樊后兴还原胺化综述

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高等有机重排反应机理

（1）C3到C8的环扩大已实现，小环产率高，因为角张力的解除提供动力，环缩小已用于四员环和C6到C8的环，环戊基阳离子缩小成环丁基体系，由于张力增大而行不通。
（2）某些羟胺发生环扩大反应：
CH2NH2 HNO2
O
OH
（3）类似的反应如溴代环醇与格氏试剂(起碱的作用)反应消去OH中的质子，加热环扩大。
HCl
N N NH
N2Cl +
NH2
NN
NH2
OH N2Cl +
NN OH
二立体化学的研究
如果反应物有旋光性，可以根据重排产物是否保持其旋光性来判断历程。后面讨论的贝克曼重排，其旋光性重排后保持不变，证明其迁移基团重排过程中未脱离原来分子，否则，生成外消旋产物。
5
三示踪原子法
用示踪原子法的方法，可以得到一些直接有用的信息。 Claisen重排是通过示踪原子方法对其历程进一步确证的。
RCOOH + HN3
RNCO
RNH2
硫酸是常用的催化剂，有时也用Lewis酸做催化剂。长链及有位阻的羧酸反应收率较高。
酮和叠氮酸反应是使NH“插入”到羰基和R基之间，这样把酮转变成酰胺。
R C R' + HN3 H+ O
醛的重排产物通常是腈
R C NH R' O
RCHO + HN3 H
RCN + RNHCHO
CH3
少量
+ CH3
CH3 C CH CH3
CH3
主要（稳定）
CH3 +
CH3 C CH CH3 CH3
10
直接产生重排的碳正离子本身必须稳定下来，通常是失去氢，因此产物多为烯烃。反应特点： (1) 如果失去质子有多种选择的话，产物由Zaitsev规则决定。

醇还原胺化反应催化剂研究进展

CHEMICAL INDUSTRY AND ENGINEERING PROGRESS 2018年第37卷第10期·3832·化工进展醇还原胺化反应催化剂研究进展余秦伟1，2，惠丰1，2，张前1，2，袁俊1，2，王为强1，2，赵锋伟1，2，杨建明1，2，吕剑1，2（1西安近代化学研究所，陕西西安 710065；2氟氮化工资源高效开发与利用国家重点实验室，陕西西安 710065）摘要：醇还原胺化反应是胺合成最有效、最有应用潜力的方法之一，而催化剂是还原胺化反应的关键。

本文详细阐述了Ru 、Ir 、Pd 、Cu 、非金属等均相催化剂和Co 、Ni 、Ru 、Pd 等非均相催化剂在醇还原胺化反应中的研究进展，介绍了不同催化体系的催化性能和反应规律、应用特点和局限性。

指出了均相催化体系的回收使用仍然是阻碍其应用的难题，研究重点应集中在高效、廉价催化体系开发、拓展应用范围和分离回收研究；非均相反应催化剂的专用性强，性能难以满足工业应用需求，加强微观结构及反应机理、高性能催化剂、高压体系中流场状态与过程研究以及提高活性、选择性和稳定性是未来的研究重点。

关键词：醇；还原胺化；催化剂；胺；合成中图分类号：O69 文献标志码：A 文章编号：1000–6613（2018）10–3832–11 DOI ：10.16085/j.issn.1000-6613.2017-2302Progress in the catalyst for reductive amination of alcoholYU Qinwei 1,2, HUI Feng 1,2, ZHANG Qian 1,2, YUAN Jun 1,2, WANG Weiqiang 1,2, ZHAO Fengwei 1,2,YANG Jianming 1,2, LÜ Jian 1,2（1Xi’an Modern Chemistry Research Institute, Xi’an 710065, Shaanxi, China; 2State Key Laboratory of Fluorine &Nitrogen Chemicals, Xi’an 710065, Shaanxi, China ）Abstract ：Reductive amination of alcohol is one of the most effective and promising methods for thesynthesis of amine, and the high-performance catalyst is the core. The progress in homogeneous catalysts of Ru, Ir, Pd, Cu, and nonmetallic ones and heterogeneous catalysts of Co, Ni, Ru, Pd, et al. for reductive amination of alcohols was outlined in detail respectively in this paper. The catalytic performance and reaction regularity of different catalytic systems were discussed together with their respective characteristics and limitations. Finally, it is pointed out that the application of homogeneous catalytic system is limited by the recovery problem. The research should focus on the development of efficient and cheap catalytic systems, the expansion of their applications and the recovery of the catalyst. The heterogeneous reaction catalysts are of high specificity and the performance is difficult to meet the need of industrial application. The studies on the microstructure and the reaction mechanism of high performance catalyst, flow field state and process of high pressure system should be strengthened to improve the activity, selectivity and stability of the catalysts. Key words: alcohol; reductive amination; catalyst; amine; synthesis应用催化研究。

还原胺化最全知识

还原胺化反应
还原胺化反应，又称鲍奇还原（Borch reduction，区别于伯奇Birch还原反应），是一种简便的把醛酮转换成胺的方法.
机理
首先是胺与羰基加成，缩合，生成羰基的结构类似物西弗碱（Schiff Base），后者接受氢供体的氢传递生成最终产物胺。

见图:
方法
将羰基跟胺反应生成亚胺（西弗碱），然后用硼氢化钠或者氰基硼氢化钠还原成胺.反应应在弱酸条件下进行,因为弱酸条件一方面使羰基质子化增强了亲电性促进了反应，另一方面也避免了胺过度质子化造成亲核性下降的发生.用氰代硼氢化钠比硼氢化钠要好,因为氰基的吸电诱导效应削弱了硼氢键的活性,使得氰代硼氢化钠只能选择性地还原西弗碱而不会还原醛、酮的羰基，从而避免了副反应的发生。

改进
用NaBH(OAc)3作还原剂,用ClCH2CH2Cl做溶剂可以缩短反应时间并显著提高产率.
生物体内的反应
生物体内存在类似的过程，是由维生素B6（吡哆醛/胺）和NADPH(大自然的硼氢化钠）来介导的,氨基酸经此可以和酮体（Ketone bodies)相互转换。

引．。

硒催化硼氢化钠还原芳香族硝基化合物制备芳胺

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硒催化硼氢化钠还原芳香族硝基化合物制备芳胺
蔡可迎。赵学娇，姚从兴。王丽
２２１０１８）（徐州工程学院化学化工学以硒粉为催化剂、硼氢化钠为还原剂在温和条件下还原芳香族硝基化舍物制备芳胺。以１０ｍｍｏｌ硝基苯为底物考察了溶剂、反应温度、硼氢化钠及硒粉用量等对苯胺收率的影响。适宜的
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反应条件如下；溶剂为乙醇一水（（乙醇）：Ｖ（水）一３：１），反应温度为５Ｏ℃ ，硒粉用量为０．１ｇ，硼氢化钠用量为１２ｍｍｏｌ。在此条件下，１０种芳香族硝基化合物被还原为相应芳胺的收率为

还原胺化相关机理与反应

还原胺化（reductive Amination）1.定义：胺和羰基化合物缩合得到亚胺，然后通过还原剂（常用的有NaCNBH3，NaBH(OAc)3等）还原生成相应的胺的反应。

2.反应机理：3.主要特点：Borch还原或者还原烷基；能够有效的将醛或者酮转化成胺；席夫碱来源于羰基和氨基，然后由氢供体还原成胺；对于迟钝反应，如含弱亲电羰基、亲核胺、空间拥挤的反应中心，通常需要添加分子筛或路易斯酸；对于反应性好的胺，容易形成席夫碱，直接还原胺化提高了效率；对于低反应性的胺，在一般条件下很难形成席夫碱。

4.优势：操作简单，方便；能形成伯胺、仲胺、叔胺。

5.经典反应：1.催化氢化；2.金属氢化物；3.甲酸-Leuckart-Wallach 反应；4.其他还原剂如硼烷、锡烷以及不对称催化反应、金属络合物也被用于还原胺化，极大的促进了还原胺化反应的高选择性及效率。

具体反应类型介绍：催化氢化：1.通常用Pd/C、Raney-Ni和Pt/C催化氢化；2.如果反应底物含不饱和基团如C=C、CN、NO2则受限；3.反应操作简单，清洁、产率高硼氢化钠还原：硼氢化钠容易还原亚胺，也能够还原醛或者酮化合物，在直接还原亚胺时，如果有此类官能团应该保护起来，防止在还原亚胺时被还原；常用溶剂醇类和四氢呋喃。

硼氢化钠与酸性添加剂和脱水剂共同使用：提高中间体亚胺的活性；体系TFA/DCM、TFA/THF、H2SO4/THF；适合低活性胺，如4-硝基苯胺；可以用分子筛、硫酸钠、硫酸镁、氯化钙做脱水剂。

硼氢化钠与钛（IV）添加剂共同使用：TiCl4或Ti(O-Pr-i)4；辅助亚胺；TiCl4在惰性溶剂中使用如苯、THF、DCM；Ti(O-Pr-i)4可以溶于乙醇、异丙醇、甲苯；这些条件对低活性胺有用硼氢化钠与其他添加剂：氯化锌溶于DCM、THF中使用；三甲基氯硅烷氰基硼氢化钠NaB(CN)H3：有醛或酮存在下，弱酸性pH5-7条件下，选择性还原碳氮双键；氰基在水或醇中有一定的水解，常采用甲醇或乙醇作溶剂；亚胺还原的最佳pH5-7，因此通过添加盐酸甲醇溶液调节酸度；分子筛能够吸水从而促进亚胺的生成，也可以采用硫酸钠或者硫酸镁脱水。

