WO2015004685A2 - Procédé amélioré de purification du boceprevir - Google Patents

Procédé amélioré de purification du boceprevir Download PDF

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Publication number
WO2015004685A2
WO2015004685A2 PCT/IN2014/000462 IN2014000462W WO2015004685A2 WO 2015004685 A2 WO2015004685 A2 WO 2015004685A2 IN 2014000462 W IN2014000462 W IN 2014000462W WO 2015004685 A2 WO2015004685 A2 WO 2015004685A2
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WO
WIPO (PCT)
Prior art keywords
boceprevir
acid
water
process according
mixtures
Prior art date
Application number
PCT/IN2014/000462
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English (en)
Other versions
WO2015004685A3 (fr
Inventor
Shankar Rama
Vipin Kumar Kaushik
Vijaya Krishna RAVI
Vikas Chandradev RVN
Chaitanya MVSRK
Original Assignee
Mylan Laboratories Ltd
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 Mylan Laboratories Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2015004685A2 publication Critical patent/WO2015004685A2/fr
Publication of WO2015004685A3 publication Critical patent/WO2015004685A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • the present invention relates to a process for the purification of Boceprevir, wherein hydroxy Boceprevir is subjected to oxidation reaction in organic solvent after completion of the reaction, product is extracted into an aqueous bisulfate solution followed by pH adjustment to get pharmaceutically acceptable Boceprevir.
  • U.S. patent number 6,992,220, U.S. patent application numbers 201 1034705, U.S. 20050249702 and U.S. 201001 13821 are disclosed process for the preparation of Boceprevir.
  • U.S. patent number 8,222,427 claims a process for the purification of Boceprevir through a corresponding bisulfite adduct, wherein the compound of Formula I is dissolved in organic solvent, which is treated with an aqueous phase comprising bisulfite, thereby forming an aqueous solution of the bisulfite adduct of the compound of Formula I, which is subsequently regenerated from the aqueous phase without isolating the bisulfite adduct.
  • the principle object of the present invention is to provide a process for the purification of Boceprevir.
  • the present invention provides a process for the purification of Boceprevir comprising the steps of: a) treating a water immiscible organic solvent containing Boceprevir with an aqueous bisulfite solution,
  • the present invention provides a purification process of Boceprevir comprising the steps of: a) dissolving Boceprevir in water miscible organic solvents or mixtures thereof,
  • step (a) adding solution of step (a) to water, and
  • the present invention relates to a process for the purification of Boceprevir, wherein hydroxyl Boceprevir is subjected to an oxidation reaction in an organic solvent, after completion of the reaction, the product is extracted into an aqueous bisulfate solution followed by pH adjustment to get pharmaceutically acceptable Boceprevir.
  • the present invention provides a process for the purification of Boceprevir comprising the steps of: a) treating a water immiscible organic solvent containing Boceprevir with an aqueous bisulfite solution,
  • the Boceprevir is dissolved in a water immiscible organic solvent.
  • the organic layer is extracted with an aqueous bisulfate solution, optionally the said aqueous layer is washed with organic solvent.
  • the separated aqueous layer is cooled then adjusted the solution pH to acidic, precipitated solid is filtered and washed with water to give pharmaceutically acceptable Boceprevir.
  • the Boceprevir is dissolved in water immiscible organic solvent selected from ester solvents that can be used but not limited to ethyl acetate, methyl acetate, butyl acetate; the ether solvents that can be used but not limited to methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether; the chlorinated solvents that can be used but not limited to chloroform, dichloromethane, dichloroethane; the ketone solvents that can be used but not limited to methyl ethyl ketone, methyl isobutyl ketone; cyclohexanone preferably ethyl acetate and methyl tert- butyl ether or mixtures thereof.
  • ester solvents that can be used but not limited to ethyl acetate, methyl acetate, butyl acetate
  • the ether solvents that can be used but not limited to methyl
  • an aqueous bisulfate solution is added to organic layer, bisulfate solution that can be used but not limited to an aqueous sodium or potassium bisulfite solution.
  • the separated an aqueous layer containing Boceprevir bisulfite adduct is diluted with water.
  • the aqueous layer containing Boceprevir bisulfite adduct is optionally washed with the water immiscible organic solvent to remove impurities.
  • the water immiscible organic solvent selected from ester solvents that can be used but not limited to ethyl acetate, methyl acetate, butyl acetate; ether solvents that can be used but not limited to methyl tert- butyl ether, butyl ether, diethyl ether, diisopropyl ether; the chlorinated solvents that can be used but not limited to chloroform, dichloromethane, dichloroethane; the ketone solvents that can be used but not limited to methyl ethyl ketone, methyl isobutyl ketone; cyclohexanone preferably ethyl acetate and methyl tert- butyl ether.
