CN101643434B - 合成阿戈美拉汀的新方法 - Google Patents

合成阿戈美拉汀的新方法 Download PDF

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CN101643434B
CN101643434B CN2009101603096A CN200910160309A CN101643434B CN 101643434 B CN101643434 B CN 101643434B CN 2009101603096 A CN2009101603096 A CN 2009101603096A CN 200910160309 A CN200910160309 A CN 200910160309A CN 101643434 B CN101643434 B CN 101643434B
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C·哈杜安
J-P·勒库夫
N·布拉格涅尔
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Abstract

本发明涉及合成阿戈美拉汀的新方法。更具体地讲，本发明涉及工业合成式(I)化合物的方法

Description

合成阿戈美拉汀的新方法
技术领域：
本发明涉及工业合成式(I)的阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的新方法：
Figure G2009101603096D00011
背景技术：
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺具有有价值的药理学性质。
实际上，其具有双重特性，其一方面是褪黑激素能系统受体的激动剂，另一方面，其又是5-HT2C受体的拮抗剂。这些性质使其具有中枢神经系统活性，并且更尤其是使其具有治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管病状、消化系统病状、由于时差导致的失眠和疲劳、食欲障碍和肥胖的活性。
已经在欧洲专利EP 0 447 285和EP 1 564 202中对阿戈美拉汀、其制备以及其在治疗中的应用进行了描述。
鉴于该化合物的药用价值，能用可容易地转移至工业规模并且能以良好的收率和极佳的纯度提供阿戈美拉汀的有效工业合成方法来制备这种化合物是很重要的。
专利说明书EP 0 447 285描述了由7-甲氧基-1-四氢萘酮开始经八步来制备阿戈美拉汀，其平均收率低于30％。
在专利说明书EP 1 564 202中，申请人建立了一种仅四步的由7-甲氧基-1-四氢萘酮开始的更有效且更易工业化的合成途径，该途径使得可以以高再现性的方式获得定义明确的结晶形式的阿戈美拉汀。
但是，对新合成途径，尤其是由成本比7-甲氧基-1-四氢萘酮低的起始材料开始的新合成途径的研究目前仍然是很有意义的。
申请人通过继续研究建立了一种由7-甲氧基-1-萘酚开始合成阿戈美拉汀的新方法：这种新起始材料的优点是简单，可以容易地以较低成本大量获得。此外，7-甲氧基-1-萘酚还具有在其结构中具有萘环结构的优点，其避免了在合成中包含芳构化的步骤，因此从工业角度看，芳构化步骤一直都很成问题。
此外，这种新方法使得可以以可再现的方式获得阿戈美拉汀并且不需要进行费力的纯化，获得的阿戈美拉汀具有与其作为药学活性成分应用相符的纯度。
发明内容
具体地讲，本发明涉及一种工业合成式(I)化合物的方法：
Figure G2009101603096D00021
该方法的特征在于使式(II)的7-甲氧基-1-萘酚进行反应：
Figure G2009101603096D00022
在将其羟基官能团转化成一种离去基团如卤素、甲苯磺酸酯或三氟甲磺酸酯基团后，使其在存在钯的情况下与式(III)的化合物：CH2＝CH-R(III)缩合，
其中R表示基团
Figure G2009101603096D00031
其中R′和R″可以相同或不同，各自表示直链或支链(C1-C6)烷基或者R′和R″一起形成一种(C2-C3)亚烷基链并且所形成的环可以与苯基稠合，
从而得到式(IV)的化合物：
其中R如上文所定义，
Figure G2009101603096D00032
使其进行催化氢化，从而得到式(V)的化合物：
其中R如上文所定义，
Figure G2009101603096D00033
使其进行碱或酸水解或用一种二元还原剂/酸系统对其进行处理，从而得到式(VI)的化合物或其盐酸盐：
Figure G2009101603096D00034
将其用乙酸钠处理，然后用乙酸酐处理，从而得到式(I)的化合物，将其以固体形式分离出来。
根据本发明的方法，式(III)的化合物优选是一种邻苯二甲酰亚胺化合物，更优选地是N-乙烯基邻苯二甲酰亚胺。式(III)的化合物还优选是丙烯酰胺。
本发明用于获得式(IV)化合物的式(III)化合物的缩合反应有利地是用四(三苯基膦)钯进行的，该反应优选地是在甲苯的回流下进行的。
优选用钯碳来将式(IV)的化合物氢化成式(V)的化合物，尤其是用钯含量最低为5％的钯碳来进行。
式(V)化合物的水解优选用一种二元还原剂/酸系统例如NaBH4和乙酸来进行，或者，当R表示C(O)NH2基团时，式(V)化合物向式(VI)化合物的转化优选用碱例如NaOBr或NaOCl来进行。
由于下面的原因，这种方法尤其有价值：
-其使得可以由简单、低成本的起始材料开始，以极佳的收率在工业规模获得式(I)的化合物；
-本发明选择的操作条件使得在与式(III)化合物偶合的过程中可以完全控制区域选择性；
-因为在起始底物中存在萘环系统，从而使得可以避免芳构化反应；
-最后，以可再现方式获得的式(I)的化合物具有专利说明书EP1564202中所述的晶形特性。
根据本发明方法获得的式(IV)化合物是新的并且可在阿戈美拉汀的合成中用作中间体，在阿戈美拉汀的合成中，使其进行还原反应，然后使其进行水解反应，然后使其与乙酸酐进行偶合反应。
具体实施方式
用下文的实施例对本发明进行非限制性说明。
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A：三氟甲磺酸7-甲氧基-1-萘基酯
