WO2024007890A1 - Method for preparing ruxolitinib intermediate - Google Patents

Method for preparing ruxolitinib intermediate Download PDF

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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
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preparation
reaction
pyrazole
cyano
cyclopentylvinyl
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PCT/CN2023/102660
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French (fr)
Chinese (zh)
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李明丽
肖川
师艳秋
杜昕昕
王晓强
常彦红
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济宁学院
山东诺明康药物研究院有限公司
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Priority to GB2406897.5A priority Critical patent/GB2626517A/en
Publication of WO2024007890A1 publication Critical patent/WO2024007890A1/en

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    • 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

Provided in the present invention is a method for preparing a ruxolitinib intermediate, which method belongs to the field of synthesis of bulk drugs. In the present invention, a 3-cyclopentyl-3-hydrazonopropionitrile compound and an ethyl 2-formyl-3-oxopropionate compound are used as raw materials and subjected to a cyclization reaction, a condensation reaction, a substitution reaction and a pyrimidine ring formation reaction to obtain a target compound. The present invention provides a new synthesis strategy. The method avoids the use of an expensive palladium catalyst, reduces the production cost, and avoids the risk of heavy metal residues. In addition, the method avoids the process risk caused by inert gas protection, reduces the difficulty of a process, and has a simple synthesis process route, mild reaction conditions, fewer by-products, high product quality and low cost, and is suitable for industrial production.

Description

一种鲁索替尼中间体的制备方法A kind of preparation method of ruxolitinib intermediate
本申请要求于2022年7月05日提交中国专利局，申请号为CN202210791601.3，发明名称为“一种鲁索替尼中间体的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requests the priority of the Chinese patent application submitted to the China Patent Office on July 5, 2022, with the application number CN202210791601.3 and the invention name "A preparation method of ruxolitinib intermediate", and its entire content is approved by This reference is incorporated into this application.
技术领域Technical field
本发明涉及原料药的合成技术领域，尤其涉及一种鲁索替尼中间体的制备方法。The present invention relates to the technical field of synthesis of raw materials, and in particular to a preparation method of ruxolitinib intermediate.
背景技术Background technique
鲁索替尼为新型JAK抑制剂，化合物3-(4-(6-氨基-5-(2,2-二甲氧基乙基)嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙烯腈是制备鲁索替尼的重要中间体，其结构如式I所示：
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:
康塞特医药品有限公司申请的专利CN202080024598.1公开了包含式I的鲁索替尼完整的合成工艺路线，如下式所示：
The patent CN202080024598.1 applied by Kangset Pharmaceutical Co., Ltd. discloses the complete synthesis process route of ruxolitinib containing formula I, as shown in the following formula:
在上述路路线中，由化合物C-2经氨水取代制备化合物C-3这步反应，两个氯原子活性相当，容易生成两个氯均能被取代的双氨基副产物，影响产品质量和收率。化合物E4制备过程使用了昂贵的三苯基膦钯作为催化剂，不仅反应过程需要惰性气体保护增加了工艺难度，而且钯催化剂的残留容易导致终产品重金属超标，影响产品质量。In the above route, the reaction of preparing compound C-3 by substituting compound C-2 with ammonia water, the two chlorine atoms are equally active, and it is easy to generate a bis-amino by-product in which both chlorines can be substituted, affecting product quality and yield. Rate. The preparation process of compound E4 uses expensive triphenylphosphine palladium as a catalyst. Not only does the reaction process require inert gas protection, which increases the difficulty of the process, but the residue of the palladium catalyst can easily lead to excessive heavy metals in the final product, affecting product quality.
发明内容Contents of the invention
有鉴于此，本发明的目的在于提供一种鲁索替尼中间体的制备方法，为鲁索替尼原料药产业化提供借鉴。In view of this, 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.
