CN109694347A - 一种2-甲酰异烟酸的制备方法 - Google Patents

一种2-甲酰异烟酸的制备方法 Download PDF

Info

Publication number
CN109694347A
CN109694347A CN201811620472.1A CN201811620472A CN109694347A CN 109694347 A CN109694347 A CN 109694347A CN 201811620472 A CN201811620472 A CN 201811620472A CN 109694347 A CN109694347 A CN 109694347A
Authority
CN
China
Prior art keywords
isonicotinic acid
formyl
preparation
methyl
iodine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201811620472.1A
Other languages
English (en)
Inventor
翁智兵
田苗
李耀中
邱玉华
周海平
陈绘如
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Changzhou Vocational Institute of Engineering
Original Assignee
Changzhou Vocational Institute of Engineering
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou Vocational Institute of Engineering filed Critical Changzhou Vocational Institute of Engineering
Priority to CN201811620472.1A priority Critical patent/CN109694347A/zh
Publication of CN109694347A publication Critical patent/CN109694347A/zh
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07D213/803—Processes of preparation

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

本发明公开一种2‑甲酰异烟酸的制备方法，属于有机化学合成领域。该方法是以2‑甲基异烟酸为原料，在碘和二甲基亚砜混合体系中通过加热直接制备得到产物2‑甲酰异烟酸的。本发明公开的2‑甲酰异烟酸的制备方法简单、易操作、原料及试剂简单易得、产率及纯度较高，适于工业化生产应用，该物质作为重要的有机合成中间体，可应用于席夫碱及新型抗肿瘤药物的制备，有广阔的医药应用前景。

