Sulfalen

Chemical properties

White to Yellow Solid

Originator

Longum,Farmitalia,W. Germany,1962

The Uses of Sulfalen

A possible antimalarial drug.

Background

Long-acting plasma-bound sulfonamide used for respiratory and urinary tract infections and also for malaria.

Indications

For the treatment of urinary tract infection and chronic bronchitis.

Definition

ChEBI: Sulfamethopyrazine is a member of pyrazines, a sulfonamide and a sulfonamide antibiotic.

Manufacturing Process

2-Amino-3,5-Dibromo-Pyrazine: 112.7 ml of bromine in 375 ml of acetic acid are slowly added at 0° to +2°C, while stirring, to a solution of 95.11 grams of 2-amino-pyrazine and 326.5 grams of acetic acid trihydrate (CH3COONa·3H2O) in 1,480 ml of acetic acid. This addition requires about 2 to 3 hours and it is carried out in the dark. The mixture is then allowed to stand at room temperature (25° to 30°C) for 15 to 16 hours. About 1.5 liters of acetic acid are distilled off under vacuum (12 to 14 mm Hg) at 35°C and the brown and viscous residue is poured into 500 grams of ice-water under stirring.
Aqueous 20% sodium hydroxide is added in order to obtain a pH = 8 and then the product is filtered and air-dried. The air-dried product is extracted 6 times with 150 ml of ether; the filtered ethereal solutions are evaporated to dryness and the residue (50 to 52 grams) is crystallized from hot water. The yield is 34.36 grams, melting at 114°C.
2-Amino-3-Methoxy-5-Bromo-Pyrazine: 7 grams of 2-amino-3,5-dibromopyrazine are boiled for 9 hours in a methanolic solution of sodium methylate (obtained from 0.65 gram of Na and 18.5 ml of methanol). By cooling a crystalline product is obtained, filtered and washed once with methanol and 2 to 3 times with water. The yield is 5.4 grams, melting at 138°C.
2-Amino-3-Methoxy-Pyrazine: 3 grams of 2-amino-3-methoxy-5-bromopyrazine are hydrogenated, in methanolic solution at room temperature and at atmospheric pressure, in the presence of 1 gram of palladium over charcoal (10%) and 0.9 gram of potassium hydroxide. When the stoichiometric amount of hydrogen is absorbed, the suspension is filtered and the filtrate is evaporated to dryness. The residue is extracted with acetone, the acetonic solution is evaporated and the residue (1.8 grams, melting at 75° to 82°C) is crystallized from cyclohexane. The yield is 1.5 grams, melting at 85°C.
2-(p-Acetylaminobenzene-sulfonamido)-3-Methoxy-Pyrazine: 1.5 grams of 2- amino-3-methoxy-pyrazine dissolved in 15 ml of anhydrous pyridine are treated, under cooling and stirring, with 2.81 grams of pacetylaminobenzenesulfonyl chloride, at small portions in about 30 minutes. The mixture is allowed to stand for 20 hours at room temperature and then is heated to 50°C for 4 hours.
The solution is concentrated to one-third of its volume, under vacuum, and poured into ice-water under stirring. The precipitate is filtered and washed with water. 2.21 grams melting at 218° to 220°C are obtained. The MP (crystallized from alcohol) is 224°C.
2-Sulfanilamido-3-Methoxy-Pyrazine: 1.5 grams of the product from the preceding step and 7 to 8 ml of aqueous 10% sodium hydroxide are boiled for 1 hour. The cooled solution is slightly acidified to pH 6 with aqueous 2 N hydrochloric acid and the product is filtered. The yield is 1.25 grams, melting at 175°C.

brand name

Kelfizina (Abbott).

Therapeutic Function

Antibacterial

Pharmaceutical Applications

2-Sulfanilamido-3-methoxypyrazine. A very long-acting compound (plasma half-life 60 h). Adequate blood levels can be maintained by giving a dose of 2 g once weekly. The protein binding is c. 70%. It has been successfully used in the single-dose treatment of urinary tract infection. As with other long-acting compounds, sulfametopyrazine has been associated with an increased incidence of erythema multiforme.

Pharmacokinetics

Sulfametopyrazine is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of p-aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus.

Synthesis

Sulfalene, 3-methoxy-2-sulfanilamidopyrazine (33.1.41), like other sulfanilamides, is synthesized by the standard scheme from 4-acetylaminobenzenesulfonyl chloride, which is reacted with 3-amino-2-methoxypyrazine, which is synthesized by two technologically available methods. The first of these methods consists of direct bromination of 2-aminopyrazine using acetic acid as a solvent, which gives 3,5-dibromo-2-aminopyrazine (33.1.34). Reacting this with sodium methoxide gives 3-methoxy-5-bromo-2-aminopyrazine (33.1.35). Hydrogen reduction using a palladium on carbon catalyst replaces the bromine atom at C5 of the product with a hydrogen atom, giving 3-methoxy-2-aminopyrazine (33.1.36).
This same 3-methoxy-2-aminopyrazine (33.1.36) is synthesized from 3-hydroxypyrazin- 2-carboxamide. Reacting this with phosphorous oxychloride replaces the hydroxyl group with a chlorine atom while the carboxamide group simultaneously undergoes dehydration to form 3-chloro-2-cyanopyrazine (33.1.37). Next, reacting this with sodium methoxide gives 3-methoxy-2-cyanopyrazine (33.1.38). The cyano group in this compound is hydrolyzed by a base in the presence of hydrogen peroxide to a carboxamide group, giving 3-methoxy-2-carboxamideopyrazine (33.1.39). The resulting product undergoes a Hofmann rearrangement when reacted with sodium hypochlorite, giving the desired 3-methoxy-2 aminopyrazine (33.1.36). Reacting this with 4-acetylaminobenzenesulfonyl chloride and subsequent hydrolysis of the acetyl group with a base to (33.1.40) gives sulfalene.

Metabolism

Not Available