5-ThiazolecarboxaMide, 2-acetyl-N-[5-chloro-4-(trifluoroMethyl)-2-pyridinyl]- synthesis

Yield:1095825-46-9 96%

Reaction Conditions:

Stage #1: 2-acetyl-1,3-thiazole-5-carboxylic acidwith oxalyl dichloride;N,N-dimethyl-formamide in 1,2-dimethoxyethane at 10 - 35; for 2 h;
Stage #2: 5-chloro-4-(trifluoromethyl)pyridin-2-amine hydrochloridewith pyridine in acetonitrile at 5 - 50; for 2 h;

Steps:

1 Synthesis of 2-acetyl-N-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-1,3-thiazole-5-carboxamide

2-Acetyl-1,3-thiazole-5-carboxylic acid (24.7 g), 1,2-dimethoxyethane (43 mL), N,N-dimethylformamide (0.047 g) and oxalyl chloride (17.8 g) were put into a four-necked eggplant flask (100 mL), and the mixture was stirred at room temperature for 2 hr (Reaction Solution 1).
Separately, 5-chloro-4-(trifluoromethyl)pyridin-2-amine hydrochloride (30.0 g), acetonitrile (96 mL) and pyridine (30.8 g) were put into a four-necked eggplant flask (500 mL), and the mixture was cooled to about 5° C. (Reaction Solution 2).
Reaction Solution 1 was added to Reaction Solution 2 at 35° C. or lower, and 1,2-dimethoxyethane (15 mL) was added thereto.
The mixture was stirred at room temperature for 1 hr, warmed to about 50° C., and stirred for 1 hr.
Water (210 mL) was added thereto at about 50° C., and the mixture was cooled to room temperature, and was stirred for 30 min.
The crystallized substance was collected by filtration, washed with a mixed solvent of acetonitrile (22.5 mL) and water (67.5 mL), washed with water (180 mL), and dried under reduced pressure at 50° C. to give the title compound. pale-brown powder, 43.4 g, yield 96%, purity 99.0% (HPLC).

References:

US2020/317659,2020,A1 Location in patent:Paragraph 0432; 0564-0567