CN103497149A - 一种5-氨甲基吡啶衍生物的制备方法 - Google Patents

一种5-氨甲基吡啶衍生物的制备方法 Download PDF

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CN103497149A
CN103497149A CN201310465395.8A CN201310465395A CN103497149A CN 103497149 A CN103497149 A CN 103497149A CN 201310465395 A CN201310465395 A CN 201310465395A CN 103497149 A CN103497149 A CN 103497149A
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邹正才
康柳
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Bio Tech Ltd Is Revived In Nanjing
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    • C07—ORGANIC CHEMISTRY
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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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    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • 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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Abstract

本发明提供的一种5-氨甲基吡啶衍生物的制备方法，包括以下步骤：3位取代的5-羟甲基吡啶、叠氮试剂、催化试剂反应，得3位取代的5-叠氮甲基吡啶；3位取代的5-叠氮甲基吡啶与还原剂反应，即得。该制备方法，工艺简单、条件温和、操作安全、收率高。

Description

一种5-氨甲基吡啶衍生物的制备方法
技术领域
本发明属于化学合成领域，特别涉及一种5-氨甲基吡啶衍生物的制备方法。
背景技术
5-氨甲基吡啶衍生物是一类重要的医药中间体，如5-氨甲基烟酸甲酯、5-氨甲基-3-溴吡啶均可用于制备多种重要的原料药。5-氨甲基吡啶衍生物通常采用将5-羟甲基吡啶衍生物中的羟基进行官能团转化制得。例如，专利US2006287522A1中公开了一种以5-羟甲基-3-溴吡啶为原料，经卤代替、胺化两步制得5-氨甲基-3-溴吡啶，然而，该方法收率较低，仅为36%。
发明内容
发明目的：本发明的目的在于提供工艺简单、反应条件温和的5-氨甲基吡啶衍生物的制备方法。
技术方案：本发明提供的一种5-氨甲基吡啶衍生物的制备方法，包括以下步骤：
（1）3位取代的5-羟甲基吡啶、叠氮试剂、催化试剂反应，得3位取代的5-叠氮甲基吡啶；
（2）3位取代的5-叠氮甲基吡啶与还原剂反应，即得。
步骤（1）中，3位取代的5-羟甲基吡啶、叠氮试剂和催化试剂的摩尔比为1.0:1.0-3.0:0.1-3.0；反应温度为-5℃到溶剂的回流温度，反应时间为3-30h。
步骤（1）中，所述叠氮试剂为叠氮钠、叠氮磷酸二苯酯或对乙酰氨基苯磺酰叠氮。
步骤（1）中，所述催化试剂选自碱性催化试剂、相转移催化剂和羟基活化剂中的一种或几种；其中，所述碱性催化试剂为非亲核性有机碱，所述非亲核性有机碱包括三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和喹啉；所述相转移催化剂包括四丁基溴化铵和四丁基碘化胺；所述羟基活化剂包括对甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、2,4,6-三异丙基苯磺酰氯、对甲基苯磺酰咪唑、2,4,6-三甲基苯磺酰咪唑和2,4,6-三异丙基苯磺酰咪唑。
步骤（1）中，反应体系的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、甲苯、乙酸乙酯、甲基叔丁基醚或石油醚。
步骤（2）中，还原剂选自氢气、水合肼、甲酸、甲酸盐、硼氢化钠和1,4-二氢吡啶及其衍生物中的一种或几种组合；反应体体系中还包括催化剂，所述催化剂选自钯碳、三碘化铝、过渡金属（如镁、钙及锌）、三氟化硼***和三苯基膦中的一种或几种。
步骤（2）中，反应温度为-5℃到溶剂的回流温度，反应时间为0.5-30h，优选8-16h。
步骤（2）中，反应体系的溶剂为低碳烷烃醇（如甲醇、乙醇及异丙醇等）、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸或甲酸。
反应方程式如下：
Figure BDA0000392280080000021
其中，R为卤素或酯基，优选溴或甲酸酯基
有益效果：本发明提供的5-氨甲基吡啶衍生物的制备方法，工艺简单、条件温和、操作安全、收率高。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例15-氨甲基-3-溴吡啶的制备
5-氨甲基-3-溴吡啶的制备，采用以下工艺：
（1）5-叠氮甲基-3-溴吡啶的制备：在三颈瓶中分别加入1.00g5-羟甲基-3-溴吡啶，2.63g叠氮磷酸二苯酯与10mL四氢呋喃；氮气保护下，将反应体系冷却到10℃以下，将0.89g1,8-二氮杂二环[5.4.0]十一碳-7-烯滴加到反应液中，室温反应12h。减压浓缩去除挥发物，柱层析得5-叠氮甲基-3-溴吡啶0.98g。
（2）5-氨甲基-3-溴吡啶的制备：将0.98g5-叠氮甲基-3-溴吡啶溶解于20ml THF和2ml水中，在冰水浴下加入2.41g三苯基膦，5℃下反应16h；乙酸乙酯萃取，浓缩，柱层析得到产品0.70g。
