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
AssigneeMsn Laboratories Private Limited
InventorsSrinivasan THIRUMALAI RAJAN, Sajja ESWARAIAH, Komati SATYANARAYANA
Life of this patent
Estimating the term…
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).
Claims17
An improved process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 or its phenylethylamine salt of formula-1a, comprising of:
- 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 provides (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 provides (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 provides (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 provides (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a and further converting it into compound of formula-1 by using a suitable acid in a suitable solvent.
The process as claimed in claim-1, wherein,
- in step-a) the suitable base is selected from organic base and suitable coupling agent is selected from dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N″,N″-dimethylamino)propyl carbodiimide hydrochloride (EDC), N, N-carbonyldiimidazole (CDI), DABAL-Me3, benzotriazolyloxytris(dimethylamino) phosphonium Hexafluoro phosphate (BOP), 2-(7-aza-1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniu hexafluorophosphate (HATU), benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluoro phosphate (PyBOP), 7-azabenzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) and suitable solvent is selected from chloro solvents, ether solvents, ester solvents, alcohol solvents and hydrocarbon solvents or mixture thereof;
- in step-b) suitable base is selected from organic base and suitable catalyst is titanium tetrachloride and suitable solvent is selected from ester solvents, chloro solvents, hydrocarbon solvents, ketone solvents and alcohol solvents or mixture thereof.
- in step-c) the suitable base is selected from inorganic base and suitable solvent is selected from alcohol solvents, ester solvents, ether solvents, chloro solvents and hydrocarbon solvents or mixture thereof.
- in step-d) the suitable acid is selected from inorganic acid, preferably hydrochloric acid;
- and
- a suitable solvent is selected from chloro solvents, ether solvents, alcohol solvents, ester solvents, hydrocarbon solvents and polar solvents such as water or mixtures thereof.
An improved process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 or its phenylethylamine salt compound of formula-1a, comprising of the following steps:
- a) Reacting the 3-phenylpropanoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in presence of dicyclohexyl carbodiimide and dimethylaminopyridine in dichloromethane provides (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 presence of diisopropyl ethylamine and titanium tetrachloride in dichloromethane provides (R)-3-((S)-2-benzyl-3-hydroxy propanoyl)-4-phenyloxazolidin-2-one compound of formula-5,
- c) hydrolyzing the compound of formula-5 with lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran provides (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1,
- d) treating the compound of formula-1 with (S)-phenyl ethylamine in isopropanol provides (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a and further converting it into compound of formula-1 by treating it with hydrochloric acid in ethylacetate and water.
An improved process for the preparation of (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of hydroxy methylating the (R)-4-phenyl-3-(3-phenylpropanoyl)oxazolidin-2-one compound of formula-4 with 1,3,5-trioxane in presence of a suitable base selected from organic base and a suitable catalyst in a suitable solvent provides (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyl oxazolidin-2-one compound of formula-5.
An improved process for the preparation of (R)-4-phenyl-3-(3-phenylpropanoyl) oxazolidin-2-one compound of formula-4, comprising of 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 selected from dicyclohexyl carbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N″,N″-dimethylamino)propyl carbodiimide hydrochloride (EDC), N, N-carbonyldiimidazole (CDI) and a suitable base selected from organic base in a suitable solvent selected from chloro solvents, ether solvents, ester solvents, alcohol solvents and hydrocarbon solvents or mixture thereof to provide (R)-4-phenyl-3-(3-phenylpropanoyl) oxazolidin-2-one compound of formula-4.
An improved process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1, comprising of:
- a) Hydroxy methylating the (R)-4-phenyl-3-(3-phenylpropanoyl)oxazolidin-2-one compound of formula-4 with 1,3,5-trioxane in presence of a suitable base and a suitable catalyst in a suitable solvent provides (R)-3-((S)-2-benzyl-3-hydroxy propanoyl)-4-phenyloxazolidin-2-one compound of formula-5,
- b) hydrolyzing the compound of formula-5 with a suitable base in the presence of hydrogen peroxide in a suitable solvent provides (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1.
