CN101321875B - 从外消旋4-(1-氨基乙基)苯甲酸甲酯通过脂酶催化的对映选择性酰化反应并随后用硫酸沉淀以制备(r)-和(s)-4-(1-铵乙基)苯甲酸甲酯硫酸盐的方法 - Google Patents
从外消旋4-(1-氨基乙基)苯甲酸甲酯通过脂酶催化的对映选择性酰化反应并随后用硫酸沉淀以制备(r)-和(s)-4-(1-铵乙基)苯甲酸甲酯硫酸盐的方法 Download PDFInfo
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Abstract
本发明涉及一种制备旋光4-(1-铵乙基)苯甲酸甲酯硫酸盐的方法,其中使外消旋4-(1-氨基乙基)苯甲酸甲酯与酰化试剂在脂酶存在下反应,得到4-(1-氨基乙基)苯甲酸甲酯,随后通过加入硫酸沉淀出4-(1-铵乙基)苯甲酸甲酯硫酸盐。
Description
本发明涉及制备(R)-和(S)-4-(1-铵乙基)苯甲酸甲酯硫酸盐的新方法。
现有技术
通过与酯的酶催化反应拆分胺的外消旋体的方法是公知的。Kitaguchi等(J.Amer.Chem.Soc.111,3094-3095,1989)描述了使用丁酸三氟乙基酯通过枯草溶菌素催化拆分胺的外消旋体。但是,此反应的对映选择性在很大程度上取决于溶剂。即使使用所描述的最合适的溶剂(3-甲基-3-戊醇),也仅仅达到中等选择性。
WO 91/19002描述了一种手性富集外消旋伯胺的方法,其中通过枯草溶菌素催化使胺与乙酸乙酯或丁酸乙酯反应。但是,达到的对映异构过量是不满意的。另外,需要一到数星期的长反应时间。
Gotor等(J.Chem.Soc.Chem.Commun.957-958,1988)描述了用乙酸乙酯通过猪胰脂酶(PPL)将2-氨基丁-1-醇进行对映选择性酰化。在这种情况下,所用的酯(乙酸乙酯)也用作溶剂。在使用其它溶剂或其它酶时没有达到满意的效果。
Brieva等(J.Chem.Soc.Chem.Commun.,1386-1387,1990)描述了从外消旋伯胺通过与2-氯丙酸酯在枯草溶菌素催化下在己烷或柱状假丝酵母脂酶中在3-甲基-3-戊醇中进行酰胺的对映选择性合成。
WO 95/08636描述了一种从相应的外消旋体制备旋光性伯胺和仲胺的方法,其中在水解酶的存在下进行对映选择性酰化反应。
但是,以此方式制备的旋光性胺根据其结构在储存时不是很稳定,并发生其它副反应。
所以,本发明的目的是提供一种方法,其能确保以高的产率、光学纯度和高的储存稳定性制备旋光4-(1-氨基乙基)苯甲酸甲酯。
发明内容
本发明涉及一种制备旋光4-(1-铵乙基)苯甲酸甲酯硫酸盐的方法,其中使外消旋4-(1-氨基乙基)苯甲酸甲酯与酰化试剂在脂酶存在下反应,得到4-(1-氨基乙基)苯甲酸甲酯,随后通过加入硫酸沉淀出4-(1-铵乙基)苯甲酸甲酯硫酸盐。
适用于本发明方法的酰化试剂优选是羧酸酯。特别优选的是所谓的活化羧酸酯,其中酸组分具有位于羰基碳原子的α位上的杂原子取代。甲氧基乙酸酯优选用作酰化试剂。羧酸酯的醇组分优选含有具有1-6个碳原子链长的烷基醇,其可以是支化或未支化的,也可以被取代。甲氧基乙酸异丙基酯是特别合适的酰化试剂。
许多酶可以用作本发明方法中的脂酶。特别优选的是微生物酶,它们可以例如从酵母或细菌分离出来。特别合适的脂酶是来自绿脓杆菌的那些,例如Amano P,或来自绿脓杆菌DSM 8246或南极假丝酵母(Candidaantarctica)的脂酶。以商品名Novozyme 435(Lipase B,南极假丝酵母)销售的Novozyme系列产品特别适用于本发明方法。
所用的酶可以以天然或固定化形式使用。
合适的溶剂一般是有机溶剂。反应特别好地在醚中进行,例如在MTBE或THF中,或在烃中,例如己烷、环己烷、甲苯或卤代烃,例如二氯甲烷。但是,反应也可以在不存在溶剂的情况下进行。
酰化试剂与外消旋4-(1-氨基乙基)苯甲酸甲酯在酶催化下的反应一般在室温进行。反应时间是1-48小时,优选5-24小时。
按照每摩尔4-(1-氨基乙基)苯甲酸甲酯计,加入1-2摩尔、优选1.2-1.6摩尔的酰化试剂。
脂酶的用量取决于脂酶的类型和酶制备的活性。对于反应而言最合适的脂酶用量可以容易地通过简单的初级实验确定。一般,每mmol胺计加入1000单位的脂酶。
反应进程可以通过常规方法容易地跟踪,例如通过气相色谱。在外消旋拆分的情况下,合理的是在外消旋胺的转化率为50%时停止反应。这一般通过从反应空间除去催化剂进行,例如过滤出酶。
