CN108440395A - 一种米力农杂质的制备方法 - Google Patents

一种米力农杂质的制备方法 Download PDF

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CN108440395A
CN108440395A CN201810297241.5A CN201810297241A CN108440395A CN 108440395 A CN108440395 A CN 108440395A CN 201810297241 A CN201810297241 A CN 201810297241A CN 108440395 A CN108440395 A CN 108440395A
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milrinone
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宋化丰
赵万年
胡永铸
刘春�
魏常青
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Delhi (nanjing) Pharmaceutical Research And Development Co Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom

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Abstract

本发明公开了一种米力农杂质的制备方法，属于药物合成领域，反应路线设计合理，可操作性强。本发明包括：以(Z)‑4‑乙氧基‑3‑（4‑吡啶基）‑3‑烯‑2‑丁酮为原料，先经还原、叠氮化、叠氮还原、与氰基乙酸缩合等四步反应合成目标化合物。本发明整个路线设计合理，后处理简单、原料价廉易得，制备得到的目标产物纯度可达99.0%以上，可用于药代动力学和临床研究，为米力农的临床研究提供测试样品，具有重要的应用价值。

Description

一种米力农杂质的制备方法
技术领域
本发明属于药物合成领域，尤其涉及一种米力农杂质的制备方法。
背景技术
米力农(milrinone)，又名米利酮，化学名为：2‐甲基‐6‐氧‐1,6‐二氢‐(3,4’‐双吡啶)‐5‐甲腈；为第二代双吡啶酮类正性肌力药，兼有外周血管扩张作用。用于治疗顽固性心力衰竭和已发生洋地黄中毒的心力衰竭患者。1987年在美国上市，此后静脉注射米力农被美国等其他国家广泛应用以改善心力衰竭患者的术后和术前。
随着时代的进步、科技水平的提高，人们对药品上市前必须对药品进行质量、安全性和效能科学评价的重要性等有了更加充分的认识，其中与药品质量密切相关的是药物所含杂质的控制。杂质往往与药品安全性有关，且在少数情况下与效能也有关，所以控制药品杂质的含量是评价药品质量和安全性的关键，米力农杂质是米力农合成过程中的一种杂质，所以对米力农杂质的研究有利于控制米力农的质量和安全性，但是关于这种杂质的合成和研究尚未有报道。
发明内容
本发明提供了一种米力农杂质的制备方法，该方法路线设计合理，可操作性强，所得物质纯度高。
为实现以上目的，本发明采用以下技术方案：
一种米力农杂质的制备方法，包括以下步骤：
(1)取(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮溶于有机溶剂中，加入还原剂，所述(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮与还原剂的摩尔比为1:1～1:2，在-10℃～30℃条件下搅拌反应1小时～5小时，得到化合物B，结构式如下：
(2)取所述化合物B溶于非极性溶剂中，化合物B与甲苯的体积比为6～25倍体积，加入叠氮化试剂，化合物B与叠氮化试剂的摩尔比为1:0.5～1:5，在0℃～50℃下搅拌2小时～5小时，再经柱层析纯化得到化合物C，结构式如下：
(3)取所述化合物C溶于极性溶剂和水的混合溶剂中，加入还原剂，所述的化合物C与还原剂的摩尔比为1:1～1:4，20℃～50℃下搅拌1小时～3小时，得到化合物D，结构式如下：
(4)取所述化合物D溶于有机溶剂中，加入缩合剂，所述化合物D与缩合剂的摩尔比为1:1～1:2，加入氰基乙酸，所述化合物D与氰基乙酸的摩尔比为1:1～1:3，在10℃～50℃下搅拌反应1小时～15小时至原料消失，经柱层析得到目标化合物 E，结构式如下：
以上所述步骤中，步骤(1)所述溶剂为甲醇、乙醇、异丙醇或水与其的混合溶剂，优选甲醇，所述还原剂为硼氢化钠、硼氢化钾或硼氢化锂，优选硼氢化钠，所述反应时间为2～4小时；步骤(2)中所述非极性溶剂为苯、甲苯、四氢呋喃、丙酮或乙腈，优选甲苯，所述叠氮化试剂为叠氮磷酸二苯酯、叠氮化钠、叠氮三甲基硅烷或叠氮化四丁基铵，优选叠氮磷酸二苯酯；步骤(3)所述极性溶剂为甲醇、乙醇、异丙醇或水与其的混合溶剂，优选甲醇，所述还原剂为三苯基膦、三乙基膦、三甲基膦、三丁基膦、硼氢化钠、硼氢化锂或硼氢化钾，优选三苯基膦；步骤(4)所述有机溶剂为二氯甲烷、氯仿、DMF、DMAC、乙腈、丙酮或四氢呋喃，所述缩合剂为DCC、EDCI、HOBT、CDI、DMAP、HATU、HBUT、BOP、 DIC或其中两种或两种以上缩合剂混合，优选EDCI、DMAP和HOBT混合缩合剂，所述反应温度为10℃～30℃。
本发明的有益效果为：本发明提供了一种米力农杂质的制备方法，经还原、叠氮化、叠氮还原、与氰基乙酸缩合四步反应合成目标化合物，路线设计合理，可操作性强，反应可控，通过大量实验筛选出最优的反应条件和最佳的反应步骤，制备得到的产物纯度高达99.0％以上，本发明的米力农杂质可以为米力农的临床研究提供测试样品，在临床药代动力学研究中具有重要研究价值。
