WO2015162551A1 - Procédé pour la préparation d'apixaban - Google Patents

Procédé pour la préparation d'apixaban Download PDF

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Publication number
WO2015162551A1
WO2015162551A1 PCT/IB2015/052894 IB2015052894W WO2015162551A1 WO 2015162551 A1 WO2015162551 A1 WO 2015162551A1 IB 2015052894 W IB2015052894 W IB 2015052894W WO 2015162551 A1 WO2015162551 A1 WO 2015162551A1
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WO
WIPO (PCT)
Prior art keywords
formula
piperazine
apixaban
process according
base
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Application number
PCT/IB2015/052894
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English (en)
Inventor
Sureshbabu JAYACHANDRA
Vipin Kumar Kaushik
Surya Nageswara Rao Achanta
Siva Prasad Reddy DORASALA
Subramanyam Dandala
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.)
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Application filed by Mylan Laboratories Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2015162551A1 publication Critical patent/WO2015162551A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to pharmaceutical compositions and more particularly to a process for the preparation of apixaban using novel intermediates.
  • Apixaban is chemically known as l-(4-methoxy-phenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)-phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4c]-pyridine-3-carboxamide and has the following structural formula:
  • Apixaban is a direct factor Xa (FXa) inhibitor, and is used as an anticoagulant for the treatment of venous thromboembolic events.
  • Apixaban is marketed by Bristol-Myers Squibb under the brand name ELIQUIS®.
  • U.S. Patent Nos. 6,413,980 and 6,673,810 which are hereby incorporated by reference, broadly disclose nitrogen-containing heterobicyclic compounds, derivatives thereof, and pharmaceutically acceptable salts thereof, as inhibitors of factor Xa.
  • the present invention provides a process for the preparation of apixaban and its intermediates which is efficient and industrially viable.
  • One aspect of the present invention provides a compound of Formula D shown below:
  • Formula D where R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • Formula D may be employed as a novel intermediate in the synthesis of apixaban.
  • apixaban Another aspect of the present invention provides a process to produce apixaban, which may be prepared by the following Scheme-I, shown below:
  • R is a Piperazine derivative such as
  • X is chlorine or bromine.
  • Scheme-I One embodiment of the present invention provides a process for the preparation of apixaban which may include the following steps (which shares some attributes of the procession of Formula B to apixaban disclosed in Scheme-I above): a) treating 4-nitroaniline with 5-chloro-pentanoyl chloride in the presence of a base to obtain 1 -(4-nitrophenyl)piperdin-2-one
  • NMP Amino compound an example of Formula B from Scheme-I
  • the present invention relates to a process for the preparation of apixaban using novel intermediates.
  • the present invention provides a compound of Formula D shown below:
  • Formula D where R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • R may be N-methyl piperazine, N-ethyl piperazine, l-(2-pyrimidinyl)piperazine, 1- (2-pyridyl)piperazine, or benzyl piperazine.
  • Formula D may be employed as a novel intermediate in the synthesis of apixaban.
  • the present invention provides a process to produce apixaban, which may be prepared by the following Scheme-I, shown below:
  • R is a Piperazine derivative such as
  • X is chlorine or bromine.
  • the 5- chloropentanoyl halide may be 5 -chloropentanoyl chlorine or 5 -chloropentanoyl bromine.
  • the base may be, for example, methylamine, ethylamine, dimethylamine, triethylamine, trimethylamine, or isopropylethylamine.
  • the acid may be an inorganic acid, for example, hydrochloric acid, sulfuric acid, or phosphoric acid.
  • l-(4-nitrophenyl)piperidin-2-one is reacted in the presence of phosphorous pentachloride and suitable solvent selected from chlorinated solvents (such as chloroform, dichloromethane, dichloroethane) or ether solvents (such as tetrahydrofuran), to result in 3 ,3-dichloro- 1 -(4-nitrophenyl)piperidin-2-one.
  • chlorinated solvents such as chloroform, dichloromethane, dichloroethane
  • ether solvents such as tetrahydrofuran
  • the piperazine derivative may be, for example, N-methyl piperazine, N-ethylpiperazine, l-(2-pyramidyl)piperizine, l-(2- pyridyl)piperazine, or benzyl piperazine.
  • Formula A may then be reduced to obtain Formula B.
  • suitable reagents for reducing Formula A include, for example, sodium sulfide, and Raney nickel, though other well- known reducing agents from the art may also be employed.
  • Formula B is converted to Formula C.
  • This reaction may be carried out by treating Formula B with a 5-chloropentanoyl halide in the presence of suitable organic or inorganic base and a solvent.
  • the 5- chloropentanoyl halide may be 5-chloropentanoyl chlorine or 5-chloropentanoyl bromine.
  • suitable organic bases include methylamine, ethylamine, dimethylamine, triethylamine, trimethylamine, and isopropylethylamine.
  • suitable inorganic base include sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • suitable solvents include chlorinated solvents such as chloroform, dichloromethane, dichloroethane or ether solvents such as tetrahydrofuran.
  • Formula C may be reacted with a hydrazine intermediate in presence of an organic or inorganic base and a solvent to yield Formula D.
  • the hydrazine intermediate may be Z-ethyl-2-chloro-2-[2-(4- methoxyphenyl)hydrazono] acetate.
  • the organic base may be, for example, pyridine, piperidine, N-methyl morpholine, N-methylpiperidine, N-phenylpiperidine, or an alkyl amine.
  • suitable alkyl amines include diethylamine, triethyl amine, di- isopropylethylamine, and diphenylamine.
  • Suitable inorganic bases include potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.
  • suitable solvents include ethyl acetate, butyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, methylene dichloride, and mixtures thereof.
  • an ester solvent was found to be particularly useful in carrying out this step of the reaction.
  • Formula D is then treated with a suitable acid to result in an ester intermediate.
  • suitable acids include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, and mixtures thereof.
