CN1946854A - 制备依他普仑的化学-酶法 - Google Patents
制备依他普仑的化学-酶法 Download PDFInfo
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Abstract
本发明涉及以4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(酰氧基甲基)苄腈为原料制备用于合成依他普仑及其可药用盐的中间体的方法,其通过酶解对映异构体拆分合成其对映异构体之一。
Description
本发明涉及制备对映异构纯的1-(3-二甲氨基丙基)-1-(4’-氟苯基)-1,3-二氢异苯并呋喃-5-甲腈的方法。
上述化合物(其结构式如下)是一种已知的活性成分,多称为“西酞普兰”,其用于制备治疗抑郁症的药物组合物。
西酞普兰首次在比利时专利申请BE850401(对应于美国专利US4,136,193)中公开;大量专利文献进一步涉及其制备方法。
由于具备手性中心,西酞普兰通常以外消旋混合物的形式被生产和销售。
如EP347066中所指出的,其S(+)对映异构体,多称为依他普仑,实际上产生了外消旋西酞普兰的全部药效活性。欧洲专利申请EP347066大体上描述了生产依他普仑的两种方法。
第一种方法以外消旋4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈为反应物,其随即使用具有对映异构活性的酰氯如(+)或(-)-α-甲氧基-α-三氟甲基苯基乙酰氯进行酯化。由(+)和(-)酰氯各获得两种非对映异构的酯,它们通过HPLC分离,从而获得对映异构纯的酯;随后在叔丁醇钾的甲苯溶液存在下进行环化,从各酯获得西酞普兰的纯对映异构体。
第二种方法以对映异构纯(例如(+))的4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈为反应物。为了获得对映异构纯的产物,将胺用具有对映异构活性的酸如酒石酸成盐,以提供两种可通过结晶分离的非对映异构的盐。由盐释放出的纯对映异构体被酯化形成特别不稳定的酯(例如使用甲烷磺酰氯),该酯通过使用强有机碱(例如三乙胺)允许获得对映异构纯的西酞普兰。
生产依他普仑的其它方法例如在美国专利US6365747、美国专利申请US2003/0060641以及国际专利申请WO03/000672、WO03/006449和WO03/051861中有描述。
然而,上述方法的特征均在于:使用了具有对映异构活性的酸和/或通过结晶或HPLC进行的非对映异构体分离,这限制了生产规模和反应产率。
现在发现一种新方法,其允许以高水平的对映异构纯度生产依他普仑且没有前述方法的缺陷。
本发明的方法包括采用来自黑曲霉(Aspergillus niger)的酯酶经酶途径对式I化合物的外消旋混合物进行拆分,
其中R代表C1-C4烷基或芳基,以获得相应的具有式II结构的(-)对映异构体,
事实上,已经出人意料地发现,来自黑曲霉的酯酶不同于本领域通常所知的酯酶,其能够选择性地唯一水解式(I)外消旋混合物中的(+)对映异构体,由此允许以高水平的产率和旋光纯度收集(-)对映异构体,这构成了本发明的主要主题。
因此,以这种方式获得的(-)对映异构体可以通过水解、优选碱性水解转化为式IV的(-)4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈。
然后式IV化合物可通过采用本领域已知的方法使两个羟基缩合而转化为式V的依他普仑,
所述的已知方法例如是EP347066中所述的方法(即在Et3N存在下用CH3SO2Cl处理),该文献引入本文作为参考。
反应流程图(包括拆分和转化为依他普仑)在图1中给出。
式I化合物的外消旋混合物又可按照本领域已知的方法来制备。
例如,其可以按照EP171943中的指示来制备,该文献引入本文做为参考。EP171943描述了一种合成方法,它提供了以5-氰基苯并吡喃酮为基础的两个连续的格氏反应;第一个反应采用4-氟苯基溴化镁,第二个反应将以这种方式所得的镁衍生物与3-(二甲氨基)丙基氯化镁反应,得到镁中间体,其进行酸性水解后获得式I’的二醇,其为西酞普兰的前体。
然后将该中间体按照本领域已知的方法对(苄腈)3-位上的羟甲基进行选择性酰化,例如通过与相应酸的酸酐或酰氯反应来进行。
在一个优选的实施方案中,采用乙酰氯使4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈的羟甲基被乙酰化。在本文中,相对于每摩尔原料使用5-20mol、优选约17mol的乙酰氯;优选将原料加入反应介质中并保持30-35℃的优选温度;一旦添加操作完成后,可采用本领域已知的方法、例如减压蒸发来容易地分离4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(酰氧基甲基)苄腈化合物。
拆分步骤有利地在由醇(优选C1-C4醇,甚至更优选甲醇)和水的混和物构成的溶剂中、在15-35℃、优选20-25℃的优选温度下进行,其中醇和水的比例优选为0.5-1.5∶1,甚至更优选为1∶1。
水有利地以磷酸盐缓冲液、优选磷酸二氢钾缓冲液的形式使用。
溶剂的用量相对于每摩尔物质有利地为3-5升,优选为3.5-4升。
在一个优选的方面,式I外消旋化合物最初加入碱性pH范围、优选约8的溶剂中,其随后使得pH值变为6。
然后加入来自黑曲霉的酯酶,优选其固定于树脂、通常为环氧树脂(Eupergit C)上,其相对于每摩尔物质有利地以2500-3200个单位、优选2800-2900个单位的量使用。
