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WO2013080221A2 - Procédé de purification d'alvimopan - Google Patents

Procédé de purification d'alvimopan Download PDF

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Publication number
WO2013080221A2
WO2013080221A2 PCT/IN2012/000775 IN2012000775W WO2013080221A2 WO 2013080221 A2 WO2013080221 A2 WO 2013080221A2 IN 2012000775 W IN2012000775 W IN 2012000775W WO 2013080221 A2 WO2013080221 A2 WO 2013080221A2
Authority
WO
WIPO (PCT)
Prior art keywords
alvimopan
solution
content
dmp
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2012/000775
Other languages
English (en)
Other versions
WO2013080221A3 (fr
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Matta Ramakrishna Reddy
Bandi Vamsi Krishna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2013080221A2 publication Critical patent/WO2013080221A2/fr
Publication of WO2013080221A3 publication Critical patent/WO2013080221A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • the present invention provides a novel process for the purification of alvimopan.
  • Alvimopan is chemically, N-[(2S)-2-[[(3R,4R)-4-(3-Hydroxyphenyl)-3,4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]glycine and has the structural formula:
  • Alvimopan is a drug which behaves as a peripherally acting ⁇ -opioid antagonist. With limited ability to cross the blood-brain barrier, many of the undesirable side-effects of the opioid agonists such as constipation are minimized without affecting analgesia or precipitating withdrawals. Alvimopan is currently marketed under the trade name ENTEREG ® by Adolor.
  • alvimopan and its process were disclosed in U.S. patent no. 5,250,542 ('542 patent). According to the '542 patent, alvimopan monohydrate is prepared by crystallizing alvimopan in a mixture of teterahydrofuran, methanol and water.
  • alvimopan monohydrate is prepared by crystallizing alvimopan in a mixture of ethanol and water in presence of sodium hydroxide.
  • U.S. patent no. 5,434, 171 described alvimopan crystalline monohydrate and alvimopan crystalline dihydrate. According to the patent, alvimopan crystalline monohydrate is prepared by crystallizing alvimopan in a mixture of methanol and water.
  • alvimopan dihydrate is prepared by crystallizing alvimopan in a mixture of ethanol and water in the presence of sodium hydroxide.
  • alvimopan is prepared by crystallizing alvimopan in a mixture of ethanol and water in the presence of sodium hydroxide and then recrystallized with a mixture of ethanol and water in the presence of sodium hydroxide to obtain alvimopan.
  • the present invention is intended to enhance the purity of alvimopan without much loss in the yield.
  • the present invention is directed to reduce or remove 3,4-DMP Mester, 3,4-DMP Acid and 2R-Alvimopan impurities from alvimopan.
  • the process of the invention may be used for obtaining alvimopan in high purity with less than 0.1% of any individual impurities, in particular impurities 3,4-DMP Mester, 3,4- DMP Acid and 2R-Alvimopan.
  • an object of the present invention is to provide a novel process for the purification of alvimopan.
  • the present invention provides a novel process for the purification of alvimopan, which comprises:
  • Figure 1 is X-ray powder diffraction spectrum of crystalline alvimopan monohydrate.
  • X-Ray Powder Diffractogram was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.020 degrees two theta per step and a step time of 10.8 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35°C.
  • pure alvimopan refers to alvimopan having the purity greater than about 98.5% by weight, preferably greater than about 99% by weight, and more preferably greater than about 99.5% by weight.
  • the alcoholic solvent used in step (b) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol and n-butanol. More preferably the alcoholic solvent is n-butanol.
  • the reaction in step (b) may preferably be carried out at 15 to 40°C.
  • step (c) Pure alvimopan may be isolated in step (c) by methods known such as filtration or centrifugation.
  • HPLC conditions for analysis are:
  • Diluent Methanol Buffer (Solution A) : Dissolve about 1.36 gm of potassium dihydrogen orthophosphate in 1000 ml of water. Adjust the pH of the solution to 3.0 ⁇ 0.05 with diluted orthophosphoric acid and mixture.
  • Solution B Prepare a mixture of buffer and acetonitrile in the ratio of 30:70
  • Alvimopan crude (10 gm; HPLC Purity: 94%) was dissolved in ethanol (250 ml) and water (60 ml) and then added sodium hydroxide solution (IN, 60 ml) slowly for 30 minutes.
  • the reaction mass was maintained for 45 minutes at 20 to 25°C and pH of the reaction mass was adjusted to 6.0 with concentrated hydrochloric acid.
  • the contents were stirred for 2 hours at room temperature and filtered. The solid obtained was dried to obtain 7 gm of alvimopan.
  • the reaction mass was stirred for 24 hours at room temperature and then cooled to 0°C.
  • the reaction mass was stirred for 2 hours at 0°C and filtered.
  • the solvent was distilled off from the filtrate thus obtained under vacuum at below 45°C to obtain a residual mass.
  • To the residual mass was dissolved in ethyl acetate (1000 ml) and pH was adjusted to 10 with a mixture of sodium carbonate and sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid.
  • To the residual solid was added ethyl acetate (1000 ml) and filtered through celyte bed.
  • the solvent was distilled off from the filtrate thus obtained under vacuum at below 45°C and co-distilled with ethanol to obtain a residual solid.
  • ethanol 4200 ml
  • water 1000 ml
  • sodium hydroxide solution I, 1000 ml
  • the reaction mass was maintained for 1 hour 30 minutes at room temperature and treated with carbon.
  • the pH of the reaction mass was adjusted to 6.14 with hydrochloric acid solution at 20°C.
  • the ethanol solvent was distilled off partially under vacuum and then cooled to 10°C.
  • the reaction mass was stirred for 2 hours and then cooled to 0°C.
  • the contents were stirred for 2 hours at 0°C and filtered.
  • the solid obtained was dried at 55°C for 8 hours to obtain 100 gm of alvimopan.
  • Alvimopan (100 gm; HPLC Purity: 98.5%) as obtained in example 1 was dissolved in dimethylformamide (300 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added n-butanol (1000 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. The solid obtained was dried at 40 to 50°C under vacuum for 5 hours to obtain
  • Alvimopan (10 gm; HPLC Purity: 97.5%) as obtained in reference example 1 was dissolved in dimethylformamide (30 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added n-butanol (100 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. To the solid obtained was added acetone (50 ml) and then heated to reflux. The solution was stirred for 1 hour at reflux and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was dried at 1 10 to 120°C under vacuum for 32 hours to obtain 9 gm of pure crystalline alvimopan monohydrate (Water content: 3.9%).
  • alvimopan Alvimopan (10 gm; HPLC Purity: 98.5%) was dissolved in dimethylacetamide (40 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added n-butanol (100 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. The solid obtained was dried at 40 to 50°C under vacuum for 6 hours to obtain 8 gm of pure alvimopan.
  • Alvimopan (10 gm; HPLC Purity: 98.5%) was dissolved in dimethyl sulfoxide (45 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added n-butanol (100 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. The solid obtained was dried at 40 to 50°C under vacuum for 5 hours to obtain 7.5 gm of pure alvimopan.
  • Alvimopan (10 gm; HPLC Purity: 98.5%) was dissolved in dimethylformamide (30 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added ethanol (95 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. The solid obtained was dried at 40 to 50°C under vacuum for 6 hours to obtain 7 gm of pure alvimopan.
  • Alvimopan (10 gm; HPLC Purity: 98.5%) was dissolved in dimethylformamide (30 ml) and then heated to 120 to 125°C to obtain a solution. The solution was treated with carbon and then added methanol (85 ml) at room temperature. The contents were stirred for 15 hours at room temperature and filtered. The solid obtained was dried at 40 to 50°C under vacuum for 5 hours to obtain 6 gm of pure alvimopan.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Catalysts (AREA)
  • Compounds Of Alkaline-Earth Elements, Aluminum Or Rare-Earth Metals (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un nouveau procédé de purification d'alvimopan. Conformément à la présente invention, de l'alvimopan est dissout dans du diméthylformamide et chauffé à 120 à 125 degrés C, puis additionné de n-butanol à température ambiante, les contenus sont agités pendant 15 heures, filtrés puis déshydratés pour obtenir de l'alvimopan pur.
PCT/IN2012/000775 2011-12-01 2012-11-29 Procédé de purification d'alvimopan Ceased WO2013080221A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4170CH2011 2011-12-01
IN4170/CHE/2011 2011-12-01