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
本发明提供了一种鲁索替尼中间体的制备方法，包括以下步骤：The invention provides a preparation method of ruxolitinib intermediate, which includes the following steps:
将3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯混合进行成环反应，得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯；Mix 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester to perform a ring-forming reaction to obtain 1-(2-cyano-1-cyclopentylvinyl )-1H-pyrazole-4-carboxylic acid ethyl ester;
将所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈混合进行缩合反应，得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈；The ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate, potassium tert-butoxide and acetonitrile were mixed for condensation reaction to obtain 3-(4-( 2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile;
将所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈在碱性条件下与溴乙烷缩二甲醚发生取代反应，得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈； The 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile is substituted with bromoethane dimethyl ether under alkaline conditions , obtaining 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile;
将所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒进行成嘧啶环反应，得到所述鲁索替尼中间体；The 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and formamidine acetate are synthesized into pyrimidine Ring reaction to obtain the ruxolitinib intermediate;
所述鲁索替尼中间体具有式I所示的结构：
The ruxolitinib intermediate has the structure shown in Formula I:
优选地，所述成环反应的溶剂包括无水乙醇、甲醇或异丙醇。Preferably, the solvent for the cyclization reaction includes absolute ethanol, methanol or isopropyl alcohol.
优选地，所述成环反应的温度为70～75℃，时间为6～8h。Preferably, the temperature of the ring-forming reaction is 70-75°C and the time is 6-8 hours.
优选地，所述3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯的摩尔比为1:1。Preferably, the molar ratio of 3-cyclopentyl-3-hydrazinopropionitrile and ethyl 2-formyl-3-oxopropionate is 1:1.
优选地，所述缩合反应的温度为45～50℃，时间为16～24h。Preferably, the temperature of the condensation reaction is 45-50°C and the time is 16-24 hours.
优选地，所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈的用量比为0.23mol:0.46mol:500mL。Preferably, 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.
优选地，所述碱性条件由碳酸钾提供。Preferably, the alkaline conditions are provided by potassium carbonate.
优选地，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈、碳酸钾和取代反应的溶剂的用量比为0.157mol:0.236mol:200mL。Preferably, 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.
优选地，所述取代反应的溶剂为极性非质子溶剂。Preferably, the solvent for the substitution reaction is a polar aprotic solvent.
优选地，所述极性非质子溶剂包括N,N-二甲基甲酰胺和/或N-甲基吡咯烷酮。Preferably, the polar aprotic solvent includes N,N-dimethylformamide and/or N-methylpyrrolidone.
优选地，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈与溴乙烷缩二甲醚的摩尔比为0.157:0.188。Preferably, the molar ratio of 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile and bromoethane dimethyl ether is 0.157: 0.188.
优选地，所述取代反应的温度为70～80℃，时间为4～8h。Preferably, the temperature of the substitution reaction is 70-80°C and the time is 4-8 hours.
优选地，所述成嘧啶环反应以叔丁醇为反应溶剂，以叔丁醇钾为碱。Preferably, the pyrimidine ring-forming reaction uses tert-butanol as the reaction solvent and potassium tert-butoxide as the base.
优选地，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈、叔丁醇与叔丁醇钾的用量比为0.13mol:250mL:0.32mol。 Preferably, the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile, tert-butanol and The dosage ratio of potassium tert-butoxide is 0.13mol:250mL:0.32mol.
优选地，所述成嘧啶环反应的温度为60～70℃，时间为10～18h。Preferably, the temperature of the pyrimidine ring-forming reaction is 60-70°C and the time is 10-18 hours.
优选地，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒的摩尔比为0.13:0.16。Preferably, 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.
本发明提供了一种鲁索替尼中间体的制备方法，包括以下步骤：将3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯混合进行成环反应，得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯；将所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈混合进行缩合反应，得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈；将所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈在碱性条件下与溴乙烷缩二甲醚发生取代反应，得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈；将所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒进行成嘧啶环反应，得到所述鲁索替尼中间体。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-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxy Butyronitrile; combine the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and formamidine acetate The pyrimidine ring-forming reaction is carried out to obtain the ruxolitinib intermediate.
