CN110759860B - 一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法 - Google Patents

一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法 Download PDF

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CN110759860B
CN110759860B CN201810841709.2A CN201810841709A CN110759860B CN 110759860 B CN110759860 B CN 110759860B CN 201810841709 A CN201810841709 A CN 201810841709A CN 110759860 B CN110759860 B CN 110759860B
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叶彬彬
王池雅
刘丽
潘晨
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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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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
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    • 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
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Abstract

本发明涉及医药合成领域，具体涉及3‑甲酸甲酯‑4‑甲氧基‑5‑氰基吡啶式I及其中间体的制备方法。该制备方法以4‑羟基烟酸为起始原料，经过溴化、甲基化、氰基取代三步反应，制备目标产物3‑甲酸甲酯‑4‑甲氧基‑5‑氰基吡啶式I。其中氰基取代一步，采用氰化亚铜进行氰基取代，优于其他氰基化合物的取代合成。本发明原料简便，反应条件温和，后处理简单，适合于工业化生产。

Description

一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法
技术领域
本发明涉及医药合成领域，具体涉及3-甲酸甲酯-4-甲氧基-5-氰基吡啶及其中间体制备方法。
背景技术
具有下列式b结构的化合物为5-溴-4-羟基吡啶-3-甲酸：
Figure BDA0001745723900000011
是一种医药中间体。可用来制备吡咯酮的类似物，该类似物可作为一种强有力的激酶抑制剂。该类似物具有如下的式2和3，
Figure BDA0001745723900000012
也可用来制备具有Ax1抑制活性的吡咯酮衍生物，Axl是Tyro3Axl Mer(TAM)受体酷氨酸激酶家族的受体酪氨酸激酶，其具有生长停滞特异性基因6(Gas6)蛋白作为配体并最初被识别为慢性粒细胞白血病中的转化基因。具有如下式4，
Figure BDA0001745723900000013
杂志Journal of Medicinal Chemistry(2008),51(17),5330-5341.和第一三共株式会社的中国专利申请号为201380017353.6(申请日：2013-1-30)专利提供了上述5-溴-4-羟基吡啶-3-甲酸式b的制备方法，其中起始原料为如下的式1化合物，
Figure BDA0001745723900000021
该反应需要在-78℃的低温环境下与干冰进行，因此成本较高，不太适合产业化。
未见文献公开具有下列式c结构的中间体，以及具有下列式I结构化学名称为3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法。
Figure BDA0001745723900000022
发明内容
本发明的制备3-甲酸甲酯-4-甲氧基-5-氰基吡啶的方法以4-羟基烟酸为起始原料，经过溴化、甲基化、氰基取代三步反应，最终合成目标产物3-甲酸甲酯-4-甲氧基-5-氰基吡啶。
为实现本发明的技术目的，本发明提供了如下的技术方案：
一种具有下列式c结构的化合物的制备方法，由具有下列式b结构的化合物经甲基化制备得到，
Figure BDA0001745723900000023
所述反应试剂为碘甲烷，硫酸二甲酯，甲苯磺酸甲酯，三氟甲磺酸甲酯，碳酸二甲酯，氟磺酸甲酯；
所述反应溶剂优选为N，N-二甲基甲酰胺和二氯甲烷；
所述反应温度范围为10～70℃，优选为20～30℃。
本发明第二方面提供了一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I的制备方法，由具有下列式b结构的化合物经甲基化制备得到下列式c结构的化合物，再由具有下列式c结构的化合物经氰化制备得到，具体方案如下：