  • the pH of the aqueous layer containing Boceprevir bisulfite adduct is adjusted to acidic, preferably, 0.5 -5.0 and more preferably, 1.0-3.0 by adding an acid.
  • the acid used for the pH adjustment is selected from an organic acid or an inorganic acid.
  • Examples of the suitable organic acid for pH adjustment include, but are not limited to, formic acid, acetic acid and propionic acid, halogenated acetic acids such as chloroacetic acid, dichloroacetic acid, trifluoroacetic acid and combinations thereof.
  • Examples of an inorganic acid used for pH adjustment include, but are not limited to, hydrohalides such as hydrochloric acid, hydrobromic acids, hydrofluoric acid, sulfuric acid, nitric acid, boric acid; preferably hydrochloric acid, hydrobromic acid and more preferably, hydrochloric acid.
  • the temperature of the reaction mixture is optionally cooled to 0-30 °C, preferably 0-20 °C and more preferably 10-15°C.
  • the present invention also relates to process for purification of Boceprevir, whereas Boceprevir of formula (I) is dissolved in water miscible organic solvent then added into water to precipitate the product, which is filtered to get pharmaceutically acceptable Boceprevir.
  • the present invention provides a process for the purification of Boceprevir comprising the steps of: a) dissolving Boceprevir in water miscible organic solvents or mixtures thereof,
  • One embodiment of the present invention relates to process for purification of Boceprevir, whereas Boceprevir of formula (I) is dissolved in water miscible organic solvent then added into water to precipitate the product, which is filtered to get pharmaceutically acceptable Boceprevir.
  • Boceprevir is dissolved in water miscible organic solvents or mixtures thereof.
  • the water miscible organic solvents such as polar organic solvent selected from alcohol that can be used may not limited to ethanol, methanol, isopropanol, n-propanol, polar aprotic solvents selected from but not limited to acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, preferably isopropanol and acetone.
  • the obtained Boceprevir solution is added to the pre cooled water; the resulting mixture stirred and filtered to isolate pure Boceprevir.
  • Ethyl acetate 600 ml was added to the reaction mass and the organic layer was separated. The product was extracted from aqueous layer with ethyl acetate. The organic layer was washed with 5% w/w hydrochloric acid followed by water. To the organic layer, aqueous solution of sodium bisulfite (300 gm in 600 ml) was added and stirred for 2 hrs. The layers were separated and organic layer was extracted with water. Thereafter, extracted aqueous layer was washed with ethyl acetate. To the aqueous layer sodium bisulfite (5.1 gm in 17 ml of water) was added and stirred for 30 min.
  • the obtained solution was degassed and the pH was adjusted to 1.0 to 2.5 with dilute hydrochloric acid (15 ml of 35% w/w hydrochloric acid and 15 ml of water) and cooled to 10-15 °C.
  • the obtained solid was filtered and washed with water to yield pure Boceprevir.
  • Ethyl acetate 600 ml was added to the reaction mass and the organic layer was separated.
  • the product was extracted from aqueous layer with ethyl acetate.
  • the both organic layers were combined and stirred with dilute hydrochloric acid solution (prepared by mixing 50 ml of ⁇ 35% w/w of hydrochloric acid and 950 mL of water).
  • the organic layer containing the product was separated and washed with water.
  • the organic layer was cooled to 1-5 °C.
  • aqueous solution of sodium bisulfite 300 gm in 600 ml
  • the organic layer was cooled without agitation and added precooled water at 5-10 °C.
  • the aqueous layer containing the product was collected.
  • the aqueous layer filtered through hyflo and washed with precooled water. Further the aqueous layer was diluted with precooled water, and adjusted the pH to 2 - 2.8 with dilute hydrochloric acid. Vacuum was applied to the aqueous layer and the temperature was slowly raised to less than 23 °C under reduced pressure.
  • the separated solid was filtered at 22-30 °C and washed with water. Further, the filtered solid was washed with water having pH 1.8-2.4 (The pH of the water was adjusted with HC1).
  • the product was dried at 24-28 °C under reduced pressure to yield pure Boceprevir.
  • Example 3 Example 3:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de purification du Boceprevir, dans lequel le Boceprevir hydroxyle est soumis à une réaction d'oxydation dans un solvant organique après l'achèvement de la réaction, un produit est extrait dans une solution de bisulfate aqueuse, puis son pH est ajusté pour obtenir du Boceprevir pharmaceutiquement acceptable.
PCT/IN2014/000462 2013-07-12 2014-07-10 Procédé amélioré de purification du boceprevir WO2015004685A2 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
IN3120/CHE/2013 2013-07-12
IN3120CH2013 2013-07-12
IN4020/CHE/2013 2013-09-10
IN4020CH2013 2013-09-10
IN5626CH2013 2013-12-06
IN5626/CHE/2013 2013-12-06
IN99CH2014 2014-01-09
IN99/CHE/2014 2014-01-09