还原胺化反应步骤

还原胺化反应是有机化学中的一种常见反应类型，它是指酮或醛与胺在还原剂的存在下发生反应，生成相应的胺化合物。

一种常见的还原胺化反应是通过氢气和催化剂进行的，这个过程一般分为几个步骤：
1.氢气的吸附：
-酮或醛在催化剂的作用下吸附氢气，形成中间体。

常用的催化剂包括铂、钯、镍等。

2.氢气的加成：
-吸附了氢气的酮或醛与氢气发生加成反应。

在此过程中，氢气的氢原子被加到羰基碳上，形成醇中间体。

3.胺的进攻：
-胺分子进攻醇中间体，发生胺化反应。

这一步形成的中间体是胺基醇。

4.脱水：
-胺基醇中间体脱水，生成最终的胺化合物。

这是一个通用的过程，具体反应条件和催化剂可能因反应物的不同而异。

在实际应用中，还原胺化反应常用于合成氨基醇、氨基酮等有机化合物。

还原胺化反应机理

还原胺化反应机理还原胺化反应是一种有效而富有启发性的重要化学反应，其原理是将醛或酮直接转化为胺类化合物。

这种反应的最重要特点是它可以把醛或酮转化为活性氨基酸，而不用使用脱氢化合物，从而可以大大降低化学反应的难度和成本。

因为还原胺化反应的重要性，一直以来都有很多研究对其机理进行了研究。

基于对重要步骤的数值计算，针对还原胺化反应机理提出了多种假说，这些假说从多角度探讨了这种反应的发生过程，使我们可以更好地理解它的机理。

一般来说，还原胺化反应发生得比较快，而且活性氨基酸是通过一系列直接步骤从醛或酮发生，而不必额外经历脱氢步骤，这显然是非常有效且富有启发性的。

因此，关于还原胺化反应的机理研究，增加了我们对这种反应的理解。

可以说，还原胺化反应的机理涉及多个步骤，也涉及多个反应路径。

大致可以归纳为三种：（1）电子供体电子受体反应路径：这是最常见的反应路径。

其中，电子供体通过改变其发生的活性形式向受体中提供电子；电子受体则采用有机键吸噬电子从而形成醛或酮和活性氨基酸中间体；最后，这些中间体重组形成胺类化合物。

（2）极性选择性取代反应路径：这是一种非常有效的反应路径，它可以大大减少化学物质的消耗，还能够有效地节省时间。

它是通过在醛或酮上引入一个有机取代基，然后该取代基沿着极性选择向预定位置转移，最终形成活性氨基酸和胺类化合物。

（3）离子取代反应路径：这也是一种有效的反应路径，其特点是通过一系列离子取代反应，可以在醛或酮构型间实现键重构，从而有效地转化为活性氨基酸或胺类化合物。

总之，还原胺化反应是一种有效的化学反应，涉及多个步骤，并具有多种不同的反应路径。

它不仅有助于我们更好地理解这种反应发生的机理，而且可以为研究者提供更多的研究机会，以推动更多的科学研究。

因此，还原胺化反应的机理研究将会给化学研究带来更多的惊喜。

综上所述，还原胺化反应的机理已经被多次研究，这种反应是一种有效而富有启发性的重要化学反应，有助于我们更好地理解它的机理，也能提供许多研究机会，以推动更多的科学研究，为化学研究带来更多的惊喜。

微反应器中连续还原胺化反应的研究进展

化工进展Chemical Industry and Engineering Progress2024 年第 43 卷第 1 期微反应器中连续还原胺化反应的研究进展张家昊，李盈盈，徐彦琳，尹佳滨，张吉松（清华大学化学工程系，化学工程联合国家重点实验室，北京100084）摘要：还原胺化反应是一种把醛（酮）转化为胺类物质的有效方法。

还原胺化反应路径复杂，影响因素众多，合适的反应条件能够提升反应效率和选择性。

本文总结了还原胺化反应常见的催化体系及催化剂、溶剂、温度、底物性质以及氨/水/酸的加入对反应的影响。

基于这些影响因素，进一步介绍了连续微反应器技术在还原胺化过程中的应用，总结了以伯胺/仲胺/叔胺为目标产物的连续还原胺化过程、以硝基化合物为原料的连续还原胺化过程、酶催化及无催化剂的连续还原胺化过程。

微反应器中的温度控制、传质强化和停留时间分布能进一步实现反应强化和选择性提升。

基于微反应器的连续还原胺化技术及该技术与新型催化材料的结合有望在胺类物质的生产领域扮演越来越重要的角色。

关键词：还原胺化；多相反应；微反应器；连续合成；催化剂中图分类号：TQ032.4 文献标志码：A 文章编号：1000-6613（2024）01-0186-12Research advancement of continuous reductive amination in microreactorsZHANG Jiahao ，LI Yingying ，XU Yanlin ，YIN Jiabin ，ZHANG Jisong(State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China)Abstract: Reductive amination is a convenient way to transform aldehydes (ketones) into amines. Reductive amination has a complex reaction pathway and numerous influencing factors. The implementation of appropriate reaction conditions can significantly enhance reaction efficiency and selectivity. This article summarizes prevalent catalytic systems and the impacts of catalysts, solvents, temperatures, substrate properties, as well as the addition of ammonia/water/acid on the reductive amination. Subsequently, the utilization of microreactors in reductive amination is further discussed. The discussion encompasses continuous reductive amination process with primary, secondary, and tertiary amines as the target product, continuous reductive amination processes utilizing nitro compounds as starting materials, enzyme-catalyzed, and catalyst-free continuous reductive amination processes. Temperature control, mass transfer enhancement, and residence time distribution within microreactors can further intensify the reaction and improve the selectivity. The continuous reductive amination technology, coupled with novel catalytic materials, is expected to play an increasingly pivotal role in the production of amine compounds.Keywords: reductive amination; multiphase reaction; microreactors; continuous synthesis; catalyst特约评述DOI ：10.16085/j.issn.1000-6613.2023-1479收稿日期：2023-08-23；修改稿日期：2023-11-21。

