Process for the preparation of alfuzosin and salts thereof

A technology of alfuzosin and process, applied in the field of N-[3-[methylamino]propyl]tetrahydro-2-furancarboxamide compounds, can solve problems such as patient injury, and achieve the effect of low toxicity

Inactive Publication Date: 2010-03-31
ACTAVIS GRP PTC EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Impurities in alfuzosin or any other active pharmaceutical ingredient (API) are undesirable and, in some extreme cases, could cause harm to patients being treated with formulations containing this API

Method used

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  • Process for the preparation of alfuzosin and salts thereof
  • Process for the preparation of alfuzosin and salts thereof
  • Process for the preparation of alfuzosin and salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] N-[3-[(4-acetylamino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide (N-acetylalfurazole oxazine) preparation

[0111] N-(4-amino-6,7-dimethoxyquinazolin-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (55gm), saturated ammonia methanol solution (550 ml) and Raney nickel (82.5gm) mixture into a pressure vessel and hydrogenated under a pressure of 10kg. The reaction mass was heated to 80°C for 10 hours. The resulting reaction mass was cooled to 40°C, the catalyst was filtered off and washed with methanol (506 mL). The filtrate was distilled to obtain N-(4-amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropylenediamine. In dichloromethane (755ml), in the presence of N,N-carbonyldiimidazole (30.8gm), this diamine compound was reacted with tetrahydro-2-furoic acid (18.2ml) at 40°C for 4 hours to prepare Reaction mass containing N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide. The reaction mass was c...

Embodiment 2

[0113] Preparation of Alfuzosin Hydrochloride

[0114] N-acetyl alfuzosin (40.0 gm) was dissolved in methanol (120 mL). The resulting solution was acidified with methanolic hydrochloride (27.68 mL). The reaction mixture was heated to 40 °C for 8 hours. The reaction mass was then cooled at 25°C. The isolated solid was filtered under nitrogen atmosphere, washed with methanol (75 mL), then dried in vacuo at 80-85 °C to prepare the title compound (yield: 90%; HPLC purity = 99.90%).

Embodiment 3

[0116] Preparation of Alfuzosin Hydrochloride

[0117] N-Acetyl alfuzosin (40.0 gm) was dissolved in isoamyl alcohol (207.66 mL). The resulting solution was acidified with methanolic hydrochloride (52.8 mL). The reaction mixture was heated to 40 °C for 16 hours. The reaction mass was then cooled at 25°C. The solid separated was filtered under nitrogen and washed with isoamyl alcohol (197.7 mL). The resulting wet cake was refluxed with ethyl acetate (280.48 mL) at 78°C for 30 minutes. The resulting solid was filtered and washed with ethyl acetate (117.51 ​​mL), and then dried in vacuo at 110° C. to prepare the title compound (yield: 90%; HPLC purity: 99.93%; N-acetyl alfuzosin impurity content : 0.04%). The isolated anhydrous alfuzosin hydrochloride was confirmed to be polymorphic Form I.

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Abstract

The present invention relates to novel N-[3-[(4-acyl- / aroyl-substituted amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide derivatives, and a process for the preparation thereof. The novel compounds are useful for preparing alfuzosin or a pharmaceutically acceptable salt thereof in high yield and purity.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from Indian Provisional Application No. 955 / CHE / 2007 filed May 4, 2007, the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to novel N-[3-[(4-acyl / aroyl-substituted amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2- Furan carboxamide compound and its preparation process. These novel compounds can be used to prepare alfuzosin or its pharmaceutically acceptable salt, and the yield and purity are high. Background of the invention [0004] U.S. Patent No. 4,315,007 discloses 4-amino-6,7-dimethoxyquinazolin-2-yl-alkyldiamine derivatives and salts thereof, preparation processes, pharmaceutical compositions comprising these derivatives and the Methods of using the pharmaceutical composition. Among these compounds, N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetraoxo-2-furancarboxami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 尤德尔·拉觉莱姆·巴帕特乔斯·保罗·波塔姆斯纳拉西姆汉·苏布拉马尼安乔恩·瓦尔盖尔森
Owner ACTAVIS GRP PTC EHF
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