CN106565540A - 苯甲脒衍生物的合成方法 - Google Patents

苯甲脒衍生物的合成方法 Download PDF

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CN106565540A
CN106565540A CN201610965142.0A CN201610965142A CN106565540A CN 106565540 A CN106565540 A CN 106565540A CN 201610965142 A CN201610965142 A CN 201610965142A CN 106565540 A CN106565540 A CN 106565540A
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benzamidoxime
ethanol
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柳东虹
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
    • B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
    • B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
    • B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明通过使用离子液体负载的金属纳米催化剂绿色、高效地完成由苯甲腈类原料制备苯甲脒衍生物的反应，催化剂活性高，可回收。苯甲腈与盐酸羟胺形成苄胺肟，然后在离子液体负载的金属纳米催化剂催化下，加氢还原得到苯甲脒。

Description

苯甲脒衍生物的合成方法
技术领域
本发明属于有机合成领域，涉及医药、农药等化合物中间体，具体涉及苯甲脒衍生物的合成方法。
背景技术
脒类化合物在农药和医药上具有很广泛的用途，是重要的医药、农药等中间体类化合物，被广泛的用于抗生素、消炎药和驱虫剂等药物。某些脒类的盐曾经被用作治疗血吸虫的药物；一些长链烷氧基取代的苯甲脒盐具有表面活性剂的作用，被称为杀虫脒。此外，脒类化合物还广泛被用于合成噻唑、咪唑、嘧啶还等含氮杂环化合物，这些化合物在医药、农药领域具有极其重要的作用，大量药物、农药分子中均含有此类杂环。此外，脒类还在其他领域有着广泛的应用，因此，合成领域有非常多的研究，关注其合成方法。
经典的合成方法有Prinner反应，腈类经过醇解和氨解反应植被得到脒类；CN103086920起始物与盐酸羟胺形成苄胺肟，通过盐酸与铁粉或锌粉还原得到邻乙氧基苯甲脒；CN1830955邻乙氧基苯甲腈与盐酸羟胺在乙醇中回流反应制得邻乙氧基苄胺肟，使用Pd/C等加氢还原制备邻乙氧基苯甲脒；“催化加氢制备对羟基苯甲脒”，蔡亮，程原 - 《化工中间体》 – 2008通过兰尼镍催化加氢还原制备对羟基苄胺肟制备得到对羟基苯甲脒；“对氨基苯甲脒二盐酸盐合成工艺改进”，韦长梅，嵇鸣 - 《化工时刊》 - 1998以对硝基苯甲酸为起始原料,经过氰基化、酯化、氨解和还原反应合成对氨基苯甲脒二盐酸盐,改进工艺中用还原铁粉作还原剂,用对甲苯磺酰胺作氰基化试剂。
众多方法，不论其优缺点，都有其独特的应用领域。也许氢气危险易爆炸，但是其仍然是应用最广、工业化最佳选择的加氢还原方式；也许盐酸-锌粉或铁粉体系酸污染、废渣多，但是更安全。各有利弊，而本发明则是提出一种新颖的高效、绿色的制备苯甲脒类衍生物的方法。
发明内容
本发明所述的苯甲脒衍生物的合成方法，反应如下所示
其中R和R’为C1-12烷基（甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等），C1-12烷氧基（甲氧基、乙氧基等），卤素，硝基，氨基，羟基，C3-12芳基等。
所述方法由下述步骤组成：
A. 将苯甲腈衍生物与盐酸羟胺在溶剂中反应制得对应的苄胺肟；
B. 将苄胺肟在催化剂条件下加氢（0.1-1MPa）还原制备得到苯甲脒(或其盐)；
C. 如果有必要，重结晶，或者将苯甲脒盐中和制备得到苯甲脒；
其中，催化剂为离子液体负载的Ni(0)催化剂，其制备过程如下：
1. 甲基咪唑与1,4-二溴丁烷在溶剂中反应制备得到MIM-(CH2)4-MIM·2Br；
2. MIM-(CH2)4-MIM·2Br-与NaBF4离子交换制备MIM-(CH2)4-MIM·2BF4；
3. NiCl2与MIM-(CH2)4-MIM·2BF4溶解在溶剂中，加入水合肼，除溶剂，得到负载催化剂。
上述所有步骤溶剂均可以为甲醇、乙醇、异丙醇、氯仿、二氯甲烷等本领域常见使用的溶剂。
具体实施方式
实施例1
0.1mol 1-甲基咪唑与0.05mol 1,4-二溴丁烷在150ml二氯甲烷中60℃搅拌反应2h，然后加入0.1mol的NaBF4，继续加热回流1h，趁热过滤，母液减压除去溶剂，几乎定量得到MIM-(CH2)4-MIM·2BF4；收率98%，黄褐色；（此步骤对于纯度要求不高，简单处理即可）；
产物全部溶于400ml乙醇，加入0.45g无水二氯化镍充分搅拌溶解，缓慢加入10ml水合肼，密封反应器，室温磁力搅拌12h，减压除去溶剂，真空干燥，得到黄褐色加深的MIM-(CH2)4-MIM·2BF4负载Ni(0)催化剂。
实施例2
0.05mol对硝基苯甲腈、0.06mol盐酸羟胺、0.03mol碳酸钾溶解在100ml 90%乙醇中（含水10%），搅拌反应至无气泡生成，升温至80℃反应1h，减压除去大部分溶剂；冷却得到白色固体结晶；固体溶于50ml无水乙醇加入10g实施例1制备的催化剂，通氢气0.15MPa（先吹扫，后密闭），室温反应4h；减压除去乙醇，20ml甲苯萃取，重复萃取2次，合并甲苯相。催化剂留在反应器中不必操作，待循环使用。减压蒸馏甲苯溶液即可得到对氨基苯甲脒，总收率95%，HPLC纯度99.3%。
实施例3
继续在实施例2的反应器中进行循环反应10次，催化剂活性未见降低。

