Ammonia → Ammonium Hydroxide

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Reaction Steps

Scheme 5 describes another variation of the chemical synthesis of compounds of Formula I. The 4-chloro group of the commercially available ethyl 2-methylthio-4-chloro-pyridin-5-carboxylate starting pyrimidine is displaced using ammonia gas in a suitable solvent such as methanol or with aqueous ammonium hydroxide to give ethyl 2-methylthio-4-amino-pyridin-5-carboxylate. Excess of the reacting amine can be employed to scavenge the HCl byproduct produced in the reaction. Reduction of the ester using LAH or other suitable reducing agent such as diborane, NaBH4—NiCl2 or the like affords the corresponding alcohol. Oxidation with MnO2 or other suitable oxidant produces the aldehyde intermediate 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde. The condensation of the aldehyde with the appropriately substituted phenyl acetate derivative yields the cyclized product. Alkylation of the 8-position with X-R7 is accomplished by first forming the anion of the cyclized intermediate with a base such as NaH, Cs2CO3, DBU, and the like. Subsequent treatment of the anion with the alkylating reagent X-R7 where X represents a leaving group such as Cl, Br, I, CH3SO3, or the like gives the desired 6-(aryl)-8-substituted-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one intermediate. Elaboration to compounds of Formula I is accomplished oxidizing the methylthio group to the sulfoxide and the nucleophilic displacement of the sulfoxide with an 4-amino pyridine derivative as described previously in Scheme 1.

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