CN113354579B - 一种4-氨基烟酸甲酯的高收率合成方法 - Google Patents
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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Abstract
本发明公开了一种4‑氨基烟酸甲酯的高收率合成方法，以3,4‑吡啶二羧酸为原料，经过分子内脱水取代、氨气氨化、改良型NBS霍夫曼重排后水解得到所述4‑氨基烟酸甲酯。本发明合成方法，操作更加简单，反应条件温和，总收率也更高，具有极高的应用价值。
Description
技术领域
本发明属于化学制药领域，具体涉及一种4-氨基烟酸甲酯的高收率合成方法。
背景技术
4-氨基烟酸甲酯是一种常用的医药中间体，其传统的合成方法主要由以下两种方法：
以3-甲基吡啶为起始原料，先氧化生成吡啶氮氧化物，再经硝化、还原引入氨基，氨基保护后，高锰酸钾氧化甲基、氨基去保护，最后进行酯化反应，经七步反应完成4-氨基烟酸甲酯的合成，合成路线如下所示。该法的关键中间体3-甲基-4-硝基吡啶氮氧化物具有***性，操作不安全；甲基的高锰酸钾氧化、硝基的铁粉还原收率均不高、反应后处理繁琐；氨基的保护、去保护操作不可避免，导致合成路线长，不宜大规模制备。
以3,4-吡啶二羧酸为原料，先与乙酸酐作用下分子内脱水得3,4-吡啶二甲酸酐，在经氨水氨化、霍夫曼降解、酯化得到目标产物，合成路线如下所示。该方法操作复杂，生产能耗高，收率低，据文献介绍收率为70％左右。
发明内容
本发明针对现有技术存在的不足，提供了一种4-氨基烟酸甲酯的高收率合成方法。本发明以3,4-吡啶二羧酸为原料，先与乙酸酐作用下分子内脱水得3,4-吡啶二甲酸酐，然后第二步溶剂换为二氯甲烷，氨水换为氨气进行氨化，使得本步反应更加完全，3-羧酸-4-酰胺吡啶中间体的产率提高，接着进行改良型NBS霍夫曼重排反应，最后直接进行水解反应即可得到4-氨基烟酸甲酯。
本发明4-氨基烟酸甲酯的高收率合成方法，包括以下步骤：
步骤1：将3,4-吡啶二羧酸、乙酸酐加入反应瓶，控制温度115℃反应，TLC监测，约2-3h反应完毕后，减压浓缩，蒸去乙酸和乙酸酐，剩余油状物冷却至室温变为固体，得到3,4-吡啶二甲酸酐；
步骤2：将3,4-吡啶二甲酸酐溶于溶剂中，室温下(20℃-30℃)通入氨气进行反应，TLC监测，约2-3h反应完毕后，用盐酸调pH至4左右，有固体析出，过滤后再用蒸馏水洗涤，抽滤烘干得3-羧酸-4-酰胺吡啶；
步骤3：将3-羧酸-4-酰胺吡啶、碱和甲醇加入带有回流装置的圆底三口烧瓶中，升温至65℃，回流15min后，缓慢加入氧化剂，继续回流反应，通过TLC监测，约1.5h反应完毕后，直接进行下一步反应，加入一定催化量的酸和两个当量的蒸馏水(以3-羧酸-4-酰胺吡啶为基准)，继续加热回流，点板观察，反应完毕后，乙酸乙酯萃取，减压弄缩，蒸去溶剂，烘干得4-氨基烟酸甲酯。
步骤2中，所述溶剂为二氯甲烷。
步骤2中，盐酸的浓度为20％。
步骤3中，所述氧化剂为NBS，所述碱为甲醇钠。
步骤3中，4-(氨基羰基)-3-吡啶羧酸和甲醇钠的摩尔比为1:2，4-(氨基羰基)-3-吡啶羧酸和NBS的摩尔比为1:1.1。
步骤3中，所述酸一般为强酸，如盐酸、硫酸等。
步骤3中，前一步反应完成后可以直接进行下一步水解反应，减少步骤操作，并提高产率。
本发明合成路线如下所示：
本发明合成方法以3,4-吡啶二羧酸为原料，经过分子内脱水取代、氨气氨化、改良型NBS霍夫曼重排后水解得到所述4-氨基烟酸甲酯，操作更加简单，反应条件温和，总收率高，具有极高的应用价值。
附图说明
图1为本发明所用原料3,4-吡啶二羧酸的核磁共振氢谱图。
图2为本发明所得产品4-氨基烟酸甲酯的核磁共振氢谱图。
具体实施方式
下面通过具体的实施例对本发明技术方案作进一步阐述，这些实施例只是为了说明问题，并不是一种限制。
实施例1：
本实施例中4-氨基烟酸甲酯的高收率合成方法包括以下步骤：
1、3,4-吡啶二甲酸酐的合成
将3,4-吡啶二羧酸(70g,0.42mol)和乙酸酐(180ml,1.91mol)加入反应瓶中，油浴加热至115℃，搅拌反应，TLC监测，约2-3h后反应完毕，减压浓缩，剩余的油状物降至室温变为固体，得到3,4-吡啶二甲酸酐55g,收率87.8％,HPLC纯度为98％。
