CN105859683B - 伊马替尼的高纯度工业制备工艺 - Google Patents

伊马替尼的高纯度工业制备工艺 Download PDF

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CN105859683B
CN105859683B CN201610222481.XA CN201610222481A CN105859683B CN 105859683 B CN105859683 B CN 105859683B CN 201610222481 A CN201610222481 A CN 201610222481A CN 105859683 B CN105859683 B CN 105859683B
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CN105859683A (zh
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张庆捷
陈之峰
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Lianyungang Hengyun Pharmaceutical Co. Ltd.
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    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

本发明涉及伊马替尼的高纯度工业制备工艺。具体涉及一种伊马替尼高纯度合成方法。化合物N‑(5‑氨基‑2‑甲基苯基)‑4‑(3‑吡啶基)‑2‑嘧啶胺与对溴甲基苯甲酸缩合后、经哌嗪取代、甲基化制备伊马替尼的方法,该方法可以高效地获得高纯度、基因杂质含量低的伊马替尼。

Description

伊马替尼的高纯度工业制备工艺
技术领域
本发明涉及医药化学领域,具体涉及一种甲磺酸伊马替尼的合成方法。
背景技术
甲磺酸伊马替尼是由由诺华公司研发,是全球第一个上市的肿瘤发生相关信号传导抑制剂,临床用于治疗费城染色体阳性的慢性髓性白血病(Ph+CML)的慢性期、加速期或急变期,治疗不能切除和/或发生转移的恶性胃肠道间质瘤(GIST)的成人患者。甲磺酸伊马替尼的化学名称为4-(4-甲基-1-哌嗪)甲基-N-4-甲基-3-4-(3-吡啶)-2-嘧啶氨基苯基-苯甲酰胺甲磺酸盐。
专利US2008/275055A1报道的伊马替尼合成路线如下:
专利US2008/275055A1报道的合成路线是伊马替尼最常用的合成路线。化合物N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-嘧啶胺是本路线合成甲磺酸伊马替尼时的中间体,属于潜在的基因毒性杂质。在欧洲药典(EP8.4)甲磺酸伊马替尼原料药质量标中,将化合物N-(5-氨基-2-甲基苯基)-4-(3-吡啶基)-2-嘧啶胺命名为杂质F,并规定其限度为不得大于20ppm,并公开了用高效液相色谱—质谱联用的检测杂质F的方法。
按照专利US2008/275055A1报道的合成路线制备的伊马替尼含有大量基因杂质,要经过多次成盐、游离、重结晶纯化才能符合欧洲药典基因杂质的标准。
专利WO2013008242A1公开制备高纯度伊马酸的合成路线如下:
以对溴甲基苯乙酸为起始原料,由N-甲基哌嗪取代得到伊马酸:4-(4-甲基哌嗪)基甲基苯乙酸。
工业生产上将六水哌嗪经甲基化反应、精馏纯化制得N-甲基哌嗪,因而N-甲基哌嗪中不可避免的含有少量的哌嗪。由于N-甲基哌嗪中少量的哌嗪参与反应,按照专利WO2013008242A1实施例1制备的伊马酸含有少量的4-哌嗪基甲基苯乙酸,从而导致制备的伊马替尼中含有约0.1~0.2%式(Ⅴ)脱甲基杂质,严重影响伊马替尼的质量。
发明内容
本发明的目的在于提供一种式式(I)所示伊马替尼的制备方法,由化合物(II)经缩合、取代、甲基化步骤得到伊马替尼,
其中,R1是卤素或者其他可离去基团。
缩合步骤的反应溶剂是水和醚类溶剂的混合物,优选水和四氢呋喃的混合物,缩合剂是EDC盐酸盐。
取代步骤的反应溶剂是高沸点醚类溶剂,优选二氧六环。
甲基化步骤以DMSO为反应溶液,甲醛和甲酸混合溶液为甲基化试剂。甲基化反应完毕后,加入适量氨水析晶,过滤收集伊马替尼,并用四氢呋喃重结晶。
本发明其中一个最优选的实施方案是:
本发明制备的伊马替尼,基因杂质的含量小于2ppm、脱甲基杂质含量小于0.01%,纯度高达99.9%。
具体实施方式
应该理解,本领域技术人员基于此处公开的内容,可以对本发明进行各种不偏离本发明精神和范围内的各种修改和改进。它们应当都落在本申请的权利要求定义的专利保护范围内。此外,应该理解,此处提供的实施例仅用于说明本发明的目的,而不应解释为本发明的限制。
实施例1:
将化合物(II)(27.7g,1eq)、对溴甲基苯乙酸(23.6g,1.1eq)加入反应瓶中,加入THF(200ml)和水(100ml)的混合溶液,搅拌10分钟后加入EDC盐酸盐(23.0g,1.2eql),加热至50℃,搅拌反应6小时。反应完毕,将反应液冷却至室温,缓慢加入10%氨水(200ml)搅拌析晶、过滤,干燥得化合物(4)45.1g,摩尔收率95.1%。
实施例2:
将化合物(4)(47.4g,1eq)、哌嗪(10.3g,1.2eq)加入反应瓶中,加入二氧六环(300ml),加热至80℃,搅拌反应3小时。反应完毕,减压浓缩回收溶剂,的化合物(5)44.1g,摩尔收率92.1%。
实施例3:
将化合物(5)(47.9g,1eq)、37%甲醛(8.1g,1eq)、98%甲酸(4.7g,1eq)加入反应瓶中,加入DMSO(200ml),加热至80℃,搅拌反应3小时。反应完毕,缓慢加入到12.5%氨水(400ml)中,过滤、用水洗涤,干燥,得伊马替尼46.8g,摩尔收率94.9%。
将上步所得伊马替尼用四氢呋喃(100ml)重结晶得伊马替尼37.0g,摩尔收率79.0%,纯度99.9%,基因杂质2ppm,脱甲基杂质0.005%。
对比例1:
按专利US2008/275055A1实施例1和实施例2制得伊马替尼,基因杂质含量0.01%,纯度99.8%。
HPLC检测脱甲基杂质含量0.11%。
对比例2:
按专利WO2013008242A1实施例1制备伊马酸。HPLC检测4-哌嗪基甲基苯乙酸含量0.11%。

Claims (10)

1.式(I)所示伊马替尼的制备方法,其特征在于,所述制备方法为由化合物(II)经缩合、取代、甲基化步骤得到伊马替尼,
其中,R1是离去基团。
2.根据权利要求1所述的制备方法,其特征在于,R1是卤素。
3.根据权利要求1所述的制备方法,其特征在于,R1是氯或溴。
4.根据权利要求1所述的制备方法,其特征在于,所述缩合步骤的反应溶剂是水和醚类溶剂的混合物,缩合剂是EDC盐酸盐。
5.根据权利要求4所述的制备方法,其特征在于,所述的醚类溶剂是四氢呋喃。
6.根据权利要求1所述的制备方法,其特征在于,取代步骤的反应溶剂是高沸点醚类溶剂。
7.根据权利要求6所述的制备方法,其特征在于,所述高沸点醚类溶剂是二氧六环。
8.根据权利要求1所述的制备方法,其特征在于,所述甲基化步骤的甲基化试剂是甲醛和甲酸的混合物。
9.根据权利要求1所述的制备方法,其特征在于,所述甲基化步骤的反应溶剂是DMSO。
10.根据权利要求1所述的制备方法,其特征在于,用四氢呋喃重结晶纯化伊马替尼。
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