Benzbromarone Chemical Properties

Melting point:

151°

Boiling point:

514.1±50.0 °C(Predicted)

Density 

1.6211 (rough estimate)

refractive index 

1.6010 (estimate)

storage temp. 

Inert atmosphere,2-8°C

solubility 

Practically insoluble in water, freely soluble in acetone and in methylene chloride, sparingly soluble in ethanol (96 per cent).

pka

4.66±0.25(Predicted)

form 

Solid

color 

White to Light yellow

Merck 

14,1065

InChIKey

WHQCHUCQKNIQEC-UHFFFAOYSA-N

CAS DataBase Reference

3562-84-3(CAS DataBase Reference)

EPA Substance Registry System

Methanone, (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-3-benzofuranyl)- (3562-84-3)

Safety Information

Hazard Codes 

Xn

Risk Statements 

22

Safety Statements 

36

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

OB1804200

HS Code 

2932.99.7000

HazardClass 

6.1(b)

PackingGroup 

III

Toxicity

LD50 oral in rat: 248mg/kg

MSDS

• Language:English Provider:SigmaAldrich

Benzbromarone Usage And Synthesis

Description

Benzbromarone,a non-competitive inhibitor of xanthine oxidase，is apotent uricosuric drug used in the treatment of gout.
Benzbromarone is a benzofuran derivative chemically related to amiodarone. It increases uric acid excretion by non-specificallyinhibiting its tubular reabsorption.
lt is used in patients with venous disorders to prevent,retard,or reverse varicose degenerative changes in the vessel wall.
Benzbromarone causes diarrhea (3-4% of patients), urate and oxalate stones,urinary sand,renal colic，and allergy in a small number of patients.Liver damage, which reverses after withdrawal, has been described (SEDA-18,108).

Chemical Properties

Pale Beige Solid

Originator

Desuric,Labaz,Switz.

Uses

Benzbromarone is a benzofuran derivative that has been reported to lower serum urate levels in animals and human studies. In normal and hyperuricaemic subjects, benzbromarone reduced serum uric acid levels by one-third to one-half. In comparison with other urate-lowering drugs, 80 mg of micronized or 100 mg of nonmicronized benzbromarone had equal urate-lowering activity to 1–1.5 g of probenecid or 400–800 mg of sulfinpyrazone.
The mechanism of the urate-lowering activity of benzbromarone appears to be attributable to its uricosuric activity. In rats, benzobromarone inhibited urate reabsorption in the proximal tubules when given at 10 mg/kg i.v. In isolated rat liver preparation, benzbromarone inhibits xanthine oxidase in vitro but not in vivo . In humans, this compound only weakly inhibits xanthine oxidase and no increase in urinary excretion of xanthine or hypoxanthine was observed. After oral administration, about 50% of benzbromarone is absorbed. The drug undergoes extensive dehalogenation in the liver and is excreted mainly in the bile and feces. For control of gout the usual therapeutic dose is 100–200 mg daily. Benzbromarone has few side effects and is usually well tolerated.

Uses

Benzbromarone is a uricosuric agent used in the treatment of gout and hyperuricemia. Studies show that use of Benzbromarone results in less complications than other uricosuric agent such as Allopurinol.

Uses

Coronarodilatator;Uric acid transport inhibitor

Definition

ChEBI: Benzbromarone is 1-Benzofuran substituted at C-2 and C-3 by an ethyl group and a 3,5-dibromo-4-hydroxybenzoyl group respectively. An inhibitor of CYP2C9, it is used as an anti-gout medication. It has a role as a uricosuric drug. It is a member of 1-benzofurans and an aromatic ketone. It derives from a 2,6-dibromophenol.

