is also the first intravenous application approved by the FDA in the United States for the treatment of atrial flutter and atrial fibrillation. The drug, whose trade name is Convert, has been marketed in 11 countries including Germany, and its clinical injection is mainly used for the conversion of atrial fibrillation and atrial flutter. At presen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/08C07C303/40A61P9/06
Inventor 田睿李勤耕陈树国王祖焕袁佩王涛罗绪
Owner 重庆医科大学医药研究所
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