本发明与现有技术相比，具有如下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
提供了一种新的合成策略，该方法避免了价格昂贵的钯催化剂的使用，降低了生产成本，规避了重金属残留的风险；同时避免了惰性气体保护带来的工艺风险，降低了工艺难度。该方法合成工艺路线简洁，反应条件温和，副产物少，产品质量高，成本低，适合工业化生产。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.
具体实施方式Detailed ways
本发明提供了一种鲁索替尼中间体鲁索替尼中间体的制备方法，包括以下步骤：The invention provides a preparation method of ruxolitinib intermediate, which includes the following steps:
将3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯混合进行成环反应，得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯；Mix 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester to perform a ring-forming reaction to obtain 1-(2-cyano-1-cyclopentylvinyl )-1H-pyrazole-4-carboxylic acid ethyl ester;
将所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈混合进行缩合反应，得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈；The ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate, potassium tert-butoxide and acetonitrile were mixed for condensation reaction to obtain 3-(4-( 2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile;
将所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈在碱性条件下与溴乙烷缩二甲醚发生取代反应，得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈； The 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile is substituted with bromoethane dimethyl ether under alkaline conditions , obtaining 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile;
将所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒进行成嘧啶环反应，得到所述鲁索替尼中间体；The 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and formamidine acetate are synthesized into pyrimidine Ring reaction to obtain the ruxolitinib intermediate;
所述鲁索替尼中间体具有式I所示的结构：
The ruxolitinib intermediate has the structure shown in Formula I:
在本发明中，若无特殊说明，使用的原料均为本领域市售商品。In the present invention, unless otherwise specified, the raw materials used are all commercially available products in this field.
本发明将3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯混合进行成环反应，得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯。In the present invention, 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.
在本发明中，所述成环反应的溶剂包括无水乙醇、甲醇或异丙醇。本发明对所述成环反应的溶剂的用量没有特殊的限定，能够保证反应原料完全溶解即可。In the present invention, 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.
在本发明中，所述3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯的摩尔比优选为1:1。In the present invention, the molar ratio of the 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester is preferably 1:1.
在本发明中，所述成环反应的温度优选为70～75℃，时间优选为6～8h。In the present invention, the temperature of the ring-forming reaction is preferably 70 to 75°C, and the time is preferably 6 to 8 hours.
所述成环反应完成后，本发明优选将所得料液依次进行自然冷却至室温、搅拌1h、抽滤和干燥滤饼，得到所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯。After the ring-forming reaction is completed, 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.
在本发明中，所述干燥滤饼优选为50℃鼓风干燥。In the present invention, the dried filter cake is preferably blast dried at 50°C.
得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯后，本发明将所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈混合进行缩合反应，得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈。After obtaining ethyl 1-(2-cyano-1-cyclopentylethylene)-1H-pyrazole-4-carboxylate, 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.
在本发明中，所述乙腈既作为反应底物也作为反应溶剂。In the present invention, the acetonitrile serves as both a reaction substrate and a reaction solvent.
在本发明中，所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈的用量比优选为0.23mol:0.46mol:500mL。 In the present invention, 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.
在本发明中，所述缩合反应的温度优选为45～50℃，时间优选为16～24h。In the present invention, the temperature of the condensation reaction is preferably 45 to 50°C, and the time is preferably 16 to 24 hours.
所述缩合反应完成后，本发明优选将所得料液依次自然冷却至室温、搅拌1h、抽滤和干燥滤饼，得到所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈。After the condensation reaction is completed, 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.
在本发明中，所述干燥滤饼优选为50℃鼓风干燥。In the present invention, the dried filter cake is preferably blast dried at 50°C.
得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈后，本发明将所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈在碱性条件下与溴乙烷缩二甲醚发生取代反应，得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈。After obtaining 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile, 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.
在本发明中，所述碱性条件优选由碳酸钾提供。In the present invention, the alkaline conditions are preferably provided by potassium carbonate.
