WO2017158615A1 - Procédé amélioré de préparation de dihydrate d'acide [[2(s)-[[4(r)-(3-hydroxyphényl)-3(r),4-diméthyl-1-pipéridinyl]méthyl]-1-oxo-3-phénylpropyl]amino]acétique - Google Patents

Procédé amélioré de préparation de dihydrate d'acide [[2(s)-[[4(r)-(3-hydroxyphényl)-3(r),4-diméthyl-1-pipéridinyl]méthyl]-1-oxo-3-phénylpropyl]amino]acétique Download PDF

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Publication number
WO2017158615A1
WO2017158615A1 PCT/IN2017/000059 IN2017000059W WO2017158615A1 WO 2017158615 A1 WO2017158615 A1 WO 2017158615A1 IN 2017000059 W IN2017000059 W IN 2017000059W WO 2017158615 A1 WO2017158615 A1 WO 2017158615A1
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Prior art keywords
acid
formula
compound
hydroxyphenyl
acetic acid
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PCT/IN2017/000059
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English (en)
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Bandla PAVAN KUMAR REDDY
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Msn Laboratories Private Limited
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Publication of WO2017158615A1 publication Critical patent/WO2017158615A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid

Definitions

  • the present invention relates to an improved process for the preparation of [[2(S)-
  • Alvimopan dihydrate chemically known as [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid dihydrate is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.
  • CN101967118 patent application discloses process for the preparation of ethyl 2-((S)- 2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperidin-l-yl)propanamido)acetate hydrochloride compound of formula-5a by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl) phenol with (S)-isobutyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate in presence of triethyl amine and toluene to provide compound of formula-4 with low yield and purity.
  • the first aspect of the present invention is to provide a process for the preparation of acid addition salts of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate compound of compound of general formula-5.
  • the second aspect of the present invention is to provide a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid compound of formula- 1.
  • the third aspect of the present invention is to provide an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo -3-phenylpropyl]amino]acetic acid dihydrate compound of formula- 1 a.
  • the fourth aspect of the present invention is to provide a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid dihydrate compound of formula- la, comprising of:
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents” such as methyl acetate, ethyl
  • suitable base refers to "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutyl
  • HA refers to acid such as hydro bromic acid, hydrochloric acid, hydro iodic acid, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, acetic acid, malic acid and formic acid.
  • the first aspect of the present invention provides a process for the preparation of acid addition salts of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate compound of general formula-5, comprising of reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxy phenyl)-3,4-dimethylpiperidin-l-yl)propanamido)acetate compound of formula-4, which on further treating with a suitable acid in a suitable solvent to provide
  • the suitable acid is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl; preferably ethyl acetate-HCl, hydro bromic acid, hydro iodic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, malic acid and formic acid.
  • the preferred embodiment of the present invention provides a process for the preparation of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin- 1-yl) propanamido)acetate hydrochloride compound of formula-5a, comprising of reacting 3- ((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in presence of sodium bicarbonate in tertiary butanol to provide ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-l-yl)propanamido)acetate compound of formula-4, which on further treating with ethyl acetate
  • CN 102127005 patent application discloses process for the preparation of ethyl 2-((S)- 2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperidin-l-yl)propanamido)acetate compound of formula-4 by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in the presence of triethyl amine and acetonitrile to provide compound of formula-4 with low yield and purity.
  • CN102757379 patent discloses process for the preparation of ethyl 2-((S)-2-benzyl-3- ((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperidin-l-yl)propanamido)acetate compound of formula-4 by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2-benzyl-3-(4-nitrophenylsulfonyloxy)propanamido)acetate in the presence of triethyl amine, ethylene glycol dimethyl ether or diethyl ether or methyl tert- butyl ether or tetrahydrofuran to provide compound of formula-4 with low yield and purity.
  • the prior art process for the preparation of compound of formula-4 involves reacting the compound of formula-2 with formula-3 in the presence of various pharmaceutical solvents such as acetonitrile, dimethyl formamide, n-butanol, ethylene glycol dimethyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran and toluene to provide compound of formula-4 with low yield and purity, which was further purified for several times to achieve pure compound.
  • the inventors of the present invention have also repeated the reaction by utilizing the same solvents. It was observed that in most of the cases the reaction was not initiated and in some cases the yields of the desired compound was very low. The results were summarized in the following table.
  • the second aspect of the present invention provides a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid compound of formula-1, comprising of the following steps:
  • the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents like water and acids like acetic acid, formic acid and mixtures thereof;
  • the suitable acid is selected from mineral acids or organic acid selected from acetic acid, oxalic acid, formic acid, methane sulfonic acid, ethane sulfonic acid, paratoluene sulfonic acid;
  • the suitable base is selected from organic or inorganic base; preferably inorganic base such as ammonia;
  • the suitable temperature is ranging from 0°C to 30°C.
  • the preferred embodiment of the present invention provides a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l - oxo-3-phenyl propyl]amino]acetic acid compound of formula-1, comprising of the following steps: a) Adding methanol to [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl] methyl]-l-oxo-3-phenylpropyl]amino]acetic acid compound of formula-1, b) adding ammonia to the reaction mixture and stirring the reaction mixture,
  • the compound of formula- la obtained according to the present invention having the piperidinyl phenol impurity, DMP ester impurity, des-methyl impurity and metabolite impurity (acid impurity) less than 0.1%; preferably less than 0.06%; more preferably less than 0.02% as measured by HPLC.
  • the third aspect of the present invention provides an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo -3-phenylpropyl] amino]acetic acid dihydrate compound of formula- la, comprising of the following steps:
  • HA acid such as HC1, HBr, HI, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, malic acid and formic acid
  • the suitable base is selected from organic or inorganic base, preferably inorganic base;
  • the suitable acid is same as defined in the first aspect of the present invention; in step-a) to d) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water, acid like acetic acid, formic acid or there mixture thereof;
  • the suitable acid is selected from mineral acids or organic acid selected from acetic acid, oxalic acid, formic acid, methane sulfonic acid, ethane sulfonic acid, para toluene sulfonic acid.
  • the preferred embodiment of the present invention provides an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula-la, comprising of the following steps:
  • the starting material (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido) acetate compound of formula-3 used in the present invention can be prepared according to the process disclosed in our PCT publication WO2016/038622 A2 or any of the process known in the art.
  • the starting material 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 used in the present invention can be prepared according to the any of the process disclosed in the art.
  • the fourth aspect of the present invention provides a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid dihydrate compound of formula- la, comprising of:
  • step-a) the suitable base is selected from inorganic base and in step-a) & b) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, ether solvents, hydrocarbon solvents, ketone solvents, polar aprotic solvents and polar solvent like water or mixture thereof,
  • suitable acid is selected from mineral acid or organic acid such as oxalic acid, acetic acid, formic acid, malic acid, maleic acid, fumaric acid and tartaric acid.
  • the preferred embodiment of the present invention provides a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l -piperidinyljmethyl]- 1 - oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula-la, comprising of: a) Treating [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid compound of formula-1 with aqueous ammonia in methanol,
  • acetic acid dihydrate compound of formula- la produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • P-XRD Method of Analysis PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03 min.
  • PSD method of Analysis Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • Formula-5a HC1 1. NaOH, IPA, Water
  • Purity by HPLC 99.65%; Purity by Chiral HPLC: 99.91%; Piperidinyl phenol impurity: Not detected; Sulfonyl ester impurity: Not detected; Olefin acid impurity: Not detected; Desmethyl ester impurity: 0.03%; DMP ester impurity: Not detected; HIUI: 0.06%; Enantiomer impurity: 0.03; RRR-Diastereomer impurity: 0.06%; SSS-Diastereomer impurity: Not detected Unknown impurities: 0.26%.
  • Triethyl amine (3.5 kgs), followed by N,N'-Dicyclohexylcarbodiimide (115 gm) and dichloromethane (7.0 Its) were slowly added to the reaction mixture at 25 to 30°C and stirred for 10 hours at the same temperature.
  • Aqueous hydrochloric acid solution was added to the reaction mixture. Cooled the reaction mixture to 0 to 5°C and stirred for 1 1 ⁇ 2 hour at the same temperature. Filtered the unwanted by-product, washed with dichloromethane. Both the organic and aqueous layers were separated and organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound at 25-30°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de dihydrate d'acide [[2(S)-[[4(R)-(3-hydroxyphényl)-3(R),4-diméthyl-1-pipéridinyl]méthyl]-1-oxo-3-phénylpropyl]amino]acétique, représenté par la formule structurelle suivante:
PCT/IN2017/000059 2016-03-14 2017-03-13 Procédé amélioré de préparation de dihydrate d'acide [[2(s)-[[4(r)-(3-hydroxyphényl)-3(r),4-diméthyl-1-pipéridinyl]méthyl]-1-oxo-3-phénylpropyl]amino]acétique WO2017158615A1 (fr)

