The synthesis of [14C]- and deuterium-labeled bisaramil hydrochloride has been reported: 1) The reduction of (14)CO2 with LiAlH4 in THF gives labeled formaldehyde (II), which by a Mannich reaction is condensed with ethylamine (IV) and N-methylpiperidin-4-one (III) by means of acetic acid in refluxing methanol to yield labeled 3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]nonan-9-one (V). The reduction of (V) with NaBH4 in methanol/NaOH affords a mixture of the alpha- and beta-isomers of the labeled 9-hydroxy derivative (VI + VII). After separation by its different solubility in isopropanol, the alpha-isomer is condensed with 4-chlorobenzoyl chloride (VIII) in hot pyridine to give [2,4-14C]-labeled bisaramil.
2) Hexadeuteroethyl alcohol (IX) is treated with red phosphorus and I2 at reflux temperature to give pentadeuteroethyl iodide (X), which is condensed with potassium phthalimide (XI) in DMF, yielding N-(pentadeuteroethyl)phthalimide (XII). The hydrolysis of (XII) with hydrazine and HCl affords pentadeuteroethylamine (XIII), which is condensed with 1-methylpiperidin-4-one (III) and formaldehyde (XIV) in a Mannich reaction to give 3-methyl-7-(pentadeuteroethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (XV). The reduction of (XV) with NaBH4 as before yields the diastereomeric mixture (XVI + XVII). Finally, the alpha-isomer (XVI) is condensed with 4-chlorobenzoyl chloride (VIII) as before to give the pentadeuterium-labeled bisaramil.