Dimethyl Sulfate → 1,3,6-Trimethyl-2,4(1H,3H)-pyrimidinedione
Reaction equation
CC1OC(C2NC3C(=CC=CC=3)N3[C:8]2=[C:9]2[N:31]([CH3:32])[C:29](=[O:30])[N:28]([CH3:33])[C:26](=[O:27])[C:10]2=C3C2C=CC=CC=2)=CC=1.S(OC)(OC)(=O)=O>>[CH3:32][N:31]1[C:9]([CH3:8])=[CH:10][C:26](=[O:27])[N:28]([CH3:33])[C:29]1=[O:30]Participants
Procedure
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.
Workup
- custombecause the original synthesis method
- customdeveloped had low yield (
Sources & evidence
- ORD record
- ord-ab77226f236d4c24917cd4ea5af518d0
- Source dataset
- uspto-grants-2015_06
- Patent number
- US09062073B2
Reaction notes
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