Applications Claiming Priority (2)

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IN201641008709 2016-03-14
IN201641008709 2016-03-14

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WO2017158615A1 true WO2017158615A1 (fr) 2017-09-21

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PCT/IN2017/000059 WO2017158615A1 (fr) 2016-03-14 2017-03-13 Procédé amélioré de préparation de dihydrate d'acide [[2(s)-[[4(r)-(3-hydroxyphényl)-3(r),4-diméthyl-1-pipéridinyl]méthyl]-1-oxo-3-phénylpropyl]amino]acétique

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101967118B (zh) * 2010-10-14 2013-01-30 成都苑东药业有限公司 爱维莫潘的制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101967118B (zh) * 2010-10-14 2013-01-30 成都苑东药业有限公司 爱维莫潘的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BEERAVALLI RAMALINGA REDDY ET AL.: "Improved Process for Preparation of (3R,4R)?3-(3,4-Dimethyl-4- piperidinyl)phenol, A Key Intermediate for the Synthesis of Alvimopan", ORG. PROCESS RES. DEV., vol. 18, no. 1, 23 December 2013 (2013-12-23), pages 163 - 167, XP055422300 *
JOHN A. WERNER ET AL.: "Synthesis of trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists: Application of the Cis-Thermal Elimination of Carbonates to Alkaloid Synthesis", J. ORG. CHEM., vol. 61, 26 January 1996 (1996-01-26), pages 587 - 597, XP002976925 *

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