Novel process for synthesizing and a novel crystal form of agomelatin as well as pharmaceutical preparations containing these

摘要

Producing agomelatin comprises reacting 7-methoxy-1-tetralone with cyanoacetic acid in presence of organo-ammonium carboxylate catalyst (V), contacting resulting 2-(7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (VI) with hydrogenation catalyst in presence of allylic compound to give 2-(7-methoxy-1-naphthyl)acetonitrile (VII), hydrogenating (VII) to give 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride (VIII) and acetylating. Producing agomelatin (N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide) comprises: (i) reacting 7-methoxy-1-tetralone with cyanoacetic acid in the presence of an organoammonium carboxylate catalyst of formula (V) while removing water; (ii) contacting the resulting 2-(7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (VI) with a hydrogenation catalyst in the presence of an allylic compound to give 2-(7-methoxy-1-naphthyl)acetonitrile (VII); (iii) hydrogenating (VII) in the presence of Raney nickel in ethanol and treating the product with hydrochloric acid to give 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride (VIII); and (iv) reacting (VIII) successively with sodium acetate and acetic anhydride. R, R' = 3-10C alkyl, aryl or aryl(1-6C alkyl), where aryl is selected from phenyl, naphthyl or biphenylyl (all optionally substituted by 1-3 1-6C alkyl, OH or 1-6C alkoxy). Independent claims are also included for: (1) producing agomelatin by production of (VI) as above followed by aromatization, reduction and reaction with acetic anhydride; (2) producing agomelatin by production of (VII) as above followed by reduction and reaction with acetic anhydride; (3) producing agomelatin by production of (VIII) as above followed by reaction with acetic anhydride; (4) crystalline form II of agomelatin with defined x-ray diffraction and physico-chemical properties; (5) pharmaceutical compositions containing crystalline form II of agomelatin. [Image] ACTIVITY : Tranquilizer; Antidepressant; Vasotropic; Neuroleptic; Anorectic; Anticonvulsant; Antidiabetic; Antiparkinsonian; Nootropic; Neuroprotective; Antimigraine; Cerebroprotective; Cytostatic; Immunomodulator. No biological data given. MECHANISM OF ACTION : Melatoninergic receptor agonist; 5-HT2C receptor antagonist.