在本发明中，所述取代反应的溶剂优选为极性非质子溶剂，所述极性非质子溶剂优选包括N,N-二甲基甲酰胺(DMF)和/或N-甲基吡咯烷酮(NMP)。In the present invention, the solvent for the substitution reaction is preferably a polar aprotic solvent, and the polar aprotic solvent preferably includes N,N-dimethylformamide (DMF) and/or N-methylpyrrolidone (NMP). ).
在本发明中，所述取代反应的温度优选为70～80℃，时间优选为4～8h。In the present invention, the temperature of the substitution reaction is preferably 70 to 80°C, and the time is preferably 4 to 8 hours.
在本发明中，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈、碳酸钾和取代反应的溶剂的用量比优选为0.157mol:0.236mol:200mL。In the present invention, 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.
在本发明中，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈与溴乙烷缩二甲醚的摩尔比优选为0.157:0.188。In the present invention, 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.
本发明优选向反应溶剂中依次加入3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈、碳酸钾和DMF，搅拌30min，滴加溴乙烷缩二甲醚，滴加完毕，升温至所述取代反应的温度，然后再升温至100℃并搅拌20h。In the present invention, it is preferred to add 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile, potassium carbonate and DMF to the reaction solvent in sequence, stir for 30 minutes, and drop Add bromoethane dimethyl ether, complete the dropwise addition, and raise the temperature to the temperature of the substitution reaction, then raise the temperature to 100°C and stir for 20 hours.
所述取代反应完成后，本发明优选将所得料液依次进行的自然冷却至室温、滴加水搅拌2h、抽滤和干燥滤饼，得到所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈。After the substitution reaction is completed, 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.
得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈后，本发明将所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒进行成嘧啶环反应，得到所述鲁索替尼中间体。After obtaining 2-(1-(2-cyano-1-cyclopentylvinyl)-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.
在本发明中，所述成嘧啶环反应优选以叔丁醇为反应溶剂，以叔丁醇钾为优选碱。 In the present invention, the pyrimidine ring-forming reaction preferably uses tert-butanol as the reaction solvent, and potassium tert-butoxide as the preferred base.
在本发明中，所述成嘧啶环反应的温度优选为60～70℃，时间优选为10～18h。In the present invention, the temperature of the pyrimidine ring-forming reaction is preferably 60 to 70°C, and the time is preferably 10 to 18 hours.
在本发明中，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒的摩尔比优选为0.13:0.16。In the present invention, 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.
在本发明中，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈、叔丁醇与叔丁醇钾的用量比优选为0.13mol:250mL:0.32mol。In the present invention, 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.
所述成嘧啶环反应完成后，本发明优选将所得料液依次进行自然冷却至室温、搅拌2h、抽滤和干燥滤饼，得到所述鲁索替尼中间体。After the pyrimidine ring-forming reaction is completed, 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.
在本发明的具体实施例中，所述鲁索替尼中间体的合成原理如式II所示：
In specific embodiments of the present invention, the synthesis principle of the ruxolitinib intermediate is shown in Formula II:
为了进一步说明本发明，下面结合实例对本发明提供的鲁索替尼中间体的制备方法进行详细地描述，但不能将它们理解为对本发明保护范围的限定。In order to further illustrate the present invention, the preparation method of the ruxolitinib intermediate provided by the present invention is described in detail below with reference to examples, but they should not be understood as limiting the protection scope of the present invention.
实施例1Example 1
化合物3：1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯的合成Compound 3: Synthesis of ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate
将3-环戊基-3-亚肼基丙腈(化合物1，50g，0.33mol)，2-甲酰基-3-氧代丙酸乙酯(化合物2，47.50g，0.33mol)和乙醇250mL依次加入到1L的三口瓶中，油浴加热至70℃，反应6h。冷却至室温，继续搅拌1h，抽滤。滤饼50℃鼓风干燥，得到化合物3，73.5g，收率86％。1HNMR(400MHz,DMSO-d6): δ8.15(s,1H,Ar),7.98(s,1H,Ar),6.23(s,1H,C＝C),4.29(t,2H,CH2),2.19(m,1H),1.38～1.88(m,11H)。Combine 3-cyclopentyl-3-hydrazinopropionitrile (compound 1, 50g, 0.33mol), 2-formyl-3-oxopropionic acid ethyl ester (compound 2, 47.50g, 0.33mol) and ethanol 250mL Add it to a 1L three-necked flask in turn, heat the oil bath to 70°C, and react for 6 hours. 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 3, 73.5 g, with a yield of 86%. 1 HNMR (400MHz, DMSO-d 6 ): δ8.15(s,1H,Ar),7.98(s,1H,Ar),6.23(s,1H,C＝C),4.29(t,2H,CH 2 ),2.19(m,1H),1.38～ 1.88(m,11H).
