CN111909160B - 一种乌帕替尼盐类化合物及其制备方法 - Google Patents
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Abstract
本申请提供一种乌帕替尼盐类化合物及其制备方法。本申请所述方法涉及的盐制备操作简便、原料便宜易得，对乌帕替尼的纯化效果好，有利于工业化生产。
Description
技术领域
本申请涉及药物合成领域，具体地，涉及一种乌帕替尼盐类化合物及其制备方法。
背景技术
类风湿性关节炎（RA），银屑病关节炎（PsA）具体发病原因不明，从医疗实践推测其与患者免疫功能存在部分缺陷有着重要的关系。类风湿性关节炎病程长，并因其多有免疫功能障碍，患者常因心血管、感染及肾功能受损等合并症而死亡。
目前JAK抑制剂是有效治疗此类免疫系统疾病的手段之一。其中，乌帕替尼(Upadacitinib)作为艾伯维治疗类风湿性关节炎、银屑病关节炎的实验性新药，通过新型靶点JAK1抑制剂，JAK1是一种激酶，在多种炎症性疾病的病理生理过程中发挥了关键作用，包括类风湿性关节炎（RA）、克罗恩病（CD）、溃疡性结肠炎（UC）、银屑病关节炎（PsA）等。目前，艾伯维也在评估乌帕替尼治疗其他免疫疾病的潜力，包括PsA、UC和AS及特应性皮炎。
目前为止，国内外相关专利报道也较少，主要报道的专利合成路线为原研艾伯维公司的合成方法（WO2017066775），其中报道了盐酸盐，酒石酸盐，马来酸盐等盐类。
化合物的多晶型是指在化合物物中存在有两种或两种以上的不同晶型物质状态。多晶型现象的在有机化合物中广泛存在。同一化合物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度的影响化合物的稳定性、均一性。不同的盐型和晶型在化合物的纯化过程中通过结晶对化合物的提纯能力有着明显的不同。因此，药物工艺研发中进行全面系统的多晶型筛选，选择最合适开发的晶型，是不可忽视的重要研究内容之一。
杂质的有效控制是药物生产中十分重要的环节，对于保证药物的品质有着巨大的意义。本着对患者负责的态度，医药企业的研发思路应予以杂质控制有密切关注。药物中间体化合物的盐型与晶型与纯化工艺的研究有利于控制药物活性分子的质量，从而保证药物制剂的品质与安全。
发明内容
本发明提供几种乌帕替尼化合物I的新的盐型与晶型，本发明提供的新晶型有良好的稳定性、工艺可开发和易处理等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。其突出优点在于可以通过此成盐过程有效的纯化合成工艺中所产生的杂质。
具体的，本发明的一个目的是提供乌帕替尼化合物I的盐型和相应晶型。
其中L-二对甲基苯甲酰酒石酸盐化合物的一个晶型命名为晶型A，
本发明提供的晶型A，其特征在于，其X射线粉末衍射图在2theta值为3.9°±0.2°，7.5°±0.2°，7.7°±0.2°, 10.4°±0.2°，15.2°±0.2°, 23.4°±0.2°处具有特征峰。
更进一步的，所述晶型A，其特征在于，其X射线粉末衍射图基本上与图1一致。
另外，化合物I乌帕替尼与草酸、对甲苯磺酸所形成的相应盐类也具有较好的纯化效果。化合物I与樟脑磺酸、苯甲酸、苹果酸、柠檬酸、磷酸、醋酸、丙酸、葡萄糖酸、丙二酸、丁二酸、甲基丙二酸、硬脂酸、软脂酸、富马酸等也可以 形成相应的盐类。
本发明的另一个目的是提供盐型及晶型的制备方法，其特征在于，包括将化合物I与相应的酸加入到一种或多种溶剂的混合体系中结晶得到。
更进一步的，所述结晶方法包括混悬搅拌，加热降温，挥发或反溶剂添加。
更进一步的，所述溶剂包括水，醇类，醚类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，脂肪烃类溶剂的单一或混合体系。
