CN101333215A - 一种舒尼替尼碱的合成方法 - Google Patents
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Abstract
舒尼替尼碱的合成方法是对舒尼替尼碱的合成路线进行改进,避免传统路线出现的问题,将合成路线缩短了一步。从最初的合成思路出发,我们设计改进了以下两个步骤:1)关键的中间体5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯和5-氟吲哚-2-酮在乙醇中,用哌啶做催化剂,直接缩合得到5-((5-氟-2-氧代吲哚-3-烯基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯;2)得到的上述产物在乙二醇二甲醚中与2-(二乙氨基)乙二胺在特定催化剂条件下通过一步胺解直接得到舒尼替尼碱,并且通过核磁谱图证实了这两个产物。这两步反应都有较高的收率,再加上缩短了反应步骤,大大降低了生产成本。
Description
技术领域
本发明涉及舒尼替尼碱制备的改进方法,属于
背景技术
苹果酸舒尼替尼是一种能够抑制多种酪氨酸激酶受体的小分子化合物,其中一些受体与肿瘤生长、病理性血管生成和癌症转移有关,它可以通过抑制血管内皮生长因子受体、血小板衍生生长因子受体、干细胞因子受体、Fms-样酪氨酸激酶-3、集落刺激因子受体I型和神经胶质细胞系衍生神经营养因子受体的酪氨酸激酶受体的活性,阻断肿瘤细胞生长的血液和营养供应,从而产生抗血管生成和抗肿瘤作用。
III期临床试验结果证实,苹果酸舒尼替尼能延缓已经对伊马替尼(imatinib,Gleevec)治疗产生耐药(或不能耐受)的胃肠道间质肿瘤患者肿瘤的发展,显著降低患者的死亡率。它对于产生耐药性肾细胞癌的患者,也有很高的应答率,能够有效地推迟肿瘤的发展。与使用干扰素-α的治疗相比,给晚期/转移性肾细胞癌(MRCC)患者使用苹果酸舒尼替尼,病情不恶化患者的存活时间由5个月增加到11个月。
目前已知的关于合成舒尼替尼碱的方法有如下几种:
一.SUN Li等人(J Med Chem,46(7):1116-1119)采用先形成吡咯环再合成相应酰胺化合物的策略,即3,5-二甲基-1H-吡咯-2,4-二羧酸-2-叔丁酯-4-乙酯经5位脱叔丁氧羰基、Vilsmeier甲酰化、酯水解反应得到中间体5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸(6),6与2-(二乙氨基)乙二胺缩合形成酰胺,最后与5-氟吲哚-2-酮缩合得到舒尼替尼,总收率为22%。此路线所用试剂较为简单,但缺点是成酰胺的反应要用过量的酰胺,而且反应生成的亚胺不易除去;只能选用N-乙基-N′-(3-二甲基丙基)碳二亚胺盐酸盐(EDC)或碳酰二咪唑(CDI)等少数缩合剂。
此方法的改进方法(J Org Prep Proced Int.1981,13,97)是中间体5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸,采用“-锅煮”方法,与碳酰二咪唑(CDI)反应生成酰基咪唑后不经分离直接与5-氟吲哚啉-2-酮和2-(二乙氨基)乙二胺反应得到舒尼替尼。这种方法的收率虽然有了提高,但是在酰胺化过程中还是要使用过量的胺。
二.Jerad M.Manley等人(J Org Chem.2003,68,6447-6450)采用形成吡咯环的同时得到相应酰胺化合物的合成策略,先将二乙烯酮和2-(二乙氨基)乙二胺缩合得到β-酮酰胺,然后与乙酰乙酸叔丁酯的肟通过Knorr吡咯合成法得到相应的吡咯-3-酰胺,最后与5-氟吲哚啉-2-酮缩合制得舒尼替尼碱。此路线可以避免羧酸和胺的缩合反应,但是起始原料二乙烯酮易燃易爆,不易得到。
发明内容
技术问题:前面提到的方法中都有一步酯的水解,但是这步水解中有醛基的存在,水解往往不能彻底。本发明的目的是提供一种舒尼替尼碱的合成方法,避免以上出现的问题,缩短反应步骤,大大提高反应收率。
技术方案:本发明的舒尼替尼碱的合成方法为:
a.将5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯和5-氟吲哚-2-酮放入乙醇中,在催化剂和氮气保护下缩合得到5-((5-氟-2-氧代吲哚-3-烯基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯,
b.将上述得到的酯进行胺解,直接得到舒尼替尼碱。
缩合反应中反应温度为50-100℃。
缩合反应中的催化剂为吡咯烷、哌啶、吡啶和二乙胺等。
缩合反应的时间为4-10小时。
胺解过程中所用的溶剂为乙二醇二甲醚、甲苯、二甲苯和二苯醚等。
胺解反应温度控制在80-120℃。
胺解反应时间为10-15小时。
有益效果:本发明与现有合成方法相比,不用经过5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯的水解,避免了前面提到的原料不易得和用过量胺的缺点。总的反应步骤较以往的方法有所缩短,本专利的最后两步反应:缩合和胺解,不受原料的控制,胺解时不必使用昂贵的缩合剂(EDC,CDI),原料的成本大大下降。反应和后处理简单,收率也很高。以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯为基准点来算反应总收率:最初的方法总收率为37.6%;改进的一锅煮的方法总收率为58.2%;本发明方法总收率为65.4%。从收率和经济效益来看,本发明有很好的经济前景。