化合物4：3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈的合成Compound 4: Synthesis of 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile
将叔丁醇钾(51.9g，0.46mol)投入到500mL乙腈中，室温搅拌2h，加入化合物3(60g，0.23mol)，升温至45℃反应16h。冷却至室温，继续搅拌1h，抽滤。滤饼50℃鼓风干燥，得到化合物4，47.1g，收率80％。1HNMR(400MHz,DMSO-d6):δ8.18(s,1H,Ar),8.01(s,1H,Ar),6.25(s,1H,C＝C),3.52(s,2H,CH2),2.17(m,1H),1.35～1.80(m,8H)。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%. 1 HNMR (400MHz, DMSO-d 6 ): δ8.18 (s, 1H, Ar), 8.01 (s, 1H, Ar), 6.25 (s, 1H, C＝C), 3.52 (s, 2H, CH 2 ),2.17(m,1H),1.35～1.80(m,8H).
化合物5：2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈的合成Compound 5: Synthesis of 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile
在室温下向500mL三口瓶中依次加入化合物4(40g,0.157mol)、碳酸钾(32.6g,0.236mol)和DMF 200mL，搅拌30min。滴加溴乙烷缩二甲醚(31.8g,0.188mol)，滴加完毕，升温至70℃，升温的同时搅拌反应4h，之后升温至100℃并继续搅拌20h。冷却至室温，滴加水200mL，继续搅拌2h。抽滤，滤饼50℃鼓风干燥，得到化合物5，47.4g，收率88％。1HNMR(400MHz,DMSO-d6):δ8.14(s,1H,Ar),7.97(s,1H,Ar),6.23(s,1H,C＝C),5.01(m,1H,CH),3.35(s,6H,CH3),3.26(m,1H,CH),2.20(m,3H),1.40～1.85(m,8H)。Add compound 4 (40g, 0.157mol), potassium carbonate (32.6g, 0.236mol) and DMF 200mL in sequence to a 500mL three-necked flask at room temperature, and stir for 30 minutes. Add bromoethane dimethyl ether (31.8g, 0.188mol) dropwise. After the dropwise addition is completed, the temperature is raised to 70°C. The reaction is stirred for 4 hours while the temperature is raised. Then the temperature is raised to 100°C and stirring is continued for 20h. Cool to room temperature, add 200 mL of water dropwise, and continue stirring for 2 h. After suction filtration, the filter cake was air-dried at 50°C to obtain compound 5, 47.4 g, with a yield of 88%. 1 HNMR (400MHz, DMSO-d 6 ): δ8.14(s,1H,Ar),7.97(s,1H,Ar),6.23(s,1H,C＝C),5.01(m,1H,CH) ,3.35(s,6H,CH 3 ),3.26(m,1H,CH),2.20(m,3H),1.40～1.85(m,8H).