总收率为70%。
反应式如下：
MS:[M+H]+188&186.
实施例25-氨甲基-3-溴吡啶的制备
5-氨甲基-3-溴吡啶的制备，采用以下工艺：
（1）5-叠氮甲基-3-溴吡啶的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-溴吡啶，0.1mol叠氮磷酸二苯酯与50mL甲苯；氮气保护下，将反应体系冷却到10℃以下，将0.01mol四丁基溴化铵滴加到反应液中，回流反应8h。减压浓缩去除挥发物，柱层析得5-叠氮甲基-3-溴吡啶。
（2）5-氨甲基-3-溴吡啶的制备：将0.05mol5-叠氮甲基-3-溴吡啶溶解于20ml甲醇和2ml水中，在冰水浴下加入5mmol钯碳，-5℃下反应30h；乙酸乙酯萃取，浓缩，柱层析得到产品。
实施例35-氨甲基-3-溴吡啶的制备
5-氨甲基-3-溴吡啶的制备，采用以下工艺：
（1）5-叠氮甲基-3-溴吡啶的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-溴吡啶，0.3mol叠氮磷酸二苯酯与50mL N,N-二甲基甲酰胺；氮气保护下，将反应体系冷却到10℃以下，将0.1mol四丁基碘化铵、0.1mol N,N-二异丙基乙胺、0.05mol对甲基苯磺酰氯、0.05mol2,4,6-三甲基苯磺酰氯滴加到反应液中，室温反应16h。减压浓缩去除挥发物，柱层析得5-叠氮甲基-3-溴吡啶。
（2）5-氨甲基-3-溴吡啶的制备：将0.05mol5-叠氮甲基-3-溴吡啶溶解于20ml N,N-二甲基甲酰胺和2ml水中，在冰水浴下加入5mmol三氯化铝，室温下反应8h；乙酸乙酯萃取，浓缩，柱层析得到产品。
实施例45-氨甲基-3-溴吡啶的制备
5-氨甲基-3-溴吡啶的制备，采用以下工艺：
（1）5-叠氮甲基-3-溴吡啶的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-溴吡啶，0.2mol叠氮磷酸二苯酯与50mL甲基叔丁基醚；氮气保护下，将反应体系冷却到10℃以下，将0.1mol四丁基碘化铵、0.1mol N,N-二异丙基乙胺、0.05mol对甲基苯磺酰氯、0.05mol2,4,6-三甲基苯磺酰氯滴加到反应液中，室温反应12h。减压浓缩去除挥发物，柱层析得5-叠氮甲基-3-溴吡啶。
（2）5-氨甲基-3-溴吡啶的制备：将0.05mol5-叠氮甲基-3-溴吡啶溶解于20ml乙酸和2ml水中，在冰水浴下加入5mmol氯化镁、5mmol三氟化硼***，回流反应0.5h；乙酸乙酯萃取，浓缩，柱层析得到产品。
实施例55-氨甲基-3-烟酸吡啶的制备
5-氨甲基烟酸甲酯的制备，采用以下工艺：
（1）5-叠氮基甲基烟酸甲酯的制备：在三颈瓶中分别加入8.00g5-羟甲基烟酸甲酯、23.70g叠氮磷酸二苯酯与80mL四氢呋喃；氮气保护下，将反应体系冷却到10℃以下，将8.00g1,8-二氮杂二环[5.4.0]十一碳-7-烯滴加到反应液中，室温反应12h，减压浓缩去除挥发物，柱层析得5-叠氮基甲基烟酸甲酯8.55g，收率93%。
（2）5-氨甲基烟酸甲酯的制备：在三颈瓶中分别加入1.00g5-叠氮基甲基烟酸甲酯，20ml THF和2ml水，在冰水浴下加入2.73g三苯基膦，-5℃下反应30h；乙酸乙酯萃取，浓缩，柱层析得到产品0.79g，收率91%。
反应式如下：
Figure BDA0000392280080000041
HPLC含量：99.3%；
1H NMR(300M Hz,DMSO-d6)δ(ppm)3.81(s,2H),3.89(s,3H),8.27(m,1H),8.74(d,J=1.8Hz,1H),8.92(d,J=2.1Hz,1H);
MS:[M+H]+167.
实施例65-氨甲基-3-烟酸吡啶的制备
5-氨甲基烟酸甲酯的制备，采用以下工艺：
（1）5-叠氮基甲基烟酸甲酯的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-烟酸吡啶，0.1mol叠氮磷酸二苯酯与50mL N,N-二甲基乙酰胺；氮气保护下，将反应体系冷却到10℃以下，将0.02mol对甲基苯磺酰咪唑、0.03mol2,4,6-三甲基苯磺酰咪唑、0.05mol三乙胺滴加到反应液中，-5℃反应16h。减压浓缩去除挥发物，柱层析得5-叠氮基甲基烟酸甲酯。
（2）5-氨甲基-3-烟酸吡啶的制备：将5-叠氮基甲基烟酸甲酯溶解于20ml甲酸和2ml水中，在冰水浴下加入5mmol氯化锌，5℃下反应8h；乙酸乙酯萃取，浓缩，柱层析得到产品。
实施例75-氨甲基-3-烟酸吡啶的制备
5-氨甲基烟酸甲酯的制备，采用以下工艺：
（1）5-叠氮基甲基烟酸甲酯的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-烟酸吡啶，0.3mol叠氮磷酸二苯酯与50mL乙酸乙酯；氮气保护下，将反应体系冷却到10℃以下，将0.05mol喹啉、0.05mol2,4,6-三异丙基苯磺酰咪唑滴加到反应液中，回流反应8h。减压浓缩去除挥发物，柱层析得5-叠氮基甲基烟酸甲酯。
（2）5-氨甲基-3-烟酸吡啶的制备：将5-叠氮基甲基烟酸甲酯溶解于20ml N,N-二甲基乙酰胺和2ml水中，在冰水浴下加入5mmol三碘化铝，室温下反应16h；乙酸乙酯萃取，浓缩，柱层析得到产品。
实施例85-氨甲基-3-烟酸吡啶的制备
5-氨甲基烟酸甲酯的制备，采用以下工艺：
（1）5-叠氮基甲基烟酸甲酯的制备：在三颈瓶中分别加入0.1mol5-羟甲基-3-烟酸吡啶，0.2mol叠氮磷酸二苯酯与50mL石油醚；氮气保护下，将反应体系冷却到10℃以下，将0.2mol2,4,6-三异丙基苯磺酰氯滴加到反应液中，室温反应12h。减压浓缩去除挥发物，柱层析得5-叠氮基甲基烟酸甲酯。
（2）5-氨甲基-3-烟酸吡啶的制备：将5-叠氮基甲基烟酸甲酯溶解于20ml异丙醇和2ml水中，在冰水浴下加入5mmol三氟化硼***，回流反应0.5h；乙酸乙酯萃取，浓缩，柱层析得到产品。