还原胺化反应综述

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.Studies on Direct and Indirect ReductiveAmination Procedures1Ahmed F.Abdel-Magid,*Kenneth G.Carson,Bruce D.Harris,Cynthia A.Maryanoff,andRekha D.ShahThe R.W.Johnson Pharmaceutical Research Institute,Department of Chemical Development,Spring House,Pennsylvania19477Received January8,1996XSodium triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones.Procedures for using this mild and selective reagent have been developed for a wide variety of substrates.The scope of the reaction includes aliphatic acyclic and cyclic ketones,aliphatic and aromatic aldehydes,and primary and secondary amines including a variety of weakly basic and nonbasic amines.Limitations include reactions with aromatic and unsaturated ketones and some sterically hindered ketones and amines.1,2-Dichloroethane(DCE)is the preferred reaction solvent,but reactions can also be carried out in tetrahydrofuran(THF)and occasionally in acetonitrile.Acetic acid may be used as catalyst with ketone reactions,but it is generally not needed with aldehydes.The procedure is carried out effectively in the presence of acid sensitive functional groups such as acetals and ketals;it can also be carried out in the presence of reducible functional groups such as C-C multiple bonds and cyano and nitro groups.Reactions are generally faster in DCE than in THF,and in both solvents,reactions are faster in the presence of AcOH.In comparison with other reductive amination procedures such as NaBH3CN/MeOH,borane-pyridine, and catalytic hydrogenation,NaBH(OAc)3gave consistently higher yields and fewer side products. In the reductive amination of some aldehydes with primary amines where dialkylation is a problem we adopted a stepwise procedure involving imine formation in MeOH followed by reduction with NaBH4.IntroductionThe reactions of aldehydes or ketones with ammonia, primary amines,or secondary amines in the presence of reducing agents to give primary,secondary,or tertiary amines,respectively,known as reductive aminations(of the carbonyl compounds)or reductive alkylations(of the amines)are among the most useful and important tools in the synthesis of different kinds of amines.The reaction involves the initial formation of the intermediate carbinol amine3(Scheme1)which dehydrates to form an imine.Under the reaction conditions,which are usually weakly acidic to neutral,the imine is protonated to form an iminium ion4.2Subsequent reduction of this iminium ion produces the alkylated amine product5. However,there are some reports that provide evidence suggesting a direct reduction of the carbinol amine3as a possible pathway leading to5.3The choice of the reducing agent is very critical to the success of the reaction,since the reducing agent must reduce imines (or iminium ions)selectively over aldehydes or ketones under the reaction conditions.The reductive amination reaction is described as a direct reaction when the carbonyl compound and the amine are mixed with the proper reducing agent without prior formation of the intermediate imine or iminium salt.A stepwise or indirect reaction involves the prefor-mation of the intermediate imine followed by reduction in a separate step.The two most commonly used direct reductive amina-tion methods differ in the nature of the reducing agent. The first method is catalytic hydrogenation with plati-num,palladium,or nickel catalysts.2a,4This is an economical and effective reductive amination method, particularly in large scale reactions.However,the reac-tion may give a mixture of products and low yields depending on the molar ratio and the structure of the reactants.5Hydrogenation has limited use with com-pounds containing carbon-carbon multiple bonds and in the presence of reducible functional groups such as nitro6,7and cyano7groups.The catalyst may be inhibited by compounds containing divalent sulfur.8The second method utilizes hydride reducing agents particularly sodium cyanoborohydride(NaBH3CN)for reduction.9The successful use of sodium cyanoborohydride is due to its stability in relatively strong acid solutions(∼pH3),its solubility in hydroxylic solvents such as methanol,and its different selectivities at different pH values.10At pHX Abstract published in Advance ACS Abstracts,May1,1996.(1)Presented in part at the33rd ACS National Organic Symposium, Bozeman,Mo,June1993,Paper A-4.Preliminary communications:(a) Abdel-Magid,A.F.;Maryanoff,C.A.;Carson,K.G.Tetrahedron Lett. 1990,31,5595.(b)Abdel-Magid,A.F.;Maryanoff,C.A.Synlett1990, 537.(2)The formation of imines or iminium ions was reported as possible intermediates in reductive amination reactions in catalytic hydrogena-tion methods,see(a)Emerson,.React.1948,4,174and references therein.It was also proposed in hydride methods,see(b) Schellenberg,.Chem.1963,28,3259.(3)Tadanier,J.;Hallas,R.;Martin,J.R.;Stanaszek,R.S.Tetra-hedron1981,37,1309(4)(a)Emerson,W.S.;Uraneck,C.A.J.Am.Chem.Soc.1941,63, 749.(b)Johnson,H.E.;Crosby,.Chem.1962,27,2205.(c)Klyuev,M.V.;Khidekel,M.L.Russ.Chem.Rev.1980,49,14.(5)Skita,A.;Keil,F.Chem.Ber.1928,61B,1452.(6)Roe,A.;Montgomery,J.A.J.Am.Chem.Soc.1953,75,910.(7)Rylander,P.N.In Catalytic Hydrogenation over Platinum Metals;Academic Press,New York,1967;p128.(8)Rylander,P.N.In Catalytic Hydrogenation over Platinum Metals;Academic Press,New York,1967;p21.(9)For a recent review on reduction of C d N compounds with hydride reagents see:Hutchins,R.O.,Hutchins,M.K.Reduction of C d N to CHNH by Metal Hydrides.In Comprehensive Organic Synthesis;Trost, B.N.,Fleming,I.,Eds.;Pergamon Press:New York,1991;Vol.8.3849.Chem.1996,61,3849-3862S0022-3263(96)00057-6CCC:$12.00©1996American Chemical Society3-4it reduces aldehydes and ketones effectively,but this reduction becomes very slow at higher pH values.11At pH6-8,the more basic imines are protonated preferen-tially and reduced faster than aldehydes or ketones.10 This selectivity allows for a convenient direct reductive amination procedure.The literature is replete with publications that document the use of sodium cyanoboro-hydride in reductive amination reactions.12Limitations are that the reaction may require up to a fivefold excess of the amine,10is usually slow and sluggish with aromatic ketones10and with weakly basic amines,13and may result in the contamination of the product with cyanide.14The reagent is highly toxic15and produces toxic byproducts such as HCN and NaCN upon workup.Other reported reductive amination reagents include borane-pyridine,13a Ti(OiPr)4/NaBH3CN,13b borohydride exchange resin,16a Zn/AcOH,16b NaBH4/Mg(ClO4)2,16c and Zn(BH4)2/ZnCl2.16d In addition,there are some reports of electrochemical reductive amination reactions.17In our work on hydride-induced reductive aminations of aldehydes and ketones,we sought an alternative to the toxic sodium cyanoborohydride to eliminate the risk of residual cyanide in the product and in the workup waste stream,particularly for large scale reactions.Af-ter surveying many of the commercially available hy-dride reagents,we selected sodium triacetoxyborohydride [NaBH(OAc)3].18This borohydride reagent is mild and exhibits remarkable selectivity as a reducing agent.It reduces aldehydes selectively over ketones,18except for -hydroxy ketones which can be reduced selectively to give1,3-trans diols.19The steric and the electron-withdrawing effects of the three acetoxy groups stabilize the boron-hydrogen bond and are responsible for its mild reducing properties.20Our selection was also based on the results of reductive alkylation of amines using sodium borohydride in neat liquid carboxylic acids reported earlier by Gribble et al.21In this paper we report the results of our comprehen-sive investigation of the scope and limitations of sodium triacetoxyborohydride in a procedure for direct reductive amination of aldehydes and ketones with a variety of aliphatic and aromatic amines.This report also includes an alternative stepwise route for the reductive amination of aldehydes with primary amines which involves the preformation of imines and their subsequent reduction with NaBH4in one-pot reactions.Results and DiscussionsThe direct reductive amination reactions were carried out in1,2-dichloroethane(DCE),tetrahydrofuran(THF), or acetonitrile.The standard reaction conditions are as follows:a mixture of the carbonyl compound and the amine(0-5%molar excess)in the desired solvent is stirred with1.3-1.6equiv of sodium triacetoxyborohy-dride under a nitrogen atmosphere at room temperature. In some reactions,acetic acid(1-2mol equiv)is added to the mixture.The progress of the reaction is followed by GC and GC/MS analysis.The results from various reductive amination reactions of ketones and aldehydes are listed in Tables1and2,respectively.Solvents such as water or methanol are not recommended.Reactions in methanol resulted in a fast reduction of the carbonyl compound,and the reagent decomposed in water. (a)Reductive Amination of Ketones.The results in Table1show that the reductive amination of a wide variety of cyclic and acyclic ketones with primary and(10)Borch,R.F.;Bernstein,M.D.;Durst,H.D.J.Am.Chem.Soc. 1971,93,2897.(11)Borch,R.F.,Durst,H.D.J.Am.Chem.Soc.1969,91,3996.(12)(a)Hutchins,R.O.;Natale,.Prep.Proced.Int.1979, 11(5),201.(b)Lane,C.F.Synthesis1975,135.(13)Occasional use of weakly basic or nonbasic amines was reported, see for example:(a)Pelter,A.,Rosser,R.M.,Mills,S.J.Chem.Soc., Perkin Trans.11984,717.(b)Mattson,R.J.,Pham,K.M.;Leuck,D. J.;Cowen,.Chem.1990,55,2552.(c)Borch,R.F.;Hassid, .Chem.1972,37,1673.(d)Marchini,P.;Liso,G.;Reho,A.; Liberatore,F.;Moracci,.Chem.1975,40,3453.(14)(a)The product from large scale reduction of the imine(i)with sodium cyanoborohydride was contaminated with cyanide.(b)A similar result was reported recently:Moormann,mun.1993, 23,789.(15)For information on the safety data and health hazards associ-ated with sodium cyanoborohydride see:The Sigma-Aldrich Library of Chemical Safety Data,1st ed.;Lenga,R.E.,Ed.,Sigma-Aldrich Corp.:Milwaukee,1985,p1609.(16)(a)Yoon,N.M.;Kim,E.G.;Son,H.S.;Choi,mun. 1993,23,1595.(b)Micovic,I.V.;Ivanovic,M.D.;Piatak,D.M.;Bojic, V.Dj.Synthesis1991,1043.(c)Brussee,J.;van Benthem,R.A.T.M.; Kruse,C.G.;van der Gen,A.Tetrahedron:Asymmetry1990,1,163.(d)Bhattacharyya,S.;Chatterjee,A.;Duttachowdhhury,S.K.J.Chem. Soc.,Perkin Trans.11994,1.(17)(a)Pienemann,T.;Schafer,H.-J.Synthesis1987,1005.(b) Smirnov,Yu.D.;Tomilov,.Chem.U.S.S.R.1992,28(1), 42.(c)Smirnov,Yu.D.;Pavlichenko,V.F.;Tomilov,.Chem. U.S.S.R.1992,28(3),374.(18)(a)Gribble,G.W.;Ferguson, D. C.J.Chem.Soc.,Chem.Commun.1975,535.(b)Nutaitis,C.F.;Gribble,G.W.TetrahedronLett.1983,24,4287.(c)Gribble,G.W.In Encyclopedia of Reagentsfor Organic Synthesis;Paquette,L.A.,Ed.,John Wiley and Sons:NewYork,1995;Vol.7,p4649.(19)See for example:(a)Saksena,A.K.;Mangiaracina,P.Tetra-hedron Lett.1983,24,273.(b)Evans, D. A.;Chapman,K.T.Tetrahedron Lett.1986,27,5939.(c)Evans,D.A.,Chapman,K.T.;Carreira,E.M.J.Am.Chem.Soc.1988,110,3560.(20)Gribble,G.W.;Nutaitis,.Prep.Proced.Int.1985,17,317.(21)Earlier work by Gribble et al.demonstrated the potential oftriacyloxyborohydrides generated from NaBH4in neat liquid carboxylic acids in reductive alkylation of amines:(a)Gribble,G.W.;Lord,P.D.;Skotnicki,J.;Dietz,S.E.;Eaton,J.T.;Johnson,J.L.J.Am.Chem.Soc.1974,96,7812.(b)Gribble,G.W.;Jasinski,J.M.;Pellicone,J.T.;Panetta,J.A.Synthesis1978,766.Scheme1.Chem.,Vol.61,No.11,1996Abdel-Magid et al.secondary amines was successful under the standard conditions and gave the desired products in good to excellent yields.The scope of the reaction includes different alicyclic ketones,from cyclobutanone to cy-clododecanone(Table1:entries1-23),bicyclic ketones such as norcamphor and tropinone(Table1:entries24-30),saturated acyclic ketones(Table1:entries31-39), and keto esters(Table1:entries47-49).Nearly all primary and nonhindered secondary amines were used successfully in these reactions.For the same ketone,the rate of the reaction was dependent on the steric and electronic factors associated with the amines.In general, primary aliphatic amines reacted faster than primary aromatic and secondary aliphatic amines(Table1:en-tries10vs11;14and15vs16and17;24vs26and27). Cyclic secondary amines such as morpholine reacted faster than acyclic secondary amines such as diethyl-amine(Table1:entry33vs36)while the sterically hindered diisopropylamine did not react even after days (Table1:entry45).In some slow reactions(e.g.,Table 1:entries11,27,32,34,and36),small amounts of side products were formed(1-5%by GC area%analysis) from N-ethylation and N-acetylation of the starting amines.22These impurities were easily removed in the workup or during the recrystallization of the salts. The reaction conditions are very mild and can tolerate the presence of acid sensitive functional groups such as acetals and ketals.For example,the reductive amination of cyclohexanedione monoethylene ketal with primary and secondary amines afforded good to excellent isolated yields of the corresponding amines(Table1:entries14-18).Another example is the reductive alkylation of aminoacetaldehyde diethyl acetal with cyclododecanone (Table1:entry9).A particularly useful example is the reaction involving cyclohexanedione monoethylene ketal and aminoacetaldehyde diethyl acetal(Table1:entry18) which provides a secondary amine product containing protected aldehyde and ketone functionalities in a nearly quantitative yield.Of all the ketones used in this study,small aliphatic cyclic ketones,ranging from cyclobutanone to cyclohex-anone,were most rger cyclic ketones such as cyclooctanone and cyclododecanone and acyclic ketones such as2-heptanone reacted somewhat slower.Reactiv-ity of cyclobutanone was so high that its reaction with benzylamine gave a mixture of mono-and dicyclobutyl-benzylamines even with the use of excess amine(Table 1:entry2).Clean formation of N,N-dicyclobutylbenzyl-amine resulted with the use of a1:2molar ratio of amine to ketone(Table1:entry1).The reactions with second-ary amines were very effective since there was no dialkylation product(Table1:entry3).The least reactive ketones were aromatic,R, -unsatur-ated,and sterically hindered ketones.Aromatic and R, -unsaturated ketones reacted very slowly(Table1:entries 40,41,and43).Experimentally,a saturated aliphatic ketone was reductively aminated,selectively,and quan-titatively in the presence of an aromatic or R, -unsatur-ated ketone(Table1:entries42and44).The unreacted ketones were recovered unchanged except for the forma-tion of trace amounts of their imines(as determined by GC/MS analysis of the reaction mixture).Sterically hindered ketones were even less reactive than aromatic and R, -unsaturated ketones,e.g.,camphor showed no reaction with benzylamine after four days(Table1:entry 46).The steric factors associated with both ketones and amines seem to be very important in determining the outcome of the reaction.In reactions where the formation of diastereomers was possible,we observed varying degrees of selectivity. Reductive amination of4-tert-butylcyclohexanone with pyrrolidine and cyclohexylamine occurred with a moder-ate diastereoselectivity to give the thermodynamically less favored cis products.This results from equatorial attack by the hydride reagent on the intermediate imine, to form the axial amine(Table1:entries19and20).23 The reductive amination of androstanolone with isopro-pylamine gave a mixture of3R-and3 -(isopropylamino)-androstan-17 -ol in about25:75ratio(Table1:entry21). The reactions involving bicyclic ketones showed higher degrees of diastereoselectivity.For example,the reduc-tive aminations of norcamphor led to the exclusive formation of the endo products,from exo attack by the hydride reagent.The reductive amination of norcamphor with benzylamine(Table1:entry24)produced a single product.This product was identical to that obtained from the reductive amination of benzaldehyde with endo-2-aminonorbornane(Table2:entry13),thus confirming the endo stereochemistry of the product.Reductive amination of tropinone with primary amines such as benzylamine and aniline(Table1:entries28and 29)was accomplished in good yield and high diastereo-selectivity giving the endo isomer as the major product (determined by1H NMR).24The reaction with benzyl-amine gave the endo and exo products in approximately 20:1ratio while the reaction with aniline showed no detectable exo product.The reaction of tropinone with piperidine was extremely sluggish giving low conversion to about a1:1mixture of the exo-and endo-products after four days of reaction(Table1:entry30).The poor solubility of ammonium acetate in DCE,THF, or CH3CN limits its use in the reductive amination of ketones to prepare primary amines.The initial primary amine product is much more soluble than ammonium acetate and reacts faster with the ketone to generate dialkylamines,so this reaction can be used for the preparation of symmetrical dialkylamines.The amina-tion reaction is relatively slow and some ketone reduction may occur if AcOH is added.Even the use of a large excess(10equiv)of ammonium acetate in THF,DCE,or CH3CN,in the presence of Et3N,did not favor the formation of the monoalkylamine,the only product formed was dicycloheptylamine(Table1:entries22 and23).N-Substituted R-amino esters were prepared by the reductive amination of R-keto esters with primary and(22)The N-ethylation of amines is a major process in reaction of amines with sodium borohydride in neat acetic acid and is believed to proceed through an acetaldehyde formation.21a(23)This result is consistent with literature reports on the reduction of4-substituted cyclohexanone imines or iminium salts which con-cluded that bulky hydride reagents such as L-Selectride attack preferentially from the less hindered equatorial side to give the cis-products,while less bulky hydride reagents such as NaBH4and NaBH3-CN slightly favor the axial approach,see:(a)Wrobel,J.E.;Ganem, B.Tetrahedron Lett.1981,22,3447.