CN101643431B - 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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CN101643431B
CN101643431B CN2009101514641A CN200910151464A CN101643431B CN 101643431 B CN101643431 B CN 101643431B CN 2009101514641 A CN2009101514641 A CN 2009101514641A CN 200910151464 A CN200910151464 A CN 200910151464A CN 101643431 B CN101643431 B CN 101643431B
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C·哈杜安
J-P·勒库夫
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Abstract

本发明涉及合成阿戈美拉汀的新方法，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阿戈美拉汀或式(I)的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的新方法：
Figure G2009101514641D00011
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，一方面，它是褪黑素能系统受体激动剂，另一方面，它是5-HT2C受体拮抗剂。这些性质使其在中枢神经系统中具有活性并且，更特别的是，使其在治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管病理学、消化系统病理学、时差引起的失眠和疲劳、食欲障碍和肥胖中具有活性。
阿戈美拉汀、其制备方法以及其在治疗中的用途已经在欧洲专利说明书EP 0 447 285和EP 1 564 202中描述。
由于该化合物的药物价值，重要的是能够应用有效的工业合成方法制备该化合物，该工业合成方法易于转化为工业规模并且使阿戈美拉汀的产率很高并且纯度很高。
专利说明书EP 0 447 285描述了阿戈美拉汀的制备，用8个步骤，从7-甲氧基-1-四氢萘酮开始，平均产率小于30％。
在专利说明书EP 1 564 202中，申请人开发了新的更有效并且可工业化的合成路线，仅用4个步骤，从7-甲氧基-1-四氢萘酮开始，其使用高度可重现方法获得确定结晶形式的阿戈美拉汀成为可能。
但是，现在仍然进行关于新的合成路线、特别是从比7-甲氧基-1-四氢萘酮花费更少的原料开始的研究。
发明内容
申请人继续其研究并且已经发明了合成阿戈美拉汀的新方法，该方法从3-甲氧基苊醌(acenaphthoquinone)开始：这个新原料具有简单、易于花费少而大量获得的优势。另外，3-甲氧基苊醌也具有在其结构中具有萘环系的优势，其避免了在合成中包括芳构化的步骤，该步骤在工业观点上常有问题。
另外，该新方法使用可重现方法获得阿戈美拉汀并且无需费力纯化成为可能，该方法的纯度符合其用作药物活性成分的需要。
更特别的是，本发明涉及工业合成式(I)化合物的方法：
Figure G2009101514641D00021
该方法的特征在于将式(II)的3-甲氧基苊醌在强碱的存在下反应：
得到式(III)化合物：
将其进行氨基化，得到式(IV)化合物：
Figure G2009101514641D00031
将其进行与还原体系的作用，得到式(V)化合物：
Figure G2009101514641D00032
将其依次进行与乙酸钠的作用，然后进行与乙酸酐的作用，得到式(I)化合物，将其以固体形式分离。
式(II)化合物是本领域技术人员通过常规化学反应和/或参考文献中描述的化学反应可得到的。
有利的是，根据本发明将式(II)化合物转化为式(III)化合物是应用NaNH2、((CH3)3-Si)2NLi(LiHMDS)或((CH3)3-Si)2NNa(NaHMDS)进行的。
氨基化反应优选应用NH4Cl和丙基膦酸酐进行。
作为根据本发明将式(IV)化合物转化为式(V)化合物中的还原体系，优选LiAlH4或BH3.THF/AlCl3对。
该方法由于以下原因特别有价值：
-其使在工业规模上以高产率，从简单、低花费原料开始获得式(I)化合物成为可能；
-由于萘环系存在于起始底物中，使其避免芳构化成为可能；
-最后，以可重现方法获得的式(I)化合物具有在专利说明书EP 1 564202中描述的结晶形式的特征。
根据本发明的方法获得的式(IV)化合物是新的并且用作合成阿戈美拉汀的中间体，其中将其进行还原反应，然后与乙酸酐进行偶联反应。
具体实施方式
以下实施例说明本发明，但不以任何方式限制本发明的范围。
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
步骤A：(7-甲氧基-1-萘基)(氧代)乙酸
在反应器中，将4mg 18-冠-6醚和230mg NaNH2依次加入至100mg3-甲氧基苊醌在1mL DMSO中的悬浮液中。将混合物在环境温度下搅拌30分钟。然后加入水(2mL)，然后加入2N HCl溶液(3mL)。用乙酸乙酯萃取2次后，将溶剂经Na2SO4干燥，然后蒸发，得到标题产物，为黄色固体形式，产率88％，并且化学纯度大于94％。
熔点：99℃
步骤B：2-(7-甲氧基-1-萘基)-2-氧代乙酰胺
在反应器中，将1g步骤A中获得的化合物加入至30mL乙腈中，然后加入4.39g丙基膦酸酐和438mg NH4Cl，并且加入完成后，在环境温度下加入3.8mL二异丙基胺。将溶液在氮气下搅拌4小时，然后将溶剂蒸发，将残留物溶于饱和的NaCl水溶液中，并且用乙酸乙酯萃取。然后将溶剂经Na2SO4干燥，然后蒸发，得到标题产物，为橙色固体形式，产率80％，并且化学纯度为90％。
熔点：112℃
步骤C：2-(7-甲氧基-1-萘基)乙胺
将溶于THF(20mL)中的480mg步骤B中获得的化合物加入至反应器中，然后加入2当量AlCl3，并且最后缓慢加入6当量BH3.THF溶液，并且将反应混合物搅拌2.5小时。然后加入水(12mL)，然后加入25mL 1N氢氧化钠溶液以及800mg固体氢氧化钠，并且用甲基叔丁基醚(20mL)萃取3次。然后将溶剂经Na2SO4干燥，然后蒸发，得到标题产物，为黄色油状物形式，产率80％，并且化学纯度为95％。
步骤D：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺
在反应器中，将5g步骤C中获得的化合物和2g乙酸钠加入至乙醇中。将混合物搅拌，然后加入2.3g乙酸酐，将反应混合物加热至回流并且加入20mL水。将反应混合物回至环境温度并且将获得的沉淀过滤，用乙醇/水35/65混合物洗涤，得到标题产物，产率80％，化学纯度为99％。
熔点：108℃
实施例2：确定实施例1中获得的化合物N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的结晶形式
记录数据应用Bruker AXS的D8高分辨衍射仪进行，参数如下：2θ角范围3°-90°，每步0.01°并且每步30秒。将实施例1中获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺粉末置于转移样品架(transmission mountingsupport)上。X-射线源是铜管(λCuKα1＝1.54056
Figure G2009101514641D00051
)。样品架包括前部的单色器(Ge(111)晶体)和能量分辨固态探测器(MXP-D1，Moxtec-SEPH)。
化合物很好地被结晶：半峰高处的谱线宽度为2θ角0.07°数量级。
因此，确定以下参数：
-晶胞的晶体结构：单斜晶
-晶胞参数：a＝20.0903
Figure G2009101514641D00052
，b＝9.3194
Figure G2009101514641D00053
，c＝15.4796
Figure G2009101514641D00054
，β＝108.667°
-空间群：P21/n
-晶胞中的分子数：8
-晶胞体积：V晶胞＝2746.742
Figure G2009101514641D00055
3
-密度：d＝1.13g/cm3。
实施例3：通过X-射线粉末衍射图确定实施例1中获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺化合物的结晶形式
实施例1中获得的化合物的结晶形式的特征在于以下X-射线粉末衍射图，应用Siemens D5005衍射仪(铜对阴极)测量并且以晶面间距d、布拉格2θ角和相对强度(表示为相对于最强谱线的百分比)表示：
Figure G2009101514641D00056