在一个反应器中，将2.7g7-甲氧基-1-萘酚、1.1当量三氟甲磺酸酐和1.1当量2，6-二-叔-丁基-4-甲基-吡啶引入到二氯甲烷(45ml)中。将该混合物在回流下加热12小时，然后对其进行过滤，将液体用1N HCl溶液洗涤，然后用饱和NaCl溶液洗涤。将有机相蒸发并将所得残余物用硅胶色谱进行纯化(洗脱剂：CH2Cl2/甲基-环己烷1/9)，从而以91％的收率得到油状的化学纯度高于99％的标题产物。
步骤B：2-[2-(7-甲氧基-1-萘基)乙烯基]-1H-异吲哚-1，3(2H)-二酮
在一个反应器中，将2g步骤A获得的化合物、2当量N-乙烯基邻苯二甲酰亚胺、1.25当量二异丙基乙基胺和0.05当量四(三苯基膦)钯引入到甲苯中并将其在回流下进行加热。使该反应在回流下继续进行12小时，然后将该反应混合物冷却至环境温度。向其中加入乙酸乙酯，然后用水和1N HCl溶液对其进行洗涤。在蒸发掉溶剂后，将所得残余物用硅胶色谱进行纯化(洗脱剂：二氯甲烷/庚烷1/1，然后是二氯甲烷)，从而以80％的收率获得化学纯度高于95％的标题产物。
熔点：146℃
步骤C：2-[2-(7-甲氧基-1-萘基)乙基]-1H-异吲哚-1，3(2H)-二酮
在一个反应器中，将2g步骤B获得的化合物和1g5％的钯碳在氢气压和环境温度下引入到甲醇/THF 1/2的混合物中。在使其反应8小时后，对该反应混合物进行过滤。在蒸发掉溶剂后，以定量收率获得化学纯度为95％的标题产物。
熔点：154℃
步骤D：2-(7-甲氧基-1-萘基)乙胺
在一个反应器中，将1g步骤C获得的化合物和5当量NaBH4引入到2-丙醇/水6/1的混合物中并将该混合物在环境温度下进行搅拌。然后，向其中加入乙酸(0.2当量)并将该反应混合物在80℃下加热8小时。在蒸发掉溶剂并进行水与甲苯的共蒸发后，将所得粗品残余物在不进行进一步纯化的情况下直接用于乙酰化反应。
步骤E：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
在一个反应器中，将5g步骤D获得的化合物和2g乙酸钠引入到乙醇中。对该混合物进行搅拌，然后向其中加入2.3g乙酸酐，将该反应混合物加热至回流并向其中加入20ml水。使该反应混合物回复至环境温度，将所得沉淀滤出，用乙醇/水35/65的混合物对其进行洗涤，从而以80％的收率(步骤D和E两步的收率)获得化学纯度高于99％的标题产物。
熔点：108℃
实施例2：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A：3-(7-甲氧基-1-萘基)-2-丙烯酰胺
通过在20℃下用氮气鼓泡10分钟来对实施例1步骤A获得的化合物(12.1g)在80mL DMF中的溶液进行脱气。向所得溶液中依次加入三乙胺(6.6mL)、丙烯酰胺(5.6g)、新铜试剂水合物(454mg)和Pd(OAc)2(445mg)。将该混合物在100℃下加热1小时，然后使其冷却至20℃。用AcOEt(100mL)稀释然后加入饱和NH4Cl溶液后，进行相分离。将有机相减压浓缩，将残余物用AcOEt(50mL)稀释。将沉淀滤出，从而得到粉末形式的标题化合物。
步骤B：3-(7-甲氢基-1-萘基)丙酰胺
将0.12g 5％Pd/C(50％湿度)加入到步骤A获得的化合物(0.5g)在MeOH(6.5mL)/THF(6.5mL)混合物中的溶液中。将该混合物用氮气、然后用氢气净化，然后将其在50℃下在大气压下加热1小时。然后，将该悬浮液用硅藻土过滤，用MeOH(5mL)/THF(5mL)混合物对滤器进行洗涤。将液体减压浓缩，从而得到固体形式的标题产物，将其在不进行进一步纯化的情况下直接用于下一步。
步骤C：盐酸2-(7-甲氧基-1-萘基)乙胺
将亚碘酰苯二乙酸盐(0.88g)加入到水(3mL)/乙腈(3mL)溶液中。将其在20℃下搅拌10分钟后，分批加入步骤B获得的化合物(500mg)，然后将该混合物在20℃下放置2小时。在起始材料已经被消耗后，减压蒸馏掉乙腈。将残余物吸收于H2O(10mL)中，然后用浓HCl溶液(0.4mL)对其进行处理。往过滤后，用乙酸乙酯对所得沉淀进行洗涤，然后将其在烘箱中干燥，从而得到标题产物。
熔点：243℃
步骤D：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
在一个反应器中，将5g步骤C获得的化合物和2g乙酸钠引入到乙醇中。对该混合物进行搅拌，然后向其中加入2.3g乙酸酐，将该反应混合物加热至回流并向其中加入20ml水。使该反应混合物回复至环境温度，将所得沉淀滤出，用乙醇/水35/56的混合物进行洗涤，从而得到标题产物。
熔点：108℃
实施例3：实施例1和2所得化合物N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺晶形的测定
用得自Bruker AXS的D8高分辨衍射仪进行数据记录，使用下面的参数：3°-90°的2θ角范围，0.01°的跨距且每个跨距30秒。将实施例1和2获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺粉末放置在一个传输固定件支撑物上。X-射线源是铜管(λCuKα1＝1.54056)。该固定件包括一个前单色器(Ge(111)结晶)和能量解析固态检测器(MXP-D1，Moxtec-SEPH)。该化合物结晶良好：半高线宽为0.07°(以2θ计)。
相应地测定下面的参数：
-晶胞的晶体结构：单斜晶，
-晶胞参数：a＝20.0903
Figure G2009101603096D00072
b＝9.3194
Figure G2009101603096D00073
c＝15.4796
Figure G2009101603096D00074
β＝108.667°
-空间群：P21/n
-晶胞中分子的数目：8
-晶胞的体积：V晶胞＝2746.742
Figure G2009101603096D00075
-密度：d＝1.13g/cm3。
实施例4：用X-射线粉末衍射图进行的实施例1和2获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺化合物的晶形测定
用下面的X-射线粉末衍射图对实施例1和2所得化合物的晶形进行表征，该衍射图是用Siemens D5005衍射仪(铜对阴极)测得的，并且以晶面间距d、Bragg′s角2θ和相对强度(表示为相对于最强线的百分比)进行表达：
Figure G2009101603096D00081

