CN112142678A - 一种利匹韦林二聚物、其中间体、及其制备方法和用途 - Google Patents
一种利匹韦林二聚物、其中间体、及其制备方法和用途 Download PDFInfo
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- CN112142678A CN112142678A CN201910582536.1A CN201910582536A CN112142678A CN 112142678 A CN112142678 A CN 112142678A CN 201910582536 A CN201910582536 A CN 201910582536A CN 112142678 A CN112142678 A CN 112142678A
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- Prior art keywords
- acid
- rilpivirine
- dimer
- formula
- compound
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- 239000012535 impurity Substances 0.000 claims abstract description 40
- 239000000543 intermediate Substances 0.000 claims abstract description 40
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- 150000003839 salts Chemical class 0.000 claims description 19
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- -1 rilpivirine dimer salt Chemical class 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学技术领域，具体涉及一种如式I所示的利匹韦林二聚物、其制备方法和用途，本发明还涉及一种利匹韦林中间体二聚物，及其制备方法和用途。本发明所要解决的技术问题是克服现有技术中：在利匹韦林合成过程及其稳定性放置过程中产生新的杂质，导致不能对利匹韦林及其中间体进行有效鉴定和质量控制的问题。本发明的利匹韦林二聚物及利匹韦林中间体二聚物是利匹韦林及其中间体质量控制的关键物质，能够有效鉴定在利匹韦林合成过程中产生的杂质，从而控制利匹韦林原料药的质量。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一种如式I所示的利匹韦林二聚物、其制备方法和用途，本发明还涉及一种如式II所示的利匹韦林中间体二聚物，及其制备方法和用途。
背景技术
盐酸利匹韦林(Rilpivirine Hydrochloride)，化学名称：4-{[4-[(4-((1E)-2-氰基乙烯基)-2,6-二甲基苯基)氨基]-2-嘧啶基]氨基}苯甲腈盐酸盐，其结构式如下：
美国FDA于2011年5月批准利匹韦林与其他抗逆转录病毒药物联用治疗I型HIV感染，主要适用于之前未曾受过药物治疗的成人HIV感染者。利匹韦林为第二代非核苷类逆转录酶抑制剂(NNRTI)，其作用机制是阻止HIV病毒复制，从而控制血液中HIV病毒的数量。相比奈韦拉平、地拉韦啶，依曲韦林等药物，利匹韦林具有每日一次，一线用药，耐药性极低，安全性高等优点。
此外，恩曲他滨利匹韦林替诺福韦二吡呋酯、恩曲他滨利匹韦林替诺福韦艾拉酚胺、利匹韦林替诺福韦艾拉酚胺等三方或复方制剂也在国内外相继上市。
专利WO2004016581公开了利匹韦林的合成方法：以4-碘-2,6-二甲基苯胺为起始物料，首先与丙烯腈在10％Pd/C存在下，在N,N-二甲基乙酰胺溶剂中反应制备(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈粗品，在异丙醇中与盐酸成盐制备(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐。然后(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐与化合物4-N-[2-(4-氯嘧啶基)]-氨基苯腈在乙腈中反应制备盐酸利匹韦林，具体路线如下：
本发明在重复WO2004016581制备利匹韦林的过程中，发现在化合物(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐的制备过程中会产生约0.5％的未知杂质，该杂质的分子量为该化合物的二倍分子量，并且最终会传递到API中形成API二聚物杂质。另外，在API的降解实验中我们也发现了API二聚物的产生。
因此，在合成利匹韦林的过程中，出于监控API质量的目的，需要纯的式I及式II化合物作为对照品，以分析目标产物的纯度。
发明内容