Claims (10)

1.工业合成式(I)化合物的方法
Figure FSB00000898759100011
该方法的特征在于将式(II)的3-甲氧基苊醌在NaNH2、((CH3)3-Si)2NLi(LiHMDS)或((CH3)3-Si)2NNa(NaHMDS)的存在下反应：
得到式(III)化合物：
Figure FSB00000898759100013
将其进行氨基化，得到式(IV)化合物：
将其进行与还原体系的作用，得到式(V)化合物：
Figure FSB00000898759100021
将其依次进行与乙酸钠的作用，然后进行与乙酸酐的作用，得到式(I)化合物，将其以固体形式分离。
2.权利要求1的合成式(I)化合物的方法，其特征在于应用NaNH2将式(II)化合物转化为式(III)化合物。
3.权利要求1的合成式(I)化合物的方法，其特征在于应用BH3.THF/AlCl3对将式(IV)化合物转化为式(V)化合物。
4.权利要求1的式(IV)化合物，其用作合成阿戈美拉汀的中间体。
5.权利要求4的式(IV)化合物在合成阿戈美拉汀中的用途。
6.权利要求1的式(II)化合物在合成阿戈美拉汀中的用途。
7.权利要求1的式(III)化合物在合成阿戈美拉汀中的用途。
8.权利要求1的合成阿戈美拉汀的方法，从式(III)化合物开始，其特征在于式(III)化合物是通过权利要求1或2中任意一项的合成方法获得的。
9.权利要求1的合成阿戈美拉汀的方法，从式(IV)化合物开始，其特征在于式(IV)化合物是通过权利要求1或2中任意一项的合成方法获得的。
10.权利要求1的合成阿戈美拉汀的方法，从式(V)化合物开始，其特征在于式(V)化合物是通过权利要求1至3中任意一项的合成方法获得的。
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CN102531956B (zh) * 2010-12-21 2014-07-09 浙江九洲药业股份有限公司 用于制备阿戈美拉汀的中间体及相关制备方法
US8561395B2 (en) 2011-03-03 2013-10-22 Tenneco Automotive Operating Company Inc. Poka-yoke mounting system for an exhaust treatment device
EP2562151A1 (en) * 2011-08-25 2013-02-27 Dr. Reddy's Laboratories Ltd. Processes for the preparation of agomelatine and its intermediates
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FR3014437B1 (fr) * 2013-12-05 2016-12-23 Servier Lab Nouveau procede de synthese de l'agomelatine

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IL199875A0 (en) 2010-05-17
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IL199875A (en) 2013-10-31
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