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CN116162055B - 一种用n-氧化吡啶衍生物制备哌啶衍生物的方法 - Google Patents

一种用n-氧化吡啶衍生物制备哌啶衍生物的方法 Download PDF

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CN116162055B
CN116162055B CN202310226204.6A CN202310226204A CN116162055B CN 116162055 B CN116162055 B CN 116162055B CN 202310226204 A CN202310226204 A CN 202310226204A CN 116162055 B CN116162055 B CN 116162055B
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pyridine
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piperidine
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CN116162055A (zh
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姜斌
孙秀伟
郑颜旭
李清霞
王欢
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Shandong Huizhi Pharmaceutical Research Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

本发明公开了一种用N‑氧化吡啶衍生物制备哌啶衍生物的方法，属于药物中间体合成领域。该方法以吡啶衍生物为原料经过氧化反应制备N‑氧化吡啶衍生物，然后经过还原得到哌啶衍生物。本发明提供了一种用N‑氧化吡啶衍生物制备哌啶衍生物的方法，该方法操作简单，反应过程可控，无需高压加氢环境与贵金属催化剂。

Description

一种用N-氧化吡啶衍生物制备哌啶衍生物的方法
技术领域
本发明属于药物中间体合成领域，涉及一种用N-氧化吡啶衍生物制备哌啶衍生物的方法。
背景技术
吡啶环的还原反应是有机合成非常重要的一类反应，其还原产物哌啶或者四氢吡啶等含氮杂环是众多药物及生物活性分子的构成片段。催化氢化是还原吡啶的常用方法，然而，已知方法多使用贵金属，例如钯碳、铑碳、钌碳、铂碳等，且反应条件剧烈，通常需要5-7MPa氢气环境，安全隐患较大，经济性和官能团兼容性都不够理想。
近年来，随着“受阻路易斯酸碱对(FLP)”化学的发展，陆续出现了几例有机硼催化吡啶还原的报道，包括氢化、硅氢化、硼氢化、转移氢化等反应。然而，氢化和转移氢化反应必须使用含大位阻邻位取代基的吡啶底物，以防止氮原子对催化剂的毒化。另外，这些反应大多不能兼容羰基、烯烃、氰基、硝基等易还原取代基。王晓晨课题组(Angew.Chem.Int.Ed.2017,56,5817–5820)在吡啶还原研究中取得了重要进展。该课题组使用B(C6F5)3作为催化剂，二苯基硅烷(或频哪醇硼烷)和二苯胺作为氢源，实现了吡啶的串联还原反应。该反应对于不同位置(邻、间、对位)取代的吡啶底物均有很好的适用性，且对非活化烯基、羰基、烷氧基、硝基、氰基、富电子杂环等官能团具有很好的兼容性。但是催化剂B(C6F5)3不易制备，价格昂贵，用量较大，不易回收，收率从62％-90％不等，难以实现工业化生产。
发明内容
本发明针对现有技术上的不足，提供一种用N-氧化吡啶衍生物制备哌啶衍生物的方法。该方法以吡啶衍生物为原料经过氧化反应制备N-氧化吡啶衍生物，然后经过还原得到哌啶衍生物，具体合成路线如下。
S1氧化反应：吡啶衍生物和氧化剂在溶剂中反应得到N-氧化吡啶衍生物；合成路线中R可为吡啶环2位取代基、3位取代基、4位取代基中的一种或者多种，R取代基为烃基、羧基、卤素、氨基、酰胺、氰基、甲氧基、硝基中的一种；所述氧化剂为双氧水、间氯过氧苯甲酸、过氧乙酸、过氧单磺酸钾，六水单过氧化酞酸镁中的一种，优选为间氯过氧苯甲酸、过氧乙酸；所述溶剂为甲醇、乙醇、乙腈、二氯甲烷、四氢呋喃、2-甲基四氢呋喃中的一种，优选为二氯甲烷。
S2还原反应：N-氧化吡啶衍生物在溶剂中，加入还原剂，加入碱，升温反应得到哌啶衍生物。所述的溶剂为水、甲醇、乙醇、乙腈中的一种，优选为水、甲醇；所述碱为氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾中的一种，优选为氢氧化钠；所述还原剂为硼氢化钠、硼氢化钾中的一种。
本发明的有益效果：
(1)本发明提供了一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，反应条件温和、高效，避免高温、高压反应条件，降低能耗；(2)避免使用钯碳、铑碳、钌碳、铂碳等贵金属和有机硼试剂作催化剂，降低了生产成本。
具体实施方式
本发明提供的一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，其方法具有通用性，可通过如下方式进行。
N-氧化吡啶衍生物的制备：向反应瓶中加入吡啶衍生物(1mol)，加入溶剂，加入氧化剂(1.5mol)，反应3h，加入饱和碳酸钠溶液洗涤，搅拌半小时，分层，水相用二氯甲烷再萃取一次，合并有机相，干燥，浓缩得到N-氧化吡啶衍生物，无需提纯可进行下一步反应。