本发明的再一目的是提供一种包含有化合物I或其相应的对甲苯磺酸盐、草酸盐、L-二对甲基苯甲酰酒石酸盐。其特征在于，所述的盐型、晶型用于免疫系统药物乌帕替尼的合成及制剂中的用途。
本发明的有益效果为：
本发明提供的盐型、晶型有较好的稳定性；
与文献披露的乌帕替尼酒石酸盐比较，本发明提供的结晶方法可以有效的将药物分子的纯度提高，有效减低杂质含量；
而本发明提供的新晶型的制备方法简单且重复性好，且过程可控，适合用于工业化生产。
附图说明
图1为化合物I 的L-二对甲基苯甲酰酒石酸晶型A的XRPD图；
图2为化合物I 的L-二对甲基苯甲酰酒石酸晶型A的DSC图；
图3为化合物I 的L-二对甲基苯甲酰酒石酸晶型A的TGA图；
图4为化合物I 的L-二对甲基苯甲酰酒石酸晶型A的HNMR图。
具体的实施方式
以下通过具体的实施例进一步的阐述本发明，但并不用于限制本发明的保护范围。本领域的技术人员可在权利要求范围内对制备方法和使用仪器做出改进，这些改进也应被视为本发明的保护范围。因此，本发明的保护范围应以权利要求为准。
下述实施例中，所述的实验方法通常按照常规条件或制造厂商建议的条件实施；所述化合物I的通过专利WO2017066775所述方法制备。
本发明中所用到的缩写解释如下：
XRPD：X射线粉末衍射
本发明所述的X射线粉末衍射图在Bruker公司D2 PHASER型 X射线粉末衍射仪上采集。本发明所述XRPD的方法参数如下：
本发明所述差示扫描量热分析（DSC）图在TA Instruments公司差示扫描量热仪DSC2000上采集。本发明所述差示扫描量热分析（DSC）的方法参数如下：
本发明所述差示扫描量热分析（TGA）图在TA Instruments公司热重分析仪 TGAQ500上采集。本发明所述差示扫描量热分析（TGA）的方法参数如下：
本发明所述高效液相色谱（HPLC）结果在Waters 2695上采集。本发明所述高效液相色谱（HPLC）的方法参数如下：
液相色谱柱：Agilent Zorbax Plus-C18, 4.6*100mm, 3.5um；
流动相：水-乙腈-三氟乙酸体系；
流速：1mL/分钟；
柱温：40°C；
检测波长：220nm。
实施例1
化合物I的草酸盐的制备方法：
将380mg的化合物I溶解于6mL的乙酸异丙酯，20°C条件下缓慢滴加100mg/2mL的草酸的乙酸异丙酯溶液，室温搅拌2h，过滤，取样测试HPLC纯度为99.51%。
实施例2
化合物I的对甲苯磺酸的制备方法：
将380mg的化合物I溶解于6mL的乙酸异丙酯，20°C条件下缓慢滴加360mg/2mL的对甲苯磺酸的乙酸异丙酯溶液，室温搅拌2h，过滤，取样测试HPLC纯度为98.73%。
实施例3
化合物I的L-二对甲基苯甲酰酒石酸的制备方法：
将380mg的化合物I溶解于6mL乙酸异丙酯，20°C条件下缓慢滴加390mg/2mL的L-二对甲基苯甲酰酒石酸的乙酸异丙酯溶液，室温搅拌2h，过滤，取样测试HPLC纯度为99.32%。
实施例4（对照结果汇总）
化合物I的成盐纯化效果对比：
| 编号 | 酸 | HPLC |
| 18603097-0 | 无（成盐起始物料） | 84.58% |
| 18603097-22 | 草酸 | 99.51% |
| 18603097-23 | 对甲苯磺酸 | 98.73% |
| 18603097-24 | L-二对甲基苯甲酰酒石酸 | 99.32% |
| 18603099-24 | L-酒石酸 | 93.49% |
实施例5
化合物I的L-二对甲基苯甲酰酒石酸晶型A的制备方法：
将390mg的化合物I溶解于1mL乙酸异丙酯、0.5mL异丙醇和0.3mL水的混合溶液中溶解完全，50°C条件下缓慢滴加400mg/2mL的L-二对甲基苯甲酰酒石酸的乙酸异丙酯溶液，50°C搅拌2h，再加入5mL乙酸异丙酯溶液缓慢降至室温，过滤抽干得固体740mg，取样测试HPLC纯度为99.78%。