Claims (10)

1.一种5-氨甲基吡啶衍生物的制备方法，其特征在于：包括以下步骤： 
（1）3位取代的5-羟甲基吡啶、叠氮试剂、催化试剂反应，得3位取代的5-叠氮甲基吡啶； 
（2）3位取代的5-叠氮甲基吡啶与还原剂反应，即得。 
2.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（1）中，3位取代基为卤素或酯基。 
3.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（1）中，3位取代的5-羟甲基吡啶、叠氮试剂和催化试剂的摩尔比为1.0:1.0-3.0:0.1-3.0；反应温度为-5℃到溶剂的回流温度，反应时间为3-30h。 
4.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（1）中，所述叠氮试剂为叠氮钠、叠氮磷酸二苯酯或对乙酰氨基苯磺酰叠氮。 
5.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（1）中，所述催化试剂选自碱性催化试剂、相转移催化剂和羟基活化剂中的一种或几种。 
6.根据权利要求4所述的一种5-氨甲基烟酸的制备方法，其特征在于：所述碱性催化试剂为非亲核性有机碱，所述非亲核性有机碱包括三乙胺、N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯和喹啉；所述相转移催化剂包括四丁基溴化铵和四丁基碘化胺；所述羟基活化剂包括对甲基苯磺酰氯、2,4,6-三甲基苯磺酰氯、2,4,6-三异丙基苯磺酰氯、对甲基苯磺酰咪唑、2,4,6-三甲基苯磺酰咪唑和2,4,6-三异丙基苯磺酰咪唑。 
7.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（1）中，反应体系的溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、甲苯、乙酸乙酯、甲基叔丁基醚或石油醚。 
8.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（2）中，还原剂选自氢气、水合肼、甲酸、甲酸盐、硼氢化钠和1,4-二氢吡啶及其衍生物中的一种或几种组合；反应体体系中还包括催化剂，所述催化剂选自钯碳、三碘化铝、过渡金属、三氟化硼***和三苯基膦中的一种或几种。 
9.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（2）中，反应温度为-5℃到溶剂的回流温度，反应时间为0.5-30h。 
10.根据权利要求1所述的一种5-氨甲基烟酸的制备方法，其特征在于：步骤（2）中， 反应体系的溶剂为低碳烷烃醇、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙酸或甲酸。 
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