CN1293048C - (7-甲氧基-2-二氢-1-萘基)乙腈的新合成方法,及其在阿戈美拉汀的合成中的应用 - Google Patents
(7-甲氧基-2-二氢-1-萘基)乙腈的新合成方法,及其在阿戈美拉汀的合成中的应用 Download PDFInfo
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Abstract
一种用于工业合成式(I)化合物的方法,及其在阿戈美拉汀的合成中的应用。
Description
本发明涉及工业合成(7-甲氧基-2-二氢-1-萘基)乙腈的新方法,以及该化合物在阿戈美拉汀或N-[2-(7甲氧基-1-萘基)乙基]乙酰胺的工业生
产中的应用
更具体地说,本发明涉及工业合成式(I)的化合物的的方法:
根据本发明的方法获得的式(I)的化合物可用于式(II)的阿戈美拉汀或N-[2-(7甲氧基-1-萘基)乙基]乙酰胺的合成:
阿戈美拉汀,或N-[2-(7甲氧基-1-萘基)乙基]乙酰胺,具有很有价值的药理性质。
实际上,它具有两方面的特征,一方面,它是褪黑激素能系统(melatoninergic system)受体的激动剂,另一方面,是5-HT2C受体的拮抗剂。这些性质使其在中枢神经系统中具备活性,并尤其在严重抑郁症、季节性压抑紊乱、睡眠障碍、心血管疾病、消化系统疾病、失眠以及由于飞行时差所导致的疲劳、食欲紊乱和肥胖症的治疗中具有活性。
在欧洲专利说明书EP 0 447 285中已经描述了阿戈美拉汀、其制备及其治疗用途。
考虑到该化合物的药用价值,能够以有效的工业合成方法,即可容易地转化为工业规模的、并以良好产率及极高的纯度得到阿戈美拉汀的合成方法,得到该化合物,是很重要的。
专利说明书EP 0 447 285描述了以7-甲氧基-1-四氢萘酮为起始原料、通过八个反应步骤合成阿戈美拉汀的方法,平均产率小于30%。
该方法包括溴乙酸乙酯的作用,随后进行芳构化和皂化以得到相应的酸,然后将它转化为乙酰胺,并随后脱水,得到(7-甲氧基-1-萘基)乙腈,随后进行还原,然后进行乙酰氯的缩合。
在转化为工业规模时,很快就发现难以实施该方法,这主要是由第一步的再现性问题导致的。第一步包括溴乙酸乙酯按照Réformatsky反应对7-甲氧基-1-四氢萘酮发生作用,产生(7-甲氧基-3,4-二氢-1(2H)-萘撑基)乙酸乙酯。
此外,(7-甲氧基-3,4-二氢-1(2H)-萘撑基)乙酸乙酯的芳构化的后续步骤常常是不完全的,并且在皂化后得到难以纯化的产品混合物。
本申请人现已开发出了一种新的工业化合成方法,该方法以可再现的方式进行,并且不需要进行繁琐的纯化,可得到具有能够将其用作药物活性成分所容许的纯度的阿戈美拉汀。
通过使氰基化合物与7-甲氧基-1-四氢萘酮直接缩合,获得了克服专利说明书EP 0 447 285所述方法中遇到的问题的又一方案。此外,可容易地对得到的缩合化合物进行芳构化得到(7-甲氧基-1-萘基)乙腈也是必要的。
显然(7-甲氧基-3,4-二氢-1-萘基)乙腈是一种满足直接由7-甲氧基-1-四氢萘酮进行合成这一需要的理想的合成中间体,并且是芳构化步骤中优良的底物。
在文献中已经描述了四氢萘酮与乙腈化合物直接缩合的反应。特别地,专利说明书US 3 992 403描述了膦酸氰甲酯与6-氟-1-四氢萘酮的缩合,专利说明书US 3 931 188描述了乙腈与四氢萘酮缩合得到一种被直接用于后续反应的氰基中间体。
根据图1,在将其应用于7-甲氧基-1-四氢萘酮时,乙腈的缩合得到了异构体混合物,其中外型(exo)占大部分,而内型(endo)占小部分。
图1
较多部分的“外型” 较少部分的“内型”得到的混合物随后需要剧烈的芳构化条件,而这些条件与进行阿戈美拉汀合成的工业化需要是不相容的。
本申请人现已开发了一种新的工业合成方法,该方法可以以一种可重现的方式、无需进行繁琐的纯化获得(7-甲氧基-3,4-二氢-1-萘基)乙腈,特别是不含式(III)的“外型”杂质:
该杂质在与进行阿戈美拉汀合成的工业化需要相容的操作条件下,不能进行随后的芳构化。
更具体地说,本发明涉及工业化合成式(I)化合物的方法:
其特征在于式(IV)的7-甲氧基-1-四氢萘酮:
与式(V)的氰基乙酸反应,
条件是除去形成的水,且存在催化量的式(VI)的化合物:
其中R与R’可以是相同的,或者是不同的,分别表示直链或者支链的(C3-C10)烷基、取代或未取代的芳基、取代或未取代的直链或支链的芳基(C1-C6)烷基,
在过滤以及用氢氧化钠溶液洗涤后,得到式(I)的化合物,所述式(I)的化合物在重结晶后以固体形式分离出来,
其中:
-芳基被理解为指苯基、萘基和联苯基,
-用于限定“芳基”和“芳基烷基”的术语“取代的”表示这些基团的芳基残基可被选自直链或支链(C1-C6)烷基、羟基和直链或支链的(C1-C6)烷氧基的1至3个相同或不同的基团所取代。
更特别地,通过蒸馏除去在反应中形成的水。优选使用沸点温度高于或等于水的反应溶剂,更优选与水形成共沸物的反应溶剂,例如二甲苯、甲苯、苯甲醚、乙苯、四氯乙烯、环己烯或1,3,5-三甲苯。
优选在甲苯或二甲苯回流的条件下、更优选在甲苯回流的条件下进行该反应。
适宜的是,所用催化剂的R或R’基团中的一个表示直链或支链的(C3-C10)烷基,且另一个表示芳基或芳基烷基。更特别地,优选的催化剂为式(VIa)的化合物:
其中R’a表示未取代的或被一个或多个直链或支链(C1-C6)烷基取代的苯基,n为0或1,Ra表示直链(C3-C10)烷基。
适宜的是,R’a表示未取代或取代的苯基,更特别地,表示未取代的苯基。
优选的基团Ra为己基。
n为1是适宜的。
本发明的方法中所用催化剂优选为式(VII)的庚酸苄基铵:
有利地,在过滤以及使用矿物或有机碱溶液,例如NaOH、KOH、Ca(OH)2、Sr(OH)2或NH4OH,并特别优选使用氢氧化钠溶液洗涤之后,得到式(VII)化合物。
该方法是特别有利的,这是因为:
-该方法能够以工业规模排它地获得“内型”化合物。考虑到在该类型的反应方面,文献中通常大都报导获得的是内型/外型混合物(Tetrahedron,1966,
22,3021-3026),这一结果更是令人惊讶的。该种结果的原因是使用了式(VI)的化合物作为反应催化剂,而不是目前在这种反应中使用的乙酸铵(Bull.Soc.Chim.Fr.,1949,884-890)。
-获得的转化率非常高,超过了97%,而不象使用乙酸的那样转化率不超过75%。
这样得到的式(I)化合物是一种新化合物,并且可用作阿戈美拉汀的合成中的中间体,其中对其进行芳构化,并随后进行还原,然后与乙酸酐偶合。
下述实施例用于说明本发明,但决不是对本发明进行限制。
实施例1:(7-甲氧基-3,4-二氢-1-萘基)乙腈
在12.7kg苄胺的存在下,将85.0kg 7-甲氧基-1-四氢萘酮、60.3kg氰基乙酸和15.6kg溶于甲苯的庚酸加入670升的反应器中。在回流下加热该混合物。当全部起始底物消失后,冷却该溶液并过滤。使用甲苯洗涤得到的沉淀,并然后使用2N的氢氧化钠溶液洗涤得到的滤出液,并随后用水洗涤直至中性。通过蒸发除去溶剂,然后在乙醇/水(80/20)的混合物中重结晶所获固体,以90%的产率和超过99%的化学纯度得到标题产物。
熔点:48-50℃
实施例2:(7-甲氧基-3,4-二氢-1-萘基)乙腈
在11.0kg苯胺的存在下,将85.0kg 7-甲氧基-1-四氢萘酮、60.3kg氰基乙酸和15.6kg溶于甲苯的庚酸加入670升的反应器中。在回流下加热该混合物。当全部起始底物消失后,冷却该溶液并过滤。使用甲苯洗涤得到的沉淀,并然后使用2N的氢氧化钠溶液洗涤得到的滤出液,并随后用水洗涤直至中性。通过蒸发除去溶剂,然后在乙醇/水(80/20)的混合物中重结晶所获固体,以87%的产率和超过99%的化学纯度得到标题产物。
熔点:48-50℃
Claims (8)
1.一种工业合成式(I)化合物的方法:
其特征在于式(IV)的7-甲氧基-1-四氢萘酮:
与式(V)的氰基乙酸反应,
条件是除去形成的水,且存在催化量的式(VI)的化合物:
其中R与R’可以是相同的,或者是不同的,分别表示直链或者支链的(C3-C10)烷基、取代或未取代的芳基、取代或未取代的直链或支链的芳基(C1-C6)烷基,
在过滤以及用氢氧化钠溶液洗涤后,得到式(I)的化合物,所述式(I)化合物在重结晶后以固体形式分离出来,
其中:
-芳基被理解为指苯基、萘基和联苯基,
-用于限定“芳基”和“芳基烷基”的术语“取代的”表示这些基团的芳基残基可被选自直链或支链(C1-C6)烷基、羟基和直链或支链的(C1-C6)烷氧基的1至3个相同或不同的基团所取代。
