CN114605420A - 一条马来酸奥拉替尼的合成方法 - Google Patents
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- 238000001308 synthesis method Methods 0.000 title abstract description 3
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及马来酸奥拉替尼的合成方法。关键步骤为N‑甲基‑1‑((顺式)‑4‑取代‑环己基)甲磺酰胺在碱和溶剂条件下与N‑甲基‑7‑对甲苯磺酰基‑7H‑吡咯并[2,3‑d]嘧啶‑4‑胺发生反应制备得到N‑甲基‑1‑((反式)‑4‑(甲基(7‑对甲苯磺酰基‑7H‑吡咯并[2,3‑d]嘧啶‑4‑基)胺基)环己基)甲磺酰胺。
Description
技术领域
本发明属于合成原料药方法技术领域，具体涉及原料药马来酸奥拉替尼的合成。
背景技术
马来酸奥拉替尼由美国硕腾公司(Zoetis)研发，属于Janus激酶(JAK)抑制剂类药物，通过抑制多种依赖于JAK1、JAK3酶活性的诱发瘙痒、炎症的细胞因子，以及与过敏有关的细胞因子起作用。研究表明，奥拉替尼能快速、有效、安全地控制犬类由过敏性和变应性皮炎引起的瘙痒。该药最早于2013年05月14日获美国食品药品监督管理局批准上市；2019年初，美国硕腾公司生产的马来酸奥拉替尼片经审查，被批准在中国注册，核发《进口兽药注册证书》。
马来酸奥拉替尼(Oclacitinib maleate)化学名为：(反式)-N-甲基-1-(-3-甲基-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)环己基)甲磺酰胺马来酸盐，其化学结构式如下：
迄今为止，已有多条马来酸奥拉替尼的合成路线得以报道：
专利WO2010/020905报道了以(反式)-4-叔丁氧基甲酰胺环己烷甲酸为起始原料，首先采用红铝还原得到(反式)-4-甲氨基-环己基甲醇，再与4-氯-7H-吡咯并[2,3-d]嘧啶在碱的存在下发生缩合反应得到(反式)-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)环己基)甲醇，随后通过对甲苯磺酰基保护、硫代乙酸钾取代、双氧水/甲酸氧化、氯化、甲胺化和脱Ts保护得到奥拉替尼，最后与马来酸成盐得到目标产物马来酸奥拉替尼。专利WO2010/020905还报道了另一种制备方法，在磺化过程中用亚硫酸钠代替双氧水/甲酸氧化，该步骤中间体纯度较低。此外，甲胺化需要甲胺四氢呋喃溶液，原料昂贵，废水中含有四氢呋喃，废水处理困难。成盐后处理时需要减压蒸馏一半体积的正丁醇，车间操作比较麻烦。专利专利WO2010/020905报道的合成路线如下：
专利CN107365312B报道，以N-苄基-N-甲基甲磺酰胺和1,4-环己二酮单乙二醇缩酮为起始原料，经缩合、氯化、消除、加氢还原、水解、还原-胺化、缩合、脱苄基、成盐得到最终产品。该路线第一步缩合需低温反应(＜-30℃)，且用到正丁基锂，工业放大危险性高；第三步加氢还原需高压催化，存在安全隐患。第五步还原-胺化未提及反式和顺式异构体比例，后处理采用甲基叔丁基醚和水混合溶剂萃取得到N-苄基-N-甲基-1-((反式)-4-(甲氨基)环己基)甲磺酰胺。专利CN107365312B报道的合成路线如下：
专利CN108699072B报道了4-溴苄基溴为原料，通过亚硫酸钠取代、甲胺取代、加氢还原、缩合、氯化、甲基化和成盐得到目标产物马来酸奥拉替尼。该路线合成步骤相对较少，Pd/C催化加氢存在顺式产物(30％)和反式产物(70％)，采用乙醇和水混合溶剂45℃浆洗得到反式产物，该路线合成马来酸奥拉替尼的总收率较低。该专利的合成路线如下：
发明内容
本发明的目的在于提供一种制备马来酸奥拉替尼的新方法。
研究发现，N-甲基-1-((顺式)-4-取代-环己基)甲磺酰胺(式I)在碱和溶剂条件下与N-甲基-7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(式II)发生反应制备得到N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III)；N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III)在碱作用下脱除对甲苯磺酰基保护，制备得到N-甲基-1-((反式)-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式IV)；最后，N-甲基-1-((反式)-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式IV)和马来酸成盐，实现马来酸奥拉替尼的制备。反应的合成路线如下：
化合物式I中的R1为对甲苯磺酰基(Ts)，三氟甲磺酰基(Tf)，甲磺酰基(Ms)。
