Process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate
AssigneeMsn Laboratories Private Limited
InventorsSrinivasan Thirumalai Rajan, Sajja Eswaraiah, Komati Satyanarayana
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Abstract
The present invention relates to an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate, represented by the following structural formula (I).
Claims13
A process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 or its phenylethylamine salt compound of formula-1a, comprising:
- (a) reacting the 3-phenylpropanoic acid compound of formula-2
- with (R)-4-phenyloxazolidin-2-one compound of formula-3
- in presence of a suitable coupling agent and a suitable base in a suitable solvent to provide (R)-4-phenyl-3-(3-phenylpropanoyl)oxazolidin-2-one compound of formula-4,
- (b) hydroxy methylating the (R)-4-phenyl-3-(3-phenylpropanoyl) oxazolidin-2-one compound of formula-4 with 1,3,5-trioxane in the presence of a suitable base and a suitable catalyst in a suitable solvent to provide (R)-3-((S)-2-benzyl-3-hydroxy propanoyl)-4-phenyloxazolidin-2-one compound of formula-5,
- (c) hydrolyzing the compound of formula-5 with a base in the presence of hydrogen peroxide in a suitable solvent to provide (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1,
- (d) optionally treating the compound of formula-1 with (S)-phenyl ethylamine in a suitable solvent to provide (S)-2-benzyl-3-hydroxypropanoic acid (S)-phenyl ethylamine salt compound of formula-1a and further treating the compound of formula-1a with a suitable acid in a suitable solvent to provide (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1.
A process for the preparation of highly pure (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1, comprising:
- (a) treating the compound of formula-1 with (S)-phenyl ethylamine in a suitable solvent to provide (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a, and
- (b) treating the compound of formula-1a with a suitable acid in a suitable solvent to provide highly pure compound of formula-1.
A process for the preparation of Alvimopan dihydrate comprising:
- (a) treating the (S)-2-benzyl-3-hydroxypropanoic acid (S)-phenyl ethylamine salt compound of formula-1a with hydrochloric acid in a mixture of ethylacetate and water to provide (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 which on in-situ reacting with ethyl 2-aminoacetate hydrochloride compound of formula-6 in presence of dicyclohexylcarbodiimide and triethylamine in dichloromethane to provide (S)-ethyl 2-(2-benzyl-3-hydroxypropanamido)acetate compound of formula-7,
- (b) treating the compound of formula-7 with methanesulfonyl chloride in presence of triethylamine in ethylacetate provides (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-8,
- (c) reacting the compound of formula-8 with 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-9 in presence of triethylamine in acetonitrile provides ethyl 24(S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-1-yl)propanamido)acetate hydrochloride compound of formula-10,
- (d) treating the compound of formula-10 with sodium hydroxide in aqueous ethanol provides Alvimopan dihydrate, and
- (e) optionally purifying the Alvimopan dihydrate by treating with aqueous sodium hydroxide in ethanol and followed by treating with conc. hydrochloric acid to provide pure Alvimopan dihydrate.
Dependencies are inferred from the claim text.