Manufacturing Process

The propyl analog of the benzbromarone intermediate containing an ethyl group is prepared as follows: to a solution of potassium hydroxide (56 g = 1 mol) in absolute ethyl alcohol (750 cc) is added one mol of salicylic aldehyde (122 grams). The mixture is brought to boiling point in a water-bath until the potassium salt formed is dissolved. One mol of ethyl chloromethyl ketone (106.5 grams) (methyl chloromethyl ketone or chloracetone in the case of benzbromarone) is gradually added and the solution boiled in a reflux condenser for two hours.
After cooling, the potassium chloride precipitate is separated off by filtration, and the greater part of the solvent removed by distillation. The residue is then puritied by distillation. In this way, 140 grams of 2-propionyl coumarone are obtained, boiling at 135°C under 15 mm Hg. A mixture is then prepared as follows: 215 grams of 2-propionyl coumarone, 550 cc of diethylene glycol and 200 grams of hydrazine hydrate at 85% and maintained at boiling point in a reflux condenser for 10 minutes. After cooling, 180 grams of potassium hydroxide are added and the mixture brought up to 120°-130°C. This temperature is maintained until no more nitrogen is liberated (about 1 hour). The mixture is then distilled by means of super-heated steam (150°-160°C). The distillate is neutralized by means of concentrated HCl, decanted, and the aqueous layer extracted by means of ether. The oily layer and the ethereal extract are mixed, washed with diluted HCl, then with water, and finally dried over sodium sulfate. The solvent is removed and the residue rectified under reduced pressure. In this way, 130 grams of 2-propyl coumarone are obtained, boiling at 112°C under 17 mm of mercury.
The following substances are then placed in a 250 cc flask fitted with a stirrer and a separatory funnel: 12.96 grams of 2-propyl coumarone, 55 cc of carbon sulfide and 14 grams of anisoyl chloride. The mixture is cooled by means of iced water and 21.5 grams of stannic chloride introduced dropwise, while the mixture is stirred. Stirring is continued for three hours at 0°C, after which the mixture is allowed to stand overnight. 50 cc of carbon sulfide is added and the mixture is treated, while being stirred, with the following: 20 cc of HCl and 100 cc of iced water. The organic layer is decanted and washed with water, dried over silica gel and rectified.
16.16 grams of 2-propyl-3-anisoyl coumarone are obtained (Yield: 72%), boiling at 189°C under 0.5 mm Hg. The methoxylated coumarone so obtained is mixed as follows: 1 part of 2-propyl-3-anisoylcoumarone and 2 parts of pyridine hydrochloride and the mixture maintained for one hour under a stream of dry nitrogen in an oil bath at 210°C (under a vertical condenser). After cooling, the mixture is triturated with 0.5 N hydrochloric acid (10 parts). The aqueous layer is separated and the residue extracted with ether. The ethereal extract is treated with 20 parts of 1% caustic soda. The alkaline layer is separated by decanting and acidified by means of diluted HCl. The precipitate is purified by recrystallization in aqueous acetic acid. 0.8 part of 2-propyl-3p-hydroxybenzoyl coumarone is obtained, melting at 123°C. Then the dibromo counterpart of benzbromarone may be prepared as follows: 8.05 g of 3-ethyl-2-p-hydroxybenzoyl coumarone, prepared as described above, are dissolved in very silght excess of 3% caustic soda. To this solution is gradually added a slight excess of bromine dissolved in a 25% aqueous solution of potassium bromide. The resultant solution is acidified with a 20% solution of sodium bisulfite, centrifuged, washed with water and then dried under vacuum. The product is then recrystallized in acetic acid and 13.6 g of 2-(4'-hydroxy-3',5'-dibromo-benzoyl)-3-ethyl coumarone obtained. MP 151°C.

Therapeutic Function

Uricosuric, Antiarthritic

Safety Profile

Poison by ingestion, intravenous, and intraperitoneal routes. Moderately toxic by subcutaneous route. Experimental teratogenic and reproductive effects. A uricosuric agent which promotesthe excretion of uric acid in the urine. A flammable liquid. When heated to decomposition it emits toxic fumes of Br-. See also KETONES.

Benzbromarone(3562-84-3)Related Product Information

• 2-Ethylbenzofuran
• Benzobromoma impurity 2
• (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxybenzofuran-3-yl)methanone
• Benzbromarone D5
• Benzbromarone Impurity 3
• Benzobromoma impurity 4
• 3,5-Dibromo-4-hydroxybenzoic acid
• bromobenzarone
• (6-BroMo-2-ethyl-3-benzofuranyl)(3,5-dibroMo-4-hydroxyphenyl)Methanone
• 3,5-dibromo-4-hydroxyBenzoyl chloride
• Benzobromoma impurity 3
• Benzobromoma impurity 1
• 2-Ethyl-3-methylbenzofuran
• 3'-Bromoacetophenone
• 3-Acetyl-2-ethylbenzofuran
• 2,6-Dibromo-4-methylphenol
• 3-BROMO-4-HYDROXYBENZALDEHYDE
• Benzarone