Hydrazine → 2-fluoro-4-nitrophenylhydrazine

From the reaction of 3,4-difluoronitrobenzene with hydrazine in isopropyl alcohol at an elevated temperature (e.g. 75°-85° C.) there is produced 2-fluoro-4-nitrophenylhydrazine. The latter is then treated with acetone and sulfuric acid in tetrahydrofuran to yield N'-(2-fluoro-4-nitrophenyl)-dimethylketone hydrazone. The latter is then treated with potassium cyanate in aqueous acetic acid to produce 1-(2-fluoro-4-nitrophenyl)-5,5-dimethyl-1,2,4-triazolidin-3-one. The latter is then reacted with pyruvic acid and sulfuric acid in 1,4-dioxane to form 2-(2-fluoro-4-nitrophenyl-1,2,4-triazine-3,4(2H,4H)-dione. The latter is then reacted first with sodium hydride in dimethylformamide followed by methyl iodide to yield 2-(2-fluoro-4-nitrophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is treated with iron powder in acetic acid to yield 2-(4-amino-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter dione is treated first with sodium nitrite in acetone and hydrochloric acid, then with methyl acrylate, and lastly with copper (I) chloride to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]phenyl]propionate. The latter is then nitrated by treatment with a mixture of nitric acid and sulfuric acid to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]-2-nitrophenyl]propionate. The latter is dissolved in acetic acid and added to a hot suspension of iron powder in acetic acid, then heated at an elevated temperature (e.g. 80°-90° C.) for about one hour to form 1-(3-chloro-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-methyl-1,2,4-triazine-3,5,(2H,4H)-dione. The latter is dehydrohalogenated with triethylamine in tetrahydroduran to yield 1-[6-fluoroquinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is dissolved in dimethylformamide and treated first with potassium carbonate followed by propargyl chloride to yield 1-[6-fluoro-1-[2-propynyl]quinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione.

ORD record

ord-0c629645831c4300978055bc428b54fe

Source dataset

uspto-grants-1989_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04878941