Dimethyl Sulfate → 1,3,6-Trimethyl-2,4(1H,3H)-pyrimidinedione

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Reaction Steps

Efforts were undertaken to improve methods for synthesizing PPQ-102 because the original synthesis method developed had low yield (see, e.g., Tradtrantip et al., J. Med. Chem. 52:6447-55 (2009); Int'l Patent Appl. Publication No. WO 2011/019737). As shown in Scheme 1,6-methyluracil 1 was exhaustively alkylated using dimethyl sulfate to give 1,3,6-trimethyluracil 2 in 98% yield. 1,3,6-Trimethyluracil 2 was subject to Friedel-Crafts acylation utilizing benzoyl chloride and anhydrous zinc chloride to give ketone 3a in 66% yield. Bromination of ketone 3a gave 4a in quantitative yield. At the first point of diversification, 4a was reacted with substituted 1,2-phenylenediamines (2 eq) to give pyrroles 5a-c in 97% (R2═H), 89% (R2═NO2), and 83% (R3=Me) yields. Pyrroles 5a-c were condensed with the appropriately substituted furfural or thiophene carbaldehyde using catalytic acid to give PPQ-(5-15, 23) with yields of 57-98%. PPQ-102 was obtained on a gram scale in 83% yield. Amide analogs were synthesized from PPQ-102 and acid halides or anhydrides to give PPQ-(1-3), in 73%, 80% and 79% yields, respectively. The nitrosamine PPQ-4 was synthesized from PPQ-102 and t-butyl nitrite in 79% yield.

Provenance & Evidence