For the first step, 2-Methylthiophenothiazine [7643-08-5] (1) is protected by sequential reaction with sodium amide and acetic anhydride to give 1-[2-(Methylthio)-10H-phenothiazin-10-yl]ethanone [23503-69-7] (2). Oxidation with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone. Upon hydrolysis of the acetate this affords 2-(methylsulfonyl)-10h-phenothiazine [23503-68-6] (3). Alkylation with 1-Bromo-3-chloropropane (4) gives 10-(3-chloropropyl)-2-methylsulfonylphenothiazine [40051-30-7] (5). Alkylation with piperidine-4-carboxamide (Isonipecotamide) [39546-32-2] (6) affords metopimazine (7).
^Herrstedt J (September 1998). "Chemotherapy-induced nausea and vomiting with special emphasis on metopimazine". Danish Medical Bulletin. 45 (4): 412–22. PMID9777292.
^Bezin J, Noize P, Mansiaux Y, Jarne A, Pariente A (March 2021). "Antidopaminergic antiemetics and trauma-related hospitalization: A population-based self-controlled case series study". Br J Clin Pharmacol. 87 (3): 1303–1309. doi:10.1111/bcp.14510. ISSN0306-5251. PMID32737898. S2CID220909387.
^Robert Michel Jacob, Jacques Georges Robert, DE 1092476 (1960 to Rhone Poulenc Sa).
^Karicherla, Venumanikanta; Phani, Kumar; Bodireddy, Mohan Reddy; Prashanth, Kumar Babu; Gajula, Madhusudana Rao; Pramod, Kumar (2017). "A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D2-Receptor Antagonist". Organic Process Research & Development. 21 (5): 720–731. doi:10.1021/acs.oprd.7b00052.