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WO2024007890A1 - Procédé de préparation d'un intermédiaire de ruxolitinib - Google Patents

Procédé de préparation d'un intermédiaire de ruxolitinib Download PDF

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Publication number
WO2024007890A1
WO2024007890A1 PCT/CN2023/102660 CN2023102660W WO2024007890A1 WO 2024007890 A1 WO2024007890 A1 WO 2024007890A1 CN 2023102660 W CN2023102660 W CN 2023102660W WO 2024007890 A1 WO2024007890 A1 WO 2024007890A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
reaction
pyrazole
cyano
cyclopentylvinyl
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/CN2023/102660
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English (en)
Chinese (zh)
Inventor
李明丽
肖川
师艳秋
杜昕昕
王晓强
常彦红
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.)
Shandong Inomic Institute Of Pharmaceutical Research Co Ltd
Jining University
Original Assignee
Shandong Inomic Institute Of Pharmaceutical Research Co Ltd
Jining University
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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Publication date
Application filed by Shandong Inomic Institute Of Pharmaceutical Research Co Ltd, Jining University filed Critical Shandong Inomic Institute Of Pharmaceutical Research Co Ltd
Priority to GB2406897.5A priority Critical patent/GB2626517A/en
Publication of WO2024007890A1 publication Critical patent/WO2024007890A1/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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the technical field of synthesis of raw materials, and in particular to a preparation method of ruxolitinib intermediate.
  • Ruxolitinib is a new JAK inhibitor, compound 3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl )-3-Cyclopentylacrylonitrile is an important intermediate for the preparation of ruxolitinib, and its structure is shown in Formula I:
  • the purpose of the present invention is to provide a preparation method for ruxolitinib intermediates and provide a reference for the industrialization of ruxolitinib raw materials.
  • the invention provides a preparation method of ruxolitinib intermediate, which includes the following steps:
  • the ruxolitinib intermediate has the structure shown in Formula I:
  • the solvent for the cyclization reaction includes absolute ethanol, methanol or isopropyl alcohol.
  • the temperature of the ring-forming reaction is 70-75°C and the time is 6-8 hours.
  • the molar ratio of 3-cyclopentyl-3-hydrazinopropionitrile and ethyl 2-formyl-3-oxopropionate is 1:1.
  • the temperature of the condensation reaction is 45-50°C and the time is 16-24 hours.
  • the usage ratio of the ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate, potassium tert-butoxide and acetonitrile is 0.23mol:0.46mol: 500mL.
  • the alkaline conditions are provided by potassium carbonate.
  • the usage ratio of 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile, potassium carbonate and the solvent for the substitution reaction is 0.157 mol :0.236mol:200mL.
  • the solvent for the substitution reaction is a polar aprotic solvent.
  • the polar aprotic solvent includes N,N-dimethylformamide and/or N-methylpyrrolidone.
  • the molar ratio of 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile and bromoethane dimethyl ether is 0.157: 0.188.
  • the temperature of the substitution reaction is 70-80°C and the time is 4-8 hours.
  • the pyrimidine ring-forming reaction uses tert-butanol as the reaction solvent and potassium tert-butoxide as the base.
  • the dosage ratio of potassium tert-butoxide is 0.13mol:250mL:0.32mol.
  • the temperature of the pyrimidine ring-forming reaction is 60-70°C and the time is 10-18 hours.
  • the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and formamidine acetate are The molar ratio is 0.13:0.16.
  • the invention provides a preparation method of ruxolitinib intermediate, which includes the following steps: mixing 3-cyclopentyl-3-hydrazinopropionitrile and ethyl 2-formyl-3-oxopropionate. Ring-forming reaction obtains 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylic acid ethyl ester; the 1-(2-cyano-1-cyclopentyl Vinyl)-1H-pyrazole-4-carboxylic acid ethyl ester, potassium tert-butoxide and acetonitrile are mixed for condensation reaction to obtain 3-(4-(2-cyanoacetyl)-1H-pyrazole-1-yl )-3-cyclopentylacrylonitrile; the 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile is mixed with The substitution reaction of bromoethane dimethyl ether gives 2-(
  • the present invention has the following beneficial effects:
  • a new synthesis strategy is provided, which avoids the use of expensive palladium catalysts, reduces production costs, and avoids the risk of heavy metal residues; at the same time, it avoids process risks caused by inert gas protection and reduces process difficulty.
  • This method has a simple synthesis process route, mild reaction conditions, few by-products, high product quality and low cost, and is suitable for industrial production.
  • the invention provides a preparation method of ruxolitinib intermediate, which includes the following steps:
  • the ruxolitinib intermediate has the structure shown in Formula I:
  • the raw materials used are all commercially available products in this field.
  • 3-cyclopentyl-3-hydrazinopropionitrile and ethyl 2-formyl-3-oxopropionate are mixed to perform a ring-forming reaction to obtain 1-(2-cyano-1-cyclopentyl Vinyl)-1H-pyrazole-4-carboxylic acid ethyl ester.
  • the solvent for the cyclization reaction includes absolute ethanol, methanol or isopropyl alcohol.
  • the present invention has no special limit on the amount of solvent used in the ring-forming reaction, as long as it can ensure that the reaction raw materials are completely dissolved.
  • the molar ratio of the 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester is preferably 1:1.
  • the temperature of the ring-forming reaction is preferably 70 to 75°C, and the time is preferably 6 to 8 hours.
  • the present invention preferably sequentially cools the obtained liquid to room temperature naturally, stirs for 1 hour, suction filtration and drying the filter cake to obtain the 1-(2-cyano-1-cyclopentylvinyl). )-1H-pyrazole-4-carboxylic acid ethyl ester.
  • the dried filter cake is preferably blast dried at 50°C.
  • the present invention converts the 1-(2-cyano-1-cyclopentylethylene base)-1H-pyrazole-4-carboxylic acid ethyl ester, potassium tert-butoxide and acetonitrile are mixed for condensation reaction to obtain 3-(4-(2-cyanoacetyl)-1H-pyrazole-1-yl) -3-Cyclopentyl acrylonitrile.
  • the acetonitrile serves as both a reaction substrate and a reaction solvent.
  • the dosage ratio of the ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate, potassium tert-butoxide and acetonitrile is preferably 0.23 mol: 0.46mol:500mL.
  • the temperature of the condensation reaction is preferably 45 to 50°C, and the time is preferably 16 to 24 hours.
  • the present invention preferably sequentially naturally cools the obtained liquid to room temperature, stirs for 1 hour, suction filtration and drying the filter cake to obtain the 3-(4-(2-cyanoacetyl)-1H-pyridine.
  • Azol-1-yl)-3-cyclopentylacrylonitrile preferably sequentially naturally cools the obtained liquid to room temperature, stirs for 1 hour, suction filtration and drying the filter cake to obtain the 3-(4-(2-cyanoacetyl)-1H-pyridine.
  • the dried filter cake is preferably blast dried at 50°C.
  • the present invention converts the 3-(4-(2-cyanoacetyl) Base)-1H-pyrazol-1-yl)-3-cyclopentyl acrylonitrile undergoes a substitution reaction with bromoethane dimethyl ether under alkaline conditions to obtain 2-(1-(2-cyano-1 -Cyclopentyvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile.
  • the alkaline conditions are preferably provided by potassium carbonate.
  • the solvent for the substitution reaction is preferably a polar aprotic solvent
  • the polar aprotic solvent preferably includes N,N-dimethylformamide (DMF) and/or N-methylpyrrolidone (NMP). ).
  • the temperature of the substitution reaction is preferably 70 to 80°C, and the time is preferably 4 to 8 hours.
  • the usage ratio of the 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile, potassium carbonate and the solvent of the substitution reaction is preferred It is 0.157mol:0.236mol:200mL.
  • the molar ratio of 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile and bromoethane dimethyl ether is preferably is 0.157:0.188.
  • the present invention preferably sequentially naturally cools the obtained material liquid to room temperature, adds water dropwise, stirs for 2 hours, suction filtration and drying the filter cake to obtain the 2-(1-(2-cyano-1- Cyclopentyvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile.
  • the present invention converts the 2- (1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile reacts with formamidine acetate to form a pyrimidine ring to obtain the Describe ruxolitinib intermediates.
  • the pyrimidine ring-forming reaction preferably uses tert-butanol as the reaction solvent, and potassium tert-butoxide as the preferred base.
  • the temperature of the pyrimidine ring-forming reaction is preferably 60 to 70°C, and the time is preferably 10 to 18 hours.
  • the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and methyl acetate The molar ratio of amidines is preferably 0.13:0.16.
  • the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile, tert-butyl The dosage ratio of alcohol and potassium tert-butoxide is preferably 0.13 mol:250 mL:0.32 mol.
  • the present invention preferably sequentially naturally cools the obtained material liquid to room temperature, stirs for 2 hours, suction filtration and drying the filter cake to obtain the ruxolitinib intermediate.
  • Potassium tert-butoxide (51.9g, 0.46mol) was put into 500mL acetonitrile, stirred at room temperature for 2h, compound 3 (60g, 0.23mol) was added, and the temperature was raised to 45°C for 16h. Cool to room temperature, continue stirring for 1 hour, and filter with suction. The filter cake was air-dried at 50°C to obtain compound 4, 47.1 g, with a yield of 80%.
  • Target compound 3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentypropene Synthesis of nitriles