  • the ester intermediate may then be treated with a suitable amine source in the presence of a suitable solvent to produce apixaban.
  • suitable amine sources include ammonia gas, liquid ammonia, and ammonium formate.
  • alcoholic solvents may be employed in this step of the reaction. Suitable alcoholic solvents include, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, amyl alcohol, methylene chloride, ethylene chloride, tetrahydrofuran, or mixture thereof.
  • Apixaban may be optionally purified by recrystallization in a suitable solvent, such as methanol, ethanol, isopropyl alcohol, water, or mixtures thereof. Apixaban may then be isolated, for example, through filtration, distillation, spray drying, or tray drying to obtain substantially pure apixaban.
  • a suitable solvent such as methanol, ethanol, isopropyl alcohol, water, or mixtures thereof. Apixaban may then be isolated, for example, through filtration, distillation, spray drying, or tray drying to obtain substantially pure apixaban.
  • One embodiment of the present invention provides a process for the preparation of apixaban which may include the following steps (which shares some attributes of the procession of Formula B to apixaban disclosed in Scheme-I above): a) treating 4-nitroaniline with a 5-chloropentanoyl halide in the presence of a base to obtain l-(4-nitrophenyl)piperdin-2-one.
  • the 5-chloropentanoyl halide may be 5-chloropentanoyl chlorine or 5- chloropentanoyl bromine.
  • the base may be, for example, methylamine, ethylamine, dimethylamine, triethylamine, trimethylamine, or isopropylethylamine.
  • suitable acids include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid.
  • NMP Nitro compound an example of Formula A from Scheme-I.
  • NMP Amino compound an example of Formula B from Scheme-I
  • suitable reagents for reducing N-methyl piperazine include, for example, sodium sulfide or Raney nickel.
  • NMP Cyclic Intermediate an example of Formula C from Scheme-I.
  • This reaction may be carried out by treating the NMP Nitro compound with a 5- chloro-pentanoyl halide in the presence of suitable organic or inorganic base and a solvent.
  • the 5-chloropentanoyl halide may be 5-chloropentanoyl chlorine or 5-chloropentanoyl bromine.
  • suitable organic bases include methylamine, ethylamine, dimethylamine, triethylamine, trimethylamine, and isopropylethylamine.
  • suitable inorganic base include sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • Suitable solvents include chlorinated solvents such as chloroform, dichloromethane, dichloroethane or ether solvents such as tetrahydrofuran. f) treating the N-methyl piperazine cyclic intermediate with a hydrazine
  • the hydrazine intermediate may be Z-ethyl-2-chloro-2-[2-(4-methoxyphenyl)hydrazono] acetate.
  • the organic base may be, for example, pyridine, piperidine, N-methyl morpholine, N- methylpiperidine, N-phenylpiperidine, or an alkyl amine.
  • suitable alkyl amines include diethylamine, triethyl amine, di-isopropylethylamine, and
  • diphenylamine examples include potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.
  • suitable solvents include ethyl acetate, butyl acetate, isopropyl acetate, methyl acetate, tetrahydrofuran, methylene dichloride, and mixtures thereof.
  • NMP Ester Intermediate Apixaban may be converted to apixaban by first treating with suitable acid to result in an ester intermediate, as well understood in the art (step not shown above, but represented in Scheme-I).
  • suitable acids may be, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, and mixtures thereof.
  • the ester intermediate may then be treated with a suitable amine source in the presence of a suitable solvent to result in apixaban.
  • suitable amine sources include ammonia gas, liquid ammonia, and ammonium formate.
  • Suitable solvents include, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, amyl alcohol, methylene chloride, ethylene chloride, tetrahydrofuran, or mixtures thereof.
  • an alcoholic solvent was found to be particularly useful for execution of this step of the reaction.
  • Apixaban may be optionally purified by recrystallization in a suitable solvent.
  • Suitable solvents include, for example, methanol, ethanol, isopropyl alcohol, water, or mixtures thereof.
  • Apixaban may then be isolated, for example, through filtration, distillation, spray drying, or tray drying to obtain substantially pure apixaban.
  • reaction mixture was cooled to 100 °C, concentrated under reduced pressure, and water was added to precipitate the product. After filtration, the obtained product was recrystallized from isopropyl alcohol to afford 5, 6-dihydro-3-(4-methylpiperazin-l-yl)-l-(4-nitrophenyl) pyridin-2(lH)-one.
  • Example 3A Preparation of l-(4-aminophenyl)-5, 6-dihydro-3-(4-methylpiperazin-l- yl)pyridin-2(lH)-one (an example of Formula B)
  • reaction mass was cooled to 27 to 30 °C, filtered, and crystallized from isopropyl alcohol to afford l-(4- aminophenyl)-5,6-dihydro-3-(4-methyl-piperazin-l-yl)pyridin-2(lH)-one.
  • Example 4 Preparation of 5, 6-dihydro-3-(4-methylpiperazin-l-yl)-l-(4-(2- oxopiperidin-l-yl)phenyl)-pyridine-2(lH)-one (an example of Formula C) 5-chloropentanoyl chloride (67.67 g, 0.44 moles) and l-(4-aminophenyl)-5,6- dihydro-3-(4-methylpiperazin-l-yl)pyridin-2(lH)one (100 g, 0.35 moles) were dissolved in methylene dichloride (2000 ml). Triethylamine (70.0 g, 0.69 moles) was then added at 0-5 °C.
  • reaction mass temperature was raised to 25-35 °C and stirred. After completion of the reaction, the reaction mass was cooled to 0-5 °C and potassium tert-butoxide was added (116 g, 1.04 moles). Again, the reaction mass temperature was raised to 25-35 °C and stirred. After completion of the reaction, the reaction mass was poured into ice water. The organic layer was separated and aqueous layer was re-extracted with methylene dichloride.
  • Example 4a Preparation of 5, 6-dihydro-3-(4-methylpiperazin-l-yl)-l-(4-(2- oxopiperidin-l-yl)phenyl)-pyridine-2(lH)-one (an example of Formula C)
  • the obtained solid was recrystallized in a mixture of methanol (800 ml) and water (2400 ml) to produce apixaban.
  • Example 7 Preparation of (Z)-ethyl 2-chloro-2-(2-(4-methoxyphenyl) hydrazono) acetate.
  • Hydrochloric acid (35% w/w, 229 g, 2.2 moles) was added to a solution of 4- methoxyaniline (100 g, 0.81 moles) in water (320 ml) at 0-5 °C.
  • Sodium nitrite (67.6 g, 0.98 moles) was added slowly to the reaction mixture at -5 to 0 °C and stirred for -30 min at the same temperature.