HNMR数据：
1H-NMR (DMSO-d6, 400 MHz) δ:12.29(1H, s), 8.58(1H, s), 7.89(4H, d),7.40-7.60(2H, m), 7.38(4H, d), 6.95-7.06(2H, m), 5.81(2H, s), 4.35(1H, dd),5.65-5.93(5H, m), 3.27(1H, dd), 2.50-2.62(1H, m), 2.40(6H, s), 1.05-1.15(1H,m), 0.75-0.88(1H, m), 0.64(3H, t)。
测试XRPD结果如下表：
| 2theta | d间隔 | 相对强度% |
| 3.88 | 22.80 | 41.36 |
| 7.47 | 11.83 | 33.28 |
| 7.70 | 11.48 | 100.00 |
| 10.40 | 8.50 | 62.44 |
| 13.03 | 6.80 | 22.55 |
| 13.40 | 6.61 | 79.74 |
| 15.26 | 5.81 | 40.57 |
| 16.46 | 5.39 | 24.26 |
| 18.40 | 4.82 | 32.10 |
| 19.32 | 4.60 | 46.82 |
| 19.98 | 4.44 | 49.06 |
| 23.13 | 3.85 | 25.62 |
| 23.44 | 3.79 | 42.78 |
| 23.96 | 3.71 | 24.54 |
实施例6
化合物I的L-二对甲基苯甲酰酒石酸晶型A的制备方法：
将415mg的化合物I，430mg的L-二对甲基苯甲酰酒石酸加入反应瓶中，于其中加入8mL乙酸异丙酯、0.5mL异丙醇和0.3mL水的混合溶液， 50°C搅拌2h，缓慢降至室温，过滤抽干得固体755mg，取样测试HPLC纯度为99.79%。
HNMR数据：
1H-NMR (DMSO-d6, 400 MHz) δ:12.29(1H, s), 8.58(1H, s), 7.89(4H, d),7.40-7.60(2H, m), 7.38(4H, d), 6.95-7.06(2H, m), 5.81(2H, s), 4.35(1H, dd),5.65-5.93(5H, m), 3.27(1H, dd), 2.50-2.62(1H, m), 2.40(6H, s), 1.05-1.15(1H,m), 0.75-0.88(1H, m), 0.64(3H, t)。
测试XRPD结果如下表：
| 2theta | d间隔 | 相对强度% |
| 3.87 | 22.81 | 43.59 |
| 7.48 | 11.82 | 52.26 |
| 7.69 | 11.50 | 100.00 |
| 10.37 | 8.53 | 70.43 |
| 13.28 | 6.66 | 60.79 |
| 15.00 | 5.91 | 20.68 |
| 15.24 | 5.81 | 60.49 |
| 16.39 | 5.41 | 24.30 |
| 18.27 | 4.86 | 30.15 |
| 19.21 | 4.62 | 28.37 |
| 19.97 | 4.45 | 32.89 |
| 23.12 | 3.85 | 22.23 |
| 23.36 | 3.81 | 58.03 |
Claims (1)
1.一种式I化合物L-二对甲基苯甲酰酒石酸盐的晶型A，其特征在于，X射线粉末衍射图在2theta值为3 .9°±0 .2°，7 .5°±0 .2°，7 .7°±0 .2°，10 .4°±0 .2°，15 .2°±0.2°，23 .4°±0 .2°处具有特征峰，
。
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