An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate in the licofelone synthesis

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Title:An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate in the licofelone synthesis
Creators:
Rádl, Stanislav
Stach, Jan
Černý, Josef
Klecán, Ondřej
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 74, 6, pp. 1011-1022
Uncontrolled Keywords:Pyrrolizines, Double bond migration, Isomerization, Amines, Allenes, Pyrroles, Alkynes, Au catalysis, Cyclization, Licofelone, Schiff bases

Abstract

An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1<i>H</i>-pyrrolizine, a key intermediate for the synthesis of licofelone, an anti-inflammatory drug currently undergoing evaluation of the phase-III clinical studies, is described. The method is based on a novel synthesis of unstable 5-benzyl-3,3-dimethyl-3,4-dihydro-2<i>H</i>-pyrrole, which is then treated with 2-bromo-1-(4-chlorophenyl)ethan-1-one. 2,2-Dimethyl-5-phenylpent-4-ynal with benzylamines provides the corresponding Schiff bases. Migration of the C=N double bond in these <i>N</i>-(2,2-dimethyl-5-phenylpent-4-yn-1-ylidene)benzylamines into conjugation with the aromatic ring using various base/solvent systems was studied. Acid hydrolysis of the formed Schiff bases then provided 2,2-dimethyl-5-phenylpent-4-yn-1-amine and 2,2-dimethyl-5-phenylpenta-3,4-dien-1-amine; their ratio was influenced mainly by the reaction conditions. Cyclization of these amines using Ag or Au catalysts then led to 5-benzyl-3,3-dimethyl-3,4-dihydro-2<i>H</i>-pyrrole.

Title:An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate in the licofelone synthesis
Creators:
Rádl, Stanislav
Stach, Jan
Černý, Josef
Klecán, Ondřej
Uncontrolled Keywords:Pyrrolizines, Double bond migration, Isomerization, Amines, Allenes, Pyrroles, Alkynes, Au catalysis, Cyclization, Licofelone, Schiff bases
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:74
Number:6
Page Range:pp. 1011-1022
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc2009026UNSPECIFIED
ID Code:4435
Item Type:Article
Deposited On:30 Jun 2009 16:11
Last Modified:30 Jun 2009 14:11

Citation

Rádl, Stanislav; Stach, Jan; Černý, Josef; Klecán, Ondřej (2009) An efficient synthesis of 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, a key intermediate in the licofelone synthesis. Collection of Czechoslovak Chemical Communications, 74 (6). pp. 1011-1022. ISSN 0010-0765

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