WO2015074464A1 - 伊鲁替尼的制备方法 - Google Patents

伊鲁替尼的制备方法 Download PDF

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WO2015074464A1
WO2015074464A1 PCT/CN2014/088178 CN2014088178W WO2015074464A1 WO 2015074464 A1 WO2015074464 A1 WO 2015074464A1 CN 2014088178 W CN2014088178 W CN 2014088178W WO 2015074464 A1 WO2015074464 A1 WO 2015074464A1
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ibrutinib
phenoxyphenyl
propen
iii
preparation
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PCT/CN2014/088178
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许学农
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苏州明锐医药科技有限公司
哲人药业南京有限公司
许学农
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Publication of WO2015074464A1 publication Critical patent/WO2015074464A1/zh
Priority to US15/159,600 priority Critical patent/US9598425B2/en

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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

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  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of ibrutinib.
  • Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor developed by Johnson & Johnson and Pharmacyclics Inc.. Because the compound does not have a standard Chinese translation, the applicant is This transliterated it as "Ibrutini". In February 2013, the drug was awarded the “Breakthrough Therapy” by the US Food and Drug Administration (FDA) and was approved for marketing on November 13, 2013. It is a single treatment for mantle cell lymphoma. A patient with a set of cell lymphoma who has previously been treated with other means, under the trade name Imbruvca. Ibrutinib is the first marketed drug to target Bruton's tyrosine kinase inhibitor.
  • BTK Bruton's tyrosine kinase
  • Ibrutinib 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D] Pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, the structural formula of which is:
  • the object of the present invention is to provide a preparation method of Ibrutinib which is easy to obtain raw materials, simple in process, economical and economical, and suitable for industrialization, in view of the defects in the prior art.
  • the present invention adopts the following main technical solutions: a preparation method of Ibrutinib (I),
  • the preparation step comprises the following steps: using 4-phenoxybenzoyl chloride (II) as a raw material, condensing with malononitrile and dimethyl sulfate, and oxidizing to form an intermediate 4-phenoxyphenyl (methoxy).
  • the molar ratio of 4-phenoxybenzoyl chloride (II), malononitrile and dimethyl sulfate in the condensation and methoxylation is from 1:1-2:2-4, preferably from 1:1 to 1.2: 3-4.
  • the pyrazole cyclization reaction temperature is from 50 to 120 ° C, preferably from 80 to 90 ° C.
  • the pyrazole cyclization solvent is xylene, toluene, tetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, dioxane, N,N-dimethylformyl or dimethyl sulfoxide, preferably ethanol. Or toluene.
  • the molar ratio of 1-(3R-mercapto-1-piperidinyl)-2-propen-1-one (IV) to the cyclizing agent in the pyrimidine cyclization reaction is 1:1-2, preferably 1: 1.5.
  • the cyclizing agent for the pyrimidine cyclization reaction is trimethyl orthoformate, triethyl orthoformate, formic acid, formamide, s-triazine, N,N-dimethylformamide, N,N-diethyl A Amide or N,N-dimethylformamide dimethyl acetal, preferably formamide or N,N-dimethylformamide dimethyl acetal.
  • the temperature of the pyrimidine cyclization reaction is from 50 to 150 ° C, preferably from 100 to 110 ° C.
  • the preparation method of Ibrutinib (I) according to the present invention has the characteristics of easy availability of raw materials, simple process and environmental protection economy, thereby facilitating the industrial production of the raw material drug and promoting its economic technology. development of.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3

Abstract

提供一种伊鲁替尼（Ibrutinib，I）的制备方法，其制备步骤包括：以4-苯氧基苯甲酰氯（II）为原料，与丙二腈和硫酸二甲酯发生缩合和甲氧化反应生成4-苯氧基苯基（甲氧基）亚乙烯基二氰甲烷（III），该中间体（III）与1-（3R-肼基-1-哌啶基）-2-丙烯-1-酮（IV）发生吡唑环化反应得1-[（3R）-[3-（4-苯氧基苯基）-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮（V），该中间体（V）与环合剂发生嘧啶环化反应制得伊鲁替尼（I）。该制备方法原料易得，工艺简洁，经济环保，适合工业化生产。

