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WO2016035014A1 - Procédés de préparation d'énamines - Google Patents

Procédés de préparation d'énamines Download PDF

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Publication number
WO2016035014A1
WO2016035014A1 PCT/IB2015/056642 IB2015056642W WO2016035014A1 WO 2016035014 A1 WO2016035014 A1 WO 2016035014A1 IB 2015056642 W IB2015056642 W IB 2015056642W WO 2016035014 A1 WO2016035014 A1 WO 2016035014A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
process according
ruxolitinib
group
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/IB2015/056642
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English (en)
Inventor
Deepshikha CHAWLA
Dhiren Chandra BARMAN
Pranab Chatterjee
Asok Nath
Mohan Prasad
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Ltd filed Critical Sun Pharmaceutical Industries Ltd
Publication of WO2016035014A1 publication Critical patent/WO2016035014A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to processes for the preparation of ruxolitinib and ruxolitinib phosphate.
  • the present invention also provides a compound of Formula IV, processes for its preparation, and its use for the preparation of ruxolitinib and ruxolitinib phosphate.
  • Ruxolitinib phosphate chemically is (i?)-3-(4-(7H-pyrrolo[2,3- ⁇ f]pyrimidin-4-yl)- lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile hosphate, represented by Formula I.
  • Ruxolitinib is indicated for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.
  • U.S. Patent No. 7,598,257 describes a process for the preparation of ruxolitinib, wherein 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-£/]- pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile of Formula Ila,
  • U.S. Patent No. 8,722,693 provides a process for the preparation of ruxolitinib phosphate.
  • U.S. Patent No. 8,410,265 describes a process for the preparation of (3i?)-3- cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-£/]-pyrimidin-4-yl)- lH-pyrazol-l-yl]propanenitrile by resolution of the compound of Formula Ila with (+)- 2,3-dibenzoyl-D-tartaric acid to predominantly obtain of (2S,3S)-2,3- bis(benzoyloxy)succinic acid-(3i?)-3-cyclopentyl-3-[4-(7- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo [2,3 -d ⁇ -pyrimidin-4-yl)- lH-pyrazol- 1 - yl]propanenitrile (1 : 1) and its subsequent treatment with a base.
  • the present invention relates to processes for the preparation of ruxolitinib and ruxolitinib phosphate.
  • the present invention also provides a compound of Formula IV, processes for its preparation, and its use for the preparation of ruxolitinib and ruxolitinib phosphate.
  • the present invention provides ruxolitinib phosphate having a chiral purity of 99.96% and the compound of Formula IV having a chiral purity of 99.95%.
  • Figure 1 High Performance Liquid Chromatography (HPLC) chromatogram of chiral purity of (25 * ,35)-2,3-bis(benzoyloxy)butanedioic acid - (3i?)-3-cyclopentyl-3-[4- (7H-pyrrolo[2,3-£/
  • HPLC High Performance Liquid Chromatography
  • Figure 2 HPLC chromatogram of chiral purity of ruxolitinib phosphate, obtained as per Example 5.
  • Figure 3 HPLC chromatogram of chiral purity of ruxolitinib phosphate, obtained as per Reference Example.
  • the present inventors have developed a process for the preparation of ruxolitinib phosphate having a chiral purity of about 99.96%.
  • room temperature refers to a temperature in the range of 25°C to 35°C.
  • a first aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • Pg is a protecting group selected from benzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, t- butoxycarbonyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, benzyloxymethyl, cyclohexyloxycarbonyl, 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl, vinyl, 2-chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, methoxymethyl, t-butoxymethyl, 2- tetrahydropyranyl, and 1, 1-diethoxymethyl,
  • a second aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a third aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a fourth aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • Pg is a protecting group selected from a group consisting of benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- (trimethylsilyl)ethoxycarbonyl, i-butoxycarbonyl, 2- (trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, benzyloxymethyl, cyclohexyloxycarbonyl, 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl, vinyl, 2-chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, methoxymethyl, t-butoxymethyl, 2- tetrahydropyranyl, and 1, 1-diethoxymethyl,
  • a fifth aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • a sixth aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • a seventh aspect of the present invention provides a process for the preparation of ruxolitinib of Formula V,
  • An eighth aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • a ninth aspect of the present invention provides a process for the preparation of ruxolitinib of Formula V,
  • Pg is a protecting group selected from benzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, t- butoxycarbonyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, benzyloxymethyl, cyclohexyloxycarbonyl, 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl, vinyl, 2-chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, methoxymethyl, t-butoxymethyl, 2- tetrahydropyranyl, and 1, 1-diethoxymethyl, in the presence of a deprotecting agent to obtain a compound of Formula HI:
  • a tenth aspect of the present invention provides a process for the preparation of ruxolitinib of Formula V,
  • An eleventh aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • Pg is a protecting group selected from benzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, t- butoxycarbonyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxymethyl, benzyloxymethyl, cyclohexyloxycarbonyl, 2-(4- trifluoromethylphenylsulfonyl)ethoxycarbonyl, vinyl, 2-chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, methoxymethyl, t-butoxymethyl, 2- tetrahydropyranyl, and 1, 1-diethoxymethyl,
  • a twelfth aspect of the present invention provides a process for the preparation of ruxolitinib phosphate of Formula I,
  • a thirteenth aspect of the present invention provides a compound of Formula IV.
  • a fourteenth aspect of the present invention provides the use of a compound of Formula IV
  • the compound of Formula II or Formula Ila may be prepared by methods known in the art, for example, the methods described in U.S. Patent No. 7,598,257, or by following the method described herein.
  • the compound of Formula II or Formula Ila may be isolated or the reaction mixture containing the compound of Formula II or Formula Ila may be used as such for the next step.
