Nitrogen mustard hydrochloride → 4-(3-Chlorophenyl)-1-methylpiperidine-4-carbonitrile

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Reaction Steps

The starting material, 4-(3-chlorophenyl)-1-methylpiperidine-4-carbonitrile was prepared as follows by the procedure of T. Cammack and P. C. Reeves, J. Heterocycl. Chem., 23, 73 (1986): a mixture of 100 g (0.52 mole) of N,N-bis(chloroethyl)methylamine hydrochloride, 80 g (0.53 mole) of 3-chlorobenzyl cyanide, 13 g of hexadecyltributylphosphonium bromide and 750 mL of 50% aqueous sodium hydroxide was stirred at 100° internal temperature for 1 hour. Water (750 mL) was added to the cooled mixture which was then extracted with 500 mL and three 100-mL portions of toluene. Removal of the solvent from the dried solution and rapid short-path distillation of the residue (160° bath temperature, 0.1 mm) gave 107.2 g (88% yield) of 4-(3-chlorophenyl)-1-methylpiperidine-4-carbonitrile as a colorless oil which slowly crystallizes. NMR (CDCl3): δ7.5 (s,1H); 2.3 (m,3H); 3.0 (d,2H); 2.5 (m,2H); 2.4 (s,3H) and 2.1 (m,4H). The hydrochloride had m.p. 235°-236° after crystallization from isopropyl alcohol.

Provenance & Evidence