通过HPLC监测拆分反应,允许反应继续直至水解产率达到55%,通常在约70-80小时后达到该水平;接着,经过滤后采用乙酸乙酯作为优选的溶剂进行萃取,随后蒸发并采用***/乙酸乙酯混合物进行适宜的结晶,获得单独的(-)4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(酰氧基甲基)苄腈。
以该中间体为原料并参考专利EP347066,经水解并随后终止循环后,可能获得单独的游离碱(V)或草酸盐(VI)形式的依他普仑。
对于本发明的目的,术语“外消旋混合物”、“外消旋物”和“外消旋化合物”意欲不仅表示两种单独对映异构体的50∶50混合物,而且表示其中两种对映异构体之一相对于另一对映异构体而言过量存在的混合物。
下述实施例仅用于解释说明,绝不应当看作是对本发明的限制。
实施例1:4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(乙酰氧基甲基)苄腈的合成
将58.7g 4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈置于4颈烧瓶中,烧瓶于30-35℃、优选35℃的水浴加热,将210ml乙酰氯(相对于每摩尔原料为17mol)滴加到反应介质中。将混和物搅拌5分钟,转移至1颈烧瓶中,减压蒸发。获得79.02g 4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(乙酰氧基甲基)苄腈,为橙色油状残余物。
1H NMR(DMSO-d6)δ7.9(d,1H),7.8(d,1H),7.75(s,1H),7.2(d,2H),7.1(d,2H)6.2(s,1H),5.2(d,1H),4.8(d,1H),3.0(m,2H),2.60(m,6H),2.3(s,2H),1.9(s,3H),1.7(m,1H),1.4(m,1H).
实施例2:4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(乙酰氧基甲基)苄腈的酶法拆分
将10g 4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(乙酰氧基甲基)苄腈(250mM)溶于52ml甲醇中,随后向其中加入52ml 25mM磷酸二氢钾缓冲液(pH8)。
然后,通过用2N盐酸进行适度修饰并用等量甲醇(ml)补偿所加入的HCl体积以保证不改变溶液组成,使溶液pH调节至6。控制溶液温度为20-25℃。
最后,加入约75个单位的酯酶衍生物,其由来自黑曲霉的脂酶提取物粗品获得,并且按照常规方法固定于环氧树脂如Eupergit C上。
反应采用自动滴定计进行以保持pH值恒定,通过HPLC监测直到水解水平达到55%(70-80小时),由此获得99%e.e。
在反应结束后,将酶过滤并用少量水-甲醇溶液(5-10ml)洗涤。
使反应溶液减压蒸发,水相适宜碱化至pH8.5后在NaCl存在下(约5g)用乙酸乙酯萃取(约70ml,4次)。
使用Shimadzu HPLC柱按照下述分析条件对萃取液进行HPLC监测:
减压蒸发包含4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(酰氧基甲基)苄腈和部分二醇的有机相。由此获得反应粗品(8g),随后通过结晶进行纯化。
实施例3:(-)4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈的合成
将前述反应分离得到的产物粗品(8g)溶于***(约40ml)中,加入少量(0.1ml)乙酸乙酯并温和加热。经冷却沉淀出固体。滤液进行第二次结晶,冷却至0-4℃后沉淀出单独的(-)4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(乙酰氧基甲基)苄腈,为白色固体(2.2g),纯度为98%,99.8%e.e.,[α]D=-39.87/-40.00。随后将所得固体溶于175ml 30%NH3和100ml甲醇中,溶液搅拌约4小时,随后蒸发,得到1.9g(-)4-(4-二甲氨基)-1-(4’-氟苯基)-1-(羟丁基)-3-(羟甲基)苄腈。
Claims (11)
2.根据权利要求1所述的方法,其特征在于所述的拆分在由醇和水的混合物构成的溶剂中进行。
3.根据权利要求2所述的方法,其特征在于所述的醇是C1-C4醇,优选甲醇。
4.根据权利要求2所述的方法,其特征在于醇和水的体积比为0.5-1.5∶1,甚至更优选为1∶1。
5.根据权利要求2-4所述的方法,其特征在于水以磷酸盐缓冲液、优选磷酸二氢钾缓冲液的形式使用。
6.根据前述任一项权利要求所述的方法,其特征在于拆分在15-35℃、优选20-25℃进行。
7.根据前述任一项权利要求所述的方法,其特征在于溶剂的用量相对于每摩尔式I化合物为3-5升,优选为3.5-4升。
8.根据前述任一项权利要求所述的方法,其特征在于来自黑曲霉的酯酶固定于树脂、优选环氧树脂上。
9.根据前述任一项权利要求所述的方法,其特征在于来自黑曲霉的酯酶相对于每摩尔式I化合物以2500-3200个单位、优选2800-2900个单位的量使用。
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IT000717A ITMI20040717A1 (it) | 2004-04-09 | 2004-04-09 | Procedimento chemo-enzimatico per la preparazione dell'escitalopram |
ITMI2004A000717 | 2004-04-09 |