附图说明
图1为本发明米力农杂质的制备方法的工艺流程图。
具体实施方式
实施例1
(1)取24.4g的(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮溶于360mL的甲醇中，分批加入4.8g的硼氢化钠，室温搅拌反应3小时后，薄层色谱显示反应完全，有机相用水洗涤，无水硫酸钠干燥后，浓缩得到21g黄棕色油状化合物B，收率85.17％；
(2)取21g的化合物B溶于210mL的甲苯中，加入叠氮磷酸二苯酯，在 30℃搅拌反应4小时，薄层色谱显示反应完全，混合液中加入200mL水，产物用二氯甲烷萃取，有机相用无水硫酸钠干燥得到22g化合物C，收率92.72％；
(3)取16g的化合物C溶于320mL的甲醇和64mL的水中，加入40g的三苯基膦，25℃反应2小时，薄层色谱显示反应完全，反应液浓缩干后得到15g 化合物D；
(4)取15g的化合物D溶于420mL的二氯甲烷中，依次加入6g的氰基乙酸，14.5g的EDCI，2g的DMAP，10g的HOBT，在20℃搅拌反应2小时，薄层色谱显示反应完全，反应液浓缩干，硅胶柱纯化得到9.3g目标化合物E，收率56％；化合物E：MS:282[M+H]；1H NMR:(400MHz,CDCl3):δ1.45(d,6H), 3.38(d,2H),4.10(m,1H),5.02(m,1H),6.55(s,1H),7.20(dd,2H),7.65(br,1H), 8.50(dd,1H)。
实施例2
(1)取24.4g的(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮溶于360mL的甲醇中，分批加入6.8g的硼氢化钾，室温搅拌反应3小时后，薄层色谱显示反应完全，有机相用水洗涤，无水硫酸钠干燥后，浓缩得到21g黄棕色油状化合物B，收率85.17％；
(2)取21g的化合物B溶于210mL的甲苯中，加入叠氮化钠，在30℃搅拌反应4小时，薄层色谱显示反应完全，混合液中加入200mL水，产物用二氯甲烷萃取，有机相用无水硫酸钠干燥得到22g化合物C，收率92.72％；
(3)取16g的化合物C溶于320mL的乙醇和64mL的水中，加入18g的三乙基膦，25℃反应2小时，薄层色谱显示反应完全，反应液浓缩干后得到15g 化合物D；
(4)取15g的化合物D溶于420mL的二氯甲烷中，依次加入6g的氰基乙酸，14.5g的EDCI，2g的DMAP，10g的HOBT，在30℃搅拌反应3小时，薄层色谱显示反应完全，反应液浓缩干，硅胶柱纯化得到9.3g目标化合物E，收率56％；化合物E：MS:282[M+H]；1H NMR:(400MHz,CDCl3):δ1.45(d,6H), 3.38(d,2H),4.10(m,1H),5.02(m,1H),6.55(s,1H),7.20(dd,2H),7.65(br,1H), 8.50(dd,1H)。
实施例3
(1)取24.4g的(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮溶于360mL的甲醇中，分批加入6.8g的硼氢化钾，室温搅拌反应4小时后，薄层色谱显示反应完全，有机相用水洗涤，无水硫酸钠干燥后，浓缩得到21g黄棕色油状化合物B，收率85.17％；
(2)取21g的化合物B溶于210mL的甲苯中，加入叠氮化钠，在30℃搅拌反应5小时，薄层色谱显示反应完全，混合液中加入200mL水，产物用二氯甲烷萃取，有机相用无水硫酸钠干燥得到22g化合物C，收率92.72％；
(3)取16g的化合物C溶于320mL的乙醇和64mL的水中，加入11.6g的三甲基膦，25℃反应2小时，薄层色谱显示反应完全，反应液浓缩干后得到15g 化合物D；
(4)取15g的化合物D溶于420mL的二氯甲烷中，依次加入6g的氰基乙酸，14.5g的EDCI，2g的DMAP，10g的HOBT，在40℃搅拌反应6小时，薄层色谱显示反应完全，反应液浓缩干，硅胶柱纯化得到9.3g目标化合物E，收率56％；化合物E：MS:282[M+H]；1H NMR:(400MHz,CDCl3):δ1.45(d,6H), 3.38(d,2H),4.10(m,1H),5.02(m,1H),6.55(s,1H),7.20(dd,2H),7.65(br,1H), 8.50(dd,1H)。
实施例4
(1)取24.4g的(Z)-4-乙氧基-3-(4-吡啶基)-3-烯-2-丁酮溶于360mL的甲醇中，分批加入6.8g的硼氢化钾，室温搅拌反应2小时后，薄层色谱显示反应完全，有机相用水洗涤，无水硫酸钠干燥后，浓缩得到21g黄棕色油状化合物B，收率85.17％；
(2)取21g的化合物B溶于210mL的甲苯中，加入叠氮化钠，在30℃搅拌反应5小时，薄层色谱显示反应完全，混合液中加入200mL水，产物用二氯甲烷萃取，有机相用无水硫酸钠干燥得到22g化合物C，收率92.72％；
(3)取16g的化合物C溶于320mL的乙醇和64mL的水中，加入30.8g的三丁基膦，25℃反应3小时，薄层色谱显示反应完全，反应液浓缩干后得到15g 化合物D；
(4)取15g的化合物D溶于420mL的二氯甲烷中，依次加入6g的氰基乙酸，14.5g的EDCI，2g的DMAP，10g的HOBT，在50℃搅拌反应10小时，薄层色谱显示反应完全，反应液浓缩干，硅胶柱纯化得到9.3g目标化合物E，收率56％；化合物E：MS:282[M+H]；1H NMR:(400MHz,CDCl3):δ1.45(d,6H), 3.38(d,2H),4.10(m,1H),5.02(m,1H),6.55(s,1H),7.20(dd,2H),7.65(br,1H), 8.50(dd,1H)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