2、3-羧酸-4-酰胺吡啶的合成
将上述3,4-吡啶二甲酸酐(50g,0.34mol)和200ml二氯甲烷加入反应瓶中，室温下(20℃-30℃)通入氨气进行反应，TLC监测，约2-3h后反应完毕，用盐酸调pH至4左右，有固体物析出，过滤，蒸馏水洗涤，干燥后得3-羧酸-4-酰胺吡啶51.3g,收率90.8％,HPLC纯度为98.4％。
3、4-氨基烟酸甲酯的合成
将3-羧酸-4-酰胺吡啶(20g,0.12mol)、甲醇钠(13g,0.24mol)和100ml甲醇加入带有回流装置的圆底三口烧瓶中，升温至65℃，回流15min后，缓慢加入NBS(23.5g,0.132mol),继续回流反应，TLC监测，约1.5h后反应完毕，加入15ml盐酸和5ml的蒸馏水，继续加热回流，点板观察，约0.5h反应完毕，用乙酸乙酯萃取三次，减压浓缩，蒸去溶剂，固体烘干得4-氨基烟酸甲酯16.1g,收率88.2％，HPLC纯度99.3％。
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
实施例2：
本实施例中4-氨基烟酸甲酯的高收率合成方法包括以下步骤：
1、3,4-吡啶二甲酸酐的合成
将3,4-吡啶二羧酸(70g,0.42mol)和乙酸酐(180ml,1.91mol)加入反应瓶中，油浴加热至115℃，搅拌反应，TLC监测，约2-3h后反应完毕，减压浓缩，剩余的油状物降至室温变为固体，得到3,4-吡啶二甲酸酐56.1g,收率89.6％,HPLC纯度为96.8％。
2、3-羧酸-4-酰胺吡啶的合成
将上述3,4-吡啶二甲酸酐(50g,0.34mol)和200ml二氯甲烷加入反应瓶中，室温下(20℃-30℃)通入氨气进行反应，TLC监测，约2-3h后反应完毕，用盐酸调pH至4左右，有固体物析出，过滤，蒸馏水洗涤，干燥后得3-羧酸-4-酰胺吡啶50.2g,收率89％,HPLC纯度为98.6％。
3、4-氨基烟酸甲酯的合成
将3-羧酸-4-酰胺吡啶(20g,0.12mol)、甲醇钠(13g,0.24mol)和100ml甲醇加入带有回流装置的圆底三口烧瓶中，升温至65℃，回流15min后，缓慢加入NBS(23.5g,0.132mol),继续回流反应，TLC监测，约1.5h后反应完毕，加入15ml盐酸和5ml的蒸馏水，继续加热回流，点板观察，约0.5h反应完毕，用乙酸乙酯萃取三次，减压浓缩，蒸去溶剂，固体烘干得4-氨基烟酸甲酯16.4g,收率89.8％，HPLC纯度98.1％。
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
实施例3：
本实施例中4-氨基烟酸甲酯的高收率合成方法包括以下步骤：
1、3,4-吡啶二甲酸酐的合成
将3,4-吡啶二羧酸(70g,0.42mol)和乙酸酐(180ml,1.91mol)加入反应瓶中，油浴加热至115℃，搅拌反应，TLC监测，约2-3h后反应完毕，减压浓缩，剩余的油状物降至室温变为固体，得到3,4-吡啶二甲酸酐55.4g,收率88.5％,HPLC纯度为97.5％。
2、3-羧酸-4-酰胺吡啶的合成
将上述3,4-吡啶二甲酸酐(50g,0.34mol)和200ml二氯甲烷加入反应瓶中，室温下(20℃-30℃)通入氨气进行反应，TLC监测，约2-3h后反应完毕，用盐酸调pH至4左右，有固体物析出，过滤，蒸馏水洗涤，干燥后得3-羧酸-4-酰胺吡啶49.7g,收率88.1％,HPLC纯度为99.1％。
3、4-氨基烟酸甲酯的合成
将3-羧酸-4-酰胺吡啶(20g,0.12mol)、甲醇钠(13g,0.24mol)和100ml甲醇加入带有回流装置的圆底三口烧瓶中，升温至65℃，回流15min后，缓慢加入NBS(23.5g,0.132mol),继续回流反应，TLC监测，约1.5h后反应完毕，加入15ml盐酸和5ml的蒸馏水，继续加热回流，点板观察，约0.5h反应完毕，用乙酸乙酯萃取三次，减压浓缩，蒸去溶剂，固体烘干得4-氨基烟酸甲酯16.2g,收率88.7％，HPLC纯度99％。
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J＝5.9Hz,1H),7.24(s,2H),6.68(d,J＝6.2Hz,1H),3.81(s,3H).
