5-bromo-3-methyl-1,2,4-thiadiazole synthesis

Yield: 81.6%

Reaction Conditions:

with hydrogen bromide;sodium nitrite in water at 40 - 45;Sandmeyer Reaction;Reagent/catalyst;Temperature;

Steps:

3.1 Step 1: Sandmeyer bromination leading to (III-1-a)
The Sandmeyer bromination procedure was successfully conducted using 100 kg of 5-amino-3-methyl-l,2,4-thiadiazole (AMTD), with a yield of 82percent: 439.5 kg (295 L) 48percent HBr solution and 100.0 kg AMTD are added to 54 kg (L) water in a reactor. The solution is warmed up to maximum 40 °C and stirred until all the starting material dissolves in - checking by sampling. If the starting material does not dissolve in completely, then 2 hours stirring at 40 °C is enough. 89.7 kg sodium nitrite are dissolved in 150 kg (L) water in another equipment then the solution is loaded into a container. The sodium nitrite solution is charged to the reactor portion wise, it takes about 6 hours, keeping the temperature between 40-45 °C. Sampling after one hour from the end of addition. End-point criteria: starting material < 1.0percent. If the starting material > 1.0percent, extra sodium nitrite solution (10-20percent) is necessary to add to the reaction mixture. In case the reaction mixture meets the end-point criteria it is cooled down to 20-25 °C and 399.0 kg (300 L) DCM is added. After 10 minutes stirring and 10 minutes settling the lower organic phase is loaded to a container. The water phase is extracted with 133.0 kg (100 L) DCM in the reactor. The pH of combined organic phase is adjusted to 10-11 by addition of 5percent sodium hydroxide solution. If the pH exceeds 11, large amount of moisture can be formed. The mixture is stirred for 20 minutes, and after 30 minutes settling the organic phase is separated to a dry equipment, and concentrated in vacuum (appr. -0,9 bar) at max 30 °C. Sampling, end-point criteria for the concentration: DCM content max 5.0 percent. After finishing the distillation, 4-6 hours stirring in vacuum is required to reach the max 5.0 percent DCM content. 2.0 percent DCM content could be favorable in the next step. In case the material meets the end-point criteria it is filled to a PE lined barrel. (126.8 kg of compound (III-1-a) were obtained; Yield: 81.6 percent; GC purity (Conditions C): 97.2 percent.

References:

OGEDA SA;HOVEYDA, Hamid;DUTHEUIL, Guillaume WO2020/128003, 2020, A1 Location in patent:Page/Page column 40-41