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Process for preparation of pure citalopram

A technology of citalopram and citalopram base, which is applied in the fields of nervous system diseases, organic chemistry, and drug combination, and can solve problems such as cumbersome, expensive purification processing, and difficult removal of impurities

Inactive Publication Date: 2002-08-28
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These impurities are difficult to remove with common post-treatment procedures, resulting in tedious and expensive purification processes

Method used

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  • Process for preparation of pure citalopram

Examples

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Effect test

example 1

[0054] Preparation of crude citalopram base (5-cyano-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)phthalane)

[0055] Cu(I)CN (197g, 2.2mol) was added to 5-bromo-1-(4-fluorophenyl)-1-(3-methylaminopropyl)phthalane (720g, 1.9mol) in sulfolane (250mL) in the solution. After the reaction mixture was heated at 150 °C for 5 h, sulfolane (500 mL) was added. The reaction mixture was cooled to 80°C, at which point ethylenediamine (aq, 50% w / v) was added. Toluene (2 L) was added and phase separation occurred. The organic phase was further washed with EDTA (500 mL 5% w / v in water) and water (2 x 500 mL). Volatile materials from the organic phase were removed under vacuum. 540 g of crude citalopram base were isolated as an oil. Purity about 85%, determined by HPLC (peak area).

example 2

[0057] Purification of crude citalopram by thin film distillation

[0058] Crude citalopram base (5-cyano-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)phthalane) (20kg, purity about 89%, according to HPLC (peak area) and sulfolane (4L) heated to about 100 ° C. The hot mixture is fed into thin film distillation equipment (wiped film distillation), where the scraper temperature is 245 ° C, resulting in a pressure of about 0.7 mm Hg. The temperature of the effluent after condensation is maintained at 120° C. to prevent crystallization of the free base. The distillate contained crude citalopram (purity about 96% by HPLC (peak area)) and sulfolane.

example 3

[0060] The above distillate (crude citalopram base) is further purified by crystallization of citalopram free base

[0061] The distillate (4 kg) was dissolved in methanol (12 L) at ambient temperature as described above. Water is added until the mixture maintains a "creamy" color. The mixture was seeded with crystals of citalopram free base. When the temperature was lowered to 10° C. for 2 h, the crystals were separated by filtration. The crystallization from methanol / water as described above was repeated. Two further recrystallizations from n-heptane yielded citalopram (2.3 kg) free base with a purity of about 99.5% (HPLC: peak area).

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Abstract

A method for preparing citalopram of general formula (I), wherein the compound of general formula (II), wherein Z is iodo, bromo, chloro or CF3-(CF2)n-SO2-O-, wherein n is 0, 1, 2, 3, 4, 5, 6, 7 or 8, a cyanide exchange reaction occurs. In the reaction, the group Z realizes the exchange with cyanide by reacting with the cyanide source; the crude citalopram produced The product is optionally subjected to some preliminary purification, and the crude citalopram base is then subjected to a liquid membrane distillation process; the citalopram product obtained is then optionally further purified, then worked up and converted to the base or a pharmaceutically acceptable salt thereof. seperate.

Description

[0001] The present invention relates to the manufacture of the well-known antidepressant citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran A method for the production of pure citalopram by cyanide exchange in particular. Background technique [0002] Citalopram is a well known antidepressant that has been on the market for several years and has the following structure: [0003] It is a selective, centrally acting serotonin (serotonin; 5-HT) reuptake inhibitor which has additionally been disclosed to show efficacy in the treatment of dementia and cerebrovascular disorders, see EP-A-474580. [0004] Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication outlines the preparation of citalopram from the corresponding 5-bromo derivatives by reaction with cuprous cyanide in a suitable solvent. WO 001 1926 and WO 0013648 disclose the use of 5-halogen or CF 3 -(CF 2 ) n -SO 2 -O-, wherein n is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/24C07D307/87
CPCC07D307/87A61P25/24
Inventor A·卡斯特林G·沃尔佩F·斯布罗吉奥
Owner H LUNDBECK AS
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