CN1633427A - 制备手性胺的方法 - Google Patents
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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Abstract
公开一种制备手性胺的方法。该方法包括将酮肟、钯、脂肪酶、供酰基化合物和叔胺反应制备酰胺，然后将酰胺水解。
Description
发明领域
本发明涉及一种制备手性胺的方法，更优选地说，涉及一种使用易于控制的原料经简便的工艺制备手性胺的方法。
背景技术
制备手性胺的方法分为两类：使用金属催化剂的化学法和使用酶催化剂的生化法。化学法和生化法具有互补的优缺点。因此曾有尝试结合两种催化剂制备手性胺。直到现在，只有德国工作者报到的一种方法使用酶-金属组合来制备手性胺(Reetz，M.T.；Schimossek，K.Chimia，1996，50，668)。
在这种方法中，手性胺是以光学纯酰胺从作为基质的外消旋1-苯乙基胺的混合物进行动态动力学拆分来制备，钯作为外消旋化催化剂、脂肪酶作为选择性的酰化催化剂。在脂肪酶存在下，用酰化剂对预定的对映体进行选择性酰化得到光学纯的酰胺；同时其它对映体在钯催化剂作用下原位进行外消旋化。反应在50-55℃下进行9天，转化率为75-77％。
然而，该方法的不足是其仅适用于基体上，并且要求很长的反应时间却得到中等的产率。
发明内容
本发明的目的是提供一种使用金属催化剂和生物催化剂组合由酮肟制备手性胺的方法，其具有高产率、优异的光学纯度、反应时间较短；而酮肟可方便地由酮合成得到。
本发明的这些或其它目的可以通过以下制备手性胺的方法实现，该方法包括将式I表示的酮肟、钯、脂肪酶、酰基供体和叔胺在有机溶剂中反应制备式IV的酰胺，然后将酰胺水解
其中R1为氢、烷基、烷氧基、苯基或烷基取代的苯基；
R2和R3个各自独立地为氢或烷基，或者R2和R3结合一起形成环，其中烷基为被氢、氧、氮、硫或卤素取代的C1-3烷基，环以下式表示：-(CH2)n-X-，n为1-3的整数；
X为亚甲基、氧、硫或氮；
Y为-CH＝CH-、-CH＝N-、硫或氧；和
R4为被氧或卤素取代的C1-5烷基。
具体实施方式
本发明涉及一种从酮肟制备手性胺的方法，手性胺在药物制造中是有用的中间体。而酮肟易于制造和处理。
在本发明中，将式I表示的酮肟、作为还原和外消旋化的催化剂的钯、作为立体选择性酰化催化剂的脂肪酶、酰基供体和叔胺在有机溶剂中反应制备式IV的手性酰胺
其中R1、R2、R3、Y和R4如上定义。
在详细的工艺中，钯催化剂在氢气存在下于40-100℃活化30分钟至1小时。将经活化的催化剂冷却至室温。加入作为基体的式I表示的酮肟、作为酰化催化剂的脂肪酶、酰基供体、叔胺和有机溶剂。反应浴(reaction bath)中充有1大气压的氢气。反应混合物优选在40-70℃下进行。
钯催化剂可为钯粉、钯黑、或钯(0价)，其载于炭、硫酸钡、碳酸钡或碳酸钙上。优选为载于炭、硫酸钡、碳酸钡或碳酸钙上的钯。
商购得到的载体上的钯包括5-10％的钯。当载体上的钯含量为5％时，钯催化剂的量为酮肟重量的40-70％。
式IIR和IIS表示反应生成的外消旋胺对映体。
其中R1、R2和R3如上所定义。
在酰基供体存在下，脂肪酶对式IIR表示的对映体的选择性酰化反应进行催化得到式IV表示的光学纯酰胺。
式IIS表示的其它对映体经叔胺和钯原位进行外消旋化得到式IIR的化合物。式IIR的化合物经酶酰化反应连续地转化成式IV的酰胺。
脂肪酶的实例为洋葱伯克霍尔德氏菌脂肪酶(如固定在陶瓷上的脂肪酶PS-C，或固定在硅藻土上的脂肪酶PS-D)(Japan，Amno-Enzymes Inc.)，南极念珠菌脂肪酶(如固定在丙烯酸树脂上，Novozym 435，Nordisk Korea)是优选的。
固定化的脂肪酶的量优选为酮肟重量的1-3倍。
酰基供体由式III表示，其实例有乙酸乙酯、乙酸2，2，2-三氟乙酯、乙酸2，2，2-三氯乙酯、乙酸对氯苯酯。基于1当量的酮肟，酰基供体的量为1.5-2当量。
R4CO2R5 (III)
其中R4如上定义；
R5为氢，被卤素、氧、氮或硫取代的C1-3烷基，C1-3链烯基、苯基或卤素取代的苯基。
叔胺由式V表示。其实例有三乙胺和二异丙基乙基胺。基于1当量的酮肟，叔胺的量为1-5当量。
R6 3N (V)
其中R6为C1-3烷基。
有机溶剂为苯、甲苯、二甲苯、四氢呋喃、二噁烷、二氯甲烷或叔丁基甲基醚。基于所用的酮肟的浓度，有机溶剂的量优选控制在0.025-0.25M。
反应完成后，过滤掉钯催化剂和脂肪酶，经柱色谱分离光学纯酰胺。
酰胺水解得到光学纯的胺，可用作中间体。水解反应在现有技术中是已知的，在此不作过多的描述。
根据本发明制备手性胺的方法见流程1
流程1
下面参照实施例对本发明进行进一步的解释，但这些实施例并不是用来限制本发明的范围。
实施例1
将载于活性炭上的钯(钯含量：5％，34mg)在氢气存在下于40℃活化30分钟。氩气气氛下，向加有载于活性炭上的活性钯(钯含量：5％，34mg)的反应器中加入苯乙酮羟肟(50mg，0.37mmol)、100mg novozym 435(NoveNordisk Korea)和3.6ml二甲苯。