Claims (4)

1.一种苯甲脒衍生物的合成方法，反应式为如下
其特征在于：
A. 将苯甲腈衍生物与盐酸羟胺反应制得对应的苄胺肟；
B. 将苄胺肟还原制备得到苯甲脒；
其中，其中R和R’为C1-12烷基（甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等），C1-12烷氧基（甲氧基、乙氧基等），卤素，硝基，氨基，羟基，C3-12芳基等；
A和B步骤均在溶剂中进行，溶剂选自甲醇、乙醇、异丙醇、氯仿、二氯甲烷等；
B步骤的还原反应在催化剂的存在下室温使用氢气还原，其催化剂通过如下步骤制备：
0.1mol 1-甲基咪唑与0.05mol 1,4-二溴丁烷在150ml二氯甲烷中60℃搅拌反应2h，然后加入0.1mol的NaBF4，继续加热回流1h，趁热过滤，母液减压除去溶剂；产物全部溶于400ml乙醇，加入0.45g无水二氯化镍充分搅拌溶解，缓慢加入10ml水合肼，密封反应器，室温磁力搅拌12h，减压除去溶剂，真空干燥。
2.如权利要求1所述的方法，其中R为4-硝基时候R’为4-氨基。
3.如权利要求1所述的方法，其中R为2-乙氧基。
4.如权利要求1所述的方法制备得到的产品。
CN201610965142.0A 2016-11-05 2016-11-05 苯甲脒衍生物的合成方法 Withdrawn CN106565540A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440149A (zh) * 2020-03-31 2020-07-24 浙江美诺华药物化学有限公司 一种达比加群酯中间体的制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440149A (zh) * 2020-03-31 2020-07-24 浙江美诺华药物化学有限公司 一种达比加群酯中间体的制备方法

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Application publication date: 20170419