(b)Hutchins,R.O.;Markowitz, .Chem.1981,46,3571.(c)Hutchins,R.O.;Su,W.-Y.; Sivakumar,R.;Cistone,F.;Stercho,.Chem.1983,48,3412.(d)Hutchins,R.O.;Adams,J.;Rutledge,.Chem.1995, 60,7396.(24)Chemical shift assignments of individual protons were arrived at by COSY,HETCOR,and Inverse HMBC NMR experiments.The stereochemistry of N-phenyl-3-aminotropane and N-benzyl-3-aminotro-pane was assigned based on1D NOE and coupling experiments.The assignments were in line with other literature reports;cf.Bagley,J. R.;Riley,T.N.J.Hetrocycl.Chem.1977,14,599and references therein.Reductive Amination of Aldehydes and Ketones .Chem.,Vol.61,No.11,19963851Table 1.Reductive Amination ofKetones.Chem.,Vol.61,No.11,1996Abdel-Magid et al.secondary amines.The reductive amination of methyl pyruvate with benzylamine was a fast and efficient reaction under the standard conditions that gave N -benzylalanine methyl ester in an excellent yield (Table 1:entry 47).The reaction was slower with hindered keto esters such as methyl 3-methyl-2-oxobutanoate (Table 1:entry 48),and the competing ketone reduction was a major reaction.The aromatic keto ester,methyl benzoyl formate reacted even slower with benzylamine and was also accompanied by considerable ketone reduction (Table 1:entry 49).Reactions involving other less reactive amines such as aniline or morpholine were much slowerTable 1.(Continued)Reductive Amination of Aldehydes and Ketones.Chem.,Vol.61,No.11,19963853and gave increasing amounts of ketone reductions. Whenever ketone reduction was a problem,the conditions were modified to use the amines as limiting reagents. The excess ketones were completely reduced to the corresponding alcohols which required the occasional addition of excess reducing agent.N-Substituted R-ami-no esters were also prepared by the reductive amination of R-amino esters with ketones,e.g.,N-(2-butyl)glycine ethyl ester was prepared in very good yield from ethyl glycinate and2-butanone(Table1:entry50).The reductive amination of cyclohexanedione mono-ethylene ketal with phenylhydrazine gave cleanly the N-substituted phenylhydrazine(Table1:entry51)in nearly quantitative yield.Other ketones such as cyclo-hexanone and2-heptanone reacted to give similar prod-ucts(Table1:entries52and53);however,there were some competing side reactions.The crude products showed the formation of byproducts,about15%with cyclohexanone and31%with2-heptanone.Attempted reductive amination of cyclooctanone with hydroxylamine was not successful and resulted in the oxime formation (Table1:entry54).Reductive aminations in which diamines containing both primary and secondary amino groups were studied and in general,primary amines reacted faster.In the case where the primary amino group was aliphatic and the secondary group was aromatic,e.g.,N-phenylethyl-enediamine,there was a clear difference in reactivity between the two amines.The reaction with4-heptanone gave a quantitative yield of the product resulting from exclusive reaction with the primary amine(Table1: entry55).In the case where both amino groups were aliphatic,such as1-(2-aminoethyl)piperazine,there was a high selectivity(94:6)for the primary group in reaction with acetylcyclohexane(Table1:entry56).(b)Reductive Amination of Aldehydes.Unlike ketones,aldehydes can be reduced with sodium triac-etoxyborohydride.18Thus,the possibility exists that the reduction of the aldehyde would compete with the reduc-tive amination process under the standard conditions. However,these conditions were so selective that the reductive aminations with aldehydes occurred very ef-fectively and resulted in fast reactions with no aldehyde reductions in most cases studied(Table2).One case in which aldehyde reduction was detected involved a reac-tion with the very sterically hindered diisopropylamine (Table2:entry6).All other examples in Table2resulted in fast and efficient reductive aminations with a variety of aliphatic primary and secondary amines as well as aniline with no detectable aldehyde reductions.Both aliphatic and aromatic aldehydes were very reactive and gave reductive amination products with a broad variety of primary and secondary amines.The reaction times ranged from20min to24h.The mildness of the reac-tion conditions is well illustrated in the reductive ami-nation of1,1′,2-tris-nor-squalene aldehyde with dieth-ylamine and diisopropylamine(Table2:entries19and 20).The aldehyde was cleanly converted to the corre-sponding amines in high yields with no detectable side reactions.In the reductive amination of aldehydes with primary amines,formation of dialkylated amines is a common side reaction.5This side reaction was rarely a problem in most reactions reported in Table2.In the few cases when it was detected,it was suppressed by the addition of up to5%molar excess of the primary amine.However, the dialkylation of amines remained a problem with certain substrates.25An alternative stepwise procedure for such systems is discussed later in this paper. Some aldehydes,such as formaldehyde and glutaral-dehyde are only available commercially as aqueous solutions which may restrict their use under the above reaction conditions because of the decomposition of the hydride reagent with water.However,the reaction may be carried out in DCE with excess hydride reagent,e.g., the reductive amination of either aqueous glutaraldehyde or formaldehyde with1-phenylpiperazine and about4 hydride equivalents was carried out on10mmol scale (Table2:entries21and22)and gave nearly quantitative yields of the corresponding amines.This,however,may not be suitable for large scale reactions.The use of phenylhydrazine in reductive amination of benzaldehyde was not successful,resulting only in hy-drazone formation.Generally,with either ketones or aldehydes,reactions in DCE were noticeably faster than those carried out in THF(e.g.,Table1:entries6vs7;25vs26and Table2: entries3vs4;9vs10).Also,in the same solvent, reactions were consistently faster in the presence of1 (or more)mol equiv of acetic acid.For most ketones, reactions were improved in the presence of acetic acid. However,the addition of acetic acid is not always advantageous to the reaction.Most reactions with al-dehydes are fast and do not require addition of AcOH. Addition of AcOH to a slow reaction,e.g.,cyclohexan-ecarboxaldehyde with diisopropylamine,resulted in a fast reaction accompanied with about25%aldehyde reduc-tion,and the yield of the isolated desired product was only41%.When the reaction was carried out in the absence of AcOH,the reaction was slower;however,the aldehyde reduction was only about5%,and the isolated yield of the purified reductive amination product in-creased to75%(Table2:entries6and7).Direct com-parisons were made between reactions in DCE and THF and with or without added acetic acid in representative reactions.The rate of product formation was determined quantitatively26in each case.The results of these com-parisons were in agreement with the above observations.(c)Reductive Amination with Weakly Basic and Nonbasic Amines.Few literature references have dealt with aromatic amines containing electron withdrawing substituents in reductive amination reactions.13,21a Cata-lytic hydrogenation conditions do not allow the presence of many of the easily reduced electron-withdrawing substituents such as cyano and nitro groups,since these substituents are often reduced under catalytic hydroge-nation conditions.6,7On the other hand,we and others13a,b have found the most used hydride reagent,sodium cyanoborohydride[NaBH3CN],to be sluggish and inef-ficient when used with these weak bases in reductive amination reactions.As a consequence of substitution by electron-withdraw-ing substituents,these amines are both poor nucleophiles and weak bases(e.g.,p K a3.98for4-chloroaniline,1.02 for4-nitroaniline,-0.29for2-nitroaniline,-4.26for2,4-dinitroaniline).27This slows the initial nucleophilic at-(25)For a discussion of the dialkylation side reactions involvingγ-andδ-amino esters with aldehydes and a mechanistic explanation, see:Abdel-Magid,A.F.;Harris,B.D.;Maryanoff,C.A.Synlett1994, 81.(26)The progress of these reactions was followed by GC.Linear standard curves of the response factors by GC areas of starting materials and expected products were determined to allow the quantitative measurements of their concentrations in the reaction mixtures..Chem.,Vol.61,No.11,1996Abdel-Magid et al.tack on the carbonyl carbon and leads to slower overall reaction rates (Scheme 2).In addition,the carbonyl group now competes effectively with the less basic intermediate imine for protonation and subsequently for the hydride in the reduction step.2b This may lead to a significant carbonyl reduction,consumption of both the carbonyl compound and the reducing agent and low yields of the reductive amination products.The reducing agent and reaction conditions should be chosen carefully to minimize such side reactions.Table 2.Reductive Amination ofAldehydesReductive Amination of Aldehydes and Ketones .Chem.,Vol.61,No.11,19963855Sodium triacetoxyborohydride is very efficient in re-ductive amination reactions with such unreactive amines. The results from several reactions are listed in Table3. In several cases such as monosubstituted anilines(e.g., p-nitro-p-carbethoxy-,and p-cyanoanilines),the standard reaction conditions described previously(about1:1ratio of carbonyl compound to amine,1.4equiv of NaBH(OAc)3 with1equiv of acetic acid)were adequate.However, with less basic amines such as o-nitroaniline,2,4-dichlo-roaniline,or2-aminothiazole,the reaction conditions were modified to compensate for the aforementioned effects and to maximize the yields of the reductive amination products.The optimum conditions included the use of the amine as the limiting reagent with1.5-2 mol equiv of the carbonyl compound,2-3equiv of NaBH-(OAc)3,and2-5equiv of AcOH in1,2-dichloroethane. Under these conditions,a variety of weakly basic amines were successfully employed in the reductive aminations of ketones and aldehydes in isolated yields ranging from 60%to96%.The reaction is convenient and the condi-tions are mild and show a high degree of tolerance for a variety of functional groups including nitro,cyano,halo, carboxy,and carbethoxy groups.Ketones reacted effectively with p-monosubstituted anilines to give good yields of the reductive amination products(Table3:entries1-8).The reaction was slightly slower with2,4-dichloroaniline and gave a high yield of the desired reductive amination product in addition to some ketone reduction and the formation of about3%of N-ethyl-2,4-dichloroaniline(Table3:entry 9).The reaction became very slow with o-nitroaniline which progressed only to about30%conversion to the reductive amination product and17%of N-ethyl-2-nitroaniline after6days(Table3:entry10).The reaction stopped completely when both ortho positions were substituted as in2,6-dibromo-and2,4,6-trichloro-anilines(Table3:entries11and12).The reactions with aldehydes were faster than those with ketones and gave higher yields from similar reac-tions.Aldehyde reductions occurred only with the least reactive amines.In the reductive amination of aldehydes with p-carboxyaniline and p-nitroaniline(Table3:en-tries13,14,and18),no competing aldehyde reduction was observed.In these cases,the standard conditions were used.With weaker amines such as2,4-dichloro-aniline and o-nitroaniline(Table3:entries15and16), the conditions were modified to use the amine as a limiting reagent since aldehyde reduction occurred to the extent of10-30%.This procedure was applied to other weakly basic primary amines such as2-aminothia-zole(Table3:entries22and23)and secondary amines such as iminostilbene(Table3:entry24).While imi-nostilbene reacted with hexanal to give a high yield of the N-hexyl product,the dihydro analogue iminodiben-zyl gave no reaction under the same conditions(Table3: entry25).One of the most unique reactions,however,was the reductive alkylation of p-toluenesulfonamide with ben-zaldehyde to give the N-benzyl derivative(Table3:entry 26).The reaction is carried out initially under the standard conditions in the presence of Et3N(2equiv). The aldehyde is usually consumed in about24h to give a mixture of N-benzyl p-toluenesulfonamide and N-benzal p-toluenesulfonamide.The reaction mixture is then treated with AcOH(2.5equiv)and additional NaBH(OAc)3(1equiv)to finish the reduction.The reaction,however,was not successful with ketones or carboxamides.The least reactive amines,2,4-dinitroaniline and2,4,6-trichloroaniline failed to undergo reductive amination with benzaldehyde(Table3:entries20and21).Cyclo-hexanecarboxaldehyde,on the other hand,reacted slowly with these two amines to give the corresponding reduc-tive amination products.In these two reactions,the aldehyde reduction became a major reaction process.To assure the presence of enough aldehyde to react with the amine,the reaction required occasional additions of aldehyde and reducing agent,up to5equiv each and over a two to four day period(Scheme3).The reactions progressed to reach90-92%conversion(as determined by GC)and gave61%and58%isolated yields,respec-tively,after chromatography.It is possible that these reactions proceed via initial formation of intermediate enamines rather than imines which may explain the lack of reactivity of aromatic aldehydes which cannot form enamines.(d)Comparison with Other Reducing Agents.In general,the results of reductive amination employing sodium triacetoxyborohydride were as good as or better than most comparable reported results whether done using hydrogenation or hydride reagents.However,in many cases,our results were far superior to others.For example,we compared the reductive amination of cyclo-hexanone with morpholine using NaBH3CN vs NaBH-(OAc)3.The reaction with NaBH3CN(6hydride equiv) in methanol and in the absence of AcOH was only34% complete after23h with the formation of about10%of the corresponding enamine.The conversion improved to 50%in23h with AcOH(1equiv)with no enamine formation.The reaction using the standard NaBH(OAc)3 conditions was99.8%complete in3h without a trace of enamine formation(Table1:entry5).In another comparison,the reductive amination of1-carbethoxy-4-piperidinone with p-chloroaniline was only45%complete with NaBH3CN after22h but was>96%with NaBH-(OAc)3in2.5h(Table3:entry4).An impressive result was obtained in the reductive amination of1,1′,2-tris-nor-squalene aldehyde with di-ethylamine and isopropylamine.These reactions were reported to give about5%yield under regular Borch conditions.28The yields were improved to46and42%, respectively,when the reactions were carried out with NaBH3CN in anhydrous THF in the presence of HCl(pH 3).29Under our standard conditions,these reactions gave(27)(a)Albert,A.;Serjeant,E.P.In The Determination of Ionization Constants;Chapman and Hall:London,1971;p91.(b)Yates,K;Wai, H.J.Am.Chem.Soc.1964,86,5408.(28)Duriatti,A.;Bouvier-Nave,P.;Benveniste,P.;Schuber,F.; Delprino,L.;Balliano,G.;Cattel,L.Biochem.Pharmacol.1985,34, 2765.(29)Ceruti,M.;Balliano,G.;Viola,F.;Cattel;L.;Gerst,N.;Schuber,F.Eur.J.Med.Chem.1987,22,199.Scheme2.Chem.,Vol.61,No.11,1996Abdel-Magid et al.。

