Synthesis Of Isotopically Labeled 1-[(2,4-Di-1-Pyrrolidinyl-9h-Pyrimido[4,5-B]Indol-9-Yl)-Acetyl)Pyrrolidi Ne Monohydrochloride, Pnu-142731a, An Orally Active Antiasthma Agent

1-[(2,4-Di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indol-9-yl)-acetyl]pyrrolidine monohydrochloride, PNU-142731A, is under investigation as a potential orally active antioxidant for the treatment of asthma. Stable isotope and radioisotope forms of this compound were needed for drug adsorption, distribution, excretion, and metabolism studies. The synthesis of carbon-14 PNU-142731A, labeled at the C-2 position of the pyrimidine ring was accomplished in 6 steps. [(2,6-Di-1-pyrrolidinyl-4-[2-C-14]pyrimidinyl)amino]acetyl pyrrolidine, [C-14]PNU-145325 was synthesized in 4 steps from 300 mCi (nominally 55 mCi/mmol) of carbon-14 labeled urea and unlabeled diethyl malonate. The synthesis was completed by the cyclization of [C-14]PNU-145325 with 2-bromocyclohexanone, followed by dehydrohalogenation to afford 31 mCi (10.3% overall yield) of [C-14]PNU-142731A as the monohydrochloride salt. The specific activity was 112.02 mu Ci/mg (51 mCi/mmol) with a radiochemical purity of 99% as determined by HPLC and TLC. In a similar manner. [C-13.N-15(2)]urea and [1,3-C-13]diethyl malonate were used to prepare 379 mg of [C-13(3), N-15(2)]PNU-142731A with excellent purity and 99% atom incorporation.