Figure BDA0001745723900000031
所述氰化反应步骤反应试剂为氰化亚铜；
所述氰化反应步骤反应溶剂优选为N，N-二甲基甲酰胺；
所述氰化反应步骤反应温度范围为80～170℃，优选为100～150℃。
本发明第三方面提供了一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I的制备方法，以4-羟基烟酸式a为起始原料，经过溴化、甲基化、氰基取代三步反应制备,具体方案如下：
Figure BDA0001745723900000032
所述溴化反应步骤反应试剂为溴化试剂；
所述溴化反应步骤反应溶剂优选为N，N-二甲基甲酰胺；
所述溴化反应步骤反应温度范围为30～80℃，优选为50～60℃。
本发明第四方面提供了一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I的制备方法，由下述方法制备得到：
第一步：4-羟基烟酸在溴化试剂作用下制备得到具有式b结构的化合物；
第二步：具有式b结构的化合物经甲基化制备具有式c结构的化合物；
第三步：具有式c结构的化合物经氰化制备得到3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I，
Figure BDA0001745723900000033
所述溴化反应步骤反应试剂为溴化试剂，反应溶剂为N，N-二甲基甲酰胺，反应温度为30～80℃，优选为50～60℃；
所述甲基化反应步骤甲基化试剂为碘甲烷，硫酸二甲酯，甲苯磺酸甲酯，三氟甲磺酸甲酯，碳酸二甲酯，氟磺酸甲酯，优选为碘甲烷，反应溶剂为N，N-二甲基甲酰胺和二氯甲烷，反应温度为10～70℃，优选为20～30℃；
所述氰化反应步骤反应试剂优选为氰化亚铜，反应溶剂为N，N-二甲基甲酰胺，反应温度为80～170℃，优选为100～150℃。
本发明第五方面提供了一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I的制备方法，由具有下列式c结构的化合物经氰化反应制备得到，具体方案如下：
Figure BDA0001745723900000041
所述氰化反应步骤反应试剂为氰化亚铜；
所述氰化反应步骤反应溶剂为N，N-二甲基甲酰胺；
所述氰化反应步骤反应温度为80～170℃，优选为100～150℃。
按照上述方法制备得到的3-甲酸甲酯-4-甲氧基-5-氰基吡啶的，原料简便，反应条件温和，后处理简单，适合于工业化生产。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明提供的3-甲酸甲酯-4-甲氧基-5-氰基吡啶的制备方法、其中间体及其制备方法进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。
实施例1：
Figure BDA0001745723900000042
往25ml四口烧瓶中投入：1g化合物a、10mlDMF、升温至溶清(60～70℃即可)，冷却至10～20℃，缓慢滴加2.5gBr2，滴加时间1～1.5h，滴毕，升温至50～60℃，保温0.5～1h，监控原料＜3.5％，反应毕。反应液冷却至20～30℃，缓慢滴加至20～30℃下的35mlH2O中，大量白色物料析出，滴加完毕，搅拌0.5～1h，抽滤，20～35mlH2O洗涤，湿品60～70℃鼓风干燥。收干品1.1g，收率70.19％。
实施例2：
Figure BDA0001745723900000051
20～30℃下往50ml烧瓶中投入1.1g化合物b、20mlDMF、2.1g K2CO3，缓慢滴加3.0gCH3I。滴毕，中控中间态甲基化完全，抽滤，淋洗，滤液真空蒸干，加入30gDCM20～30℃下剧烈打浆，抽滤，淋洗，得到物料，60～65℃真空干燥，得到干品，收率98.92％。
实施例3：
Figure BDA0001745723900000052
往50ml四口瓶中投入：2.6gCuCN，30mlDMF，升温至100℃，加入4.58g化合物c，150℃保温搅拌。保温毕，抽滤，浓缩，过柱，得到产物。

Claims (1)

1.一种3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I的制备方法，其特征在于，由下述方法制备得到，
第一步：4-羟基烟酸在溴化试剂作用下制备得到具有式b结构的化合物；
第二步：具有式b结构的化合物经甲基化制备具有式c结构的化合物；
第三步：具有式c结构的化合物经氰化制备得到3-甲酸甲酯-4-甲氧基-5-氰基吡啶式I；
溴化反应步骤反应试剂为溴化试剂，反应溶剂为N，N-二甲基甲酰胺，反应温度为30-80℃；甲基化反应步骤甲基化试剂为碘甲烷，硫酸二甲酯，甲苯磺酸甲酯，三氟甲磺酸甲酯，碳酸二甲酯，氟磺酸甲酯，反应溶剂为N，N-二甲基甲酰胺和二氯甲烷，反应温度为10-70℃；氰化反应步骤反应试剂氰化亚铜，反应溶剂为N，N-二甲基甲酰胺，反应温度为80-170℃；
Figure DEST_PATH_IMAGE002
。
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