CN104961674B - 用于合成依托考昔的对照品的制备方法 - Google Patents

用于合成依托考昔的对照品的制备方法 Download PDF

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CN104961674B
CN104961674B CN201510437924.2A CN201510437924A CN104961674B CN 104961674 B CN104961674 B CN 104961674B CN 201510437924 A CN201510437924 A CN 201510437924A CN 104961674 B CN104961674 B CN 104961674B
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etoricoxib
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CN104961674A (zh
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张庆华
陈波
徐广宇
高清姣
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GUANGDONG JIDA GENETIC MEDICINE ENGINEERING RESEARCH CENTER Co.,Ltd.
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HUNAN FANGSHENG PHARMACEUTICAL CO Ltd
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    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals

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  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于有机合成的技术领域，公开了一种新的化合物，该化合物具有式A的结构，它是依托考昔的制备过程中产生的一种杂质。本发明公开了其产生的来源以及制备方法，方便在合成依托考昔时提供对照品，辨别此类杂质，从而避免或减少此类杂质的产生。

Description

用于合成依托考昔的对照品的制备方法
技术领域
本发明属于药物合成的领域，涉及一种非甾体抗炎药依托考昔制备过程中所使用的对照品的制备方法。
背景技术
依托考昔商品名为安康信，最早由Merck公司研发成功，2002年在墨西哥上市，分子式为：C18H15ClN2O2S，化学名为：5-氯-6-甲基-3-[4-(甲磺酰基)苯基]-2,3-联吡啶。结构式为：
依托考昔是一种高选择性地环氧化酶-2(COX-2)抑制剂，目前已被全球70多个国家证明可被用于治疗类风湿性关节炎、银屑病关节炎、强直性脊柱炎、慢性腰痛、急性疼痛、骨关节炎、痛风等疾病。
专利US5861419、EP6040319等报道依托考昔的合成方法为：以对甲砜基苯乙酸与6-甲基烟酸甲酯为原料，在格氏试剂作用下缩合制得关键中间体1-(6-甲基-3-吡啶基)-2-[4-(甲磺酰基)苯基]乙酮(化合物C)，然后与2-氯-N,N-二甲氨基三亚甲基六氟磷酸盐进行加成、环合得到依托考昔，具体合成路线如方案1所示：
EP2551265报道了在合成依托考昔关键中间体化合物C的过程中，会产生一种性质与其非常相似的物质，即1-(6-甲基-3-吡啶基)-2-[[4-[6-甲基3-吡啶基]-2-氧代乙基]苯基]磺酰基乙酮(化合物D)，很难通过重结晶等常规方法将其除去，通常会留在中间产物中进入下一步反应体系，最终会与2-氯-N,N-二甲氨基三亚甲基六氟磷酸盐进一步反应生成另一种难以除去的杂质2-((4-(5-氯-6'-甲基-[2,3'-联吡啶]-3-基)苯基)磺酰基)-1-(6-甲基吡啶-3-基)乙酮，即化合物A。因此，在依托考昔的工业合成中，总是需要杂质化合物A作为对照品，以跟踪反应体系中化合物A的生成情况。
为了获得化合物A，本发明的发明人原先是通过柱层析分离化合物C粗产品时收集杂质化合物D，然后通过高效制备液相色谱进行提纯，最后将提纯的化合物D与2-氯-N,N-二甲氨基三亚甲基六氟磷酸盐反应，得到化合物A(Scheme2)。
这种制备方法非常艰难，因为在制备化合物C时，所生成的化合物D的含量很低，不超过4％，想富集到足以合成化合物A的量，需要花费大量的劳动。
因此为了方便在合成依托考昔时提供对照品，辨别此类杂质，从而避免或减少此类杂质的产生，提供一种此类杂质的制备方法十分必要。
发明内容
本发明第一方面提供化合物2-((4-(5-氯-6'-甲基-[2,3'-联吡啶]-3-基)苯基)磺酰基)-1-(6-甲基吡啶-3-基)乙酮(化合物A)的合成方法，其反应方程式为：
本发明第二方面提供1-(6-甲基-3-吡啶基)-2-[[4-[6-甲基3-吡啶基]-2-氧代乙基]苯基]磺酰基乙酮(化合物D)的合成方法，其反应式如下：
