CN112574205B - 一种托法替布水解杂质的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
Abstract
本发明属于药物合成技术领域,具体涉及一种托法替布水解杂质的制备方法。本发明是将丙二酸环异丙酯溶于有机溶剂中,加入N‑甲基‑N‑((3R,4R)‑4‑甲基哌啶‑3‑基)‑7H‑吡咯并[2,3‑d]嘧啶‑4‑胺室温搅拌至反应结束后,反应液经重结晶制得托法替布水解杂质。本发明提供的合成方法简单,且该方法所得托法替布水解杂质经重结晶析出纯度高,收率高,该杂质化合物可作为托法替布成品检测标准中的杂质对照品。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种托法替布水解杂质的制备方法。
背景技术
枸橼酸托法替布(Tofacitinib citrate),化学名为(3R,4R)-4-甲基-3-(甲基-7H-吡咯[2,3-d] 嘧啶-4-基氨基)-β-羰基-1-哌啶丙腈-2-羟基-1,2,3-丙烷三羧酸盐(1:1)。枸橼酸托法替布是美国辉瑞公司开发的一种新型口服JAK抑制剂,2012年11月经美国FDA批准上市,商品名为Xeljanz,用于对氨甲喋呤治疗应答不充分或不耐受的,中至重度活动性类风湿关节炎的成人患者的治疗,结构式如下所示:
在托法替布的制备过程中,哌啶环上的N-腈乙酰化反应是必不可少的步骤。考虑到实际生产中的效率和成本控制,目前多采用先制得其中间体((3R,4R)-4-甲基-3-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]哌啶)再进行哌啶环上N-腈乙酰化反应的策略。现有托法替布合成工艺的公开报道主要如下:
美国专利US6627754及中国专利申请CN1409712报道了一种以苄基保护的4-甲基-哌啶 -3-酮为起始原料,先经酮的还原氨化反应上甲胺基,然后经N-烷基化、氢解脱苄基、哌啶 N-腈乙酰化后进行拆分得到托法替布方法:
中国专利申请CN1195755C、CN106146517A、CN101233138A及文献(Chem Med Chem,2014:9(11),2516-2527、Tetrahedron Letters,2013:54(37),5096-5098、Journal ofMedicinal Chemistry,2010:53(24),8468-8484)都以腈乙酸为酰化试剂经脱水缩合制得托法替布。
综合上述公开报道可知,托法替布的酰基化过程中遇酸极易形成水解杂质,另外,原料药稳定性研究数据显示,托法替布枸橼酸盐的储存过程中仍可缓慢降解产生杂质3-((3R, 4R)-4-甲基-3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)-3-氧代丙酸,结构如式II所示:
新药研究和开发过程中,药物的质量是衡量药物品质的一个重要标准,药物的质量标准对药物有效成分的纯度和杂质的限度都有较为严格的规定,一般而言,超过0.1%的药物杂质应通过选择性方法来鉴定并定量,对于药物研发人员来说,开发高效的杂质合成路线定向合成工艺中所产生的杂质,以便获得杂质对照品,保证每批原料药质量检测工作的开展(如杂质HPLC定位、杂质含量测定等)也是十分重要的工作。
随着国家对药品一致性研究工作的推进,确定托法替布水解杂质的制备方法,提供合格的对照品,能够对托法替布的质量控制起到积极的作用。目前对于该水解杂质化合物的制备方法只有中国专利申请CN109336892对其进行了报道。该工艺以托法替布为反应物料,在酸性条件下控温使托法替布水解完全后,将反应液中和、萃取、析晶,得到托法替布水解杂质。但该方法操作繁琐,且得到两种水解杂质分离困难,并且收率较低,仅为31.7%。
因此,为托法替布水解杂质探究一种生产成本低,操作简便、收率更高的工艺路线仍然是目前需要解决的问题。
发明内容
本发明的目的是提供一种托法替布水解杂质化合物及其制备方法,该杂质化合物可作为托法替布成品检测标准中的杂质对照品,用于托法替布生产过程中的杂质定性及定量分析的质量控制环节。其制备方法新颖、原料易得、操作简单、样品纯度高。
本发明的具体技术方案如下:
本发明提供一种托法替布水解杂质化合物的制备方法,包括如下步骤:将丙二酸环异丙酯即式SM-2溶于有机溶剂中,加入N-甲基-N-((3R,4R)-4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺即式SM-1室温搅拌至反应结束后,反应液经析晶制得目标产品托法替布水解杂质II。
优选方案,所述的SM-1与SM-2的投料摩尔比为1:1.1~1.6,其中特别优选1:1.2。
