The synthesis of [U‐¹⁴C phenyl] LS 840606, an agricultural fungicide

Abstract

2,2′4′‐Trichloro‐[ring U‐14C]acetophenone 3 was the key intermediate of this synthesis patterned after the industrial route. An unexpected poor yield was observed during the preparation of 3 by the Friedel‐Crafts reaction of chloroacetyl chloride with 1,3‐dichloro‐[U‐14C]benzene 10, possibly the result of an isotope effect although this poor yield might be explained by other factors. Two routes were checked for the preparation of 1,3‐dichloro‐[U‐14C]benzene 10. The action of CCL4 with 1,3‐dinitro‐[U‐14C]benzene at 280°C was entailed with explosions. A safer route started from [U‐14C]aniline via 2,4‐dichloro‐[ring U‐14C]acetanilide. Friedel‐Crafts reaction of 10 with acetyl chloride gave rise in 52% yield to 2′,4′‐dichloro‐[ring U‐14C]acetophenone 16 which was brominated to 2‐bromo‐2′,4′‐dichloro‐[ring U‐14C]acetophenone 17;17 was condensed with 2,2‐(ethylenedioxy)ethylmagnesium bromide to compound 18; 18 was condensed with 1,2,4‐triazole to 5 then successively treated with HCl:water:dioxane and 2,2,2‐trifluoroethanol/HCl. Separation of the two diastereomers by medium pressure liquid chromatography. 7% overall radioactive yield from [U‐14C]aniline. Radiochemical purity 99%.

Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon‐13 and carbon‐14

“…30 Thus, aniline-13 C 6 was first protected as the acetanilide [ 13 C 6 ]- (6) in 94% using acetyl chloride and pyridine in methylene chloride. 31 Treatment of this acetanilide with NCS in trifluoroacetic acid (TFA) at room temperature gave 2,4-dicholoacetanilide [ 13 C 6 ]- (7) in 96% yield despite the fact that the reaction was slow and required four equivalents of NCS. Shorter reaction times were observed when we used freshly crystallized NCS.…”

Synthesis of [3,5‐dichlorobenzenesulfonamide‐U‐14C)] labeled VLA‐4 antagonists

“…4 Acetamide 7 was then sulfonated with chlorosulfonic acid to give sulfonyl chloride 8, 5 which was stirred in an ammonium hydroxide/ acetone solution to provide the corresponding sulfonamide 9.…”