本发明的上述方法所合成的化合物A和D可以作为工业合成非甾体抗炎药依托考昔过程中的杂质对照品。使用该方法，反应原料易得，合成方法也很简单。
具体实施方式
本发明中，将化合物B或者C溶于有机溶剂中，然后加入6-甲基烟酸甲酯以及强碱，搅拌反应1-12h，生成化合物A或者D。反应完毕后，加入水，用二氯甲烷或者乙酸乙酯萃取，减压抽除溶剂，经柱层析纯化得白色固体或淡黄色固体。优选使用的溶剂包括四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、甲醇、乙醇、异丙醇，其中更优选四氢呋喃；使用的强碱可以是叔丁醇钾、叔丁醇锂、甲醇钠、乙醇钠、氢化钠、丁基锂中的一种，其中优选叔丁醇钾；反应物B或者C的质量与有机溶剂的体积比为1:5-1:15(优选1:10)；化合物B或者C与6-甲基烟酸甲酯及强碱的摩尔比为1:1.0-3.0:1.0-3.0(优选1:1.5:1.5)；反应温度为0℃-溶剂回流温度(优选溶剂回流温度)。
以下结合具体实施例对本发明作进一步详细说明，但不应构成对本发明的限制。
实施例1
将1.44g(4.0mmol)依托考昔、0.60g(4.0mmol)6-甲基烟酸甲酯、0.22g(4.0mmol)甲醇钠与6ml二氯甲烷混合，室温反应10h。TLC监测反应完毕后，加入15ml水，15ml二氯甲烷，分液，水相用二氯甲烷萃取(15ml×2)，合并二氯甲烷，用饱和食盐水洗涤两次，分液，有机相用无水硫酸钠干燥，减压抽除溶剂，经柱层析纯化得1.10g白色固体，即化合物A，收率57.9％，m.p.187-189℃。EIMS m/z(％):478.0(M+,100).
1H NMR(500MHz,CDCl3):δ2.588(s,3H),2.658(s,3H),4.739(s,2H),7.126(d,J＝8.5Hz,1H),7.316(d,J＝8.5Hz,1H),7.390(d,J＝8.5Hz,2H),7.498(s,1H),7.762(d,J＝2.5Hz,1H),7.858(d,J＝8Hz,2H),8.161(m,1H),8.491(d,J＝2.0Hz,1H),8.732(d,J＝2.5Hz,1H),9.023(d,J＝2.0Hz,1H).13C NMR(125MHz,CDCl3):24.270,24.981,63.688,122.693,123.426,128.722,129.164,130.326,131.092,131.136,135.173,136.812,137.362,137.906,138.040,144.490,148.528,149.836,150.332,152.405,158.602,164.915,186.676.
实施例2
将1.44g(4.0mmol)依托考昔、0.73g(4.8mmol)6-甲基烟酸甲酯、0.19g(4.8mmol)氢化钠(含量为60％)与12ml四氢呋喃混合，加热至回流反应4h。TLC检测反应完毕后，缓慢加入15ml水，15ml二氯甲烷，分液，水相用二氯甲烷萃取(15ml×2)，合并二氯甲烷，用饱和食盐水洗涤两次，分液，有机相用无水硫酸钠干燥，减压抽除溶剂，经柱层析纯化得1.01g白色固体，即化合物A，收率52.9％。
实施例3
将2.88g(8.0mmol)依托考昔、1.81g(12.0mmol)6-甲基烟酸甲酯、1.35g(12.0mmol)叔丁醇钾与25ml四氢呋喃混合，加热至回流反应4h。TLC检测反应完毕后，缓慢加入30ml水，35ml二氯甲烷，分液，水相用二氯甲烷萃取(35ml×2)，合并二氯甲烷，用饱和食盐水洗涤两次，分液，有机相用无水硫酸钠干燥，减压抽除溶剂，经柱层析纯化得2.32g白色固体，即化合物A，收率60.7％。
实施例4
1,3-双(6-甲基吡啶-3-基)-2-[4-(甲磺酰基)苯基]丙烷-1,3-二酮的制备
将1.74g(6.0mmol)化合物C、1.36g(9.0mmol)6-甲基烟酸甲酯、1.01g(9.0mmol)叔丁醇钾与21mL四氢呋喃混合，加热至回流反应3h。TLC检测反应完毕后，缓慢加入30mL水，40mL二氯甲烷，分液，水相用二氯甲烷萃取(40mL×2)，合并二氯甲烷，用饱和食盐水洗涤两次，分液，有机相用无水硫酸钠干燥，减压抽除溶剂，经柱层析纯化得1.56g淡黄色固体，即化合物D，收率63.8％,m.p.167.5-169.5℃。EIMS m/z(％):408.0(M+,100).
1H NMR(500MHz,CDCl3):δ2.655(d,J＝2.0Hz,6H),4.382(s,2H),4.701(s,2H),7.307(dd,J＝5.5Hz,2H),7.465(d,J＝8.0Hz,2H),7.872(d,J＝8.0Hz,2H),8.160(m,2H),9.028(d,J＝2.0Hz,1H),9.122(d,J＝2.0Hz,1H).13C NMR(500MHz,CDCl3):δ24.859,24.954,45.190,63.614,123.415,123.588,128.801,128.912,129.099,130.689,136.135,136.820,137.440,140.972,149.515,150.297,164.055,164.791,186.782,194.634。