本发明所要解决的技术问题是克服现有技术中：在利匹韦林合成过程及其稳定性放置过程中产生新的杂质，导致不能对利匹韦林及其中间体进行有效鉴定和质量控制的问题。
为了解决上述技术问题，本发明提供一种利匹韦林二聚物、及其制备方法和用途；另外，本发明还提供一种利匹韦林中间体二聚物、及其制备方法和用途。
本发明的利匹韦林二聚物及利匹韦林中间体二聚物是利匹韦林及其中间体质量控制的关键物质，能够有效鉴定在利匹韦林合成过程中产生的杂质，从而控制利匹韦林原料药的质量。
本发明首先提供一种如式I所示的利匹韦林二聚物：
本发明还提供一种如上所述的利匹韦林二聚物的制备方法，包括以下步骤：
在合适的溶剂存在下，式II化合物或其盐与至少2摩尔当量的4-N-[2-(4-氯嘧啶基)]-氨基苯腈反应，制备得到式I化合物：
优选地，其中所述合适的溶剂选自乙腈、乙醇或异丙醇；
更优选地，其中所述合适的溶剂选自乙腈。
本发明的上述利匹韦林二聚物的制备方法，所述制备方法中式II化合物与4-N-[2-(4-氯嘧啶基)]-氨基苯腈的投料摩尔比为1:2～1:5。
本发明还提供一种利匹韦林二聚物或其盐的用途，即：上述利匹韦林二聚物或其盐作为利匹韦林中的杂质检测对照品的用途，
优选地，所述利匹韦林二聚物的盐为式I所示利匹韦林二聚物与酸反应所形成的盐，所述的酸选自无机酸或有机酸；
优选地，所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸或磷酸，所述有机酸选自甲酸、乙酸、丙酸、丙二酸、枸橼酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、苦味酸或甲磺酸。
本发明的一种利匹韦林二聚物或其盐的用途，其中，所述利匹韦林二聚物或其盐在利匹韦林与所述利匹韦林二聚物或其盐的组合物中的百分含量小于0.10％，优选小于0.05％。
本发明的一种利匹韦林二聚物或其盐的用途，其中，所述杂质检测时采用HPLC方法，色谱柱型号为Agilent Zorbax Extend C18，填充剂为十八烷基硅烷键合硅胶，流动相A为0.01mol/L醋酸铵缓冲液-乙腈(95:5)，流动相B为乙腈，柱温为25～35℃，检测波长为280nm。
作为一个非限制性实例，所述醋酸铵缓冲液可以由以下方法制得：取醋酸铵0.77g，加水1000ml溶解而成。
本发明还提供一种如式II所示的利匹韦林中间体二聚物：
本发明还提供如上所述的利匹韦林中间体二聚物的制备方法，包括以下步骤：
在合适的溶剂存在下，化合物(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐在光照或者加热条件下反应，制备得到式II所示的利匹韦林中间体二聚物，
优选地，所述加热条件的温度范围为50℃～90℃，更优选70℃～85℃；
优选地，所述合适的溶剂选自乙酸乙酯、乙酸异丙酯、甲醇、乙醇、异丙醇、乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺；
更优选地，所述合适的溶剂选自乙腈。
本发明还提供一种如上所述的利匹韦林中间体二聚物或其盐作为利匹韦林中间体中的杂质检测对照品的用途，所述利匹韦林中间体的结构式如下：
优选地，所述利匹韦林中间体二聚物的盐为式II所示利匹韦林中间体二聚物与酸反应所形成的盐，所述的酸选自无机酸或有机酸；
优选地，所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸或磷酸，所述有机酸选自甲酸、乙酸、丙酸、丙二酸、枸橼酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、苦味酸或甲磺酸。
本发明还提供一种如上所述利匹韦林中间体二聚物用于制备化合物I的用途，化合物I的结构式如下：
其中所述用途是根据权利要求2～3中任一项所述的方法来制备化合物I。
本发明中，所述的如式I和式II所示的化合物还可按本领域成盐反应的常规方法和条件制备。
本发明的技术效果在于：
将利匹韦林二聚物/利匹韦林中间体二聚物作为利匹韦林/利匹韦林中间体中的杂质检测时的杂质对照品使用，能有效、方便地监控利匹韦林/利匹韦林中间体中的杂质，以便有效地控制利匹韦林的质量，从而为利匹韦林成品的质量控制和稳定性分析用作参考标准，以保证利匹韦林及其制剂在临床使用时的安全性和有效性。
附图说明：
图1-a是实施例3中批号PN180201-1中的利匹韦林中间体中杂质检测水平的HPLC色谱图；
图1-b是图1-a的局部放大图；
图2是实施例5中批号为API180801-1的利匹韦林中杂质的检测水平的HPLC色谱图。
具体实施方式
以下通过具体的实施方式，对本发明的上述内容做进一步的详细说明，但不应将此理解为对本发明保护主题的任何限制。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。
若无特别说明，本发明文本中的“利匹韦林中间体”均指代如下结构式的化合物：
实施例中所使用的利匹韦林及利匹韦林中间体均是参照WO2004016581描述的制备方法制备得到。
实施例1式II化合物的制备