Description

伊鲁替尼的制备方法 技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种伊鲁替尼的制备方法。
背景技术
Ibrutinib是美国强生公司(Johnson&Johnson)与美国制药循环公司(Pharmacyclics Inc.)共同研发的布鲁顿酪氨酸激酶(BTK)抑制剂，因该化合物还不具有标准的中文译名，故本申请人在此将其音译为“伊鲁替尼”。2013年2月该药获得美国食品药品管理局(FDA)的“突破性疗法”(Breakthrough Therapy)资格，并与2013年11月13日获得上市批准，作为套细胞淋巴癌的单个治疗药物，适用于之前用其他手段治疗过的套细胞淋巴癌患者，商标名为Imbruvca(英布克)。伊鲁替尼是首个上市的靶向布鲁顿酪氨酸激酶抑制剂药物。
伊鲁替尼(Ibrutinib)的化学名为：1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3，4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮，其结构式为：
Figure PCTCN2014088178-appb-000001
有关伊鲁替尼的制备方法已有研究报道，美国专利第US20080108636号、第US2008058528号、第US2009050897号、第US2010254905号和第US2011039190号报道了伊鲁替尼及其类似物的合成方法。该方法以4-苯氧基苯甲酸为原料，经过酰化、缩合、甲氧基化、吡唑环化、嘧啶环化、N-烷基化、脱保护和烯丙酰化等反应，使官能团不断累加，最 终制得目标产物。但该路线步骤多，需要使用多种非常规的原料和试剂，特别是三甲基硅重氮甲烷和高分子负载的三苯基膦等具有潜在的危险性和环境污染性，因而不利于工业化。
Figure PCTCN2014088178-appb-000002
世界专利申请第WO2013003629号及中国专利第CN103121999号则报道了另一种改进的伊鲁替尼的制备方法，其都以1H-吡唑并[3，4-d]嘧啶-4-胺为原料，分别通碘代或溴代制备3-碘-1H-吡唑并[3，4-d]嘧啶-4-胺或3-溴-1H-吡唑并[3，4-d]嘧啶-4-胺。所得的卤代物再依次经Suzuki偶联反应、Mitsunobu耦合反应、脱保护及酰胺化反应得到目标产物。与原研反应相比，该合成方法步骤有所减少，总收率有所提高。但由于没有涉及母环1H-吡唑并[3，4-d]嘧啶-4-胺的制备，且制备过程要使用卤代、Suzuki偶联、Mitsunobu耦合等反应，使得制造成本及反应条件均不理想。
Figure PCTCN2014088178-appb-000003
发明内容
本发明的目的在于针对现有技术中的缺陷，提供一种具有原料易得、工艺简洁、环保经济且适合工业化的伊鲁替尼的制备方法。
为实现上述发明目的，本发明采用了如下主要技术方案：一种伊鲁替尼(I)的制备方法，
Figure PCTCN2014088178-appb-000004
其制备步骤包括：以4-苯氧基苯甲酰氯(II)为原料，与丙二腈和硫酸二甲酯发生缩合及甲氧化反应生成中间体4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)，所述中间体4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)与1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)发生吡唑环化反应得到中间体1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)，中间体1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)与环化剂发生嘧啶环化反应制得伊鲁替尼(I)。
Figure PCTCN2014088178-appb-000005
此外，本发明还提出如下附属技术方案：
所述缩合及甲氧化反应中4-苯氧基苯甲酰氯(II)、丙二腈和硫酸二甲酯的投料摩尔比为1∶1-2∶2-4，优选1∶1-1.2∶3-4。
所述吡唑环化反应中4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)与1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)的投料摩尔比为1∶0.5-1.5，优选1∶1。
所述吡唑环化反应温度为50-120℃，优选80-90℃。
所述吡唑环化反应溶剂为二甲苯、甲苯、四氢呋喃、甲醇、乙醇、异丙醇、正丁醇、二氧六环、N，N-二甲基甲酰或二甲亚砜，优选乙醇或甲苯。
所述嘧啶环化反应中1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)与环化剂的投料摩尔比为1∶1-2，优选1∶1.5。
所述嘧啶环化反应的环化剂为原甲酸三甲酯、原甲酸三乙酯、甲酸、甲酰胺、均三嗪、N，N-二甲基甲酰胺、N，N-二乙基甲酰胺或N，N-二甲基甲酰胺二甲基缩醛，优选甲酰胺或N，N-二甲基甲酰胺二甲基缩醛。
所述嘧啶环化反应的温度为50-150℃，优选100-110℃。
相比于现有技术，本发明所涉及的伊鲁替尼(I)的制备方法，具有原料易得、工艺简洁和环保经济等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。
实施例一：
于三颈反应瓶中加入丙二腈(6.6g，0.1mol)、氢化钠(4.8g，0.2mol，80％分散在石蜡中)和新处理过的无水四氢呋喃100mL，搅拌下滴加4-苯氧基苯甲酰氯(II)(23.2g，0.1mol)的50mL四氢呋喃溶液。保持室温反应2小时后，加入1M的稀盐酸250mL，搅拌反应30分钟后，用乙酸乙酯萃取3次。合并有机相，无水硫酸镁干燥，浓缩所得固体用二氧六环150mL和饱和碳酸氢钠溶液50mL溶解。加入硫酸二甲酯(37.8g，0.3mol)，升温至80-90℃，搅拌反应3小时， TLC检测反应。加入去离子水400mL，用甲基叔丁基醚萃取3次，合并有机相，无水硫酸钠干燥。减压回收溶剂，所得粗品用甲醇重结晶得白色固体4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)17.6g，收率63.8％。
实施例二：
于三口反应瓶中依次加入4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)(13.8g，50mmol)、1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)(8.5g，50mmol)和乙醇200mL，搅拌下滴加三乙胺(5g，50mmol)。升温至回流，搅拌反应5小时，TLC检测反应。减压浓缩，残留物加入去离子水，室温搅拌结晶。过滤，所得固体乙醇和水(1∶1)重结晶，得到类白色固体1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)16.6g，收率80.4％。
实施例三：
于三口反应瓶中加入1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)(4.13g，10mmol)、N，N-二甲基甲酰胺二甲基缩醛(1.19g，15mmol)和甲苯50mL，搅拌下加入乙酸3mL，升温至105-110℃，用油水分离器分出产生的甲醇，保温反应3小时，TLC检测反应。减压浓缩除去甲苯，残余物中加入30％的浓氨水，有固体析出。搅拌下升温至体系回流，3小时后TLC检测反应。降至室温，有固体析出，缓慢搅拌结晶12小时。过滤，粗品用乙醇重结晶得伊鲁替尼(I)3.2g，收率为72.7％。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (8)

