CN105837515B - 一种JAK抑制剂Momelotinib的制备方法 - Google Patents
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- C07D239/32—One oxygen, sulfur or nitrogen atom
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Abstract
本发明涉及一种JAK抑制剂Momelotinib的合成方法，属于药物化学、化学工程与工艺技术领域。包括以下步骤：(a)将4‑吗啉‑苯胺与50％单腈胺水溶液溶于有机溶剂中，逐滴加入浓盐酸后，在80‑90℃下加热回流得到中间体C1；(b)以对乙酰基苯甲酸甲酯为原料在DMF‑DMA溶液中加热回流得到中间体C2；(c)将中间体C1与C2加入到有机溶剂中，然后加入氢氧化钠，回流反应得黄色固体C3。然后在氢氧化锂水溶液中水解得中间体C4；(d)C4与氨基乙腈盐酸盐经酰胺化反应得到目标产物momelotinib。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
技术领域
本发明涉及小分子化学药物制备领域，更特别设计一类JAK抑制剂药物Momelotinib的制备方法。
背景技术
原发性骨髓纤维化(PMF)，又称骨髓纤维瘤，属于骨髓增殖性肿瘤的一种。异常的造血细胞克隆产生细胞因子致使骨髓中的造血组织被胶原纤维替换，导致患者再生新血液细胞的功能丧失。PMF可以导致脾脏肿大，引起脾机能亢进，可以引起全血细胞减少症，尤其是血小板减少症和贫血，PMF还可以引起其他的骨髓恶性肿瘤。PMF患者生存质量极差，常年忍受各种症状，并且没有非常有效的治疗手段。近年研究表明，PMF与JAK2-STAT信号通路异常调控密切相关，在超过50％的PMF患者中发现了JAK2 V617F突变产生。2011年11月FDA批准第一个JAK抑制剂卢克替尼(ruxolitinib)用于IPSS中危-2和高危组原发性骨髓纤维化(PMF)患者的治疗。因此，靶向JAK2抑制JAK2-STAT信号通路的异常调控成为治疗PMF的一个重要手段。
JAK家族是存在于细胞质中的一种非受体酪氨酸激酶，参与调控人类许多生理作用，包括先天性与适应性免疫功能，炎症反应，造血细胞分化与生长，组织生长以及胚胎发育等。该激酶家族共有4个亚型，包括JAK1，JAK2，JAK3与TYK2。他们之间的同源性可以达到40％～70％，但各自所参与调控的生理功能却相异。
其中，JAK2参与调节的信号通路参与维持造血细胞分化与生长。JAK2由1132个氨基酸组成，从N末端到C末端依次存在JH1-JH7同源域。其中JH1又称激酶域，位于C末端，具有催化功能；JH2为伪激酶域，JH2可以通过抑制JH1活化以维持JAK2的活性处于正常水平；JH3-JH4为Src同源域(SH2)；JH5-JH7为FERM域，介导JAK2与受体的结合。在正常生理情况下，当细胞或生长因子结合了受体后，受体发生同源或者异源聚合作用，使与之偶联的JAK2活化并发生自磷酸化。活化后的JAK2促使细胞因子受体在细胞质的部分发生磷酸化作用，为STAT提供结合位点；STAT与受体结合后，STAT发生磷酸化作用并相互聚集形成同源或异源二聚体，然后转移到细胞核内诱导基因转录。当位于JAK2第617位密码子中的鸟嘌呤被胸腺嘧啶替换时，可导致JH2域617位缬氨酸向苯丙氨酸(V617F)突变的发生，致使JH2活性下降，导致其对JH1域抑制活性的减弱，进而JAK2得以持续激活。因此，V617F突变可以造成JAK2-STAT通路在不依赖细胞因子刺激的情况下持续激活，导致血液细胞持续增殖与生长。统计数据表明，在多数血液肿瘤，尤其是在骨髓增生性肿瘤的患者中检测出了V617F突变。该突变在超过95％的真性红细胞增多症患者，超过50％的原发性血小板增多症和原发性骨髓纤维化患者中均存在，V617F突变引起的JAK2信号通道的过度活化是导致这些疾病的主要原因。因此，通过抑制JAK2调控JAK2-STAT的过度活化，治疗PMF成为一种可能。
Momelotinib(CYT-387)是一个JAK1/2抑制剂，对JAK1和JAK2的IC50分别达到11nM和18nM。其与JAK2的结合模式表明，嘧啶环1位的N与2位的NH，分别作为氢键受体与氢键供体同铰链区Leu932主链上的NH和羰基形成关键性的氢键。与其他JAK2抑制剂类似，苯环对位上的CONHCH2CN可以占据P-loop区氨基酸形成的口袋，提高针对JAK2的活性。在细胞试验中，Momelotinib可以抑制红细胞集落和红白血细胞的生长，同时也可以有效抑制STAT5的磷酸化。在小鼠模型中，Momelotinib可以使小鼠的红细胞计数、白细胞计数和脾脏大小恢复正常。