Claims (11)

1.工业合成式(I)化合物的方法
Figure FSB00000614457900011
该方法的特征在于使式(II)的7-甲氧基-1-萘酚进行反应：
在将其羟基官能团转化成一种离去基团后，使其在存在钯的情况下与式(III)的化合物：CH2＝CH-R(III)缩合，
其中R表示基团
Figure FSB00000614457900013
其中R′和R″可以相同或不同，各自表示直链或支链(C1-C6)烷基或者R′和R″一起形成一种(C2-C3)亚烷基链并且所形成的环可以与苯基稠合，从而得到式(IV)的化合物：
其中R如上文所定义，
使其进行催化氢化，从而得到式(V)的化合物：
Figure FSB00000614457900015
其中R如上文所定义，
使其进行碱或酸水解或用一种二元还原剂/酸系统对其进行处理，从而得到式(VI)的化合物或其盐酸盐：
Figure FSB00000614457900021
或当R表示基团
Figure FSB00000614457900022
时，式(V)化合物向式(VI)化合物的转化用亚碘酰苯二乙酸盐进行，
将式(VI)化合物用乙酸钠处理，然后用乙酸酐处理，从而得到式(I)的化合物，将其以固体形式分离出来。
2.如权利要求1所述的合成式(I)化合物的方法，其特征在于所述离去基团选自卤素、甲苯磺酸酯或三氟甲磺酸酯基团。
3.如权利要求1所述的合成式(I)化合物的方法，其特征在于式(III)的化合物是N-乙烯基邻苯二甲酰亚胺。
4.如权利要求1所述的合成式(I)化合物的方法，其特征在于式(III)的化合物是丙烯酰胺。
5.如权利要求1所述的合成式(I)化合物的方法，其特征在于用于获得式(IV)化合物的式(III)化合物的缩合反应是用四(三苯基膦)钯进行的。
6.用作合成阿戈美拉汀的中间体的如权利要求1所述的式(IV)的化合物。
7.如权利要求6所述的式(IV)的化合物在合成阿戈美拉汀中的应用。
8.如权利要求1所述的式(II)的化合物在合成阿戈美拉汀中的应用。
9.如权利要求1所述的式(V)的化合物在合成阿戈美拉汀中的应用。
10.由式(IV)的化合物开始的如权利要求1所述的阿戈美拉汀的合成方法，其特征在于式(IV)的化合物是用如权利要求1至5中任意一项所述的合成方法获得的。
11.由式(V)的化合物开始的如权利要求1所述的阿戈美拉汀的合成方法，其特征在于式(V)的化合物是用如权利要求1至5中任意一项所述的合成方法获得的。
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