Dibenzosuberone is an organic chemical with use in drug synthesis. Chemically speaking, it is benzophenone bonded by a 2 carbon bridge into a seven membered ring. In contrast to dibenzosuberenone, the 2 carbon bridge is saturated with hydrogen and is not an olefin. In the dihydro series, the two benzene rings are not only out of plane, but also helical with respect to one another.The Organic Chemistry of Drug Synthesis, Volume 2, by Daniel Lednicer & Lester Mitscher (page 222).
Applications It is the precursor needed to make many tricyclic antidepressants: Amitriptyline AmineptineDE2011806 idem J Pignant, C Malen, B Danree, (1973 to Science Union & Cie, Rech Medicale Soc De).J Poignant, C Malen & B Danree, (1974 to FR DE RECH MEDICALE SOC). Butaclamol (& Taclamine & Dexclamol) Butriptyline Cotriptyline Cyheptamide Cyheptropine Deptramine [2521-79-1] (c.f. Diphenhydramine) Deptropine Hepzidine Piroheptine Nortriptyline Noxiptiline Oxitriptyline Trecadrine Ciheptolane WAS-4206Cirera, Xavier D. et al. (1989 & 1992 to Espanola De Especialidades Farmaco-Terapeuticas Sa Soc). AY-8794 [19660-95-8]Engelhardt, Edward L. (1976 to Merck and Co Inc). Desoxypipradrol analogWinthrop, S. O.; Davis, M. A.; Myers, G. S.; Gavin, J. G.; Thomas, R.; Barber, R. (1962). "New Psycho-tropic Agents. Derivatives of Dibenzo[a,d]-1,4-cycloheptadiene". The Journal of Organic Chemistry 27: 230. doi:10.1021/jo01048a057. PC10895908 (Amitriptyline-Pethidine hybrid)Martin Arnold Davis & Stanley Oscar Winthrop, DE1200300 (1965 to Wyeth Canada Inc).A. Davis Martin & O. Winthrop Stanley, CA724166A (1965 to Wyeth Canada Inc).Martin A Davis & Stanley O Winthrop, (1963 to Wyeth LLC). ReN-1869 [170149-99-2]
Synthesis Although in Lednicer's notes hydroiodic acid (HI) reduction gave the stilbene, according to background literature it appeared as if it the reduction went straight through to (3). Synthesis:
The aldol reaction between phthalide [87-41-2] (1) and benzaldehyde gave benzalphthalide [575-61-1] (2). This was then reduced with hydroiodic acid and red phosphorus to give 2-bibenzylcarboxylic acid [4890-85-1] (3). Alternatively, a catalytic hydrogenation can be performed using dipentene as the source of hydrogen. Although this is a slightly lower yielding method, it does not have the limitations of using hydroiodic acid, which is a safety hazard on a large scale. The ring closure with polyphosphoric acid gave dibenzosuberone (4) in good yield, although Friedel–Crafts reaction is an alternative method.
An alternative procedure is described:CJPH, 2013, 44(5): 434–435.Kollonitsch, Janos GB937378 (1963 to Merck and Co Inc).Bernstein, Jack and Losee, Kathryn A. (1962 to Olin Corp).Kollonitsch Janos, CA692692 (1964 to Merck and Co Inc).
Phthalic anhydride (1) and phenylacetic acid (2) in the presence of sodium acetate also gives benzalphthalide [575-61-1] (3). Apparently an aldol type addition, followed by a dehydration and decarboxylation explains the mechanism. Base catalyzed hydrolysis to 2-(Phenylacetyl)benzoic acid [33148-55-9] (4), and catalytic hydrogenation also gives 2-bibenzylcarboxylic acid [4890-85-1] (5).
Alternatively, benzalphthalide [575-61-1] can be catalytically hydrogenated over Raney Nickel in IPA solvent to 2-(2-phenylethyl)benzoic acid in 96% yield (importantly methanol and ethanol gave no reduction.
The intramolecular cyclization step was optimized with Nafion-H.
A milder and greener approach was recently devised:
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