Publications (2)

Publication Number Publication Date
WO2015004685A2 true WO2015004685A2 (fr) 2015-01-15
WO2015004685A3 WO2015004685A3 (fr) 2015-03-12

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WO (1) WO2015004685A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114702545A (zh) * 2022-04-19 2022-07-05 海化生命(厦门)科技有限公司 一种抗新冠病毒药物尼玛瑞韦的制备方法

Citations (6)

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Publication number Priority date Publication date Assignee Title
US20050249702A1 (en) 2004-05-06 2005-11-10 Schering Corporation (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease
US6992220B2 (en) 2003-06-17 2006-01-31 Schering Corporation Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof
US7326795B2 (en) 2003-06-17 2008-02-05 Schering Corporation Process and intermediates for the preparation of (1R,2S,5S)-3-azabicyclo[3,1,0]hexane-2-carboxamide, N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[1,1-dimethylethyl]amino]carbonylamino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl
US20100113821A1 (en) 2006-12-19 2010-05-06 Schering-Plough Corporation Preparation of 3-amino-3-(cyclobutylmethyl)-2-(hydroxy)-propionamide hydrochloride
US20110034705A1 (en) 2007-12-21 2011-02-10 Schering-Plough Corporation Process For the Synthesis of 3- Amino-3-Cyclobuthylmethyl-2-Hydroxypropionamide or Salts Thereof
US8222427B2 (en) 2006-12-15 2012-07-17 Merck Sharp & Dohme Corp. Bisulfite purification of an alpha-keto amide

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
US6992220B2 (en) 2003-06-17 2006-01-31 Schering Corporation Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof
US7326795B2 (en) 2003-06-17 2008-02-05 Schering Corporation Process and intermediates for the preparation of (1R,2S,5S)-3-azabicyclo[3,1,0]hexane-2-carboxamide, N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[1,1-dimethylethyl]amino]carbonylamino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl
US20050249702A1 (en) 2004-05-06 2005-11-10 Schering Corporation (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease
US8222427B2 (en) 2006-12-15 2012-07-17 Merck Sharp & Dohme Corp. Bisulfite purification of an alpha-keto amide
US20100113821A1 (en) 2006-12-19 2010-05-06 Schering-Plough Corporation Preparation of 3-amino-3-(cyclobutylmethyl)-2-(hydroxy)-propionamide hydrochloride
US20110034705A1 (en) 2007-12-21 2011-02-10 Schering-Plough Corporation Process For the Synthesis of 3- Amino-3-Cyclobuthylmethyl-2-Hydroxypropionamide or Salts Thereof

Non-Patent Citations (1)

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Title
JERRY MARCH: "Advanced Organic Chemistry", 1972, JOHN WILEY AND SONS, 4TH ED.,

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114702545A (zh) * 2022-04-19 2022-07-05 海化生命(厦门)科技有限公司 一种抗新冠病毒药物尼玛瑞韦的制备方法

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