优选方案,所述的有机溶剂为乙腈、四氢呋喃、乙醇、1,4-二氧六环,甲苯、DMF中的一种或其组合,其中特别优选乙腈。
优选方案,所述的析晶溶剂为甲基叔丁基醚、***、乙酸乙酯、异丙醚、丙酮、石油醚中的一种或其组合,其中特别优选甲基叔丁基醚。
优选方案,所述的析晶温度为-5~5℃,特别优选0℃。
所述的式II化合物可转化为药学上可接受的盐、溶剂化物。
所述的式II化合物及其盐或溶剂化物在检测托法替布中间体、原料药和/或制剂中的应用。
本发明取得的技术效果是:
1.提供了一种高纯度的托法替布水解杂质,其可作为杂质对照品,用于生产过程中的托法替布的质量控制。
2.提供了一条简便高效的制备托法替布水解杂质化合物II的方法,整个合成方法路线短,操作步骤简单,反应收率高,产品纯度高。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属于本发明要求保护的范围。
以下各实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1
将丙二酸环(亚)异丙酯(17.28g,0.12mol)溶于50ml乙腈中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至0℃,加入20ml甲基叔丁基醚析晶得到托法替布水解杂质,收率87.7%,HPLC 纯度为99.95%。
实施例2
将丙二酸环(亚)异丙酯(17.28g,0.12mol)溶于50mlDMF中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至5℃,加入30ml丙酮析晶得到托法替布水解杂质,收率85.5%,纯HPLC度为 99.92%。
实施例3
将丙二酸环(亚)异丙酯(17.28g,0.12mol)溶于50ml甲苯中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至8℃,加入25ml异丙醚析晶得到托法替布水解杂质,收率84.1%,HPLC纯度为99.81%。
实施例4
将丙二酸环(亚)异丙酯(15.84g,0.11mol)溶于50ml四氢呋喃中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至0℃,加入20ml***析晶得到托法替布水解杂质,收率80.2%,HPLC纯度为 99.82%。
实施例5
将丙二酸环(亚)异丙酯(23.04g,0.16mol)溶于50ml乙腈中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至-5℃,加入20ml乙酸乙酯析晶得到托法替布水解杂质,收率81.4%,HPLC纯度为99.77%。
实施例6
将丙二酸环(亚)异丙酯(14.41g,0.10mol)溶于50ml乙醇中,加入N-甲基-N-((3R,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至0℃,加入30ml石油醚析晶得到托法替布水解杂质,收率73.8%,HPLC纯度为99.58%。
实施例7
将丙二酸环(亚)异丙酯(24.50g,0.17mol)溶于50ml1.4-二氧六环中,加入N-甲基-N- ((3R,4R)-4-甲基哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(24.53g,0.10mol),室温下搅拌至反应结束后反应液降至-8℃,20ml加入甲基叔丁基醚重结晶得到托法替布水解杂质,收率收率72.9%,HPLC纯度为99.45%。
对比实施例
将托法替布3.12g(10mmol)、硫酸(85%,75ml)加入反应瓶中,加热至90℃搅拌反应3~4小时;HPLC确认反应完全,降温至5~10℃,加入二氯甲烷50ml并以氢氧化钠溶液(10%)中和至pH值为8~9;取水相萃取液酸化至pH值为3~4后加入三氯甲烷(50ml×3) 萃取三次;萃取液经干燥、过滤、浓缩后加入甲基叔丁基醚(25ml),缓慢搅拌析出类白色固体即托法替布水解杂质,收率28.9%,HPLC纯度为95.45%。
Claims (1)
1.一种托法替布水解杂质的制备方法,其特征在于,将17.28g丙二酸环(亚)异丙酯溶于50ml乙腈中,加入24.53g N-甲基-N-((3R ,4R) -4-甲基哌啶-3-基)-7H-吡咯并[2 ,3-d]嘧啶-4-胺,室温下搅拌至反应结束后反应液降至0℃,加入20ml甲基叔丁基醚析晶得到托法替布水解杂质,反应路线如下所示:
。
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