Process for the preparation of S 2 tert butoxycarbonyl amino 3 4 carbamoyl 2 6 dimethylphenyl propanoic acid
Publication Date: 2015-Oct-29
The IP.com Prior Art Database
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Process for the preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-
carbamoyl-2,6 dimethylphenyl)propanoic acid
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-carbamoyl-2,6-dimethylphenyl)propanoic acid, referred to herein as compound 1, may be an intermediate in the preparation of 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H- imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoic acid (referred to as compound A).
Compound 1 was prepared from (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2,6- dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate [named compound 2 in Tetrahedron 61 2005 (6836-6838)] in a one pot process by converting it to a mixture of cyano intermediates in the forms of a methyl ester, i.e., (S)-methyl 2-((tert- butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoate (which is disclosed in US8853445) and a carboxylic acid, i.e., (S)-2-((tert- butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoic acid and a subsequent hydrolysis.
The reaction was carried out in the presence of a palladium catalyst and a potassium salt and followed by hydrolysis using CsOH.
The introduction of the cyano group was performed by employing the process discussed in the literature, for example, the process described in RSC Advances 2015, 5, 21001, which utilizes Br instead of TfO as a leaving group.
The product was obtained in a high enantiomeric purity and yield, which may be further adapted by process optimization