外消旋4-(1-氨基乙基)苯甲酸甲酯与脂酶的对映选择性反应使得从一种对映体得到了相应的酰化产物(酰胺),而另一种对映体保持不变。目前存在的胺和酰胺的混合物可以容易地通过常规方法分离。萃取或蒸馏方法例如非常适合于分离胺和酰胺的混合物。被选择性酰化的对映体取决于脂酶的选择,并可以容易地通过初级实验确定;Novozyme435例如选择性地酰化了(R)-4-(1-氨基乙基)苯甲酸甲酯。
在已经制备旋光4-(1-氨基乙基)苯甲酸甲酯之后,通过加入硫酸将其转化成旋光4-(1-铵乙基)苯甲酸甲酯硫酸盐。在反应中,按照每摩尔4-(1-氨基乙基)苯甲酸甲酯计加入至少0.5mol的硫酸,从而确保完全成盐(转化成4-(1-铵乙基)苯甲酸甲酯硫酸盐)。
硫酸可以直接加入酶催酰化反应或在预先从反应介质分离出4-(1-氨基乙基)苯甲酸甲酯之后加入。也可以仅仅从反应介质除去脂酶;这在使用固定化脂酶时是特别有利的。
4-(1-铵乙基)苯甲酸甲酯硫酸盐一般从反应介质沉淀,并可以容易地从溶解的酰化4-(1-氨基乙基)苯甲酸甲酯(即,酰胺)分离出来。如果两种反应产物都是溶解的形式,则它们可以容易地在它们不同的物理化学性能基础上通过标准操作分离,例如结晶、萃取、蒸馏和色谱法。
4-(1-铵乙基)苯甲酸甲酯硫酸盐在反应条件下是稳定的,且不会象4-(1-氨基乙基)苯甲酸甲酯那样发生分子间酰胺化反应。可以通过进一步提纯以高光学纯度得到4-(1-铵乙基)苯甲酸甲酯硫酸盐,例如通过重结晶。
实验部分
实施例1
制备(S)-4-(1-铵乙基)苯甲酸甲酯硫酸盐(S-1-硫酸盐)
工序:
将甲氧基乙酸异丙酯IPMA(19.8g,0.15mol)和Novozym435(500mg)加入4-(1-氨基乙基)苯甲酸甲酯1(17.9g,0.1mol)在甲苯(150ml)中的溶液中并在室温搅拌。在24小时后的HPLC分析显示所有R-1已经被转化成R-酰胺R-2,现在仅仅能检测到未反应的S-胺S-1。通过硅藻土吸滤除去酶,在过滤器上的残余物用甲苯(20ml)洗涤,向搅拌的滤液中加入硫酸(6.45g的38%水溶液,25mmol)。分离出许多白色沉淀物。沉淀的盐被吸滤出来,用甲苯(2×20ml)洗涤,过滤器上的残余物从水(10ml)重结晶。作为结晶白色固体分离出8.9g(78%)的硫酸盐S-1,根据HPLC分析测定这里结合的S-胺S-1是对映纯的。熔点:280℃(分解),光学旋转:[α]D=-3.5°(c=1,在H2O中)。
合并的甲苯滤液再用水(10ml)洗涤一次,在硫酸钠上干燥并浓缩。在50℃在油泵真空下从剩余的残余物脱除残余溶剂。作为油状固体回收11g(88%)的R-酰胺R-2,(熔点50-60℃),根据GC分析是90%纯的。
1H-NMR-光谱:
胺1:
1H-NMR(400MHz,CDCl3)δ=1.40(d,J=7Hz,3H);1.60(s,宽,2H),3.90(s,3H),4.15(q,J=7Hz,1H),7.45和8.03(AA’,BB’体系,JAB=10.7Hz,4H)。
S-胺硫酸盐S-1硫酸盐:
1H-NMR(400MHz,D2O)δ=1.65(d,J=7Hz,3H);3.95(s,3H),4.65(q,J=7Hz,1H),7.60和8.10(AA’,BB’体系,JAB=10.7Hz,4H)。
R-酰胺R-2:
1H-NMR(400MHz,CDCl3)δ=1.55(d,J=7Hz,3H);3.42(s,3H),3.88和3.93(AB体系,JAB=15Hz,2H),3.90(s,3H),5.23(sept,J=7Hz,1H),6.80(d(宽),J=7Hz,1H),7.40和8.03(AA’,BB’体系,JAB=10.7Hz,4H)。
Claims (7)
1.一种制备旋光4-(1-铵乙基)苯甲酸甲酯硫酸盐的方法,其中使外消旋4-(1-氨基乙基)苯甲酸甲酯与酰化试剂在脂酶存在下反应,得到4-(1-氨基乙基)苯甲酸甲酯,随后通过加入硫酸沉淀出4-(1-铵乙基)苯甲酸甲酯硫酸盐,其中酰化试剂是羧酸酯,脂酶是来自南极假丝酵母的Lipase B。
2.权利要求1的方法,其中甲氧基乙酸酯用作酰化试剂。
3.权利要求1的方法,其中435用作脂酶。
4.权利要求1的方法,其中反应在溶剂中进行。
5.权利要求1的方法,其中在加入硫酸之前从反应介质除去酶。
6.(S)-4-(1-铵乙基)苯甲酸甲酯硫酸盐。
7.(R)-4-(1-铵乙基)苯甲酸甲酯硫酸盐。
