Dibenzosuberone

Last updated
Dibenzosuberone
Dibenzosuberone.svg
Names
Other names
10,11-dihydro-5H-Dibenzo[a,d]cyclohepten-5-one, dibenzocycloheptanone
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.013.557 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 214-912-3
PubChem CID
UNII
  • InChI=1S/C15H12O/c16-15-13-7-3-1-5-11(13)9-10-12-6-2-4-8-14(12)15/h1-8H,9-10H2
    Key: BMVWCPGVLSILMU-UHFFFAOYSA-N
  • C1CC2=CC=CC=C2C(=O)C3=CC=CC=C31
Properties
C15H12O
Molar mass 208.25 g/mol
Density g/cm3 (20°C)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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. [1]

Contents

Applications

It is the precursor needed to make many tricyclic antidepressants:

  1. Amitriptyline [2]
  2. Amineptine
  3. Butaclamol (& Taclamine & Dexclamol)
  4. Butriptyline
  5. Cotriptyline
  6. Cyheptamide
  7. Deptramine [2521-79-1]
  8. Deptropine
  9. Hepzidine
  10. Piroheptine
  11. Nortriptyline
  12. Noxiptiline
  13. Oxitriptyline
  14. Trecadrine
  15. Ciheptolane
  16. WAS-4206 [3]
  17. AY-8794 [19660-95-8] [4] [5]
  18. Desoxypipradrol analog: [6]
  19. PC10895908 (Amitriptyline-Pethidine hybrid) [7] [8] [9] [10] [11]

Synthesis

Although in Lednicer’s notes hydroiodic acid (HI) reduction gave the stilbene, [12] according to background literature it appeared as if it the reduction went straight through to (3). Synthesis: [13] [14] [15] [16]

Dibenzosuberone synthesis.svg

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: [17] [18] [19] [20]

Dibenzosuberone synthesis2.svg

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. [21]

The intramolecular cyclization step was optimized with Nafion-H. [22] [23]

A milder and greener approach was recently devised: [24]

References

  1. ↑ The Organic Chemistry of Drug Synthesis, Volume 2, by Daniel Lednicer & Lester Mitscher (page 222).
  2. ↑ Miodownik, A.; Kreisberger, J.; Nussim, M.; Avnir, D. (1981). "One-Step Grignard Reactions with Dimethylaminopropyl Chloride: Application to the Synthesis of Tricyclic Drugs". Synthetic Communications. 11 (3): 241–246. doi:10.1080/00397918108061867.
  3. ↑ Cirera, Xavier D. et al. U.S. patent 4,835,156 U.S. patent 5,112,826 (1989 & 1992 to Espanola De Especialidades Farmaco-Terapeuticas Sa Soc).
  4. ↑ Engelhardt, Edward L. U.S. patent 3,981,917 (1976 to Merck and Co Inc).
  5. ↑ Lippmann, W. (1969). "Blockade of norepinephrine uptake and other activities of 5-(3′-dimethylaminopropyl)-dibenzo[a,d][1,4]cycloheptadiene hydrochloride (AY-8794) and structurally related compounds". Biochemical Pharmacology. 18 (10): 2517–2529. doi:10.1016/0006-2952(69)90367-0. PMID   5403988.
  6. ↑ Winthrop, 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.
  7. ↑ Davis, M. A., Herr, F., Thomas, R. A., Charest, M.-Paule. (July 1967). "New Psychotropic Agents. VIII. 1 Analogs of Amitriptyline Containing the Normeperidine Group". Journal of Medicinal Chemistry. 10 (4): 627–635. doi:10.1021/jm00316a024. PMID   6037052.
  8. ↑ Davis, M. A., Herr, F., Thomas, R. A., Charest, M.-Paule. (November 1967). "Additions and Corrections - New Psychotropic Agents. VIII. Analogs of Amitriptyline Containing the Normeperidine Group". Journal of Medicinal Chemistry. 10 (6): 1197. doi:10.1021/jm00318a607.
  9. ↑ Martin Arnold Davis & Stanley Oscar Winthrop, DE1200300 (1965 to Wyeth Canada Inc).
  10. ↑ A. Davis Martin & O. Winthrop Stanley, CA724166A (1965 to Wyeth Canada Inc).
  11. ↑ Martin A Davis & Stanley O Winthrop, U.S. patent 3,074,953 (1963 to Wyeth LLC).
  12. ↑ Lednicer, Daniel (2009). Strategies for Organic Drug Synthesis and Design. p. 106. doi:10.1002/9780470399613. ISBN   9780470399613.
  13. ↑ Saracoglu, Nurullah; Dastan, Arif; Kilic, Haydar (2018). "The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application". Synthesis. 50 (3): 391–439. doi:10.1055/s-0036-1589518.
  14. ↑ Campbell, Tod W.; Ginsig, R.; Schmid, H. (1953). "Synthese des 2′-Acetamino-2,3;6,7-dibenzo-tropilidens und des 2-Acetamino-9,9-dimethyl-fluorens". Helvetica Chimica Acta. 36 (6): 1489–1499. doi:10.1002/hlca.19530360635.
  15. ↑ Treibs, W.; Klinkhammer, H. (July 1950). "Über das 1.2;45-Dibenz-suberon-(3)". Chemische Berichte. 83 (4): 367–371. doi:10.1002/cber.19500830409.
  16. ↑ Ramesha, A. R.; Roy, Anjan K. (2001). "Convenient Synthesis of 2-(2-Phenylethyl)Benzoic Acid: A Key Intermediate in the Synthesis of Dibenzosuberone". Synthetic Communications. 31 (16): 2419–2422. doi:10.1081/SCC-100105118.
  17. ↑ CJPH, 2013, 44(5): 434–435.
  18. ↑ Kollonitsch, Janos GB937378 (1963 to Merck and Co Inc).
  19. ↑ Bernstein, Jack and Losee, Kathryn A. U.S. patent 3,052,721 (1962 to Olin Corp).
  20. ↑ Kollonitsch Janos, CA692692 (1964 to Merck and Co Inc).
  21. ↑ Regla, Ignacio; Reyes, Adelfo; Körber, Claudia; Demare, Patricia; Estrada, Osvaldo; Juaristi, Eusebio (1997). "Novel Applications of Raney Nickel/Isopropanol: Efficient System for the Reduction of Organic Compounds". Synthetic Communications. 27 (5): 817–823. doi:10.1080/00397919708004201.
  22. ↑ Olah, George A.; Mathew, Thomas; Farnia, Morteza; Prakash, G. K. Surya (1999). "Nafion-H Catalysed Intramolecular Friedel-Crafts Acylation: Formation of Cyclic Ketones and Related Heterocycles". Synlett (7): 1067–1068. doi:10.1055/s-1999-2770.
  23. ↑ Yamato, Takehiko; Hideshima, Chieko; Prakash, G. K. Surya; Olah, George A. (1991). "Organic reactions catalyzed by solid superacids. 5. Perfluorinated sulfonic acid resin (Nafion-H) catalyzed intramolecular Friedel-Crafts acylation". The Journal of Organic Chemistry. 56 (12): 3955–3957. doi:10.1021/jo00012a033.
  24. ↑ Nori, V., Della Penna, F., Cocco, E., Mantegazza, S., Razzetti, G., Quattrocchi, G., Pesciaioli, F., Carlone, A. (21 July 2023). "A Sustainable and Catalytic Synthesis of Dibenzosuberone". ChemCatChem. 15 (14): e202300642. doi:10.1002/cctc.202300642.
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