Publications (2)

Publication Number Publication Date
WO2013080221A2 true WO2013080221A2 (fr) 2013-06-06
WO2013080221A3 WO2013080221A3 (fr) 2013-10-10

Family

ID=48536198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2012/000775 Ceased WO2013080221A2 (fr) 2011-12-01 2012-11-29 Procédé de purification d'alvimopan

Country Status (1)

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WO (1) WO2013080221A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037248A (zh) * 2015-08-10 2015-11-11 山东罗欣药业集团股份有限公司 一种爱维莫潘的合成方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794510B2 (en) * 2002-08-08 2004-09-21 Adolor Corporation Processes for the preparation of peripheral opioid antagonist compounds and intermediates thereto
US6943249B2 (en) * 2003-03-17 2005-09-13 Ash Stevens, Inc. Methods for isolating crystalline Form I of 5-azacytidine
US7700626B2 (en) * 2004-06-04 2010-04-20 Adolor Corporation Compositions containing opioid antagonists
US20110190267A1 (en) * 2010-01-05 2011-08-04 Shire Pharmaceuticals, Inc. Prodrugs of opioids and uses thereof
US8461171B2 (en) * 2010-02-09 2013-06-11 QRxPharma Ltd. Hybrid opioid compounds and compositions
WO2011161646A2 (fr) * 2010-06-25 2011-12-29 Ranbaxy Laboratories Limited Procédé de préparation d'alvimopan ou de son sel ou solvate pharmaceutiquement acceptable

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105037248A (zh) * 2015-08-10 2015-11-11 山东罗欣药业集团股份有限公司 一种爱维莫潘的合成方法

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WO2013080221A3 (fr) 2013-10-10

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