The synthesis of volinanserin has been reported.[9][10][11][12] Beginning with protection of ethyl isonipecotate (1) withBoc anhydride gives ethylN-Boc-4-piperidinecarboxylate (2). Ester-amide interchange withN-methoxymethylamine HCl in the presence ofcarbonyldiimidazole (CDI) coupling agent gives 1-Boc-4-[methoxy(methyl)carbamoyl]piperidine (3).Weinreb ketone synthesis occurs upon benzoylation with1,2-dimethoxybenzene (4) to give 1-Boc-4-(2,3-dimethoxybenzoyl)piperidine (5). Acid removal of the urethane protecting group gives (2,3-dimethoxyphenyl)-piperidin-4-ylmethanone (6). The reduction of the ketone withsodium borohydride leads to (2,3-dimethoxyphenyl)-piperidin-4-ylmethanol (7). Resolution of the alcohol gives (8). SN2 alkylation of the secondary nitrogen with 4-fluorophenethyl bromide (9) completes the synthesis of volinanserin (10).
^Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (November 1992). "5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine".European Journal of Pharmacology.223 (1):65–74.doi:10.1016/0014-2999(92)90819-P.PMID1362159.
^Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM, et al. (April 2009). "Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET".Bioorganic & Medicinal Chemistry.17 (8):2989–3002.CiteSeerX10.1.1.519.5663.doi:10.1016/j.bmc.2009.03.021.PMID19329329.
^Offord SJ, Wong DF, Nyberg S (August 1999). "The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action".Journal of Clinical Pharmacology.39 (S1):17S –24S.doi:10.1002/j.1552-4604.1999.tb05933.x.PMID10434243.S2CID21311671.
^Charney DS, Nestler PS, Sklar P, Buxbaum JD (July 2013).Neurobiology of Mental Illness. OUP USA. p. 767.ISBN9780199934959.
^Teegarden BR, Al Shamma H, Xiong Y (2008). "5-HT(2A) inverse-agonists for the treatment of insomnia".Current Topics in Medicinal Chemistry.8 (11):969–76.doi:10.2174/156802608784936700.PMID18673166.
^Schmidt, C. J., Kehne, J. H., Carr, A. A. (March 1997). "MDL 100,907: A Selective 5-HT 2A Receptor Antagonist for the Treatment of Schizophrenia".CNS Drug Reviews.3 (1):49–67.doi:10.1111/j.1527-3458.1997.tb00316.x.
^Németh K, Palkó R, Kovács P, Visy J (January 2014). "Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT2A) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound".Journal of Pharmaceutical and Biomedical Analysis.88:579–583.doi:10.1016/j.jpba.2013.10.017.PMID24216279.
^WO 1991018602, Carr AA, Kane JM, Hay DA, "(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol", published 12 December 1991, assigned to Merrell Dow Pharmaceuticals Inc.
^Huang Y, Mahmood K, Mathis CA (1999). "An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions".Journal of Labelled Compounds and Radiopharmaceuticals.42 (10):949–957.doi:10.1002/(SICI)1099-1344(199910)42:10<949::AID-JLCR253>3.0.CO;2-S.
^WO 1998004289, Blackburn TP, "Pharmaceutical composition containing a 5HT2c antagonist and a D2 antagonist", published 5 February 1998, assigned to SmithKline Beecham Ltd.
