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Process for the preparation of (2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate

IP.com Disclosure Number: IPCOM000244650D
Publication Date: 2016-Jan-05
Document File: 1 page(s) / 207K

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Process for the preparation of (2R,4S)-ethyl 5-([1,1'-biphenyl]-4-yl)-4-((tert-

butoxycarbonyl)amino)-2-methylpentanoate

(2R,4S)-ethyl_5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoate, referred to herein as compound 1, may be an intermediate in the preparation of 4-{[(2S,4R)- 1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid (referred to as compound A).

Compound 1 was prepared in two steps from (2R,4S)-5-(4-bromophenyl)-4-((tert- butoxycarbonyl)amino)-2-methylpentanoic acid (referred to as compound 2). In the first step compound 2 in the presence of base with ethyl iodide forms (2R,4S)-ethyl 5-(4-bromophenyl)-4- ((tert-butoxycarbonyl)amino)-2-methylpentanoate which is in the second step via Suzuki coupling coupled with phenylboronic acid in the presence of palladium catalyst to form compound 1.

Compound 2 was prepared in two steps from (R,E)-ethyl 5-(4-bromophenyl)-4-((tert- butoxycarbonyl)amino)-2-methylpent-2-enoate which can be prepared by employing the process discussed in the literature (for example WO2010136474 ). In the first step (R,E)-ethyl 5-(4-bromophenyl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoate in the presence of the base is converted to (R,E)-5-(4-bromophenyl)-4-((tert-butoxycarbonyl)amino)-2- methylpent-2-enoic acid which is in the second step hydrogenated using diiodo(p- cymene)ruthenium (II) dimer catalyst and chiral ligand (from Mandyphos, Josiphos or Walphos families) to form co...