Catechol → 1,3-Benzodioxole

The 3-(1,3-benzodioxol-4-yl)-6-fluoroalkyluracils of this invention may be synthesized by first reacting a 1,2-dimethoxybenzene, for example, 1,2-dimethoxy-4-fluorobenzene, with boron tribromide to give the corresponding 1,2-dihydroxybenzene. The dihydroxybenzene and a ketone or aldehyde, for example, acetone, are then reacted with phosphorous pentoxide to yield the 1,3-benzodioxole. The corresponding 1,3-benzodioxol-4-carboxylic acid is produced by treating the 1,3-benzodioxole with n-butyl lithium after which carbon dioxide is introduced into the reaction mixture. The tertiary butyl N-(1,3-benzodioxol-4-yl)carbamate is then prepared from the acid and t-butanol in the presence of diphenylphosphoryl azide. The carbamate is cleaved by stirring it in trifluoroacetic acid to give the corresponding 4-amino-1,3,benzodioxole, for example, 4-amino-2,2-dimethyl-5-fluoro-1,3-benzodioxole. The 4-amino-1,3-benzodioxole may be chlorinated in the 7-position using N-chlorosuccinimide in dimethylformamide. The dioxole is then converted to the corresponding isocyanate by reaction with trichloromethyl chloroformate. The isocyanate may be used in the next reaction without purification where it is reacted with sodium hydride and a 3-amino-3-fluoroalkylacrylate, for example, 3-amino-4,4,4-trifluorocrotonate, to produce the 3-( 1,3-benzodioxol-4-yl)-6-haloalkyluracil, for example, 3-(7-chloro-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)-6-trifluoromethyluracil. This compound may be isolated or, alternatively, reacted with an alkyl iodide and potassium carbonate without isolation to produce the 3-(1,3-benzodioxol-4-yl)-1-alkyl-6-haloalkyluracil, for example, 3-(7-chloro-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil. Example 1 provides details of this synthetic procedure.

ORD record

ord-8c92ff3612bb41afb4ff3992ba5f14de

Source dataset

uspto-grants-1994_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05346881