将2.1g(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐加入到24ml乙腈中，升温至70-85℃反应，TLC监测反应，反应结束后，过滤，将母液减压浓缩后柱层析提纯得产物得到0.43g式II化合物。ESI(+):m/z＝343.31[M+H]+,1H NMR(400MHz,DMSO-d6):δ＝7.32(s,2H),7.13(s,1H),6.80(s,2H),5.33(s,2H),4.59(s,2H),3.89(t,1H),3.10(d,J＝8.0Hz,2H),2.08-2.09(d,J＝6.4Hz,12H)。
具体结构解析如下：
表1核磁共振1H、NOESY谱数据列表
表2核磁共振13C、HSQC、HMBC谱数据列表
实施例2式II化合物的制备
将2.1g(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐加入到24ml乙腈中，放置于紫外等下照射3天，TLC监测反应，反应结束后，过滤，将母液减压浓缩后柱层析提纯得到0.50g式II化合物。
实施例3：化合物II作为杂质对照品测定利匹韦林中间体中的杂质
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以0.01mol/L磷酸二氢铵-甲醇(85：15)为流动相A，以乙腈-甲醇(60:40)为流动相B；柱温为35℃；流速为每分钟1.0ml；检测波长为210nm。
供试品溶液：取利匹韦林中间体化合物适量，精密称定，置合适的棕色量瓶中，加乙腈-水(20:80)使溶解并稀释制成每1ml中约含0.5mg的溶液，作为供试品溶液。
杂质对照品溶液：取化合物II杂质对照品适量，精密称定，置合适的棕色量瓶中，加乙腈-水(20:80)使溶解并稀释制成每1ml中约含0.03mg的溶液，作为杂质对照品溶液。
测定法：精密量取供试品溶液和杂质对照品溶液各10μl，分别注入液相色谱仪，记录色谱图。供试品溶液的色谱图中如有杂质峰，按峰面积归一化法计算，利匹韦林中间体中含杂质化合物II不得超过0.6％。
化合物II作为杂质对照品检测利匹韦林中间体中的杂质，结果如下：
| 批号 | PN180201-1 | PN180201-2 | PN180201-2 |
| 化合物Ⅱ | 0.53％ | 0.43％ | 0.11％ |
| 利匹韦林中间体纯度 | 96.05％ | 96.39％ | 99.05％ |
其中，批号为PN180201-1的利匹韦林中间体中杂质的检测水平的HPLC色谱图如图1-a所示，图1-a的局部放大图如图1-b所示。
实施例4式I化合物的制备
将2.5g式II化合物、4.5g 4-N-[2-(4-氯嘧啶基)]-氨基苯腈加入至乙腈中，回流搅拌反应9h；反应完毕，调pH值至7～8，浓缩，柱层析得1.8g式I化合物。ESI(+)：m/z＝733.59[M+H]+；1H NMR(400MHz,DMSO-d6):δ＝11.35-11.44(m,2H),10.91-11.01(m,2H),8.13-8.14(d,J＝6.4Hz,2H),7.98-8.01(m,1H),7.75(s,1H),7.63-7.65(d,J＝6.0Hz,2H),7.49-7.56(m,2H),7.34-7.44(m,7H),6.70-6.72(d,J＝6.8Hz,2H),4.43-4.47(m,1H),3.39-3.47(m,1H),2.21(s,1H)。
实施例5：化合物I作为杂质对照品测定利匹韦林中的杂质
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以0.01mol/L醋酸铵缓冲液-乙腈(95:5)为流动相A，乙腈为流动相B；柱温为30℃；流速为每分钟1.0ml；检测波长为210nm。
供试品溶液：避光操作。取利匹韦林适量，精密称定，置合适的棕色量瓶中，加乙腈-水使溶解并稀释制成每1ml中约含1.0mg的溶液，作为供试品溶液。
杂质对照品溶液：取化合物I杂质对照品适量，精密称定，置合适的棕色量瓶中，加稀释剂使溶解并稀释制成每1ml中约含0.02mg的溶液，作为杂质对照品溶液。
测定法：精密量取供试品溶液和杂质对照品溶液各10μl，分别注入液相色谱仪，记录色谱图。供试品溶液的色谱图中如有杂质峰，按峰面积归一化法计算，利匹韦林中含杂质化合物I不得超过0.1％。
化合物I作为杂质对照品检测利匹韦林中的杂质，结果如下：
原料药强制降解试验结果
| 批号 | API180801-1 | API180801-2 | API180801-3 |
| 化合物I | 0.04％ | 未检测到 | 未检测到 |
| 盐酸利匹韦林 | 99.90％ | 99.91％ | 99.88％ |
其中，批号为API180801-1的利匹韦林中杂质的检测水平的HPLC色谱图如图2所示。
Claims (10)
1.一种如式I所示的利匹韦林二聚物：
2.一种权利要求1所述的利匹韦林二聚物的制备方法，其特征在于，包括以下步骤：
在合适的溶剂存在下，式II化合物或其盐与至少2摩尔当量的4-N-[2-(4-氯嘧啶基)]-氨基苯腈反应，制备得到式I化合物：
优选地，其中所述合适的溶剂选自乙腈、乙醇或异丙醇；