甲酸铵PdC体系进行胺化反应的研究

浙江大学学报(理学版)第40卷第2期Jour nal of Zhejiang University(Science Edition) V o t．40No．2 2013年3月http：／／www．journals．zju．edu．cn／sci Mar．2013DOI：10．3785／j．issn．1008—9497．2013．02．009甲酸铵一Pd／C体系进行胺化反应的研究戴立言，胡斯军，尹胜，王晓钟，陈英奇(浙江大学制药工程研究所，浙江杭州310027)摘要：介绍了一种用于羰基胺化的合成方法．该方法以酮为底物，HCOONH。

为氢源和氮源，Pd／C为催化剂，CH。

0H与H：()为溶剂，对羰基进行还原胺化制得相应的胺．甲酸铵作为氢供体，具有廉价、易得、还原性能好等优点，Pd／C催化加氢可使反应在温和的条件下进行．该方法反应速度快、后处理方便、选择性好．最佳反应条件：常温常压、CH30H：H20(y：V)一9；l、HCOONH4：原料：Pd／C(M：M：M)一100：10：1．实验过程中，分别对2一金刚烷酮；5一氨基羟基一2一金刚烷酮；3一奎宁酮进行了胺化反应研究，获得较好的结果，产物均经1H—N MR、GC—M S 或MS确证结构．关键词：甲酸铵；Pd／C；催化转移氢化(CTH)；2-金刚烷胺；4-氨基金刚烷一1一醇；3-氨基奎宁中图分类号：O 624．6 文献标志码：A文章编号：1008—9497(2013)02—161 05DA I Li—ya n，H U Si—jun，YIN Sheng，WANG Xia o—z h o n g，C H E N Ying-qi(I nstit uteo f Pharmaceutical Eng i n e er i n g，Zhejiang Uni v e rs i ty，H a n gz h o u 310027，C hi na)Am i n at i on based on the system of am mon iu m for mate-Pd／C．Jou rnal of Zhej iang University(Science Edition)，20 1 3，40(2)：16卜165Ab st ra ct：A m et ho d for the am inatio n of c om po un ds w i th c ar bo ny l groups was des cr ib e d．T h e process was carr i ed o u t by using ke to n e s sub str ate s，amm oni um f orm ate the of h y dr o g e n and nitrogen，Pd／C cat al y st an d the mixt ure of me t ha no l a n d water a s solvent under normal tempe rature an d pressure．Ammonium format e hy dr o—gen sup p li e r has the ad van tag es of lO W cost，easy availability well a s exc el l en t r e du c i bi l it y．w h il e Pd／C ca ta l ys te n a b le s the r e a c t io n to take place u nde r mild cond itions．The process r e a c t s q u ic k l y with con ven ien t w ork up and hi ghs el e c t i vi t y．T h e o p t i m al r e a ct i o n c o n d it i o n s w e re fo llo ws：CH3 O H：H2O(V：y)一9：1，H C O O N H4：k e t o n e。

