US 12,391,710 B2
Method for the industrial preparation of the disodium salt of ((2S)-3-([1,1′-biphenyl]-4-yl-2-((hydroxy((1R)-1-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)ethyl)phosphoryl) methyl)propanoyl)-l-alanine
Hervé Poras, Villepreux (FR); Alain Priour, Rennes (FR); Guillaume Grach, Liffre (FR); Roberto Fanelli, Bollate (IT); and Xinjun Zhao, Dalian (CN)
Assigned to KOS THERAPEUTICS, INC., Raleigh, NC (US)
Appl. No. 17/784,533
Filed by PHARMALEADS, Paris (FR)
PCT Filed Dec. 11, 2020, PCT No. PCT/FR2020/052385
§ 371(c)(1), (2) Date Jun. 10, 2022,
PCT Pub. No. WO2021/116617, PCT Pub. Date Jun. 17, 2021.
Claims priority of application No. 1914158 (FR), filed on Dec. 11, 2019.
Prior Publication US 2023/0041504 A1, Feb. 9, 2023
Int. Cl. C07F 9/30 (2006.01)
CPC C07F 9/301 (2013.01) [C07B 2200/13 (2013.01)] 13 Claims
 
1. A method for the industrial preparation of ((2S)-3-([1,1′-biphenyl]-4-yl)-2-((((R)-1-aminoethyl)(hydroxy)phosphoryl)methyl)propanoyl)-L-alanine acid of following formula (E):

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comprising the following steps:
(1) preparation of the compound of following formula (A):

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by:
(1a) reaction of (S)-1-phenylethylamine in a polar and protic solvent with an aqueous solution of hypophosphorous acid H3PO2 and acetaldehyde in the presence of a molar equivalent of hydrochloric acid with respect to (S)-1-phenylethylamine, then (1b) treatment of the salt resulting from step (1a) with propylene oxide, then (1c) crystallisation using a polar and protic solvent and recovery of the compound of formula (A) by filtration,
(2) preparation of the compound of following formula (B):

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by:
(2a) reaction of the compound of formula (A) derived from step (1) with the benzylic ester of (2-(4-biphenyl)methyl)acrylate in the presence of a source of trimethylsilyl groups, then
(2b) recovery of the compound of formula (B) by:
(2b.1) crystallisation using a mixture of apolar aprotic solvent and water then filtration, or
(2b.2) trituration in acetone, filtration and evaporation of the filtrate,
(3) preparation of the compound of following formula (C):

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in which P′ is a protective group of the amine function,
by:
(3a) hydrogenolysis of the compound of formula (B) under hydrogen atmosphere in the presence of 10% by weight of Pd/C compared to the weight of the compound of formula (B), then
(3b) protection of the amine resulting from step (3a) with a protective group P′ and recovery of the compound of formula (C),
(4) preparation of the compound of formula (E) by
(4a) peptide coupling of the compound of formula (C) with the tert-butyl ester of (L)-alanine and recovery of the compound of following formula (D):

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(4b) deprotection of the protective group P′ in N-terminal position and the tert-butyl group in C-terminal position and recovery of the compound of formula (E).