  • the deprotection of the compound of Formula II or Formula Ila to give the compound of Formula III is carried out in the presence of a deprotecting agent in a solvent.
  • the deprotecting agent is selected from the group consisting of boron trifluoride etherate, lithium tetrafluoroborate, and stannic chloride.
  • the solvent is selected from the group consisting of nitriles and halogenated hydrocarbons.
  • nitrile is acetonitrile.
  • halogenated hydrocarbons include dichloroethane, dichloromethane, chloroform, and carbon tetrachloride.
  • the deprotection of the compound of Formula II is carried out for about 2 hours to about 8 hours, for example, for about 4 hours to about 5 hours.
  • the deprotection of the compound of Formula II is carried out at a temperature of about 10°C to about 50°C, for example, about 25°C to about 40°C.
  • the compound of Formula III may be isolated or the reaction mixture containing the compound of Formula III may be used as such for the next step.
  • the compound of Formula III may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula III may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, and agitated thin film drying.
  • the solvent is selected from the group consisting of ethers, ketones, nitriles and mixtures thereof.
  • ethers include tetrahydrofuran, diisopropylether, 1,4- dioxane, and methyl fert-butyl ether.
  • ketones include acetone, methyl vinyl ketone, methyl isobutyl ketone, and methylethyl ketone.
  • An example of a nitrile is acetonitrile.
  • the treatment of the compound of Formula III with (+)-2,3-dibenzoyl-D-tartaric acid to give the compound of Formula IV is carried out for about 15 minutes to about 5 hours, for example, for about 30 minutes to about 2 hours.
  • the treatment of the compound of Formula III with (+)-2,3-dibenzoyl-D-tartaric acid to give the compound of Formula IV is carried out at a temperature of about 20°C to about 75°C, for example, about 25°C to about 70°C.
  • the compound of Formula IV may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization.
  • the compound of Formula IV may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, and agitated thin film drying.
  • the compound of Formula IV is treated with a base in a solvent to give ruxolitinib of Formula V.
  • the base is an inorganic or an organic base.
  • inorganic bases include sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • organic bases include triethylamine, pyridine, N,N-diisopropylethylamine, and 1,8- diazabicylo [5.4.0]undec-7-ene .
  • the solvent is selected from the group consisting of water, esters, halogenated hydrocarbons, ketones, and mixtures thereof.
  • esters include ethyl acetate, methyl acetate, propyl acetate, and butyl acetate.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • ketones include acetone, methyl vinyl ketone, methyl isobutyl ketone, butanone, 2- pentanone, and 3-pentanone.
  • the treatment of the compound of Formula IV with the base is carried out for about 5 minutes to about one hour.
  • the treatment of the compound of Formula IV with the base is carried out at a temperature of about 15°C to about 35°C, for example, about 20°C to about 25°C.
  • Ruxolitinib of Formula V may be isolated or the reaction mixture containing ruxolitinib of Formula V may be used as such for the next step.
  • Ruxolitinib of Formula V may be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, or recrystallization. Ruxolitinib of Formula V may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, and agitated thin film drying.
  • ruxolitinib of Formula V may be converted into ruxolitinib phosphate of
  • IR was recorded using a Perkin Elmer ® Spectrum One FTIR Spectrometer.
  • Step a Preparation of (2 ,3S)-2,3-bis(benzoyloxy)succinic acid-(3i?)-3-cyclopentyl-3- [4-(7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-i/]-pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile
  • Step b Preparation of (3i?)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxymethyl]- 7H-pyrrolo[2,3-i/
  • Step c Preparation of (i?)-3-(4-(7H-pyrrolo[2,3- ⁇ pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- cyclopentylpropanenitrile (Formula V)
  • Step a Preparation of 4-chloro-7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3- i/
  • Step b Preparation of 4-(lH-pyrazol-4-yl)-7- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -7H- pyr rolo [2,3-i/j pyrimidine
  • Tetrakis-triphenyl phosphine palladium (0) 15 g was added to the reaction mixture under nitrogen atmosphere and the temperature of the reaction mixture was raised to 50°C to 60°C. Nitrogen purging was stopped and the reaction mixture was refluxed at 78°C to 80°C for 14 hours to 15 hours. The reaction mixture was cooled to room temperature and DI water (3700 mL) was added slowly at 25 °C to 30°C. The reaction mixture was stirred for 1 hour and the solid obtained was filtered and dried in an air oven at 55°C to 60°C. Methyl fert-butyl ether (370 mL) was added to the dried solid (230 g) and the mixture was stirred at 25 °C to 30°C for 30 minutes. The solid obtained was filtered, washed with methyl fert-butyl ether (2 ⁇ 92.5 mL), and then dried under vacuum at 40°C to 45°C for 10 hours to 12 hours to obtain title compound.
  • Step c Preparation of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxym ethyl] -7H- pyrrolo[2,3-i/
  • 3-Cyclopentylacrylonitrile (76.06 g) (prepared as per the procedure disclosed in U.S. Patent No. 7,598,257) was added to a mixture of 4-(lH-pyrazol-4-yl)-7- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -7H-pyrrolo[2,3-£/]pyrimidine (165 g, as prepared in Step b) in dimethylsulfoxide (825 mL). Powdered potassium carbonate (16.58 g) was added to the reaction mixture and the temperature of the reaction mixture was raised to 43 °C to 45 °C. The reaction mixture was stirred for 24 hours.
  • the reaction mixture was cooled to 20°C to 25°C and DI water (3300 mL) was added to the reaction mixture at 10°C to 25°C.
  • the aqueous layer was extracted with ethyl acetate (825 mL) and the organic layer was collected.
  • the aqueous layer was again extracted with ethyl acetate (825 mL) and the organic layer was collected.
  • the combined organic layers were washed with DI water (825 mL) and concentrated under reduced pressure at 45°C to 50°C to obtain title compound, which was used as such for next step.
  • the reaction mixture was again heated to 68°C to 70°C and the reaction mixture was stirred for 30 minutes.
  • the reaction mixture was cooled to 25 °C gradually, and then stirred for 1 hour to 2 hours at 20°C to 25°C to obtain a solid.
  • the solid was filtered and washed with acetonitrile (100 mL).
  • the wet solid thus obtained was purified further three times with acetonitrile (3 ⁇ 600 mL) and three times with acetonitrile: acetone :tetrahydrofuran (300 mL

