The Chemical Development of CI-972 and CI-1000:  A Continuous Nitration, A MgCl₂/Et₃N-Mediated C-Alkylation of a Chloronitropyrimidine, A Catalytic Protodediazotization of a Diazonium Salt, and an Air Oxidation of an Amine

Abstract

Efficient, large-scale processes were developed for the preparation of the potent PNP inhibitors 2,6-diamino-3,5-dihydro-7-(3-thienylmethyl)-4 H -pyrrolo[3,2- d ]pyrimidin-4-one hydrochloride, monohydrate ( 1 ) and 2-amino-3,5-dihydro-7-(3-thienylmeth-yl)-4 H -pyrrolo[3,2- d ]pyrimidin-4-one hydrochloride, monohydrate ( 2 ). We report (1) a safe, continuous nitration process for the preparation of 2-amino-6-chloro-5-nitro-4-pyrimidinol ( 8a ) and its stable diisopropylamine salt ( 8b ), (2) the first MgCl 2 /Et 3 N-mediated C-alkylation of a chloronitropyrimidine, (3) a rare catalytic protodediazotization of the diazonium salt 2-amino-4-oxo-7-thiophen-3-ylmethyl-4,5-dihydro-3H-pyrrolo[3,2- d ]pyrimidine-6-diazonium chloride ( 14 ), (4) a single-step process to prepare 2 directly from 2-amino-6-hydroxy-5-nitro-α-(3-thienylmethyl)-4-pyrimidineacetonitrile ( 12 ) using a sponge nickel-catalyzed reduction, and (5) a method to convert the over-reduction by-product 2,5-diamino-6-(1-aminomethyl-2-thiophen-3-yl-ethyl)-pyrimidin-4-ol ( 16 ) into 2 using air oxidation.