1.一种米力农杂质的制备方法，其特征在于，包括以下步骤：
取(Z)-4-乙氧基-3-（4-吡啶基）-3-烯-2-丁酮溶于有机溶剂中，加入还原剂，所述(Z)-4-乙氧基-3-（4-吡啶基）-3-烯-2-丁酮与还原剂的摩尔比为1:1~1:2，在-10℃~30℃条件下搅拌反应1小时~5小时，得到化合物(B)；
（2）取化合物(B)溶于非极性溶剂中，化合物(B)与甲苯的体积比为6~25倍体积，加入叠氮化试剂，化合物(B)与叠氮化试剂的摩尔比为1:0.5~1:5，在0℃~50℃下搅拌2小时~5小时，再经柱层析纯化得到化合物(C)；
（3）取化合物(C)溶于极性溶剂和水的混合溶剂中，加入还原剂，化合物(C)与还原剂的摩尔比为1:1~1:4，20℃~50℃下搅拌1小时~3小时，得到化合物(D)；
（4）取化合物(D)溶于有机溶剂中，加入缩合剂，化合物(D)与缩合剂的摩尔比为1:1~1:2，加入氰基乙酸，化合物(D)与氰基乙酸的摩尔比为1:1~1:3，在10℃~50℃下搅拌反应1小时~15小时至原料消失，经柱层析得到目标化合物(E)。
2.根据权利要求1所述的米力农杂质的制备方法，其特征在于，步骤(1)所述溶剂为甲醇、乙醇、异丙醇或水与其的混合溶剂，所述还原剂为硼氢化钠、硼氢化钾或硼氢化锂。
3.根据权利要求1或2所述的米力农杂质的制备方法，其特征在于，步骤(1)所述溶剂为甲醇，所述还原剂为硼氢化钠。
4.根据权利要求1所述的米力农杂质的制备方法，其特征在于，步骤(2)中所述非极性溶剂为苯、甲苯、四氢呋喃、丙酮或乙腈，所述叠氮化试剂为叠氮磷酸二苯酯、叠氮化钠、叠氮三甲基硅烷或叠氮化四丁基铵。
5.根据权利要求1或4所述的米力农杂质的制备方法，其特征在于，步骤(2)中所述非极性溶剂为甲苯，所述叠氮化试剂为叠氮磷酸二苯酯。
6.根据权利要求1所述的米力农杂质的制备方法，其特征在于，步骤(3)所述极性溶剂为甲醇、乙醇、异丙醇或水与其的混合溶剂，所述还原剂为三苯基膦、三乙基膦、三甲基膦、三丁基膦、硼氢化钠、硼氢化锂或硼氢化钾。
7.根据权利要求1或6所述的米力农杂质的制备方法，其特征在于，步骤(3)所述极性溶剂为甲醇，所述还原剂为三苯基膦。
8.根据权利要求1所述的米力农杂质的制备方法，其特征在于，步骤(4)所述有机溶剂为二氯甲烷、氯仿、DMF、DMAC、乙腈、丙酮或四氢呋喃，所述缩合剂为DCC、EDCI、HOBT、CDI、DMAP、HATU、HBUT、BOP、DIC或其中两种或两种以上缩合剂混合。
9.根据权利要求1或8所述的米力农杂质的制备方法，其特征在于，步骤(4)所述缩合剂为EDCI、DMAP和HOBT混合缩合剂。
10.根据权利要求1所述的米力农杂质的制备方法，其特征在于，步骤(1)所述反应时间为2小时~4小时，步骤(4)所述反应温度为10℃~30℃。
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