具体实施方式
直接从5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯和5-氟吲哚-2-酮缩合得到5-((5-氟-2-氧代吲哚-3-烯基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯,然后与2-(二乙氨基)乙二胺经胺解得到舒尼替尼碱。
缩合步骤中,5-氟吲哚-2-酮和5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯的摩尔比优选1∶1.1-1.5,溶剂优选乙醇,缩合反应温度为50-100℃。
胺解步骤中,溶剂优选乙二醇二甲醚,反应温度为80-120℃,反应时间优选10-15小时。
下面结合实施案例对本发明作进一步说明。5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯的合成方法与前面提到的方法一致。
实施例1
在50mL烧瓶中加入5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯0.70g(3.59mmol)、5-氟吲哚-2-酮0.45g(3mmol)、乙醇9mL、哌啶数滴,氮气保护下,80℃反应3h后出现大量固体。冷却后抽滤,滤饼用乙醇洗涤、真空干燥得固体0.88g,收率89.3%。
外观:黄色固体
熔点:284-286℃
1H-NMR(DMSO2-d6)δ:1.29(t,3H),2.422(s,3H),2.442(s,3H),4.203(q,2H),6.847(q,1H),6.947(t,1H),7.762(s,1H,vinylH),7.801(d,1H),10.948(s,1H,indoleNH),13.921(s,1H,pyrroleNH)。
实施例2
5-((5-氟-2-氧代吲哚-3-烯基)甲基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯0.8g(2.5mmol),2-(二乙氨基)乙二胺0.5ml,催化剂0.05g,二甲苯20ml,100℃反应12h后冷却,加氯仿稀释,过滤,减压蒸出二甲苯,得固体0.81g,收率73.2%。
外观;橙黄色固体
熔点:214-216℃
1H-NMR(DMSO2-d6)δ:0.977(t,6H)、2.420(s,3H)、2.440(s,3H)、2.518~2.556(m,6H)、3.275(m,2H)、6.837(br s,1H)、6.923(dd,1H)、7.423(m,1H)、7.712(s,1H)、7.764(dd,1H)、10.873(s,indoleNH)、13.676(s,pyrroleNH)。
从5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯开始将传统的三步反应合并成两部,而且每一步的收率都较高,大大提高了反应收率。
Claims (7)
2.如权利要求1所述的舒尼替尼碱的合成方法,其特征是,缩合反应中反应温度为50-100℃。
3.如权利要求1所述的舒尼替尼碱的合成方法,其特征是缩合反应中的催化剂为吡咯烷、哌啶、吡啶和二乙胺等。
4.如权利要求1所述的舒尼替尼碱的合成方法,其特征是缩合反应的时间为4-10小时。
5.如权利要求要求1所述的舒尼替尼碱的合成方法,其特征是,胺解过程中所用的溶剂为乙二醇二甲醚、甲苯、二甲苯和二苯醚。
6.如权利要求1所述的舒尼替尼碱的合成方法,其特征是,胺解反应温度控制在80-120℃。
7.如权利要求1所述的舒尼替尼碱的合成方法,其特征是,胺解反应时间为10-15小时。
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CN101885698B (zh) * | 2009-05-15 | 2012-07-11 | 浙江海正药业股份有限公司 | 一种吡咯基丙烯酰胺类化合物及其在舒尼替尼合成中的应用 |
CN103254110A (zh) * | 2012-02-17 | 2013-08-21 | 上海医药工业研究院 | 卤代吡咯取代吲哚满酮、其中间体及其制备方法 |
CN103319392A (zh) * | 2013-07-10 | 2013-09-25 | 张家港市华昌药业有限公司 | 一种舒尼替尼中间体的制备方法 |
WO2013140232A1 (en) * | 2012-03-23 | 2013-09-26 | Laurus Labs Private Limited | An improved process for the preparation of sunitinib and its acid addition salts thereof |
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CN101033226B (zh) * | 2007-04-06 | 2010-05-19 | 复旦大学 | 1-呋喃甲基-3-取代吲哚啉-2-酮衍生物 |
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