哌啶衍生物的制备：向3L反应瓶中加入N-氧化吡啶衍生物(1mol)，加入溶剂，开启搅拌，加入碱调pH＝9-10，分批加入还原剂，加毕，升温至85℃反应3小时，降至室温，加入乙酸乙酯萃取，合并有机相，干燥，浓缩，得到哌啶衍生物粗品，通过重结晶或精馏提纯，得到纯品哌啶衍生物。
实施例1：
N-氧化-3-甲基吡啶的制备：向500mL反应瓶中加入3-甲基吡啶(93.1g，1mol)，加入二氯甲烷(400mL)，开启搅拌，然后加入间氯过氧苯甲酸(258.8g，1.5mol)，升温至35-40℃，反应3h，降至室温，加入饱和碳酸钠溶液(500mL)洗涤，搅拌半小时，分层，水相用二氯甲烷(200mL)再萃取一次，合并有机相，干燥，浓缩得到N-氧化-3-甲基吡啶，无需提纯可进行下一步反应。
3-甲基哌啶的制备：向5L反应瓶中加入N-氧化-3-甲基吡啶(109.1g，1mol)，加入水(500mL)，开启搅拌，加入氢氧化钠调pH＝9-10，分批加入硼氢化钠(83.2g，2.2mol)，加毕，升温至85℃反应3小时，降至室温，加入乙酸乙酯(350mL+150mL)萃取，合并有机相，干燥，浓缩，得到3-甲基哌啶粗品，经精馏提纯，得到纯品(91.2g，收率91％，纯度99.3％)。
实施例2：
N-氧化-3-吡啶甲酸的制备：向500mL反应瓶中加入3-吡啶甲酸(123.1g，1mol)，加入乙腈(400mL)，开启搅拌，然后加入过氧乙酸(114.1g，1.5mol)，升温至55-60℃，反应3h，降至室温，加入饱和碳酸钠溶液(500mL)洗涤，搅拌半小时，加入二氯甲烷(400mL+200mL)萃取，合并有机相，干燥，浓缩得到N-氧化-3-吡啶甲酸，无需提纯可进行下一步反应。
3-哌啶甲酸的制备：向5L反应瓶中加入N-氧化-3-吡啶甲酸(139.1g，1mol)，加入水(500mL)，开启搅拌，加入氢氧化钠调pH＝9-10，分批加入硼氢化钠(83.2g，2.2mol)，加毕，升温至85℃反应3小时，降至室温，加入浓盐酸调pH＝6.5-7，加入乙酸叔丁酯(350mL+150mL)萃取，合并有机相，干燥，浓缩，得到3-哌啶甲酸粗品，经乙醇重结晶，得到纯品(115.0g，收率89％，纯度99.1％)。
实施例3：
N-氧化-4-氨基吡啶的制备：向500mL反应瓶中加入4-氨基吡啶(94.1g，1mol)，加入四氢呋喃(400mL)，开启搅拌，然后加入双氧水(170.0g，质量30％，1.5mol)，升温至55-60℃，反应3h，降至室温，加入水(500mL)洗涤，搅拌半小时，加入乙酸乙酯(400mL+200mL)萃取，合并有机相，干燥，浓缩得到N-氧化-4-氨基吡啶，无需提纯可进行下一步反应。
4-氨基哌啶的制备：向5L反应瓶中加入N-氧化-4-氨基吡啶(110.0g，1mol)，加入甲醇(500mL)，开启搅拌，加入氢氧化钠溶液调pH＝9-10，分批加入硼氢化钠(83.2g，2.2mol)，加毕，升温至60℃反应3小时，降至室温，加入乙酸乙酯(350mL+150mL)萃取，合并有机相，干燥，浓缩，得到4-氨基哌啶粗品，经精馏提纯，得到纯品(87.0g，收率87％，纯度99.6％)。
实施例4：
N-氧化-4-吡啶甲酰胺的制备：向500mL反应瓶中加入4-氨基吡啶(122.1g，1mol)，加入二氯甲烷(400mL)，开启搅拌，然后加入间氯过氧苯甲酸(258.9g，1.5mol)，升温至35-40℃，反应3h，降至室温，加入饱和碳酸氢钠溶液(500mL)洗涤，搅拌半小时，加入乙酸乙酯(400mL+200mL)萃取，合并有机相，干燥，浓缩得到N-氧化-4-吡啶甲酰胺粗品，无需提纯可进行下一步反应。
4-哌啶甲酰胺的制备：向5L反应瓶中加入N-氧化-4-吡啶甲酰胺(138.1g，1mol)，加入乙腈(500mL)，开启搅拌，加入氢氧化钠溶液调pH＝9-10，分批加入硼氢化钠(83.2g，2.2mol)，加毕，升温至80℃反应3小时，降至室温，加入乙酸乙酯(350mL+150mL)萃取，合并有机相，干燥，浓缩，得到4-哌啶甲酰胺粗品，经甲醇重结晶，得到纯品(118.0g，收率92％，纯度99.2％)。
上述虽然对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，所属领域技术人员应该明白，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。

Claims (4)

1.一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，其特征在于，所述制备方法合成路线如下：
S1氧化反应：吡啶衍生物和氧化剂在溶剂中反应得到N-氧化吡啶衍生物；
S2还原反应：N-氧化吡啶衍生物在溶剂中，加入还原剂，加入碱，升温反应得到哌啶衍生物，其中所述还原剂为硼氢化钠，所述碱为氢氧化钠；
其中R为吡啶环2位取代基、3位取代基、4位取代基中的一种，R取代基为烃基、羧基、卤素、氨基、氰基、甲氧基、硝基中的一种。
2.根据权利要求1中所述的一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，其特征在于，S1氧化反应中所述氧化剂为双氧水、间氯过氧苯甲酸、过氧乙酸、过氧单磺酸钾、六水单过氧化酞酸镁中的一种。
3.根据权利要求1中所述的一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，其特征在于，S1氧化反应所述溶剂为甲醇、乙醇、乙腈、二氯甲烷、四氢呋喃、2-甲基四氢呋喃中的一种。
4.根据权利要求1中所述的一种用N-氧化吡啶衍生物制备哌啶衍生物的方法，其特征在于，S2还原反应中所述的溶剂为水、甲醇、乙醇、乙腈中的一种。
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