Description

一种2-甲酰异烟酸的制备方法
技术领域
本发明属于有机合成、药物中间体开发领域，特别涉及一种2-甲酰异烟酸的制备方法。
背景技术
2-甲酰基吡啶类化合物是一种重要的医药中间体，能够与氨基缩合形成席夫碱，继而与过渡金属形成配合物。该席夫碱类过渡金属配合物具有抗肿瘤、抗病毒、抗菌等多种生物活性。2-甲酰异烟酸作为重要的药物中间体，具有良好的市场前景。
专利WO2006/201801公开了该化合物的制备方法，反应过程如下述路线(1)所示：
上述路线(1)中以2-溴-4甲基吡啶为原料，通过高锰酸钾氧化、钯催化偶联、臭氧氧化等反应步骤制得2-甲酰异烟酸，操作步骤繁琐，试剂昂贵不易得，反应条件苛刻(如需要微波辅助下170℃高温加热)，限制了2-甲酰异烟酸的高效大批量的制备。
专利CN107686464公开了另一种制备方法，反应过程如下述路线(2)所示：
上述路线(2)中以2-甲基异烟酸为原料，通过二氧化硒氧化得到2-甲酰异烟酸。采用了昂贵的重金属氧化剂二氧化硒，成本高，且存在重金属残留等问题，后续处理流程繁琐且处理成本较高，限制了该路线的工业化应用。
因此，有必要设计出一种操作简单、成本低廉，适于大批量合成2-甲酰异烟酸的方法来解决现有技术中存在的不足。
发明内容
针对现有技术中存在的制备原料昂贵，合成步骤繁琐的问题，本发明提供了一种新的2-甲酰异烟酸的制备方法，该制备方法过程简单、易操作，2-甲酰异烟酸的产率和纯度均较高。
本发明的技术方案为：一种2-甲酰异烟酸的制备方法，包括如下步骤：以2-甲基异烟酸为起始原料，与碘混合后在二甲基亚砜中加热反应，TLC监测反应终点，反应液冷却后倒入水中析出固体，抽滤得到粗品，粗品用无水乙醇重结晶，真空干燥，得到2-甲酰异烟酸。
进一步地，2-甲基异烟酸与碘的摩尔比为1:1-5，作为优选，所述2-甲基异烟酸与碘的摩尔比为1:1-2。
进一步地，2-甲基异烟酸与二甲基亚砜的质量比为1：5-50，作为优选，2-甲基异烟酸与二甲基亚砜的质量比为1:5-20。
进一步地，热反应温度为80-150℃，作为优选，热反应温度为120-150℃。
进一步地，加热反应时间为0.5-10小时，作为优选，加热反应时间为0.5-2小时。
本发明制备的2-甲酰异烟酸的结构式如下：
本发明的具体反应路线如下：
本发明的有益效果是：
本发明以2-甲基异烟酸为原料，在碘和二甲基亚砜的混合体系中通过加热直接制备得到产物2-甲酰异烟酸，制备方法简单、易操作、原料及试剂简单易得、制备成本低廉、产率及纯度较高，适于大批量工业化生产；本发明制备的2-甲酰异烟酸，作为重要的有机合成中间体，可应用于席夫碱及新型抗肿瘤药物的制备，具备广阔的医药领域应用前景。
附图说明
图1是本发明实施例1制备的2-甲酰异烟酸的1H-NMR谱图。
具体实施方式
以下实施例进一步说明本发明的内容，但不应理解为对本发明的限制。在不背离本发明实质的情况下，对本发明方法、步骤或条件所作的修改和替换，均属于本发明的范围。
实施例1
将2-甲基异烟酸(10.0g，73.0mmol)，碘(20.3g，80.3mmol)加入到120mL二甲基亚砜中，升温至120℃，磁力搅拌反应1小时，TLC检测反应完全，反应液冷却至室温，倒至400mL蒸馏水中，固体析出，抽滤，石油醚洗涤，所得粗品用无水乙醇重结晶，真空干燥得2-甲酰异烟酸，收率70％，纯度98％。
1H NMR(400MHz,CDCl3)δ10.15(s,1H),8.95(dd,J＝4.9,0.8Hz,1H),8.49(dd,J＝1.6,0.9Hz,1H),8.09(dd,J＝4.9,1.6Hz,1H).
实施例2
将2-甲基异烟酸(10.0g，73.0mmol)，碘(20.3g，80.3mmol)加入到120mL二甲基亚砜中，升温至150℃，磁力搅拌反应1小时。TLC检测反应完全，反应液冷却至室温，倒至400mL蒸馏水中，固体析出，抽滤，石油醚洗涤，所得粗品用无水乙醇重结晶，真空干燥得2-甲酰异烟酸，收率72％，纯度97％。
实施例3
将2-甲基异烟酸(10.0g,73.0mmol)，碘(20.3g,80.3mmol)加入到120mL二甲基亚砜中，升温至120℃，磁力搅拌反应10小时。TLC检测反应完全，反应液冷却至室温，倒至400mL蒸馏水中，固体析出，抽滤，石油醚洗涤，所得粗品用无水乙醇重结晶，真空干燥得2-甲酰异烟酸，收率72％，纯度96％。
以上显示和描述了本发明的基本原理、主要特征及优点。但是以上所述仅为本发明的具体实施例，本发明的技术特征并不局限于此，任何本领域的技术人员在不脱离本发明的技术方案下得出的其他实施方式均应涵盖在本发明的专利范围之中。

Claims (6)

1.一种2-甲酰异烟酸的制备方法，其特征在于，包括如下步骤：以2-甲基异烟酸为起始原料，与碘混合后在二甲基亚砜中加热反应，TLC检测反应终点，反应液冷却后倒入水中析出固体，抽滤得到粗品，粗品用无水乙醇重结晶，真空干燥，得到2-甲酰异烟酸；
其中，2-甲基异烟酸与碘的摩尔比为1:1-5，2-甲基异烟酸与二甲基亚砜的质量比为1：5-50，热反应温度为80-150℃，加热反应时间为0.5-10小时。
2.如权利要求1所述的一种2-甲酰异烟酸的制备方法，其特征在于，所述2-甲基异烟酸与碘的摩尔比为1:1-2。
3.如权利要求1所述的一种2-甲酰异烟酸的制备方法，其特征在于，2-甲基异烟酸与二甲基亚砜的质量比为1：5-20。
4.如权利要求1所述的一种2-甲酰异烟酸的制备方法，其特征在于，热反应温度为120-150℃。
5.如权利要求1所述的一种2-甲酰异烟酸的制备方法，其特征在于，加热反应时间为0.5-2小时。
6.如权利要求1所述的一种2-甲酰异烟酸的制备方法，其特征在于，具体反应路线如下：
CN201811620472.1A 2018-12-27 2018-12-27 一种2-甲酰异烟酸的制备方法 Pending CN109694347A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811620472.1A CN109694347A (zh) 2018-12-27 2018-12-27 一种2-甲酰异烟酸的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811620472.1A CN109694347A (zh) 2018-12-27 2018-12-27 一种2-甲酰异烟酸的制备方法

