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1. 发明申请

WO2013008044A1 SYNTHESIS OF (+) AND (-) 1 -(5,5-DIPHENYLTETRAHYDROFURAN-3- YL)-N,N-DIMETHYLMETHANAMINE, (+) AND (-) 1-(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N- DIMETHYLMETHANAMINE AND (+) AND (-) 1-(2,2- DFFHENYLTETRAHYDROFURAN-3-YL)-N-METIHYLMETHANAMINE 审中-公开
标题翻译：（+）和（ - ）1-（5,5-二苯基四氢呋喃-3-基）-N，N-二甲基甲胺，（+）和（ - ）1-（2,2-二苯基四氢呋喃-3-基） N，N-二甲基甲胺和（+）和（ - ）1-（2,2-三氟甲磺酰氧基）-3-甲氧基甲基胺
公开(公告)号：WO2013008044A1
公开(公告)日：2013-01-17
申请号：PCT/GR2012/000030
申请日：2012-07-05
申请人： ANAVEX LIFE SCIENCES CORP. , WAMVAKIDES, Alexandre , MOUTSOS, Vassilios , SCHMITT, Martine
发明人： WAMVAKIDES, Alexandre , MOUTSOS, Vassilios , SCHMITT, Martine
IPC分类号： C07D307/14 , A61K31/341 , A61P25/00
CPC分类号： C07D307/14
摘要： The current invention covers the synthesis of (+) and (-) l-(5,5-diphenyItetrahydrofuran-3- yl)-N,N-dimethylmethanamine [(±)1] and [(-)1] respectively, including their pharmacologically acceptable acid addition salts. The new products can be synthesized starting from 5,5-diphenyltetrahydrofuran-2(3H)-one (4) after insertion of an aldehyde group in the α-position, reduction to the prochiral 3-(hydroxymethyl)-1, 1-diphenylbutane-1,4-diol (6), chemoenzymatic desymmetrization using the enzyme Amano Lipase PS30, tosylation, intramolecular nucleophilic attack, hydrolysis, reaction with trifluoromethanesulfonic anhydride and substitution by dimethylamine, thus producing (+) 1-(5,5-diphenyl- tetrahydrofuran-3-yl)-N,N-dimethylmethanamine [(+)1]. Protection of the product of the chemoenzymatic desymmetrization with tert-butyldimethylsilyl chloride, hydrolysis, tosylation, intramolecular nucleophilic attack, removal of tert-butyldimethylsilyl group, reaction with trifluoromethanesulfonic anhydride and substitution by dimethylamine produces (-) 1-(5,5-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine [(-)1]. It also covers the synthesis of (+) and (-) 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N- dimethylmethanamine [(+)2] and [(-)2] respectively and (+) and (-) 1-(2,2-diphenyl- tetrahydrofuran-3-yl)-N-methylmethanamine \(+)3] and [(-)3] respectively, including their pharmacologically acceptable acid addition salts. The new products can be synthesized either starting from the reduction of 5-oxo-2,2-diphenyltetrahydrofuran-3-carboxylic acid (13) with LiA1H 4 , followed by the cyclization of the obtained triol (14) under acidic conditions, reaction with 1S-(-) or1R-(+)camphanic chloride, recrystallization, hydrolysis, reaction with trifluoromethanesulfonic anhydride and substitution by dimethylamine or methylamine, or by the reaction of R-(-) or S-(+) Mandelic acid and acetic acid with racemic 1-(2,2-diphenyltetrahydrofuran-3-yl)-N,N-dimethylmethanamine (2), recrystallization, followed by reaction with an aqueous solution of NaOH. The compounds mentioned in the invention present neuroprotective, antiepileptic and antidepressant activity and can be used as therapeutic agents.
摘要翻译：本发明涵盖了（+）和（ - ）1-（5,5-二苯基四氢呋喃-3-基）-N，N-二甲基甲胺[（±）1]和[（ - ）]]的合成，包括它们药理学上可接受的酸加成盐。新产物可以从5-二苯基四氢呋喃-2（3H） - 酮（4）开始合成，在a位插入醛基后，还原成前手性3-（羟甲基）-1,1-二苯基丁烷 -1,4-二醇（6），使用酶Amano脂肪酶PS30的化学酶不对称，甲苯磺酰化，分子内亲核攻击，水解，与三氟甲磺酸酐反应并用二甲胺取代，从而产生（+）1-（5,5-二苯基 - 四氢呋喃-3-基）-N，N-二甲基甲胺[（+）1]。用叔丁基二甲基甲硅烷基氯化物保护化学酶不对称的产物，水解，甲苯磺酰化，分子内亲核攻击，叔丁基二甲基甲硅烷基的去除，与三氟甲磺酸酐的反应和二甲胺取代产生（ - ）1-（5,5-二苯基四氢呋喃 - 吡啶-3-基）-N，N-二甲基甲胺[（ - ）1]。它还分别包括（+）和（ - ）1-（2,2-二苯基四氢呋喃-3-基）-N，N-二甲基甲胺[（+）2]和[（ - ）2] 和（ - ）1-（2,2-二苯基 - 四氢呋喃-3-基）-N-甲基甲胺（+）3]和[（ - ）3]，包括它们的药理学上可接受的酸加成盐。可以从以下方法合成新产物：从LiAlH4还原5-氧代-2,2-二苯基四氢呋喃-3-羧酸（13）开始，然后在酸性条件下使得到的三醇（14）环化，与1S反应 - （ - ）或1R-（+）樟脑氯化物，重结晶，水解，与三氟甲磺酸酐反应并用二甲胺或甲胺取代，或通过R - （ - ）或S - （+）扁桃酸与乙酸与外消旋 1-（2,2-二苯基四氢呋喃-3-基）-N，N-二甲基甲胺（2），重结晶，然后与NaOH水溶液反应。本发明提及的化合物具有神经保护，抗癫痫和抗抑郁活性，可用作治疗剂。

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