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation de dérivés d'oxazolidinone. La présente invention concerne également un composé de Formule IV, sur des procédés pour sa préparation et son utilisation pour la préparation de ruxolitinib et ruxolitinib phosphate. La présente invention concerne ruxolitinib phosphate ayant une pureté chirale 99,96 % et le composé de Formule IV chiral ayant une pureté de 99,95 %
PCT/IB2015/056642 2014-09-01 2015-09-01 Procédés de préparation d'énamines Ceased WO2016035014A1 (fr)

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IN2477/DEL/2014 2014-09-01

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3892279A1 (fr) 2020-04-09 2021-10-13 Children's Hospital Medical Center Compositions destinées au traitement de l'infection par le coronavirus 2 du syndrome respiratoire aigu sévère (sras-cov-2)
EP3892280A2 (fr) 2020-04-09 2021-10-13 Children's Hospital Medical Center Biomarqueurs d'une infection sars-cov-2 et leurs utilisations
CN113820414A (zh) * 2021-09-17 2021-12-21 重庆华邦胜凯制药有限公司 分离测定磷酸芦可替尼中间体z1及杂质含量的方法
CN113820413A (zh) * 2021-09-17 2021-12-21 重庆华邦胜凯制药有限公司 高效液相色谱法分离测定磷酸芦可替尼及杂质的方法
US11275091B2 (en) 2020-04-09 2022-03-15 Children's Hospital Medical Center SARS-COV-2 infection biomarkers and uses thereof
WO2023223253A1 (fr) * 2022-05-19 2023-11-23 Glenmark Life Sciences Limited Procédé de préparation de ruxolitinib
US11897889B2 (en) 2020-08-18 2024-02-13 Incyte Corporation Process and intermediates for preparing a JAK1 inhibitor
US11905292B2 (en) 2020-08-18 2024-02-20 Incyte Corporation Process and intermediates for preparing a JAK inhibitor
CN118047782A (zh) * 2024-02-06 2024-05-17 南京道尔医药研究院有限公司 制备芦可替尼中间体的方法
CN118255768A (zh) * 2022-12-26 2024-06-28 上海科胜药物研发有限公司 一种jak抑制剂及其中间体的制备方法
US12071439B2 (en) 2021-07-12 2024-08-27 Incyte Corporation Process and intermediates for preparing a JAK inhibitor
WO2024184926A1 (fr) * 2023-03-08 2024-09-12 Aarti Pharmalabs Limited Procédé de préparation de ruxolitinib chiral et de sels de celui-ci