目标化合物：3-(4-(6-氨基-5-(2,2-二甲氧基乙基)嘧啶-4-基)-1H-吡唑-1-基)-3-环戊基丙烯腈的合成Target compound: 3-(4-(6-amino-5-(2,2-dimethoxyethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentypropene Synthesis of nitriles
室温下向500mL三口瓶中加入叔丁醇250mL、叔丁醇钾(29.1g，0.32mol)和醋酸甲脒(16.6g，0.16mol)并在室温下搅拌1h，然后再加入化合物5(45g，0.13mol)，之后升温至60℃反应10h。冷却至室温，继续搅拌2h。抽滤，滤饼50℃鼓风干燥，得到终产品，39.7g，收率83％，HPLC纯度99.5％。1HNMR(400MHz,DMSO-d6):δ8.65(s,1H,Ar),8.28，(s,1H,Ar)，8.16(s,1H,Ar),5.72(s,1H,C＝C),4.63(m,1H,CH),3.41(m,1H),3.27(s,6H,CH3),2.94(m,2H),1.47～1.90(m,8H)。 Add 250 mL of tert-butanol, potassium tert-butoxide (29.1g, 0.32mol) and formamidine acetate (16.6g, 0.16mol) to a 500mL three-necked flask at room temperature and stir at room temperature for 1h, then add compound 5 (45g, 0.13 mol), and then the temperature was raised to 60°C for 10 h. Cool to room temperature and continue stirring for 2 hours. After suction filtration, the filter cake was air-dried at 50°C to obtain the final product, 39.7 g, with a yield of 83% and an HPLC purity of 99.5%. 1 HNMR (400MHz, DMSO-d 6 ): δ8.65(s,1H,Ar),8.28, (s,1H,Ar), 8.16(s,1H,Ar),5.72(s,1H,C＝C ), 4.63(m,1H,CH), 3.41(m,1H), 3.27(s,6H,CH 3 ), 2.94(m,2H), 1.47～1.90(m,8H).
以上所述仅是本发明的优选实施方式，并非对本发明作任何形式上的限制。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。 The above descriptions are only preferred embodiments of the present invention and do not limit the present invention in any form. It should be noted that for those of ordinary skill in the art, several improvements and modifications can be made without departing from the principles of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims (16)

  1. 一种鲁索替尼中间体的制备方法，其特征在于，包括以下步骤：A preparation method of ruxolitinib intermediate, characterized by comprising the following steps:
    将3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯混合进行成环反应，得到1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯；Mix 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester to perform a ring-forming reaction to obtain 1-(2-cyano-1-cyclopentylvinyl )-1H-pyrazole-4-carboxylic acid ethyl ester;
    将所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈混合进行缩合反应，得到3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈；The ethyl 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylate, potassium tert-butoxide and acetonitrile were mixed for condensation reaction to obtain 3-(4-( 2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile;
    将所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈在碱性条件下与溴乙烷缩二甲醚发生取代反应，得到2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈；The 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile is substituted with bromoethane dimethyl ether under alkaline conditions , obtaining 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile;
    将所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒进行成嘧啶环反应，得到所述鲁索替尼中间体；The 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4-dimethoxybutyronitrile and formamidine acetate are synthesized into pyrimidine Ring reaction to obtain the ruxolitinib intermediate;
    所述鲁索替尼中间体具有式I所示的结构：
    The ruxolitinib intermediate has the structure shown in formula I:
  2. 根据权利要求1所述的制备方法，其特征在于，所述成环反应的溶剂包括无水乙醇、甲醇或异丙醇。The preparation method according to claim 1, characterized in that the solvent for the cyclization reaction includes absolute ethanol, methanol or isopropyl alcohol.
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述成环反应的温度为70～75℃，时间为6～8h。The preparation method according to claim 1 or 2, characterized in that the temperature of the ring-forming reaction is 70-75°C and the time is 6-8 hours.
  4. 根据权利要求1或2所述的制备方法，其特征在于，所述3-环戊基-3-亚肼基丙腈和2-甲酰基-3-氧代丙酸乙酯的摩尔比为1:1。The preparation method according to claim 1 or 2, characterized in that the molar ratio of the 3-cyclopentyl-3-hydrazinopropionitrile and 2-formyl-3-oxopropionic acid ethyl ester is 1 :1.
  5. 根据权利要求1所述的制备方法，其特征在于，所述缩合反应的温度为45～50℃，时间为16～24h。The preparation method according to claim 1, characterized in that the temperature of the condensation reaction is 45-50°C and the time is 16-24 hours.
