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Processes for the synthesis of levocetirizine and intermediates for use therein

A technology of levocetirizine and compounds, which is applied in the field of new intermediates and can solve problems such as carcinogenesis

Inactive Publication Date: 2011-05-04
CIPLA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] An alternative route to the synthesis of (-)-1-[(4-chlorophenyl)-phenylmethyl]piperazine disclosed in the prior art involves the use of dichloroethylamine, which is carcinogenic in nature

Method used

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  • Processes for the synthesis of levocetirizine and intermediates for use therein
  • Processes for the synthesis of levocetirizine and intermediates for use therein
  • Processes for the synthesis of levocetirizine and intermediates for use therein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Preparation of 2-[(2-hydroxy-ethyl)-(4-methoxybenzyl)-amino]-ethanol

[0135] 25 gms (0.2380 moles) of diethanolamine and 60 ml (0.4312 moles) of triethylamine in 75 ml of dichloromethane were placed in a reaction vessel and cooled to 0-5°C with stirring. Then 40 gms (0.2554 mole) p-methoxybenzyl chloride in 50 ml dichloromethane was added slowly. Further, the reaction mass was stirred with dichloromethane and kept at a temperature of 25-30° C. for about 16 hours. The resulting solution was concentrated to obtain a residue. 200 ml of acetone were added to the residue, cooled to 0-5°C for about 1 hour and filtered. The filtrate was concentrated to give the title compound as an oil (50.8 gms).

Embodiment 2

[0137] Preparation of 2-[(2-methanesulfonyloxy-ethyl)-(4-methoxy-benzyl)-amino]-ethyl methanesulfonate

[0138] 25 gms (0.1111 moles) of the product obtained in Example 1 and 45 gms (0.4455 moles) of triethylamine and 125 ml of dichloromethane were placed in a reaction vessel and cooled to -5 to -10°C. A solution of methanesulfonyl chloride (45 gms, 0.3888 mol) in dichloromethane (50 ml) was slowly added at -5 to 10°C and stirred at 25-30°C for about 16 hours. The resulting mixture was washed with water (25ml). The collected organic layers were concentrated to give the title compound (36 gms).

Embodiment 3

[0140] Preparation of (-)-1-[(4-chloro-phenyl)-phenyl-methyl]4-(4-methoxy-benzyl)piperazine

[0141] i) 7 gms (0.03218 moles) of (-)-(4-chlorophenyl) phenylmethylamine and 10 gms (0.02624 moles) of the compound prepared in Example 2 were mixed with 14 ml of dimethylsulfoxide and 14 gms (0.1083 moles) of N -Ethyldiisopropylamine mixed. Next, the mixture was heated at 90° C. for about 4 hours and then cooled. The reaction mass was quenched in water and extracted with dichloromethane. The collected organic layers were concentrated to give a residue (13 gms).

[0142] ii) To the residue obtained in step i) were added 130 ml of ethyl acetate and 14 gms (0.1111 mol) of oxalic acid dihydrate. The mixture was heated to give a clear solution and cooled to give (-)-1-[(4-chloro-phenyl)-phenyl-methyl]-4-(4-methoxy-benzyl)piperazine. salt. The salt was filtered and dried under vacuum (15 gms) at 55°C.

[0143] iii) The oxalate was further treated with sodium hydroxide solution until...

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Abstract

The present invention provides a compound of formula (IV) wherein R is Cl, Br, NO2, OH or OR', and R' is alkyl, and its use in the synthesis of levocetirizine, including its use in the synthesis of (-)-1-[(4-chlorophenyl)-phenyl methyl] piperazine, an intermediate useful in the synthesis of levocetirizine. The present invention also provides compounds (II) and (III) which are useful in the synthesis of compound (IV).

Description

technical field [0001] The present invention relates to a method for preparing (-)-1-[(4-chlorophenyl)-phenylmethyl]piperazine (I), a key intermediate for synthesizing levocetirizine, and a method used in the method new intermediates in . Background technique [0002] Cetirizine, whose chemical name is [2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, is an antihistamine non-sedating Histamine H 1 - A receptor antagonist shown to reduce symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and related diseases. [0003] [0004] cetirizine [0005] US4525358 and its sibling EP58146 disclose cetirizine and pharmaceutically acceptable salts thereof. The method for the synthesis of cetirizine involves the condensation of 1-[(4-chlorophenyl)-phenylmethyl]piperazine with 2-chloroethoxyacetamide to give 2-[2-[4-[(4 -chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxyacetamide, which is hydrolyzed to give cetirizine. [0006] I...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D295/073C07D295/096C07C27/00
CPCC07C217/58C07C309/66C07D295/073C07D295/088C07D295/096
Inventor D·R·拉奥R·N·坎坎M·加加雷S·V·希卡利卡尔
Owner CIPLA LTD
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