结构式如通式1所示的JAK抑制剂Momelotinib，其名称为N-(氰基甲基)-4-[2-[[4-(4-吗啉基)苯基]氨基]-4-嘧啶基]苯甲酰胺
目前关于Momelotinib的合成方法的报道，主要由以下方法合成：YM BioSciences公司在专利WO2012149602中报道了一条Momelotinib的合成路线，如下式所示：
分析上述合成路线，反应路线繁多，副产物复杂大大限制了该化合物的工业化生产。
发明内容
本发明的目的在于提供一种原料易得、工艺简洁、经济环保且适合工业化生产的Momelotinib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Momelotinib的制备方法，包括以下步骤：
(a)将4-吗啉-苯胺与50％单腈胺水溶液溶于有机溶剂中，逐滴加入浓盐酸后，在80-90℃下加热回流2h，然后补加浓盐酸，继续反应8h。浓缩除去乙醇，加入碳酸钠水溶液，析出固体，过滤，滤饼用丙酮洗涤后，得中间体C1；
(b)将对乙酰基苯甲酸甲酯加入到DMF-DMA溶液，加热回流，过滤，得中间体C2；
(c)将中间体C1与C2加入到有机溶剂中，然后加入碱，加热至回流反应24h，***洗涤后得黄色固体。将所得的固体溶于丙酮中，加入氢氧化锂水溶液，常温下反应过夜，浓缩除去有机溶剂后，用稀盐酸调PH至酸性，析出固体，过滤得中间体C4；
(d)在中间体C4中加入碱，氨基乙腈盐酸盐，EDCI，HOBT后，溶于DMF中，常温下反应过夜后，浓缩至干，加入二氯甲烷，依次用饱和碳酸氢钠溶液、食盐水洗涤后，浓缩后，用甲醇重结晶得到目标产物Momelotinib。
进一步的，在步骤(a)中，所述有机溶剂选自乙醇，甲醇，二氧六环，甲基叔丁基醚，四氢呋喃，2-甲基四氢呋喃和苯，甲苯，乙苯，叔丁苯和二甲苯中的一种或几种。
优选的的，在步骤(b)中，回流温度为85℃。
进一步的，在步骤(b)中，回流时间10～20h。
进一步的，在步骤(c)中，所用到的有机溶剂选自正丁醇，正丙醇，乙醇，甲醇，二氧六环，甲基叔丁基醚，四氢呋喃和苯，甲苯，乙苯，叔丁苯和二甲苯中的一种或几种。
优选的，在步骤(c)中，所述碱选自碳酸钾，磷酸钾，乙酸钾，氢氧化钠，氢氧化钾，醋酸钾，碳酸钠，碳酸铯，碳酸锂，氟化铯和氟化钾中的一种或几种。
优选的的，在步骤(c)中，回流温度在95℃。
进一步的，在步骤(d)中，所述碱选自三乙胺。
本发明涉及一种2-氨基嘧啶类JAK抑制剂药物的Momelotinib合成方法的改进方法，属于药物化学，化学工程与工艺技术领域。本发明经四步反应合成JAK抑制剂药物Momelotinib，反应条件温和，所得产品总收率高达90％，具有良好的市场应用前景。
本发明涉及的合成方法，工艺步骤简单，可控性强，因而不需要繁琐反应和后续处理过程，且收率高，成本低，产物纯度高，适合工业化生产。
本发明的方法中所使用的原料可以通过商业途径购买，也可以根据本领域的常规化学合成方法制备。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目
的，而不限制本发明的范围和实质。
实例1
制备中间体C1
将1.78g(10mmol)4-吗啉-苯胺与1.7ml(20mmol)50％单腈胺水溶液溶于50ml无水乙醇中，逐滴加入浓盐酸1.5ml后，在80-90℃下加热回流2h，然后补加浓盐酸1.5ml，继续反应8h。浓缩除去乙醇，加入碳酸钠水溶液，析出固体，过滤，滤饼用丙酮洗涤后，得白色固体2.3g，收率82％。
目标产物中间体C2的HNMR的数据如下：
1H NMR(300MHz，DMSO-d6)：δ7.16(brs，2H)，6.88(m，4H)，6.59(brs，1H)，4.25(brs，1H)，3.72(m，4H)，3.04(m，4H)；13C NMR(75MHz，DMSO-d6)：δ160.0，154.9，147.7，124.7，116.1，66.1，48.9.
实施例2
制备中间体C2
将2g(10mmol)对乙酰基苯甲酸甲酯加入到9ml(60mmol)DMF-DMA溶液，在85℃下加热回流15h，过滤，得黄色固体2.3g，收率86％。
目标产物中间体C2的HNMR的数据如下：
1H NMR(300MHz，DMSO-d6)：δ7.99(m，4H)，7.76(d，J＝12Hz，1H)，5.84(d，J＝12Hz，1H)，3.88(s，3H)，3.17(s，3H)，2.94(s，3H)；13C NMR(75MHz，DMSO-d6)：δ184.6，165.8，154.7，144.2，131.1，128.9，127.3，91.0，52.2，44.5，37.2.