反应第一步使用的碱为碳酸钾，碳酸钠，氢氧化钠，氢氧化钾，叔丁醇钾，甲醇钠。
反应第一步使用的溶剂为四氢呋喃，二氧六环，二甲基亚砜。
反应第二步使用的碱为氢氧化钠，氢氧化钾，氢氧化锂。
反应第二步使用的溶剂为水，四氢呋喃，二氧六环以及这些溶剂的混合物。
利用本发明公开的技术方案制备马来酸奥拉替尼具有收率高，可工业化等优点，具有良好的市场前景。
具体实施方式
通过下面的实施例可以更具体的理解本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例
1、N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III)的合成
在氮气保护下，将N-甲基-1-((顺式)-4-三氟甲磺酰氧基-环己基)甲磺酰胺(式I，R1＝Tf)(61.08g，0.18mol)，碳酸钾(49.75g，0.36mol)以及600mL四氢呋喃加入到2L四口烧瓶中，搅拌30min，加入N-甲基-7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(式II)(57.45g，0.19mol)，升温至50-60℃，搅拌反应12h。取样中控，原料反应完，40℃减压浓缩除去四氢呋喃，加入到1L水中，搅拌1h，过滤，滤饼用100mL水漂洗，滤饼加入到200mL丙酮中，浆洗2h，过滤，所得固体60℃真空干燥6h得到80.79g白色固体，收率91.3％。
2、N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺((式III)的合成
在氮气保护下，将N-甲基-1-((顺式)-4-对甲苯磺酰氧基-环己基)甲磺酰胺(式I，R1＝Ts)(65.06g，0.18mol)，碳酸钠(38.16g，0.36mol)以及500mL二氧六环加入到2L四口烧瓶中，搅拌30min，加入N-甲基-7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(式II)(57.45g，0.19mol)，升温至75-85℃，搅拌反应16h。取样中控，原料反应完，50℃减压浓缩除去二氧六环，加入到1000mL水中，搅拌1h，过滤，滤饼用100mL水漂洗，滤饼加入到250mL丙酮中，浆洗2h，过滤，所得固体50℃真空干燥12h得到79.69g白色固体，收率90.05％。
3、N-甲基-1-((反式)-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式IV)的合成
三口烧瓶中加入N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III)(58.99g，0.12mol)、氢氧化钾(20.20g，0.36mol)、500mL水和500mL四氢呋喃，磁力搅拌30分钟，油浴升温至60-70℃，保温反应6小时。取样中控，原料反应完，冷却至室温，缓慢滴加盐酸，调节pH至3-4，加入碳酸氢钠至无气泡产生，搅拌1h，过滤，滤饼用20mL水漂洗，滤饼中加入300mL乙醇，升温至回流浆洗3-4h，冷却至室温，过滤，所得固体40℃真空干燥4h得到38.14g淡黄色固体，收率94.2％。
4、马来酸奥拉替尼(式V)的合成
三口烧瓶中加入150mL无水乙醇、N-甲基-1-((反式)-4-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式IV)(27.0g，0.08mol)和马来酸(9.29g，0.08mol)，升温至80-85℃，搅拌2-3h，降温至10-20℃，搅拌2h，抽滤，滤饼用20mL无水乙醇漂洗，所得固体50℃真空干燥8h得到34.94g马来酸奥拉替尼，收率96.3％。
Claims (4)
1.制备N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III)的方法，具体为N-甲基-1-((顺式)-4-取代-环己基)甲磺酰胺(式I)在碱和溶剂条件下与N-甲基-7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-胺(式II)发生反应制备得到N-甲基-1-((反式)-4-(甲基(7-对甲苯磺酰基-7H-吡咯并[2,3-d]嘧啶-4-基)胺基)环己基)甲磺酰胺(式III),反应式如下:
2.如权利要求1所示的制备方法，反应使用的碱为碳酸钾，碳酸钠，氢氧化钠，氢氧化钾，叔丁醇钾，甲醇钠。
3.如权利要求1所示的制备方法，反应使用的溶剂为四氢呋喃，二氧六环，二甲基亚砜。
4.如权利要求1所示的制备方法，化合物式I中的R1为对甲苯磺酰基(Ts)，三氟甲磺酰基(Tf)，甲磺酰基(Ms)。
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