Publications (1)

Publication Number Publication Date
CN109694347A true CN109694347A (zh) 2019-04-30

Family

ID=66232949

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811620472.1A Pending CN109694347A (zh) 2018-12-27 2018-12-27 一种2-甲酰异烟酸的制备方法

Country Status (1)

Country Link
CN (1) CN109694347A (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048399A (zh) * 2004-08-26 2007-10-03 库多斯药物有限公司 4－杂芳基甲基取代的酞嗪酮衍生物
CN107686464A (zh) * 2017-10-24 2018-02-13 锦州医科大学 一种2‑甲酰基‑4‑吡啶羧酸的合成方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048399A (zh) * 2004-08-26 2007-10-03 库多斯药物有限公司 4－杂芳基甲基取代的酞嗪酮衍生物
CN107686464A (zh) * 2017-10-24 2018-02-13 锦州医科大学 一种2‑甲酰基‑4‑吡啶羧酸的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ABDUL RAHIM,等: "Iodine mediated oxidative cross-coupling of unprotected anilines and heteroarylation of benzothiazoles with 2-methylquinoline", 《ORG. BIOMOL. CHEM.》 *

Similar Documents

Publication Publication Date Title
CN108047107B (zh) 二苯基二硒醚类化合物的制备方法
CN103570617B (zh) 一种3-氰基-吡啶n-氧化物的制备方法
CN105294558A (zh) 一种2-氰基-3-(8-羟基喹啉-5-基)丙烯酸及其制备方法和用途
CN104926798A (zh) 阿法替尼中间体的高纯度制备方法
CN102079737A (zh) 一种制备芹菜素的方法
CN102992376A (zh) 一种片状纳米氧化铈的制备方法
CN103755645A (zh) 一种化合物吡咯烷基二氨基嘧啶氧化物的合成工艺
CN104086545A (zh) 1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-甲脒盐酸盐的合成方法
CN109694347A (zh) 一种2-甲酰异烟酸的制备方法
CN103626697B (zh) 一种2‑氯‑4‑三氟甲基‑3‑氰基吡啶的制备方法
CN107936048A (zh) 一种2‑氟‑4‑甲基‑3‑吡啶硼酸的制备方法
CN110627754B (zh) 一种利用连续流微通道反应器制备2-氧代-2-呋喃基乙酸的方法
CN102146113B (zh) 一种16α-羟基泼尼松龙合成方法
CN107382819A (zh) 一种3‑硫代吲哚类化合物的制备方法
CN107325078B (zh) 一种西洛他唑的制备方法
CN106632075B (zh) 一种2,4,6-三苯基嘧啶类衍生物的合成方法
CN102659757B (zh) 一种合成5-氯-3-噻吩甲醛的中间体及其制备方法
CN107686464A (zh) 一种2‑甲酰基‑4‑吡啶羧酸的合成方法
CN109438422A (zh) 一种奥希替尼杂质及其制备方法
CN112321525B (zh) 一种一步法合成3,4-双(4’-氨基呋咱-3’-基)氧化呋咱的方法
CN110577496A (zh) 一种尿嘧啶的制备方法
CN105037261B (zh) 一种合成米力农的方法
CN104230717B (zh) 一种制备2,2′-二(三氟甲基)-4,4′-二硝基二苯醚的方法
CN109336936A (zh) 一种异帕米星的精制方法
CN104496892A (zh) 一种合成4-二甲氨基吡啶的新工艺

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20190430

RJ01 Rejection of invention patent application after publication