在所得的混合物中，加入乙酸乙酯(72.3μl，0.74mmol)和二异丙基乙基胺(193μl，1.11mmol)，并于真空进行脱氧。反应器充入1大气压的氢气，于60℃搅拌5天。
反应完成后，过滤反应混合物，经柱色谱得到(R)-N-乙酰基-1-苯基乙基胺。分离的产品溶于1.2N HCl溶液中，回流9小时，冷却，中和得到所希望的胺。
手性胺衍生物的最终化学结构由1H NMR和13C-NMR确定。用手性高效液相色谱(装有Whelk-O1或Chiraldex OD-H柱)测定的光学纯度为95％ee，产率为80％。
实施例2-8
按实施例1相同的工艺步骤制备光学纯胺，不同的是采用表1所示的肟代替苯乙酮羟肟。
实施例1-8的手性胺的产率和光学纯度见表1。
表1
表1清楚地表明采用钯催化剂和脂肪酶组合从酮肟制备得到了高光学纯(94-99％ee)和高产率(70-89％)的光学纯胺。钯催化剂催化酮肟的还原反应和所得到的胺的外消旋化反应，而脂肪酶对映选择性地催化胺的酰化。这些结果表明本发明提供了一种有效地制备手性胺的方法。
本发明的方法采用钯催化剂和脂肪酶组合从非手性的酮肟制备得到了酰胺形式的胺，这种方法的优点是采用易于得到的酮肟作基质、产率高、具有优异的对映体纯度。
由于本发明的方法适于制备各种胺，因此它为传统化学或生化方法提供了一种替代方案。本发明得到的手性胺可作为手性的结构单元用于合成医药或精细化学品。
Claims (11)
1.一种制备手性胺的方法，包括
将式I表示的酮肟、钯催化剂、脂肪酶、酰基供体和叔胺在有机溶剂中反应制备式IV的酰胺，和
将酰胺水解
其中R1为氢、烷基、烷氧基、苯基或烷基取代的苯基；
R2和R3为相同或独立地为氢或烷基，或者R2和R3结合一起形成环，其中烷基为被氢、氧、氮、硫或卤素取代的C1-3烷基，环以下式表示：
-(CH2)n-X-，n为1-3的整数；
X为亚甲基、氧、硫或氮；
Y为-CH＝CH-、-CH＝N-、硫或氧；和
R4为被氧或卤素取代的C1-5烷基。
2.权利要求1的方法，其中钯催化剂选自钯粉、钯黑、钯，其载于炭、硫酸钡、碳酸钡或碳酸钙上。
3.权利要求1的方法，其中钯催化剂的量为酮肟重量的40-70％。
4.权利要求1的方法，其中脂肪酶为固定化的洋葱伯克霍尔德氏菌脂肪酶或固定化的南极念珠菌脂肪酶。
5.权利要求1的方法，其中脂肪酶的量为酮肟重量的1-3倍。
6.权利要求1的方法，其中酰基供体由式III表示
R4CO2R5 (III)
其中R4为被卤素或氧取代的C1-5烷基；
R5为被氢、氧、氮、硫或卤素取代的C1-3烷基或C1-3链烯基、苯基或卤素取代的苯基。
7.权利要求1的方法，其中基于1当量的酮肟，酰基供体的量为1.5-2当量。
8.权利要求1的方法，其中叔胺由式V表示
R6 3N (V)
其中R6为C1-3烷基。
9.权利要求1的方法，其中基于1当量的酮肟，叔胺的量为1-3当量。
10.权利要求1的方法，其中反应在40-70℃下进行。
11.权利要求1的方法，其中基于酮肟的浓度，有机溶剂的量控制在0.025-0.25M。
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| KR1020010077030 | 2001-12-06 | ||
| KR10-2001-0077030A KR100423875B1 (ko) | 2001-12-06 | 2001-12-06 | 키랄 아민의 제조 방법 |
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| JP (1) | JP2005511041A (zh) |
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| CN113083362A (zh) * | 2021-03-23 | 2021-07-09 | 河北工业大学 | 半均相金属酶集成纳米催化剂及其制备方法和应用 |
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| US8134029B2 (en) | 2002-09-16 | 2012-03-13 | Sunovion Pharmaceuticals Inc. | Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine |
| EP1904066B1 (en) | 2005-07-06 | 2018-05-23 | Sunovion Pharmaceuticals Inc. | COMBINATIONS OF ESZOPICLONE AND TRANS 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-1-NAPTHALENAMINE OR TRANS 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHALENAMINE, for treating MENOPAUSE, perimenopause AND COGNITIVE DISORDERS |