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

Abstract

La présente invention concerne un procédé de préparation d'un intermédiaire de ruxolitinib, se rapportant au domaine de la synthèse de médicaments en vrac. Dans la présente invention, un composé de 3-cyclopentyl-3-hydrazonopropionitrile et un composé 2-formyl-3-oxopropionate d'éthyle sont utilisés comme matières premières et sont soumis à une réaction de cyclisation, une réaction de condensation, une réaction de substitution et une réaction de formation de cycle pyrimidine pour obtenir un composé cible. La présente invention concerne une nouvelle stratégie de synthèse. Le procédé évite l'utilisation d'un catalyseur au palladium coûteux, réduit le coût de production, et évite le risque de résidus de métaux lourds. De plus, le procédé évite le risque de traitement provoqué par une protection contre les gaz inertes, réduit la difficulté de traitement, et a une voie de traitement de synthèse simple, des conditions de réaction modérées, moins de sous-produits, une qualité de produit élevée et un faible coût, et est approprié pour une production industrielle.
PCT/CN2023/102660 2022-07-05 2023-06-27 Procédé de préparation d'un intermédiaire de ruxolitinib Ceased WO2024007890A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB2406897.5A GB2626517A (en) 2022-07-05 2023-06-27 Method for preparing ruxolitinib intermediate

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CN202210791601.3 2022-07-05
CN202210791601.3A CN115141180B (zh) 2022-07-05 2022-07-05 一种鲁索替尼中间体的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115141180B (zh) * 2022-07-05 2023-06-20 济宁学院 一种鲁索替尼中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107674026A (zh) * 2017-11-03 2018-02-09 厦门海乐景生化有限公司 鲁索替尼中间体（3r)‑3‑(4‑溴‑1h‑吡唑‑1‑基)‑环戊烷基丙腈的制备方法
CN113906032A (zh) * 2019-02-06 2022-01-07 康塞特医药品有限公司 用于制备对映异构体富集的jak抑制剂的方法
WO2022036030A1 (fr) * 2020-08-12 2022-02-17 Concert Pharmaceuticals, Inc. Procédé de préparation d'inhibiteurs de jak enrichis en énantiomères
CN115141180A (zh) * 2022-07-05 2022-10-04 济宁学院 一种鲁索替尼中间体的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107915738B (zh) * 2017-11-14 2019-07-26 海化生命(厦门)科技有限公司 用于合成巴瑞替尼的关键中间体2的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107674026A (zh) * 2017-11-03 2018-02-09 厦门海乐景生化有限公司 鲁索替尼中间体（3r)‑3‑(4‑溴‑1h‑吡唑‑1‑基)‑环戊烷基丙腈的制备方法
CN113906032A (zh) * 2019-02-06 2022-01-07 康塞特医药品有限公司 用于制备对映异构体富集的jak抑制剂的方法
WO2022036030A1 (fr) * 2020-08-12 2022-02-17 Concert Pharmaceuticals, Inc. Procédé de préparation d'inhibiteurs de jak enrichis en énantiomères
CN115141180A (zh) * 2022-07-05 2022-10-04 济宁学院 一种鲁索替尼中间体的制备方法

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CN115141180B (zh) 2023-06-20
GB202406897D0 (en) 2024-06-26
GB2626517A (en) 2024-07-24

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