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IT (1) | ITMI20040717A1 (zh) |
MX (1) | MXPA06011609A (zh) |
PL (1) | PL1733042T3 (zh) |
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ITMI20041872A1 (it) | 2004-10-01 | 2005-01-01 | Adorkem Technology Spa | Processo per la preparazione di citalopram e di scitalopram |
EP1736550A1 (en) * | 2005-06-22 | 2006-12-27 | Adorkem Technology SpA | Chemoenzymatic process for the synthesis of escitalopram |
MY198279A (en) * | 2014-04-10 | 2023-08-21 | Genomatica Inc | Semisynthetic routes to organic compounds |
EP3137614B1 (en) | 2014-07-18 | 2018-09-19 | REG Life Sciences, LLC | Microbial production of 1,3 diols |
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GB1526331A (en) | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
GB8419963D0 (en) | 1984-08-06 | 1984-09-12 | Lundbeck & Co As H | Intermediate compound and method |
JPS62151196A (ja) * | 1985-09-26 | 1987-07-06 | Nitto Electric Ind Co Ltd | l−プロプラノロ−ルの生化学的分離法 |
GB8814057D0 (en) | 1988-06-14 | 1988-07-20 | Lundbeck & Co As H | New enantiomers & their isolation |
JP3097145B2 (ja) * | 1991-02-27 | 2000-10-10 | 日産化学工業株式会社 | コーリーラクトンジオールの光学分割方法 |
HU228576B1 (en) | 1998-10-20 | 2013-04-29 | Lundbeck & Co As H | Method for the preparation of citalopram |
SI1246812T1 (en) | 1999-12-28 | 2004-08-31 | H. Lundbeck A/S | Method for the preparation of citalopram |
AR034612A1 (es) | 2001-06-25 | 2004-03-03 | Lundbeck & Co As H | Proceso para la preparacion del citalopram racemico y/o del s- o r-citalopram mediante la separacion de una mezcla de r- y s-citalopram |
AR034759A1 (es) | 2001-07-13 | 2004-03-17 | Lundbeck & Co As H | Metodo para la preparacion de escitalopram |
IS7239A (is) | 2001-12-14 | 2004-04-29 | H. Lundbeck A/S | Aðferð til framleiðslu á essítalóprami |
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HK1101827A1 (en) | 2007-10-26 |
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PL1733042T3 (pl) | 2008-10-31 |
US20070238887A1 (en) | 2007-10-11 |
JP2007532106A (ja) | 2007-11-15 |
ITMI20040717A1 (it) | 2004-07-09 |
CA2561888A1 (en) | 2005-10-20 |
ES2308465T3 (es) | 2008-12-01 |
EP1733042B1 (en) | 2008-05-14 |
DE602005006770D1 (de) | 2008-06-26 |
SI1733042T1 (sl) | 2008-10-31 |
WO2005098018A1 (en) | 2005-10-20 |
ATE395429T1 (de) | 2008-05-15 |
US7470526B2 (en) | 2008-12-30 |
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EP1733042A1 (en) | 2006-12-20 |
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