| JP5377285B2 (ja) | 2006-03-31 | 2013-12-25 | サノビオン ファーマシューティカルズ インク | キラルアミドおよびキラルアミンの調製 |
| CN102675122A (zh) * | 2012-01-12 | 2012-09-19 | 东莞达信生物技术有限公司 | 一种2,3-二氢-1h-茚-1-胺的制备工艺 |
| CN104418775B (zh) * | 2013-09-05 | 2017-01-18 | 中国科学院大连化学物理研究所 | 一种钯催化氨基醇的不对称氢解合成手性胺的方法 |
| CN108658784B (zh) * | 2018-04-26 | 2020-12-18 | 联化科技股份有限公司 | (r)-1-(4-甲基苯基)乙胺的合成方法 |
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| DE3743824C2 (de) * | 1987-12-23 | 1997-03-06 | Hoechst Ag | Verfahren zur enzymatischen Racematspaltung von racemischen Alkoholen mit/in Vinylestern durch Umesterung |
| US5629200A (en) * | 1993-11-18 | 1997-05-13 | Daicel Chemical Industries, Ltd. | Production of optically active 2-amino-1-phenylethanol derivatives by asymetrical assimilation |
| DE19529293A1 (de) * | 1995-08-09 | 1997-02-13 | Bayer Ag | Verfahren zur Herstellung von racemischen Amino-Derivaten |
| DE19530205A1 (de) * | 1995-08-17 | 1997-02-20 | Bayer Ag | Verfahren zur Herstellung von optisch aktiven l-Aryl-alkylaminen |
| DE19534208A1 (de) * | 1995-09-15 | 1997-03-20 | Basf Ag | Spaltung von optisch aktiven Amiden |
| EP0865500B1 (de) * | 1995-12-06 | 2002-02-13 | Bayer Ag | Verfahren zur herstellung von optisch aktiven aminen |
| DE19603575A1 (de) * | 1996-02-01 | 1997-08-07 | Bayer Ag | Verfahren zur Herstellung von optisch aktiven Aminen |
| US5981267A (en) * | 1996-01-24 | 1999-11-09 | The Scripps Research Institute | Enantioselection of amines using homocarbonates with hydrolase |
| AU2697297A (en) * | 1996-04-25 | 1997-11-19 | Novartis Ag | Biocatalysts with amine acylase activity |
| CA2307390C (en) * | 2000-05-01 | 2005-06-28 | Torcan Chemical Ltd. | Enzymatic resolution of aminotetralins |
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| EP1451171A4 (en) | 2004-11-10 |
| CA2437251A1 (en) | 2003-06-12 |
| US20040077864A1 (en) | 2004-04-22 |
| EP1451171A1 (en) | 2004-09-01 |
| KR100423875B1 (ko) | 2004-03-22 |
| KR20030046777A (ko) | 2003-06-18 |
| JP2005511041A (ja) | 2005-04-28 |
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