还原胺化最全知识

还原胺化最全知识
胺化是一种重要的生物学反应，它涉及细胞中特定的氨基酸的化学改变。

它发生在氨
基酸被氨基噻吩进行支链氧化反应（transamination）时，氨基酸的偶联位置上消失，从
而产生由胺基组成的硫醇和水溶性产物。

这种形式的反应不仅发生在脂肪酸代谢中，也发
生在蛋白质代谢中。

胺化反应在分子生物学和生物化学中被认为是一种重要的生物学反应，因为它可以从一种氨基酸转换到另一种氨基酸。

此外，在胺化反应中，细胞也会逆转氨基酸，这里也称作逆胺化（deamination）。

逆胺化包括在氨基酸的某个偶联位置上的水分子的添加而产生氨基磷酸（aminephosphate）。

逆胺化反应是生物氨基酸被氨基噻吩进行去氧化反应（transamination）时所发生的一个重要化学反应。

胺化反应不仅仅发生在生物体中，在医学上也可以用于检测不适症状，因为它和人体
免疫系统有关系，可以通过监测血清氨基转移酶（aminotransferase）的活性来检测。

近
年来，胺化技术也被广泛用于新药研发，它可以帮助科学家快速了解药物的作用机制，在
这个过程中，ラット体内的氨基酸及其衍生的分子相互作用及其中间体被评估，这有助于
优化特定药物剂量和安全性。

最后，由于某些氨基酸是不具备活性的，因此，在实验研究中经常使用被称为“小核
胺化”（minor reaction of amination）的一种方法。

该方法可用于制备多种不同类型
的以氨基酸为活性组分的化合物，从而为实验室提供了有用的相互作用物质。

小核胺化是
一种非常有用的合成技术，更重要的是，它可以使这类氨基酸衍生物在体内获得有效的活性。

樊后兴还原胺化综述共37页文档

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樊后兴还原胺化综述
41、实际上，我们想要的不是针对犯罪的法律，而是针对疯狂的法律。 ——马克·吐温 42、法律的力量应当跟随着公民，就像影子跟随着身体一样。— —贝卡利亚 43、法律和制度必须跟上人类思想进步。— —杰弗逊 44、人类受制于法律，法律受制于情理。— —托·富勒

还原胺化反应的新进展

2007年第27卷有机化学V ol. 27, 2007第1期, 1～7 Chinese Journal of Organic Chemistry No. 1, 1～7* E-mail: wangdq@Received December 8, 2005; revised March 20, 2006; accepted May 8, 2006.2有机化学 V ol. 27, 2007合成中得到广泛应用[2].最近Blechert 等[3]报道了多官能团化合物1在Pd/C 催化氢化条件下“一锅”完成双键还原、酮羰基还原胺化、醛的脱保护、醛的还原胺化、苄氧羰基的脱除5步反应形成双环哌啶并吡咯啉化合物2(Eq. 1).除了Pd 以外, 其它金属如Ni, Pt 等也被用作氢化胺化催化剂.Nugent 等[4]报道了在烷氧钛的存在下, 不对称烷基酮与(R )-1-甲基苄胺(MBA)反应, Raney-Ni 催化氢化产生立体选择性非常高的二级胺3, 然后Pd/C 催化氢解给出收率和旋光性比较好的一级胺4 (71%～78%收率, 72%～98% ee ) (Scheme 1). 同样如果烷基酮与 (S )-MBA 反应、氢解可以得到与3和4相反构型的胺. 该方法尽管从酮开始需要两步反应产生手性一级胺, 但试剂价廉易得, 有利于规模化生产.Scheme 11.2 金属络合物催化还原胺化金属络合物在催化氢化方面具有优异的催化活性, 而且比仅用金属催化氢化具有更好的选择性. Beller 等[5]报道了0.05 mol%的[Rh(cod)Cl]2与TPPTS (tris so-dium salt of meta trisulfonated triphenylphosphine)形成络合物催化各种醛与氨的还原胺化, 得到高收率的胺化产物(最高97%) (Eq. 2). Rh 络合物易溶于水, 反应可在水溶液中进行.Angelovski 等[6]应用0.5 mol%的[Rh(acac)(CO)2]催化氢化大环二醛与二胺形成大环二胺, 收率57%～76%, 而用其它还原胺化试剂[NaBH 3CN, NaB(AcO)3H]只得到不超过30%收率的产物. Rh 络合物在参与关环过程中具有更好的模板效应.2005年, Ohta [7]报道了以离子液体咪唑盐7为反应介质, 2 mol% [Ir(cod)2]BF 4进行的直接还原胺化, 不需任何配体的参与, 往离子液体中通入一定压力氢气, 获得收率79%～99%的二级胺(Eq. 3). 离子液体的阴离子部分对反应影响很大, 以[Bmim]BF 4为介质时收率最好. 氢气压力增大、温度升高有利于反应速率和收率的提高.天然含有胺基的化合物(吗啡、麻黄碱、氨基酸等)往往都是光活性的, 手性胺基的获得有着更重要的意义, 也是该领域研究的热点. 由醛(酮)直接或间接还原胺化为立体专一异构体是获得手性胺基化合物的重要途径. 目前已报道的是手性过渡金属络合物不对称催化还原亚胺[8], 其中以Ir, Rh 和Ru 与手性配体形成的络合物进行的不对称还原胺化较为常见.2004年Andersson [9]报道了Ir 的络合物催化亚胺还原胺化反应(Eq. 4). 由酮与胺反应, 经过亚胺8, 然后被膦-噁唑啉与铱的络合物10进行催化氢化, 可得R 型为主的手性胺9.Kadyrov 等[10]报道了同样的反应, 以[(R )-tol-binap]- RuCl 2为催化剂对芳香酮的还原胺化, 得到84% ee 的R -异构体, 而对脂肪酮的反应, 对映选择性一般低于30%.由酮与胺形成亚胺, 不需分离直接进行还原是更简单实用的方法, 然而成功的报道为数不多[11]. 2003年,Zhang 等[12]报道了在Ti(OPr-i )4存在下, Ir-f-Binaphane (14)催化氢化各种芳香酮与对甲氧苯胺的还原胺化, 取得收率和对映选择性都非常好的结果(最低93%收率, 最高96% ee ), 其反应过程见Scheme 2. 首先在Lewis 酸No. 1傅滨等：还原胺化反应的新进展3(与亚胺12成平衡状态); 然后在I 2的引发下, Ir-f-Binaphane 络合物催化亚胺氢化得到手性胺13. Ti(OPr-i )4能够促进羰基与胺缩合, 但对产物的对映选择性无任何影响. 然而该方法对于烷基亚胺的还原无对映选择性.Scheme 22006年, Devisi 等[13]应用[Ir(ddppm)(COD)]X (15, 图1)催化各种芳香亚胺的还原胺化, 得到80%～94%的对映选择性和100%的收率, 氢气压力仅需要常压即可, 高压反而使催化剂失活. 溶剂对催化活性影响很大, 二氯乙烷为最佳溶剂, 催化剂阴离子部分以4BF -,6PF -对反应活性和选择性有着非常重要的促进作用, 如果是Cl －则反应速率和收率会大大降低.图1 化合物15分子结构Figure 1 Molecular structure of compound 15关于金属络合物催化氢化进行的还原胺化在化学选择性方面的应用已经比较成功, 而在立体选择性方面仍然需要提高, 高效、高对映选择性、适于工业生产的还原胺化金属络合物催化剂亟待开发.2 金属氢化物为还原剂2.1 NaBH 4硼氢化钠能够成功地还原C ＝N 成C —N, 同时也可容易地将醛(或酮)羰基还原成醇, 因此该方法必须分步进行, 尽管需要两步才能完成胺化过程, 但由于该反应试剂简单且条件温和, 文献报道其应用非常之多. 其它与NaBH 4相似的还原体系如NaBH 4-ZnCl 2[14a],ZnBH [14b], NaBH -NiCl [14c]等也被应用.值得一提的是Lewis 酸或Brönsted 酸与NaBH 4形成的催化体系, 催化活性和选择性都得到提高. Bhat-tacharyya 等[15]报道了利用NaBH 4-Ti(OPr-i )4进行酮的直接还原胺化, 生成高收率的伯胺(72%～96%), 而当与醛进行胺化反应时可得到中等收率以上的对称二级胺(50%～78%). 机理是首先生成氨基醇的钛氧化物中间体16, 然后被硼氢化钠还原(Scheme 3). 最近Cho 等[16]报道固体酸H 3BO 3, PTSA, 己酸分别与NaBH 4配合还原各种芳香亚胺, 反应时间由原来的几个小时缩短至几十分钟, 收率达到99%.Scheme 32.2 NaBH 3CN 和NaB(OAc)3H源于NaBH 4的NaBH 3CN 和NaB(OAc)3H 在直接还原胺化时有更好的化学选择性, 能够避免羰基还原成醇的副反应, 因而可以使醛(或酮)与胺发生“一锅”反应, 直接进行还原胺化, 二者在合成中应用的文献随处可见[17]. 但是它们在使用时又有不同的特点. NaBH 3CN 易溶于质子溶剂, 在不同pH 值的溶液中显示出不同的还原能力, pH ＝6～8时活性最好, NaBH 3CN 进行还原胺化时用量要超过5倍甚至更多, 而且后处理时往往产生少量剧毒的HCN 和NaCN 副产物. NaB(OAc)3H 是另一种广泛应用的还原胺化试剂. Abdel-Magid [18]曾详细研究了NaB(OAc)3H 用于各种醛和酮与不同胺的还原胺化反应, 均取得比较好的收率, 即使对碱性较弱的芳香胺与酮进行还原, 同样得到比较高的收率, 一般在非质子溶剂中应用, 如CH 2Cl 2, THF 和乙氰等. 所得产物立体异构体的比例主要取决于底物的结构. NaB(OAc)3H 在醇和水中不稳定、易分解, 因此在进行反应时可根据需要选择合适的还原剂. 微波辐射有利于提高还原剂的活性和化学选择性[19].与NaBH 4相似, Lewis 酸如ZnCl 2, Ti(OPr-i )4等能够使NaBH 3CN 和NaB(OAc)3H 的还原活性得到提高, 然而如何使活性和选择性的提高达到恰如其分, 往往在实际应用时有所改进. 最近McDonald 等[20]报道了将Ti(OPr-i )4中的一个异丙氧基用Cl 代替即TiCl(OPr-i )3,然后与NaBH(OAc)3组成还原体系, 对醛与各种缺电子芳香胺及杂环胺的还原反应, 得到收率比较好的胺化产物.2005年, Kim 等[21]报道了与NaBH(OAc)3相似的NaBH(OEh)3 (Eh 为2-乙基己酰氧基)作为还原剂, 还原甾体酮17与胺18的反应, 给出收率97%和异构体比例4有机化学 V ol. 27, 200724∶1 (3α/3β)的胺基甾体化合物19 (Eq. 5), 而用NaBH(OAc)3进行还原时两种异构体比例为3∶1. NaBH(OEh)3由2-乙基己酸与NaBH 4反应制备. 体积比较大的2-乙基己酰氧基和甾体分子本身空间构象决定了产物的高立体选择性.3 硼烷还原法1995年, Dimare 等[22]曾报道了BH 3•Py 体系在甲醇中4 Å分子筛的辅助下对醛(酮)与二级胺的直接还原胺化, 得到不同收率的胺化产物, 与醛(酮)和胺的结构有关, 空间位阻大则收率低, 以环己酮与苄胺的还原胺化收率最高(96%).此后, Kikugawa 等[23]发展了Picoline-BH 3作为还原胺化试剂, 以MeOH-AcOH 为溶剂, 各种醛(或酮)与胺反应都得到比较满意的收率(醛45%～95%, 酮73%～95%). Picoline-BH 3是易得的固体, 能够承受150 ℃高温, 另外很容易通过重结晶纯化, 长期保存不分解; 即使在少量水的存在下, 收率基本不变, 作者还专门发展了MeOH-HOAc-H 2O 体系作为溶剂, 与仅用甲醇为溶剂相对照, 收率略有降低.2003年Yoon 等[24]报道了癸硼烷作为还原剂对醛(或酮)与芳香胺进行的胺化及氨烷基化反应(Scheme 4).癸硼烷在极性溶剂中还原性比较低, 但在质子溶剂中还原性增强, 当R 1为芳基时都能得到收率比较好的叔胺产物(64%～98%). 当R 1为烷基时, 该反应不能发生, 原因可能是烷基胺碱性较强, 在碱性溶液中癸硼烷的还原活性会大大降低.Scheme 44 有机小分子催化的还原胺化近几年来, 有机小分子催化在有机合成中应用取得比较大的进展, 同样被用于催化还原胺化反应. 2002年Ohsawa [25a]研究了等计量的Hantzsch 二氢吡啶酯20(图2)与催化量的Sc(OTf)3对各种取代芳香醛与对甲氧苯胺的还原胺化, 都得到比较好的结果(收率高达98%). 2004年, 作者[25b]分别比较了各种芳香酮和芳香醛与对甲氧苯胺的还原胺化结果, 其中醛显示出更好的还原胺化选择性, 而芳香酮与胺的反应必须有分子筛的加入才能顺利完成, 收率普遍低于醛与胺的反应(62%～82%) (Eq. 6), 这是由于酮的空间位阻较大所致. 对于其它胺与醛或酮的反应尚有待于进一步研究.图2 化合物20分子结构Figure 2 Molecular structure of compound 202005年, List 等[26]报道了用等计量的Hantzsch 二氢吡啶羧酸酯20与1 mol%的催化剂Brönsted 酸22(图3)催化各种芳香亚胺的还原反应, 收率高达96%, 对映选择性80%～93% (Eq. 7). 这是有机催化剂在不对称还原胺化反应中取得的突破性进展. 其反应机理被认为是通过Scheme 5循环过程进行. 亚胺与Brönsted 酸22结合成手性亚胺离子对23(可能通过氢键使之稳定), 然后Hantzsch 二氢吡啶酯20提供活性氢对亚胺加成, 经过中间体25, 产生手性胺26, 同时二氢吡啶转化为吡啶环化合物24. 从该过程可以看出Brönsted 酸在催化活性、尤图3 化合物22分子结构No. 1傅滨等：还原胺化反应的新进展5Scheme 5其是对映选择性方面起着决定性作用. 作者研究了R 为不同基团时22对反应的催化作用, 发现为1,3,5-三(异丙基)苯基时催化剂的活性和对映选择性最好.不久MacMillan 等[27]报道了有机小分子催化剂进行的直接还原胺化反应. Terada-Akiyama 催化剂27(图4)与二氢吡啶酯20, 在5 Å分子筛的存在下, 催化对芳香甲酮与对甲氧苯胺的还原胺化达到非常好的对映选择性(82%～97%)和转化率(60%～87%). 对各种烷基酮与对甲氧苯胺的还原胺化同样显示出比较好的催化性能 (49%～75%收率和81%～94% ee 值), 对苯乙酮与各种芳香胺的胺化也给出比较好的结果. 直接还原胺化可以减少操作步骤, 避开亚胺的制备, 一些烷基酮所得的亚胺很不稳定. 直接进行还原胺化并取得比较好的结果正是我们所希望的. 这是迄今为止, 有机小分子催化剂在不对称还原胺化方面最为成功的应用. 相信随着有机催化剂的不断开拓, 将会为还原胺化提供更多更好的方法.图4 化合物27分子结构Figure 4 Molecular structure of compound 275 其它来源氢的还原胺化法甲酸常作为胺(氨)基中还原氢的来源. 2002年, Al-legretti[28]报道了用HCOONH 4与Pd/C 高立体选择性的对环己酮类化合物还原胺化(Eq. 8). HCOONH 4既是氢的来源又是氨基的来源. 协同式氢转移机理被用于解释该类反应(Scheme 6). 第一步, 氨与羰基缩合形成α-羟基胺31, 此时氨基在空间位阻较小的一面; 第二步, Pd催化氢转移, 避免了外式胺的形成. 协同式氢转移可能是由Pd(0)氧化插入甲酸形成中间体后发生的(原文电子转移方式可能有误, 此处已改正). 该反应试剂对于空间位阻较大的环烷酮的还原胺化具有立体专一性, 即氨基从空间位阻较小的一面进攻.Scheme 6α-氨基酸作为生命有机体的基本组成单位, 其合成一直受到广泛关注. 由α-羰基酸进行还原胺化是非常简便的方法. 2001年Ogo 等[29]报道了Cp*Ir 络合物催化的丙酮酸与HCOONH 4在水溶液中室温反应得到氨基酸, 收率与溶液的pH 值密切相关. 2004年Ogo 和Fukuzumi [30]详细考察了[Cp*Ir III (bpy)H]n X (X ＝SO 4, n ＝2; X ＝PF 6, n ＝1)催化α-羰基酸还原胺化成为氨基酸, 反应在NH 3/H 2O 和HCOOH 中进行, pH 值5～6.5是最佳介质条件, 作者应用该法于各种氨基酸的合成, 都得到比较高的收率(81%～97%). 反应过程见Scheme 7, 酸性质子使羰基活化, 氨亲核进攻羰基碳, 形成α-亚胺羧酸, 然后被[Cp*Ir III (bpy)H]n 还原得到氨基酸. 该方法化学选择性非常好, 而立体选择性尚未解决.2004年, Wills [31]报道了分子内的“一锅”还原胺化反应(Eq. 9), 由被保护了的脂肪胺基酮36与甲酸和甲酸铵反应, 然后加入0.25 mol%的[(p -cymene)RuCl]2 (cy-mene 为甲基异丙基苯), 0.5 mol%的(R ,R )-TsDPEN (38)和HCO 2H/Et 3N, 最后得到收率和对映选择性比较高的分子内还原胺化产物37.还原胺化还有其它许多种方法, 如Bu 3SnH/SiO 2[32],6有机化学V ol. 27, 2007Scheme 7Bu2SnCl2/PhSiH4[33]等, 它们在应用中不断改进和发展. 在此不一一赘述.6 结束语合理的应用直接或间接还原胺化方法可以制备含有胺基(包括一级、二级、三级胺)的化合物. 尽管有些反应详细的机理还不十分清楚, 但它们已经在合成中得到广泛应用, 并在应用中不断得到发展. “绿色”、高效是发展方向之一, 如以支载的NaBH(OAc)3进行反应[34], 以水(或含水)溶剂[35]或离子液体[7]为反应介质, 微波辐射提高还原剂活性和选择性等. 同时在不对称还原胺化方面仍然有待于提高[36], 已经报道的有限的实例都是过渡金属络合物催化亚胺还原获得比较高的活性和立体选择性, 底物结构往往起着重要作用; 有机小分子催化反应方兴未艾, 为还原胺化反应提供了新的思路. 尽管还原胺化这一普通、经典的反应已经成为形成C—N键的方便的工具之一, 然而面对众多含手性胺(氨)基的化合物, 发展高效、高选择性的不对称还原胺化方法仍然是该领域的主要研究目标.References1 (a) Emerson, W. 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还原胺化