Abstract

La présente invention concerne des procédés et des intermédiaires pour la préparation d'apixaban.
PCT/IB2015/052894 2014-04-21 2015-04-21 Procédé pour la préparation d'apixaban WO2015162551A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2035/CHE/2014 2014-04-21
IN2035CH2014 2014-04-21
IN4367CH2014 2014-09-05
IN4367/CHE/2014 2014-09-05

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WO2015162551A1 true WO2015162551A1 (fr) 2015-10-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108503580A (zh) * 2018-04-13 2018-09-07 上海皓元医药股份有限公司 一种阿哌沙班中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6413980B1 (en) 1998-12-23 2002-07-02 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
US6919451B2 (en) 2001-12-10 2005-07-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
WO2014044107A1 (fr) * 2012-09-18 2014-03-27 上海恒瑞医药有限公司 Dérivé de pyrazol[3,4-c] pyridine, son procédé de préparation et son utilisation comme médicament
CN103923079A (zh) * 2014-03-25 2014-07-16 沈阳中海药业有限公司 一种阿哌沙班中间体的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6413980B1 (en) 1998-12-23 2002-07-02 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor Xa inhibitors
US6673810B2 (en) 1998-12-23 2004-01-06 Bristol-Myers Squibb Pharma Company Imidazo-heterobicycles as factor Xa inhibitors
US6967208B2 (en) 2001-09-21 2005-11-22 Bristol-Myers Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6989391B2 (en) 2001-09-21 2006-01-24 Bristol-Myers-Squibb Pharma Company Lactam-containing compounds and derivatives thereof as factor Xa inhibitors
US6919451B2 (en) 2001-12-10 2005-07-19 Bristol-Myers Squibb Company Synthesis of 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones
WO2014044107A1 (fr) * 2012-09-18 2014-03-27 上海恒瑞医药有限公司 Dérivé de pyrazol[3,4-c] pyridine, son procédé de préparation et son utilisation comme médicament
CN103923079A (zh) * 2014-03-25 2014-07-16 沈阳中海药业有限公司 一种阿哌沙班中间体的制备方法

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Title
XING, J. ET AL: "Synthesis and factor Xa inhibitory activity of apixaban derivatives", JOURNAL OF CHINA PHARMACEUTICAL UNIVERSITY, vol. 44, no. 4, 15 April 2013 (2013-04-15), pages 289 - 295, XP002740642 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108503580A (zh) * 2018-04-13 2018-09-07 上海皓元医药股份有限公司 一种阿哌沙班中间体的制备方法

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