更优选地，其中所述合适的溶剂选自乙腈。
3.根据权利要求2所述的制备方法，其特征在于，所述制备方法中式II化合物与4-N-[2-(4-氯嘧啶基)]-氨基苯腈的投料摩尔比为1:2～1:5。
4.一种权利要求1所述的利匹韦林二聚物或其盐作为利匹韦林中的杂质检测对照品的用途，
优选地，所述利匹韦林二聚物的盐为式I所示利匹韦林二聚物与酸反应所形成的盐，所述的酸选自无机酸或有机酸；
优选地，所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸或磷酸，所述有机酸选自甲酸、乙酸、丙酸、丙二酸、枸橼酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、苦味酸或甲磺酸。
5.根据权利要求4所述的用途，其中，所述利匹韦林二聚物或其盐在利匹韦林与所述利匹韦林二聚物或其盐的组合物中的百分含量小于0.10％，优选小于0.05％。
6.根据权利要求4所述的用途，其中，所述杂质检测时采用HPLC方法，填充剂为十八烷基硅烷键合硅胶，流动相A为0.01mol/L醋酸铵缓冲液-乙腈(95:5)，流动相B为乙腈，柱温为25～35℃，检测波长为280nm。
7.一种如式II所示的利匹韦林中间体二聚物：
8.一种权利要求7所述的利匹韦林中间体二聚物的制备方法，包括以下步骤：
在合适的溶剂存在下，化合物(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈盐酸盐在光照或者加热条件下反应，制备得到式II所示的利匹韦林中间体二聚物，
优选地，所述加热条件的温度范围为50℃～90℃，更优选70℃～85℃；
优选地，所述合适的溶剂选自乙酸乙酯、乙酸异丙酯、甲醇、乙醇、异丙醇、乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺；
更优选地，所述合适的溶剂选自乙腈。
9.一种权利要求7所述的利匹韦林中间体二聚物或其盐作为利匹韦林中间体中的杂质检测对照品的用途，所述利匹韦林中间体的结构式如下：
优选地，所述利匹韦林中间体二聚物的盐为式II所示利匹韦林中间体二聚物与酸反应所形成的盐，所述的酸选自无机酸或有机酸；
优选地，所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸或磷酸，所述有机酸选自甲酸、乙酸、丙酸、丙二酸、枸橼酸、琥珀酸、富马酸、乳酸、苹果酸、柠檬酸、酒石酸、苦味酸或甲磺酸。
10.一种权利要求7所述的利匹韦林中间体二聚物用于制备化合物I的用途，化合物I的结构式如下：
其特征在于，所述用途是根据权利要求2～3中任一项所述的方法来制备化合物I。
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| CN113720926A (zh) * | 2021-03-03 | 2021-11-30 | 浙江致新医药科技有限公司 | 一种依曲韦林中间体1中杂质含量检测方法 |
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| WO2013038425A1 (en) * | 2011-09-16 | 2013-03-21 | Hetero Research Foundation | Rilpivirine hydrochloride |
| CN107162987A (zh) * | 2016-03-07 | 2017-09-15 | 宜昌人福药业有限责任公司 | 一种利匹韦林的工业化合成方法及中间体化合物 |
| CN109293581A (zh) * | 2018-09-21 | 2019-02-01 | 宜昌人福药业有限责任公司 | 一种制备盐酸利匹韦林异构体z和杂质x的方法及杂质x作为杀虫剂在农业中的应用 |
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| WO2013038425A1 (en) * | 2011-09-16 | 2013-03-21 | Hetero Research Foundation | Rilpivirine hydrochloride |
| CN107162987A (zh) * | 2016-03-07 | 2017-09-15 | 宜昌人福药业有限责任公司 | 一种利匹韦林的工业化合成方法及中间体化合物 |
| CN109293581A (zh) * | 2018-09-21 | 2019-02-01 | 宜昌人福药业有限责任公司 | 一种制备盐酸利匹韦林异构体z和杂质x的方法及杂质x作为杀虫剂在农业中的应用 |
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| CN113720926A (zh) * | 2021-03-03 | 2021-11-30 | 浙江致新医药科技有限公司 | 一种依曲韦林中间体1中杂质含量检测方法 |
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