Process for preparing tricyclic compound having antihistaminic activity

A kind of compound, cycloalkyl technology, applied in the field of improvement of preparing antihistamine drugs

Inactive Publication Date: 2002-02-06
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Von Braun reaction to loratadine from compound (3) produces toxic methyl chloride gaseous by-products

Method used

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  • Process for preparing tricyclic compound having antihistaminic activity

Examples

Experimental program
Comparison scheme
Effect test

preparation example A

[0046] To a suspension of 3-methyl-picolinic acid (400 g; 2.92 mol) in dichloromethane ("DCM") (1600 ml) was added triethylamine (406.4 ml; 2.92 mol). The solution was cooled to -20°C and ethyl chloroformate (278.8ml; 2.92mol) was added dropwise keeping the reaction temperature between -10 and -20°C. The reaction mixture was stirred for a further 2 hours at this temperature. A solution of 4-chloroaniline (372.1 g; 2.92 mol) in dichloromethane (150 ml) was then added dropwise keeping the internal temperature between -10 and -20°C. Stirring was continued at this temperature for 2 hours, then the reaction was allowed to warm to room temperature. Water (400ml) was added to quench the reaction. The layers were separated, and the organic layer was washed with water (400ml). The reaction mixture was concentrated to about 800ml by removing the solvent in vacuo. Isopropanol (400ml) was added and 1 volume of solvent was evaporated under reduced pressure. Isopropanol (400ml) was add...

preparation example B

[0048] To a solution of amide 2 (150 g; 0.61 mol) in THF (750 ml) was added 2.5M butyllithium in hexane (486 ml; 1.22 mol) at -25°C while maintaining the internal temperature between -20 and -30°C between. The mixture was stirred at -25°C for 1 hour, then 3-chlorobenzyl chloride was added dropwise over 55 minutes, also maintaining the internal temperature between -20 and -30°C. The reaction mixture was stirred at -25°C for 1 hour and then allowed to warm to room temperature. Water (300ml) was added and the resulting mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (150ml). The combined organic phases were evaporated to dryness in vacuo and the residue was crystallized from isopropanol (900ml) to give 205.5g of amide 3 (91%).

preparation example C

[0050] Add N-(4-chlorophenyl)-3-[2- (3-Chlorophenyl)ethyl]-2-pyridinecarboxamide (30g; 0.081mol) in dichloromethane (60ml). The resulting mixture was stirred at 5 to 10°C for 1 hour and then allowed to warm to room temperature over 30 minutes. Aluminum chloride (43.1 g; 0.323 mol) was added in 4 portions over 45 minutes keeping the reaction temperature below 30°C. The mixture was stirred for 1 hour then poured onto ice (300g). Dichloromethane was removed from the mixture by distillation, and the remaining aqueous solution was heated at 80°C for 1 hour. Trisodium citrate dihydrate (70 g; 0.24 mol) was added followed by aqueous sodium hydroxide (10 M, 140 ml) to adjust the pH to 7. Toluene (150ml) was added followed by a solution of maleic anhydride (12.0g 0.122mol) in toluene (50ml). The resulting mixture was stirred for 30 minutes, then the pH of the aqueous phase was adjusted to 12 with aqueous sodium hydroxide (10M, 60ml). The mixture was heated to 70°C and separated. ...

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Abstract

Disclosed is a process for preparing a compound having formula (I) wherein R<1> is selected from the group consisting of: alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, and cycloalkyalkyl, R<1> being optionally substituted by substituents selected from halo, -OH, alkyl, alkoxy, or -CF3, said process comprising the following steps: (a) reacting a ketone having formula (A) with a carbanion having formula (B) wherein R<1> is defined above, and R<2> and R<3> are independently selected from the group consisting of -OR and -R; wherein R is alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; (b) treating the reaction mixture from step (a) with a protonating agent to form a beta-hydroxy intermediate having formula (C) wherein R<1>, R<2> and R<3> are as defined above; and (c) thermally decomposing the beta-hydroxy intermediate to form the compound of formula (I). The compounds made by this process have antihistaminic activity, e.g., loratadine. Also disclosed is a process for preparing descarboethoxyloratadine, by carrying out the process above, and converting the product to descarboethoxyloratadine. Also disclosed are novel intermediates having formula (II) and (III) wherein R<1>, R<2> and R<3> are as defined above.

Description

Background of the invention [0001] The present invention provides improved processes and novel intermediates for the preparation of antihistamines. In particular, the methods and intermediates of the present invention can be used to prepare loratadine disclosed in U.S. 4,282,233 and desethoxycarbonyl loratadine (8-chloro-6,11-dihydro -11-(4-piperidinylene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine) ("DCL"). [0002] U.S. 4,659,716 discloses a process for the preparation of loratadine and DCL as follows: According to this method, a tricyclic ketone (1) is coupled with a Grignard reagent derived from 4-chloro-N-methylpiperidine. The alcohol (2) formed by this addition reaction is dehydrated under acidic conditions to give compound (3). Then compound (3) is subjected to Von Braun reaction with ethyl chloroformate to generate loratadine. DCL can be prepared by dealkoxycarbonylation of loratadine. This method has a number of serious disadvantages. The halide 4-chloro-N-methylpi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07F9/59C07F9/6558
CPCC07F9/65583C07F9/597C07D401/04C07F9/59
Inventor H·J·多兰P·M·奥内尔
Owner MERCK & CO INC
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