通过以上三个实施例可得出以下结论：
1、在合成3,4-吡啶二甲酸酐时，应当加入过量的乙酸酐，使其能与3,4-吡啶二羧酸能够充分的反应，从而提高3,4-吡啶二甲酸酐的产率。
2、在合成3-羧酸-4-酰胺吡啶时，应当让氨气与反应液充分地接触，使3,4-吡啶二甲酸酐能够充分的反应，从而提高3-羧酸-4-酰胺吡啶的产率。
3、在合成4-氨基烟酸甲酯时，应当加入过量的NBS，使3-羧酸-4-酰胺吡啶能够充分的反应，从而提高最终产品4-氨基烟酸甲酯的产率。
本发明所提供的实验路径可行，所得最终产品4-氨基烟酸甲酯的产率和纯度也较之前方法有较大的提升。
本发明提供了一种4-氨基烟酸甲酯的高收率合成方法，以3,4-吡啶二羧酸为原料，经过分子内脱水取代、氨气氨化、改良型NBS霍夫曼重排后水解得到所述4-氨基烟酸甲酯，反应条件温和，总收率在85％以上，据文献所介绍的总收率70％有较大提高，并且操作也更加简化，具有极高的应用。
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，在不脱离发明原理的前提下，还可以做出若干改进，这些改进也应视为本发明的保护范围。
Claims (4)
1.一种4-氨基烟酸甲酯的高收率合成方法，其特征在于：
以3,4-吡啶二羧酸为原料，经过分子内脱水取代、氨气氨化、改良型NBS霍夫曼重排后水解得到目标产物4-氨基烟酸甲酯；合成路线如下所示：
包括以下步骤：
步骤1：将3,4-吡啶二羧酸、乙酸酐加入反应瓶，控制温度115℃反应，TLC监测反应完毕，减压浓缩，蒸去乙酸和乙酸酐，剩余油状物冷却至室温变为固体，得到3,4-吡啶二甲酸酐；
步骤2：将3,4-吡啶二甲酸酐溶于溶剂二氯甲烷中，室温下通入氨气进行反应，TLC监测反应完毕，用盐酸调pH至4，有固体析出，过滤后再用蒸馏水洗涤，抽滤烘干得3-羧酸-4-酰胺吡啶；
步骤3：将3-羧酸-4-酰胺吡啶、甲醇钠和甲醇加入带有回流装置的圆底三口烧瓶中，升温至65℃，回流15min后，缓慢加入氧化剂NBS，继续回流反应，通过TLC监测反应完毕，直接进行下一步反应，加入一定催化量的酸和以3-羧酸-4-酰胺吡啶为基准当量下两个当量的蒸馏水，继续加热回流，反应完毕后乙酸乙酯萃取，减压浓缩，蒸去溶剂，烘干得4-氨基烟酸甲酯。
2.根据权利要求1所述的合成方法，其特征在于：
步骤2中，盐酸的浓度为20％。
3.根据权利要求1所述的合成方法，其特征在于：
步骤3中，4-(氨基羰基)-3-吡啶羧酸和甲醇钠的摩尔比为1:2，4-(氨基羰基)-3-吡啶羧酸和NBS的摩尔比为1:1.1。
4.根据权利要求1所述的合成方法，其特征在于：
步骤3中，所述酸为盐酸或硫酸。
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