2.如权利要求1所述的式(I)化合物的合成方法,其特征在于在甲苯回流的条件下进行反应。
3.如权利要求1所述的式(I)化合物的合成方法,其特征在于所用催化剂为式(VIa)的化合物
其中R’a表示未取代的或被一个或多个直链或支链(C1-C6)烷基取代的苯基,n为0或1,Ra表示直链(C3-C10)烷基。
4.如权利要求1所述的式(I)化合物的合成方法,其特征在于R表示己基。
5.如权利要求1所述的式(I)化合物的合成方法,其特征在于R’表示苄基。
6.如权利要求1所述的式(I)化合物的合成方法,其特征在于所用催化剂为式(VII)的庚酸苄基铵:
7.式(I)的化合物,其为(7-甲氧基-3,4-二氢-1-萘基)乙腈,用作阿戈美拉汀的合成中的中间体。
8.由式(I)化合物合成阿戈美拉汀的方法,其包括通过根据权利要求1至6任一项所述的合成方法合成式(I)的化合物,并对该化合物进行芳构化,随后将其还原,然后用乙酸酐偶合。
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FR2866334B1 (fr) * | 2004-02-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese du (7-methoxy-1-naphtyl) acetonitrile et application a la synthese de l'agomelatine |
FR2889522B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iv de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
FR2889521B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
FR2889523B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
WO2007079317A2 (en) * | 2005-12-06 | 2007-07-12 | Neurocrine Biosciences, Inc. | Use of sedative hypnotics for treating obesity or maintaining weight loss |
CN101638376B (zh) * | 2008-07-29 | 2011-04-27 | 江苏恩华药业股份有限公司 | 阿戈美拉汀的制备方法及其中间体 |
EP2580183B1 (en) | 2010-06-10 | 2014-07-23 | Gador S.A. | New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide |
CN102060733B (zh) * | 2010-12-06 | 2014-01-29 | 威海迪素制药有限公司 | (7-甲氧基-3,4-二氢-1-萘基)乙腈的制备方法 |
WO2013054273A2 (en) | 2011-10-11 | 2013-04-18 | Ranbaxy Laboratories Limited | Process for the preparation of agomelatine |
US20140336380A1 (en) | 2011-12-01 | 2014-11-13 | Ranbaxy Laboratories Limited | Process for the preparation of agomelatine |
WO2014001939A1 (en) * | 2012-06-30 | 2014-01-03 | Alembic Pharmaceuticals Limited | Process for preparation of agomelatine and crystalline form i thereof |
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