还原胺化一.还原胺化还原胺化主要有一般化合物的还原法及直接的还原胺化法。

1.C-N化合物还原法硝基化合物、亚硝基化合物、肟、腈、酰胺、偶氮化合物、氧化偶氮化合物、氢化偶氮化合物等均可经还原得到胺类。

(1).硝基及亚硝基的还原学还原法和催化加氢还原法。

硝基和亚硝基化合物的还原较易进行，主要有化化学还原法根据催化剂的不同，又分为铁屑还原，含硫化合物的还原，碱性介质中的锌粉还原等。

铁屑还原法的适用范围较广，凡能与铁泥分离的芳胺皆可采用此法，其还原过程包括还原反应、还原产物的分离与精制、芳胺废水与铁泥处理等几个基本步骤。

对于容易随水蒸气蒸出的芳胺如苯胺、邻（对）甲苯胺、邻（对）氯苯胺等都可采用水蒸气蒸馏法将产物与铁泥分离；对于易溶于水且可蒸馏的芳胺如间（对）苯二胺、2，4-二氨基甲苯等，可用过滤法先除去铁泥，再浓缩滤液，进行真空蒸馏，得到芳胺；能溶于热水的芳胺如邻苯二胺、邻氨基苯酚、对氨基苯酚等，用热过滤法与铁泥分离，冷却滤液即可析出产物；对含有磺基或羧基等水溶性基团的芳胺，如1-氨基萘-8-磺酸（周位酸）、1-氨基萘-5-磺酸等，可将还原产物中和至碱性，使氨基磺酸溶解，滤去铁泥，再用酸化或盐析法析出产品，难溶于水而挥发性又小的芳胺，例如1-萘胺，在还原后用溶剂将芳胺从铁泥中萃取出来。