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US20080312259A1 (en) * 2007-06-13 2008-12-18 Incyte Corporation SALTS OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE
US20120214825A1 (en) * 2011-02-18 2012-08-23 Vannucchi Alessandro M mTOR/JAK INHIBITOR COMBINATION THERAPY
US20130253190A1 (en) * 2009-01-15 2013-09-26 Incyte Corporation Processes for preparing jak inhibitors and related intermediate compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080312259A1 (en) * 2007-06-13 2008-12-18 Incyte Corporation SALTS OF THE JANUS KINASE INHIBITOR (R)-3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-3-CYCLOPENTYLPROPANENITRILE
US20130253190A1 (en) * 2009-01-15 2013-09-26 Incyte Corporation Processes for preparing jak inhibitors and related intermediate compounds
US20120214825A1 (en) * 2011-02-18 2012-08-23 Vannucchi Alessandro M mTOR/JAK INHIBITOR COMBINATION THERAPY

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3892280A2 (fr) 2020-04-09 2021-10-13 Children's Hospital Medical Center Biomarqueurs d'une infection sars-cov-2 et leurs utilisations
US11275091B2 (en) 2020-04-09 2022-03-15 Children's Hospital Medical Center SARS-COV-2 infection biomarkers and uses thereof
US11324750B2 (en) 2020-04-09 2022-05-10 Children's Hospital Medical Center Compositions and methods for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
EP3892279A1 (fr) 2020-04-09 2021-10-13 Children's Hospital Medical Center Compositions destinées au traitement de l'infection par le coronavirus 2 du syndrome respiratoire aigu sévère (sras-cov-2)
US11897889B2 (en) 2020-08-18 2024-02-13 Incyte Corporation Process and intermediates for preparing a JAK1 inhibitor
US12428426B2 (en) 2020-08-18 2025-09-30 Incyte Corporation Process and intermediates for preparing a JAK1 inhibitor
US12479851B2 (en) 2020-08-18 2025-11-25 Incyte Corporation Process and intermediates for preparing a JAK inhibitor
US11905292B2 (en) 2020-08-18 2024-02-20 Incyte Corporation Process and intermediates for preparing a JAK inhibitor
US12071439B2 (en) 2021-07-12 2024-08-27 Incyte Corporation Process and intermediates for preparing a JAK inhibitor
CN113820413A (zh) * 2021-09-17 2021-12-21 重庆华邦胜凯制药有限公司 高效液相色谱法分离测定磷酸芦可替尼及杂质的方法
CN113820414B (zh) * 2021-09-17 2023-04-07 重庆华邦胜凯制药有限公司 分离测定磷酸芦可替尼中间体z1及杂质含量的方法
CN113820413B (zh) * 2021-09-17 2023-04-07 重庆华邦胜凯制药有限公司 高效液相色谱法分离测定磷酸芦可替尼及杂质的方法
CN113820414A (zh) * 2021-09-17 2021-12-21 重庆华邦胜凯制药有限公司 分离测定磷酸芦可替尼中间体z1及杂质含量的方法
WO2023223253A1 (fr) * 2022-05-19 2023-11-23 Glenmark Life Sciences Limited Procédé de préparation de ruxolitinib
CN118255768A (zh) * 2022-12-26 2024-06-28 上海科胜药物研发有限公司 一种jak抑制剂及其中间体的制备方法
WO2024184926A1 (fr) * 2023-03-08 2024-09-12 Aarti Pharmalabs Limited Procédé de préparation de ruxolitinib chiral et de sels de celui-ci
CN118047782A (zh) * 2024-02-06 2024-05-17 南京道尔医药研究院有限公司 制备芦可替尼中间体的方法

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