Claims (10)

1.一种用于合成依托考昔的对照品化合物Ａ的制备方法，其通过下述反应制得：
2.权利要求1所述的制备方法，其中，所用的有机溶剂为四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、甲醇、乙醇和异丙醇中的一种。
3.权利要求1所述的制备方法，其中，所述的强碱为叔丁醇钾、叔丁醇锂、甲醇钠、乙醇钠、氢化钠和丁基锂中的一种。
4.权利要求1所述的制备方法，其中，依托考昔与6-甲基烟酸甲酯及强碱的摩尔比为1:1.5:1.5。
5.权利要求1所述的制备方法，其中，使用的有机溶剂是四氢呋喃，使用的强碱是叔丁醇钾。
6.一种用于合成依托考昔的对照品化合物Ｄ的制备方法，其通过下述反应制得：
7.权利要求6所述的制备方法，其中，所用的有机溶剂为四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、甲醇、乙醇和异丙醇中的一种。
8.权利要求6所述的制备方法，其中，所述的强碱为叔丁醇钾、叔丁醇锂、甲醇钠、乙醇钠、氢化钠和丁基锂中的一种。
9.权利要求6所述的制备方法，其中，化合物Ｃ与6-甲基烟酸甲酯及强碱的摩尔比为1:1.5:1.5。
10.权利要求6所述的制备方法，其中，使用的有机溶剂是四氢呋喃，使用的强碱是叔丁醇钾。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1681763A (zh) * 2002-07-27 2005-10-12 阿斯特拉曾尼卡有限公司 化合物
CN102898357A (zh) * 2011-07-29 2013-01-30 意大利合成制造有限公司 用于制备依托考昔的中间体1-(6-甲基吡啶-3-基)-2-[4-(甲磺酰基)苯基]乙酮的新方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1681763A (zh) * 2002-07-27 2005-10-12 阿斯特拉曾尼卡有限公司 化合物
CN102898357A (zh) * 2011-07-29 2013-01-30 意大利合成制造有限公司 用于制备依托考昔的中间体1-(6-甲基吡啶-3-基)-2-[4-(甲磺酰基)苯基]乙酮的新方法

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