ChEBI: Hydroflumethiazide is a benzothiadiazine consisting of a 3,4-dihydro-HH-1,2,4-benzothiadiazine bicyclic system dioxygenated on sulfur and carrying trifluoromethyl and aminosulfonyl groups at positions 6 and 7 respectively. A diuretic with actions and uses similar to those of hydrochlorothiazide. It has a role as a diuretic and an antihypertensive agent. It is a benzothiadiazine and a thiazide.
(a) Preparation of 5-Trifluoromethylaniline-2,4-Disulfonyl Chloride: 113 ml of
chlorosulfonic acid was cooled in an ice-bath, and to the acid was added
dropwise while stirring 26.6 grams of α,α,α-trifluoro-m-toluidine. 105 grams of
sodium chloride was added during 1 to 2 hours, whereafter the temperature
of the reaction mixture was raised slowly to 150° to 160°C, which
temperature was maintained for 3 hours. After cooling the mixture, ice-cooled
water was added, whereby 5-trifluoromethylaniline-2,4-disulfonyl chloride
separated out from the mixture.
(b) Preparation of 5-Trifluoromethyl-2,4-Disulfamylaniline: The 5-
trifluoromethylaniline-2,4-disulfonyl chloride obtained in step (a) was taken up
in ether and the ether solution dried with magnesium sulfate. The ether was
removed from the solution by distillation, the residue was cooled to 0°C and
60 ml of ice-cooled, concentrated ammonia water was added while stirring.
The solution was then heated for one hour on a steam bath and evaporated in
vacuo to crystallization. The crystallized product was 5-trifluoromethyl-2,4-
disulfamylaniline, which was filtered off, washed with water and dried in a
vacuum exsiccator over phosphorus pentoxide. After recrystallization from a
mixture of 30% ethanol and 70% water the compound had a MP of 247° to
248°C.
(e) Preparation of 6-Trifluoromethyl-7-Sulfamyl-3,4-Dihydro-1,2,4-
Benzothiadiazine-1,1-Dioxide: 3.2 grams of 5-trifluoromethyl-2,4-
disulfamylaniline was added to a solution of 0.33 gram of paraformaldehyde in
25 ml of methyl Cellosolve (2-methoxy ethanol) together with a catalytic
amount of p-toluenesulfonic acid, and the mixture was boiled with reflux for 5
hours. The solvent was then distilled off in vacuo, and the residue triturated
with 30 ml of ethyl acetate. 6-trifluoromethyl-7-sulfamyl-3,4-dihydro-1,2,4-
benzothiadiazine-1,1-dioxide crystallized out. After recrystallization from methanol/water the substance had a MP of 272° to 273°C.