  6. 根据权利要求1或5所述的制备方法，其特征在于，所述1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羧酸乙酯、叔丁醇钾和乙腈的用量比为0.23mol:0.46mol:500mL。 The preparation method according to claim 1 or 5, characterized in that the 1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carboxylic acid ethyl ester, tert-butanol The dosage ratio of potassium and acetonitrile is 0.23mol:0.46mol:500mL.
  7. 根据权利要求1所述的制备方法，其特征在于，所述碱性条件由碳酸钾提供。The preparation method according to claim 1, characterized in that the alkaline condition is provided by potassium carbonate.
  8. 根据权利要求7所述的制备方法，其特征在于，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈、碳酸钾和取代反应的溶剂的用量比为0.157mol:0.236mol:200mL。The preparation method according to claim 7, characterized in that the 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile, potassium carbonate The usage ratio of the solvent for the substitution reaction is 0.157mol:0.236mol:200mL.
  9. 根据权利要求1或8所述的制备方法，其特征在于，所述取代反应的溶剂为极性非质子溶剂。The preparation method according to claim 1 or 8, characterized in that the solvent for the substitution reaction is a polar aprotic solvent.
  10. 根据权利要求9所述的制备方法，其特征在于，所述极性非质子溶剂包括N,N-二甲基甲酰胺和/或N-甲基吡咯烷酮。The preparation method according to claim 9, wherein the polar aprotic solvent includes N,N-dimethylformamide and/or N-methylpyrrolidone.
  11. 根据权利要求1所述的制备方法，其特征在于，所述3-(4-(2-氰基乙酰基)-1H-吡唑-1-基)-3-环戊基丙烯腈与溴乙烷缩二甲醚的摩尔比为0.157:0.188。The preparation method according to claim 1, characterized in that the 3-(4-(2-cyanoacetyl)-1H-pyrazol-1-yl)-3-cyclopentylacrylonitrile and ethyl bromide The molar ratio of alkyl dimethyl ether is 0.157:0.188.
  12. 根据权利要求1或11所述的制备方法，其特征在于，所述取代反应的温度为70～80℃，时间为4～8h。The preparation method according to claim 1 or 11, characterized in that the temperature of the substitution reaction is 70-80°C and the time is 4-8 hours.
  13. 根据权利要求1所述的制备方法，其特征在于，所述成嘧啶环反应以叔丁醇为反应溶剂，以叔丁醇钾为碱。The preparation method according to claim 1, characterized in that the pyrimidine ring-forming reaction uses tert-butanol as the reaction solvent and potassium tert-butoxide as the base.
  14. 根据权利要求13所述的制备方法，其特征在于，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈、叔丁醇与叔丁醇钾的用量比为0.13mol:250mL:0.32mol。The preparation method according to claim 13, characterized in that, the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4- The dosage ratio of dimethoxybutyronitrile, tert-butanol and potassium tert-butoxide is 0.13mol:250mL:0.32mol.
  15. 根据权利要求1或13所述的制备方法，其特征在于，所述成嘧啶环反应的温度为60～70℃，时间为10～18h。The preparation method according to claim 1 or 13, characterized in that the temperature of the pyrimidine ring-forming reaction is 60-70°C and the time is 10-18 hours.
  16. 根据权利要求1所述的制备方法，其特征在于，所述2-(1-(2-氰基-1-环戊基乙烯基)-1H-吡唑-4-羰基)-4,4-二甲氧基丁腈与醋酸甲脒的摩尔比为0.13:0.16。 The preparation method according to claim 1, characterized in that, the 2-(1-(2-cyano-1-cyclopentylvinyl)-1H-pyrazole-4-carbonyl)-4,4- The molar ratio of dimethoxybutyronitrile to formamidine acetate is 0.13:0.16.
PCT/CN2023/102660 2022-07-05 2023-06-27 Method for preparing ruxolitinib intermediate WO2024007890A1 (en)

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