BENDROFLUMETHIAZIDE Chemical Properties

Melting point:

205-207°C

Boiling point:

602.1±65.0 °C(Predicted)

Density 

1.4711 (estimate)

storage temp. 

Refrigerator

solubility 

Practically insoluble in water, freely soluble in acetone, soluble in ethanol (96 per cent).

pka

pKa 8.53±0.05(H2O t=25 I=0.2) (Uncertain)

color 

Crystals from MeOH/CHCl3

Water Solubility 

40mg/L(room temperature)

EPA Substance Registry System

2H-1,2,4-Benzothiadiazine-7-sulfonamide, 3,4-dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-, 1,1-dioxide (73-48-3)

Safety Information

WGK Germany 

2

RTECS 

DK8225000

HS Code 

2935904000

Hazardous Substances Data

73-48-3(Hazardous Substances Data)

Toxicity

LD50 oral in mouse: > 10gm/kg

MSDS

• Language:English Provider:SigmaAldrich

BENDROFLUMETHIAZIDE Usage And Synthesis

Description

Bendroflumethiazide (Item No. 21311) is an analytical reference standard categorized as a diuretic. Diuretics, including bendroflumethiazide, have been abused as performance-enhancing drugs and masking agents in sports doping. This product is intended for research and forensic applications.

Chemical Properties

White Solid

Originator

Naturetin,Squibb,US,1959

Uses

Bendroflumethiazide may be used for the same indications as the aforementioned drugs; however, it is primarily used as an adjuvant agent for relieving edema associated with cardiac insufficiency, liver cirrhosis, and edema caused by taking corticosteroids.

Uses

expectorant

Uses

Diuretic; antihypertensive.

Definition

ChEBI: A sulfonamide consisting of 7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide in which the hydrogen at position 6 is substituted by a trifluoromethyl group and that at position 3 is substituted by a benzyl group.

Manufacturing Process

The process is described in US Patent 3,392,168 as follows:
(A) Preparation of 5-Trifluoromethylaniline-2,4-Disulfonylchloride - 113 ml of chlorosulfonic acid is cooled in an ice bath, and to the acid is added dropwise while stirring 26.6 grams of α,α,α-trifluoro-m-toluidine. 105 grams of sodium chloride is added during 1-2 hours, where after the temperature of the reaction mixture is raised slowly to 150° - 160°C which temperature is maintained for three hours. After cooling the mixture, ice-cooled water is added, whereby 5-trifluoromethylaniline-2,4-disulfonyl chloride separates out from the mixture.
(B) Preparation of 5-Trifluoromethyl-2,4-Disulfamylaniline - The 5- trifluoromethylaniline-2,4-disulfonyl chloride obtained in step (A) is taken up in ether and the ether solution dried with magnesium sulfate. The ether is removed from the solution by distillation, the residue is cooled to 0°, and 60 ml of ice-cooled, concentrated ammonia water is added while stirring. The solution is then heated for one hour on a steam bath and evaporated in vacuo to crystallization. The crystallized product is 5-trifluoromethyl-2,4- disulfamylaniline, which is filtered off, washed with water and dried in a vacuum-desiccator over phosphorus pentoxide. After recrystallization from a mixture of 30% ethanol and 70% water, the compound has a MP of 247°- 248°C.
(C) Preparation of 3-Benzyl-6-Trifluoromethyl-7-Sulfarnyl-3,4-Dihydro-1,2,4- Benzothiadiazine-1,1-Dioxide - 6.4 grams of 5-trifluoromethyl-2,4- disulfamylaniline is dissolved in 12 ml of dioxane, 2.7 ml of phenylacetaldehyde and a catalytic amount of p-toluenesulfonic acid are added. After boiling for a short time under reflux, the reaction mixture crystallizes, and, after filtration and recrystallization from dioxane, the desired product is obtained with a MP of 224.5°-225.5°C.
(D) Alternative to (C) - 9.6 grams of 5-trifluoromethyl-2,4-disulfarnylaniline and 4.9 grams of ω-ethoxystyrene are dissolved in 35 ml of n-butanol. 0.5 grams of p-toluenesulfonic acid is added, and the mixture is heated on a steam bath while stirring. When the solution is clear, 55 ml of hexane is added, whereafter the mixture is heated further for one and a half hours. After cooling, the substance identical to that of Example (C) is filtered off and has a MP of 222°-223°C.
Sterile compositions containing Bendroflumethiazide for parenteral administration may be prepared as described in US Patent 3,265,573.

brand name

Naturetin (Apothecon).

Therapeutic Function

Diuretic, Antihypertensive

Clinical Use

Thiazide diuretic:

Hypertension

Oedema

Safety Profile

Poison by intravenous route.Human systemic effects by ingestion: convulsions andsomnolence. Mutation data reported. When heated todecomposition it emits toxic fumes of F^-, SOx, and NOx.

Synthesis

Bendroflumethiazide, 1,1-dioxide 3-benzyl-6-(trifluoromethyl)- 3,4-dihydro-2H-1,2,4-benzothiadiazin-7-sulfonamide (21.3.6), is synthesized by the same scheme of making the aforementioned drugs using phenylacetaldehyde or its acetale as a carbonyl component, and using 2,4-disulfonamido-5-trifluoromethylaniline (21.3.5) as an o-aminosulfonamide component.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of nephrotoxicity with NSAIDs; antagonism of diuretic effect.
Anti-arrhythmics: hypokalaemia leads to increased cardiac toxicity; effects of lidocaine and mexiletine antagonised.
Antibacterials: avoid administration with lymecycline.
Antidepressants: increased risk of hypokalaemia with reboxetine; enhanced hypotensive effect with MAOIs; increased risk of postural hypotension with tricyclics.
Antiepileptics: increased risk of hyponatraemia with carbamazepine.
Antifungals: increased risk of hypokalaemia with amphotericin.
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotension with postsynaptic alpha-blockers like prazosin; hypokalaemia increases risk of ventricular arrhythmias with sotalol.
Antipsychotics: hypokalaemia increases risk of ventricular arrhythmias with amisulpride; enhanced hypotensive effect with phenothiazines; hypokalaemia increases risk of ventricular arrhythmias with pimozide - avoid.
Atomoxetine: hypokalaemia increases risk of ventricular arrhythmias.
Cardiac glycosides: increased toxicity if hypokalaemia occurs.
Ciclosporin: increased risk of nephrotoxicity and hypomagnesaemia. Cytotoxics: increased risk of ventricular arrhythmias due to hypokalaemia with arsenic trioxide; increased risk of nephrotoxicity and ototoxicity with platinum compounds. Lithium excretion reduced, increased toxicity.

Metabolism

There are indications that bendroflumethiazide is fairly extensively metabolised. About 30% is excreted unchanged in the urine with the remainder excreted as uncharacterised metabolites.

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