An improved process for the preparation of highly pure (S)-2-benzyl-3-hydroxy propanoic acid compound of formula-1, comprising of:
- a) Treating the compound of formula-1 with (S)-phenyl ethylamine in a suitable solvent provides (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a,
- b) converting the compound of formula-1a into compound of formula-1 by using a suitable acid selected from inorganic acid in a suitable solvent provides highly pure compound of formula-1.
A process for the preparation of Alvimopan dihydrate comprising of:
- a) Preparing the (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 according to the process claimed in claim-1,
- b) reacting (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 with ethyl 2-aminoacetate hydrochloride of formula-6 in presence of dicyclohexyl carbodiimide and triethylamine in dichloromethane provides (S)-ethyl 2-(2-benzyl-3-hydroxy propanamido)acetate compound of formula-7,
- c) treating the compound of formula-7 with methanesulfonyl chloride in presence of triethylamine in dichloromethane provides (S)-ethyl 2-(2-benzyl-3-(methylsulfonyl oxy)propanamido)acetate compound of formula-8,
- d) 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 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-1-yl)propanamido)acetate hydrochloride compound of formula-10,
- e) treating the compound of formula-10 with sodium hydroxide in aqueous ethanol provides Alvimopan dihydrate,
- f) optionally, purifying the obtained compound from a suitable solvent provides pure Alvimopan dihydrate.
An improved process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 or its phenylethylamine salt compound of formula-1a, comprising of the following steps:
- a) Reacting the 3-phenylpropanoic acid compound of formula-2 with (R)-4-phenyloxazolidin-2-one compound of formula-3 in presence of dicyclohexyl carbodiimide and dimethylaminopyridine in dichloromethane provides (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 presence of triethylamine and titanium tetrachloride in dichloromethane provides (R)-3-((S)-2-benzyl-3-hydroxy propanoyl)-4-phenyloxazolidin-2-one compound of formula-5,
- c) hydrolyzing the compound of formula-5 with lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran provides (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1,
- d) treating the compound of formula-1 with (S)-phenyl ethylamine in isopropanol provides (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a and further converting it into compound of formula-1 by treating it with hydrochloric acid in ethylacetate and water.
A process for the preparation of (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyloxazolidin-2-one compound of formula-5, comprising of hydroxy methylating the (R)-4-phenyl-3-(3-phenylpropanoyl)oxazolidin-2-one compound of formula-4 with 1,3,5-trioxane in presence of triethylamine and titanium tetrachloride in dichloromethane provides (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyl oxazolidin-2-one compound of formula-5.
An improved process for the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1, comprising of;
- a) Hydroxy methylating the (R)-4-phenyl-3-(3-phenylpropanoyl)oxazolidin-2-one compound of formula-4 with 1,3,5-trioxane in presence of triethylamine and titanium tetrachloride in dichloromethane provides (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyloxazolidin-2-one compound of formula-5,
- b) hydrolyzing the compound of formula-5 with lithium hydroxide in presence of hydrogen peroxide in tetrahydrofuran provides (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1.
An alternate process for the preparation of Alvimopan dihydrate comprising of:
- a) Treating the (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a with hydrochloric acid in ethylacetate and water provides (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 which on in-situ reacting with ethyl 2-aminoacetate hydrochloride of formula-6 in presence of dicyclohexyl carbodiimide and triethylamine in dichloromethane provides (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-(methylsulfonyl oxy)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 2-((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,
- e) optionally, purifying the obtained compound from a suitable solvent provides pure Alvimopan dihydrate.
A process for the preparation of highly pure (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 comprising of, treating the compound of formula-1 with (S)-phenyl ethylamine in isopropanol provides (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a and further converting it into compound of formula-1 by treating it with hydrochloric acid in ethylacetate and water.
Compound having the following structural formula:
Use of novel (R)-3-((S)-2-benzyl-3-hydroxypropanoyl)-4-phenyloxazolidin-2-one compound of formula-5 of the present invention in the preparation of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 or its phenylethylamine salt compound of formula-1a.
Use of (S)-phenyl ethylamine salt of (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1a in the preparation of highly pure (S)-2-benzyl-3-hydroxypropanoic acid compound of formula-1 as well as in the preparation of Alvimopan dihydrate.
Dependencies are inferred from the claim text.