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DE200510062966 DE102005062966A1 (de) | 2005-12-28 | 2005-12-28 | Verfahren zur Herstellung von (R)- und (S)-4-(Ammoniumethyl)benzoesäuremethylester-sulfat |
DE102005062966.0 | 2005-12-28 | ||
DE200610001160 DE102006001160A1 (de) | 2006-01-06 | 2006-01-06 | Verfahren zur Herstellung von (R) und (S)-4-(1-Aminoethyl)benzoesäure-methylester |
DE102006001160.0 | 2006-01-06 | ||
PCT/EP2006/069890 WO2007077120A1 (de) | 2005-12-28 | 2006-12-19 | VERFAHREN ZUR HERSTELLUNG VON (R) - UND (S) -4- (1-AMMONIUMETHYL) BENZOESÄUREMETHYLESTER-SULFAT AUS RACEMISCHEM 4-(l-AMIN0ETHYL)BENZ0ESÄUREMETHYLESTER DURCH LIPASE-KATALYSIERTE ENANTIOSELEKTIVE ACYLIERUNG UND ANSCHLIESSENDEM AUSFÄLLEN MIT SCHWEFELSÄURE |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1995008636A1 (de) * | 1993-09-25 | 1995-03-30 | Basf Aktiengesellschaft | Racematspaltung primärer und sekundärer amine durch enzym-katalysierte acylierung |
CN1281438A (zh) * | 1997-10-14 | 2001-01-24 | 卫福有限公司 | 哌嗪化合物及其作为医药的用途 |
WO2005105732A1 (en) * | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Substituted methyl aryl or heteroaryl amide compounds |
-
2005
- 2005-12-28 DE DE200510062966 patent/DE102005062966A1/de not_active Withdrawn
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WO1995008636A1 (de) * | 1993-09-25 | 1995-03-30 | Basf Aktiengesellschaft | Racematspaltung primärer und sekundärer amine durch enzym-katalysierte acylierung |
CN1281438A (zh) * | 1997-10-14 | 2001-01-24 | 卫福有限公司 | 哌嗪化合物及其作为医药的用途 |
WO2005105732A1 (en) * | 2004-05-04 | 2005-11-10 | Pfizer Japan Inc. | Substituted methyl aryl or heteroaryl amide compounds |
Non-Patent Citations (1)
Title |
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Rachel S. Dickins,et al.,.Synthesis, Time-Resolved Luminescence, NMR Spectroscopy,Circular Dichroism and Circularly Polarised Luminescence Studies of Enantiopure Macrocyclic Lanthanide Tetraamide Complexes.《chemistry》.1991,第5卷(第3期),1095-1105. * |
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