铁屑还原法中产生大量含胺废水，必须进行处理、回收。

例如在硝基苯用铁屑还原过程中会产生大量含苯胺废水（约含4%苯胺），一部分可加入到还原锅中循环使用，其余的要先用硝基苯萃取。

萃取后含苯胺的硝基苯可作为还原的原料使用；废水中的苯胺和硝基苯的含量分别降为0.2%和0.1%以下。

此后还必须经过生化处理，才可排放。

铁泥的利用途径之一是制铁红颜料。

含硫化合物的还原主要包括硫化碱类，如硫化钠、硫氢化铵、多硫化铵，这类反应称为齐宁反应(Zinin)，该反应比较缓和，可使多硝基化合物中的硝基选择性的部分还原，或只还原硝基偶氮化合物中的硝基，而保留偶氮基，并应用于从硝基化合物获得的不溶于水的胺类。

贵金属还原胺化及借氢偶联反应

贵金属还原胺化及借氢偶联反应2016-10-31 14:41来源：内江洛伯尔材料科技有限公司作者：研发部还原胺化是有机合成中形成C－N键还原胺化是有机合成中形成C－N键的重要手段之一。

2009年，Haruta等报道了首例纳米Au催化的还原胺化反应，在120 °C和2 MPa H2的条件下，以Au/Fe2O3为催化剂能够实现硝基化合物和醛类化合物的还原胺化反应，对不同取代基的底物均实现了较好的收率(58%–96%)。

最近，Artiukha等报道了通过流动反应进行纳米Au催化的还原胺化的新方法，通过调节反应底物的比例和反应温度，Au/Al2O3催化剂可有效催化还原胺化反应进行。

尽管如此，由于Au催化剂对于H2的解离能力较弱，以H2为还原剂的纳米金催化还原胺化反应往往需要在比较苛刻的条件下(T > 100 °C,p(H2) > 2 MPa)才可进行，并且作为还原剂的H2在使用过程中也存在较大安全隐患。

考虑到催化氢转移在还原过程中所具有的独特优势，有研究小组尝试以安全无毒且廉价安全的可再生甲酸作为还原剂，使用纳米Au催化剂进行温和条件下的还原胺化反应(图 9)。

发现使用单一金红石相的Ti O2-R负载的纳米Au催化剂(Au/Ti O2-R)可有效催化该反应，80 °C时化学计量甲酸的反应条件下，还原胺化反应可在水中高效完成，且对于含有碳碳双键、羰基、卤素等易被还原官能团的底物均可实现良好的目标产物收率。

通过增加催化剂用量和延长反应时间，反应甚至可在室温下进行。

通过进一步结构性质解析研究发现，金红石氧化钛表面独特的酸碱性对保障并实现整个还原胺化反应的高效进行起到了至关重要的作用。

除还原胺化反应外，使用醇与胺作为反应原料，通过“借氢”反应策略实现的直接N-烷基化也是高级胺类化合物的有效制备方法。

该过程经“醇脱氢-缩合氢转移还原”等多步反应直接实现，反应过程中无需使用其他还原剂，且副产物仅为水。

硼氢化锌还原苯乙酰胺的研究

硼氢化锌还原苯乙酰胺的研究何嘉俊;李翔;刘小成;刘昱;刘端【摘要】以硼氢化锌还原苯乙酰胺为苯乙胺,探讨了溶剂、反应时间及反应温度对苯乙胺收率的影响.确定苯乙酰胺最佳还原反应条件为:V(甲苯)∶V(THF)=3∶7、反应时间为4 h、反应温度为95℃,此时苯乙胺收率可达84.8%.【期刊名称】《化学与生物工程》【年(卷),期】2009(026)009【总页数】2页(P34-35)【关键词】硼氢化锌;苯乙酰胺;还原【作者】何嘉俊;李翔;刘小成;刘昱;刘端【作者单位】湖北省化学研究院,湖北,武汉,430074;湖北省化学研究院,湖北,武汉,430074;湖北省化学研究院,湖北,武汉,430074;湖北省化学研究院,湖北,武汉,430074;湖北省化学研究院,湖北,武汉,430074【正文语种】中文【中图分类】O625.631硼氢化锌Zn(BH4)2用于有机还原反应已有近40年的历史[1], 但近10年来才对其进行全面、系统的研究。

Zn(BH4)2不仅价格较便宜、还原能力可与氢化铝锂(LiAlH4) 媲美, 而且选择性好, 对醛(酮)、羧酸及其衍生物、酰胺、亚胺、腈、环氧化合物、烯(炔) 等均可进行选择性还原, 对手性分子还具有良好的立体选择性。

虽然LiAlH4还原能力强,但选择性差，副反应较多，并且价格比较昂贵，不适合工业化生产；NaBH4比较温和，但不能还原酰胺。

因此，Zn(BH4)2应用潜力很大。

作者在此采用硼氢化锌还原苯乙酰胺，以提高收率、降低成本，避免用其它还原剂时出现多种产物的缺点[2]，并探讨了溶剂、反应时间以及反应温度对苯乙酰胺还原反应的影响。

1 实验1.1 主要原料苯乙酰胺，上海邦成化工有限公司；硼氢化钠，江苏张家港化工有限公司；无水氯化锌，杭州江城化工有限公司；四氢呋喃，浙江欧华进出口公司；甲苯，浙江宁波中化有限公司；以上试剂均为分析纯。

1.2 硼氢化锌的制备[1,3]ZnCl2+2NaBH4Zn(BH4)2+2NaCl在装有回流冷凝装置的250 mL烧瓶中加入13.6 g (0.1 mol) 新熔融的ZnCl2 和7.6 g (0.2 mol)NaBH4,然后加入无水四氢呋喃150 mL, 室温下搅拌24 h, 静置。

新药临床前药效学评价(上)

药学评价是基础基础不牢大楼要倒药效评价是前提没有药效进行不了毒性评价是核心安全没保证临床不敢用临床评价是关键临床有效开发成功
二非临床药效学研究概述
新药非临床药效学研究——主要药效学试验
研究与新药防治作用有关的药理效应，是新药非临床评价的主要内容之一。
目的：
确定受试药物有无疗效
临床药理学评价
临床试验分为I、II、III、IV期。 I期临床试验：初步的临床药理学及人体安全性评价试验。
观察人体对于新药的耐受程度和药代动力学，为制定给药方案提供依据。 II期临床试验：治疗作用初步评价阶段。其目的是初步评价药物对目标适应症患者的治疗作用和安全性，也包括为III 期临床试验研究设计和给药剂量方案的确定提供依据。此阶段的研究设计可以根据具体的研究目的，采用多种形式，包括随机盲法对照临床试验。
过分灵敏—假阳性不够灵敏—假阴性同类药已较多的，应订高一点尚缺理想药的，可订低一点
定性(qualitative) —性质不同，主观判断
兴奋-抑制，激动-拮抗，活化-抑制死亡-存活，增加-减少，扩大-缩小…
定量(quantitative)—数量多寡，客观测量
绝对量：有度、量、衡单位计量 (International System)
6). 重复上述过程，将30只♂鼠随机分入6个实验组中。分组结果，各实验组小鼠同性别鼠数量相等，各组平均体重相近，各组在不同体重档次中的小鼠数相近。各组鼠的营养状态及活泼程度接近。
对照原则
没有比较就没有区别。所谓“对照”，即设立非处理因素相同、而处理因素与试
验组不一样的一组对象。实验组与对照组的实验动物在种属、性别、窝别、体重、
健康状况等方面要尽可能相同。对照有多种形式。

4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成工艺改进

4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成工艺改进焦家盛;樊珊珊;张勇【摘要】以对氨基水杨酸为起始原料,经过甲基化、硫氰化、还原乙基化、氧化、水解得到4氨基5乙磺酰基-2-甲氧基苯甲酸.探讨了甲基化反应和硫乙基引入方法问题,并对各步反应合成条件进行了优化.改进后工艺总收率达55％,目标化合物和各中间体经IR,1 H NMR和MS等确证结构.【期刊名称】《河北科技大学学报》【年(卷),期】2014(035)003【总页数】6页(P255-260)【关键词】4-氨基-5-乙磺酰基-2-甲氧基苯甲酸;中间体;氨磺必利;医药原料【作者】焦家盛;樊珊珊;张勇【作者单位】河北科技大学化学与制药工程学院,河北石家庄 050018;河北科技大学化学与制药工程学院,河北石家庄 050018;河北科技大学化学与制药工程学院,河北石家庄 050018;河北省药用分子化学重点实验室,河北石家庄 050018【正文语种】中文【中图分类】R971.4氨磺必利(结构式见图1)是由法国赛诺菲圣德拉堡公司开发的具有显著优点的新型非经典抗精神病药物，1997年1月在美国上市，2001年在中国上市，可选择性作用于多巴胺D2和D3受体。

与传统的抗精神病药物相比，氨磺必利具有锥体外系不良反应少、不会升高血糖等优点[1-6]，4-氨基-5-乙磺酰基-2-甲氧基苯甲酸(见图2中的化合物1)是合成氨磺必利的重要中间体，本文对其进行了合成研究。

根据起始原料和官能团引入途径的不同，已报道的关于4-氨基-5-乙磺酰基-2-甲氧基苯甲酸的合成方法主要有以下4种：1)文献[7]和文献[8]以4-氨基-2-甲氧基-5-巯基苯甲酸为原料，在碱性条件下与硫酸二乙酯发生乙基化反应得到4-氨基-2-甲氧基-5-乙硫基苯甲酸，经过双氧水-乙酸氧化后得到化合物1；2)文献[9]以4-乙酰氨基-2-甲氧基苯甲酸甲酯为原料，先经过浓硫酸磺化得到3-甲氧甲酰基-6-乙酰氨基-4-甲氧基苯磺酸，再水解得到6-氨基-3-甲氧甲酰基-4-甲氧基苯磺酸，经过氯化、还原、与溴乙烷发生乙基化反应得到4-氨基-3-乙基磺酰基-6-甲氧基苯甲酸甲酯，然后水解得到化合物1；3)文献[10]以4-氨基-2-甲氧基苯甲酸为原料，经氯磺酸磺酰化，与氯化亚锡-盐酸反应得到二硫化物，经碱水解得到硫醇，再与硫酸二乙酯乙基化得到化合物1；4)文献[11]和文献[12]以对氨基水杨酸为原料，经过甲基化、硫氰化、乙基化、氧化、水解得到化合物1。