实施例3
制备中间体C4
将1.68g中间体C1(0.6mmol)与1.16g(0.5mmol)C2加入到35ml正丁醇中，然后加入0.8g(10mmol)氢氧化钠，加热至98℃回流反应24h，***洗涤后得黄色固体。将0.58g所得的固体溶于10ml丙酮中，加入0.12g氢氧化锂的1.6ml水溶液，常温下反应过夜，浓缩除去有机溶剂后，用稀盐酸调PH至酸性，析出固体，过滤得中间体C4，两步收率85％。
目标产物中间体C4的HNMR的数据如下：
1H NMR(300MHz，DMSO-d6)：δ9.45(s，1H)，8.53(d，J＝5.1Hz，1H)，8.23(d，J＝8.1Hz，2H)，8.09(d，J＝8.1Hz，2H)，7.67(d，J＝8.7Hz，2H)，7.37(d，J＝5.1Hz，1H)，6.93(d，J＝8.7Hz，2H)，3.75(m，4H)，3.06(m，4H)；13C NMR(75MHz，DMSO-d6)：δ162.6，160.3，159.2，146.2，140.4，132.8，129.6，128.1，126.8，120.3，115.6，107.6，66.1，49.2.
实施例4
制备目标产物Momelotinib
2g(5.3mmol)C4中加入4.42mL(32mmol)三乙胺，0.98g(10.6mmol)氨基乙腈盐酸盐，1.22g(6.6mmol)EDCI，860mL(6.6mmol)HOBT后，溶于20mLDMF中，常温下反应过夜后，浓缩至干，加入二氯甲烷，依次用饱和碳酸氢钠溶液、食盐水洗涤后，浓缩后，用甲醇重结晶得到黄色固体，收率90％。
目标产物Momelotinib的HNMR的数据如下：
1H NMR(300MHz，DMSO-d6)：δ9.47(s，1H)，9.32(t，J＝5.4Hz，1H)，8.54(d，J＝5.1Hz，1H)，8.27(d，J＝8.1Hz，2H)，8.03(d，J＝8.1Hz，2H)，7.67(d，J＝8.7Hz，2H)，7.40(d，J＝5.1Hz，1H)，6.94(d，J＝8.7Hz，2H)，4.35(d，J＝5.1Hz，2H)，3.75(m，4H)，3.06(m，4H)；13CNMR(75MHz，DMSO-d6)：δ166.1，162.4，160.3，159.2，146.2，139.9，134.5，132.8，127.8，126.9，120.3，117.5，115.6，107.6，66.1，49.2，27.7.
以上对本发明的特定实施例进行了说明，但本发明的保护内容不仅仅限定于以上实施例，在本发明的所属技术领域中，只要掌握通常知识，就可以在其技术要旨范围内进行多种多样的变更。
Claims (7)
1.一种JAK抑制剂药物Momelotinib的制备方法，其特征在于，包括以下步骤：
(a)将4-吗啉-苯胺与50％单腈胺水溶液溶于有机溶剂中，逐滴加入浓盐酸后，在80-90℃下加热回流2h，然后补加浓盐酸，继续反应8h，浓缩除去乙醇，加入碳酸钠水溶液，析出固体，过滤，滤饼用丙酮洗涤后，得中间体C1；
(b)将对乙酰基苯甲酸甲酯加入到DMF-DMA溶液，加热回流，过滤，得中间体C2；
(c)将中间体C1与C2加入到正丁醇中，然后加入碱，加热至回流反应24h，***洗涤后得黄色固体，将所得的固体溶于丙酮中，加入氢氧化锂水溶液，常温下反应过夜，浓缩除去有机溶剂后，用稀盐酸调PH至酸性，析出固体，过滤得中间体C4；
(d)在中间体C4中加入碱，氨基乙腈盐酸盐，EDCI，HOBT后，溶于DMF中，常温下反应过夜后，浓缩至干，加入二氯甲烷，依次用饱和碳酸氢钠溶液、食盐水洗涤后，浓缩后，用甲醇重结晶得到目标产物Momelotinib
2.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(a)中，所述有机溶剂选自乙醇，甲醇，二氧六环，甲基叔丁基醚，四氢呋喃，2-甲基四氢呋喃和苯，甲苯，乙苯，叔丁苯和二甲苯中的一种或几种。
3.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(b)中，回流温度在75～95℃。
4.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(b)中，回流时间10～20h。
5.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(c)中，所述碱选自碳酸钾，磷酸钾，乙酸钾，氢氧化钠，氢氧化钾，碳酸钠，碳酸铯，碳酸锂，氟化铯和氟化钾中的一种或几种。
6.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(c)中，回流温度在80～110℃。
7.如权利要求1所述的JAK抑制剂药物Momelotinib的制备方法，其特征在于：在步骤(d)中，所述碱选自三乙胺。
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| WO2014114274A1 (zh) * | 2013-01-28 | 2014-07-31 | 苏州泽璟生物制药有限公司 | 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物 |
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