1,8-Diazabicyclo(5.4.0)undec-7-ene → 6-(Trifluoromethyl)uracil

In the method of Schema I, a 2-fluoro-5-(optionally substituted)-nitro-benzene was reacted with an appropriately substituted amine, for example, 2-propynylamine, under basic conditions, affording the corresponding N-substituted-4-optionally substituted-2-nitroaniline (1), for example, N-(2-propyn-1-yl)-4-fluoro-2-nitroaniline. Intermediate (1) was in turn reduced with either iron powder and acetic acid in ethyl acetate or with tin(II) chloride dihydrate and sodium borohydride in ethanol, yielding the corresponding 2-(substituted amino)-5-optionally substituted aniline (2), for example, 2-(2-propyn-1-ylamino)-5-fluoroaniline. The so-prepared aniline (2) was then cyclized with either trifluoroacetic acid (when R1 is --CF3) or acetic acid (when R1 is --CH3), affording the corresponding 1-substituted-2-(methyl or trifluoromethyl)-5-optionally substituted benzimidazole (3), for example, 1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazole. Nitration of the benzimidazole (3) with 70% nitric acid in concentrated sulfuric acid yielded an isomeric mixture of 1,2-disubstituted-4-nitro-5-optionally substituted benzimidazole (4A) and 1,2-disubstituted-5-optionally substituted-6-nitrobenzimidazole (4B). The nitrobenzimidazole isomers (4A) and (4B) were separated by column chromatography, and isomer (4B), for example, 2-propyn-1-yl-2-trifluoromethyl-5-fluoro-6-nitrobenzimidazole, was reduced with iron powder in ethyl acetate and acetic acid, affording the corresponding 1,2-disubstituted-5-optionally substituted-6-aminobenzimidazole (5). Intermediate (5) was then treated with ethyl chloroformate in pyridine, yielding the corresponding 1,2-disubstituted-5-optionally substituted-6-ethoxycarbonylaminobenzimidazole [generic structure (6), where V is C--R1 ]. The 6-substituted-aminobenzimidazole (6) was, in turn, cyclized with ethyl 3-amino-4,4,4-trifluoro-2-butenoate and sodium methoxide in the presence of DBU in N,N-dimethylformamide, affording the corresponding 3-(1,2-disubstituted)-5-optionally substituted benzimidazol-6-yl)-6-trifluoromethyluracil (7). The intermediate uracil (7) was in turn alkylated with an appropriate alkyl halide and potassium carbonate in acetone, yielding the desired 1-alkyl-3-(1,2-disubstituted-5-optionally substituted benzimidazol-6-yl)-6-trifluoromethyluracil (II), for example, 1-methyl-3-[1-(propyn-2-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil (Compound 12). Example 1 provides a detailed description of how these reactions were conducted.

ORD record

ord-3cc94a7560614b8593df5747295f9097

Source dataset

uspto-grants-1997_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05661108