  1. 一种伊鲁替尼(I)的制备方法，
    Figure PCTCN2014088178-appb-100001
    其制备步骤包括：以4-苯氧基苯甲酰氯(II)为原料，与丙二腈和硫酸二甲酯发生缩合及甲氧化反应生成中间体4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)，所述中间体4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)与1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)发生吡唑环化反应得到中间体1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)，所述中间体1-[(3R)-[3-(4-苯氧基苯基)-4-腈基-5-氨基-1H-吡唑基]-1-哌啶基]-2-丙烯-1-酮(V)与环合剂发生嘧啶环化反应制得伊鲁替尼(I)。
  2. 如权利要求1所述伊鲁替尼(I)的制备方法，其特征在于：所述4-苯氧基苯甲酰氯(II)、丙二腈和硫酸二甲酯的投料摩尔比为1∶1-2∶2-4。
  3. 如权利要求1所述伊鲁替尼(I)的制备方法，其特征在于：所述4-苯氧基苯基(甲氧基)亚乙烯基二氰甲烷(III)和1-(3R-肼基-1-哌啶基)-2-丙烯-1-酮(IV)的投料摩尔比为1∶0.5-1.5。
  4. 如权利要求3所述伊鲁替尼(I)的制备方法，其特征在于：所述吡唑环化反应的温度50-120℃。
  5. 如权利要求3所述伊鲁替尼(I)的制备方法，其特征在于：所述吡唑环化反应的溶剂为二甲苯、甲苯、四氢呋喃、甲醇、乙醇、异丙醇、正丁醇、二氧六环、N，N-二甲基甲酰或二甲亚砜。
  6. 如权利要求1所述伊鲁替尼(I)的制备方法，其特征在于：所述嘧啶环化反应的中1-(3R- 肼基-1-哌啶基)-2-丙烯-1-酮(IV)与环化剂的投料摩尔比为1∶2。
  7. 如权利要求6所述伊鲁替尼(I)的制备方法，其特征在于：所述嘧啶环化反应的环化剂为原甲酸三甲酯、原甲酸三乙酯、甲酸、甲酰胺、均三嗪、N，N-二甲基甲酰胺、N，N-二乙基甲酰胺或N，N-二甲基甲酰胺二甲基缩醛。
  8. 如权利要求6所述伊鲁替尼(I)的制备方法，其特征在于：所述嘧啶环化反应温度为50-150℃。
PCT/CN2014/088178 2013-11-20 2014-10-09 伊鲁替尼的制备方法 WO2015074464A1 (zh)

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WO2017163257A1 (en) * 2016-03-21 2017-09-28 Ind-Swift Laboratories Limited Process for preparing pure lh-pyrazolo[3,4-d] pyrimidine derivative

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CN106008515A (zh) * 2014-01-29 2016-10-12 苏州晶云药物科技有限公司 依鲁替尼的新晶型及其制备方法
CN105085529A (zh) * 2014-05-15 2015-11-25 广东东阳光药业有限公司 依鲁替尼新晶型及其制备方法
CN105294571B (zh) * 2014-07-03 2019-04-23 浙江九洲药业股份有限公司 一种依鲁替尼中间体及其制备方法和用途
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CN105859721B (zh) * 2015-01-22 2018-04-17 浙江京新药业股份有限公司 一种伊布鲁替尼的制备方法
CN104557945B (zh) * 2015-01-27 2017-08-04 安润医药科技（苏州）有限公司 依鲁替尼合成方法
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