14293-44-8

Basic information

• Product Name: Xipamide
• Synonyms: Xipamide;XIPAMIDE (IN HOUSE);4-Chloro-5-sulfamoyl-2',6'-salicyloxylidide;5-(Aminosulfonyl)-4-chloro-N-(2,6-dimethylphenyl)-2-hydroxybenzamide;Benzamide,5-(aminosulfonyl)-4-chloro-N-(2,6-dimethylphenyl)-2-hydroxy-;4-Chloro-2-hydroxy-N-(2,6-dimethylphenyl)-5-sulfamoylbenzamide;Aquaphor(diuretic);Be-1293
• CAS NO: 14293-44-8
• Molecular Formula: C₁₅H₁₅ClN₂O₄S
• Molecular Weight: 354.8086
• EINECS: 238-216-4
• Product Categories: APIs;Xipamide;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 14293-44-8.mol
• Article Data: 1

Chemical Properties

• Melting Point: 255-256 °C
• Appearance: white to beige/
• Density: 1.2743 (rough estimate)
• Refractive Index: 1.6100 (estimate)
• Storage Temp.: Refrigerator
• Solubility: DMSO: soluble20mg/mL, clear
• PKA: pKa 4.75±0.04(0.4% MeOH in H2O) (Uncertain)
• Water Solubility: 58mg/L(25 oC)
• CAS DataBase Reference: Xipamide(CAS DataBase Reference)
• NIST Chemistry Reference: Xipamide(14293-44-8)
• EPA Substance Registry System: Xipamide(14293-44-8)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• Hazardous Substances Data: 14293-44-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Originator

Aquaphor,Beiersdorf,W. Germany ,1971

Uses

Xipamide is a diuretic and antihypertensive agent.

Manufacturing Process

The 4-chloro-5-sulfamyl salicylic acid used as starting point was prepared in the following way:(a) 4-Chloro-5-Chlorosulfonyl Salicylic Acid: 100 grams 4-chloro salicylic acid was added portionwise with stirring at about -5°C to 275 ml chlorosulfonic acid. The temperature was not allowed to rise above +3°C. At the end of the addition, the solution formed was stirred for 1 hour in an ice bath, then for 1 hour at 20°C and finally for 2 1/2 hours at 80°C oil bath temperature. Then the dark brown solution, after ensuing slow cooling with vigorous stirring, was poured onto ice; the precipitate was vacuum filtered, washed with water and dried. After recrystallization from toluene the compound formed had a melting point of 181° to 183°C.(b) 4-Chloro-5-Sulfamyl Salicylic Acid: 40 grams 4-chloro-5-chlorosulfonyl salicylic acid obtained from (a) was added portionwise with stirring to 250 ml liquid ammonia. This was allowed to stand for 2 hours, then the precipitate was vacuum filtered and dissolved in 500 ml water. The solution was filtered and the filtrate was treated with 2 N hydrochloric acid until no more precipitation occurred. The 4-chloro-5-sulfamyl salicylic acid obtained as the precipitate was filtered off and finally recrystallized from water, MP 258° to 260°C.5.0 grams 4-chloro-5-sulfamyl salicylic acid was suspended in 100 ml water- free chlorobenzene and then 2.44 grams of 2,6-dimethylaniline and 0.9 ml phosphorus trichloride were added to the suspension in turn. The reaction mixture was heated under reflux for 5 hours. After cooling, the chlorobenzene was separated from the precipitate by decantation. The latter was finally collected on a filter and washed, first with chlorobenzene and, after drying, with 2 N hydrochloric acid and water. The compound obtained by recrystallization from methanol had a melting point of 256°C.

Therapeutic Function

Diuretic, Antihypertensive

Clinical Use

Thiazide diuretic: Hypertension Oedema

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 concomitant use. Atomoxetine: hypokalaemia increases risk of ventricular arrhythmias. Cardiac glycosides: increased toxicity if hypokalaemia occurs. Ciclosporin: increased risk of nephrotoxicity and possibly 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

Xipamide is excreted in the urine, partly unchanged and partly in the form of the glucuronide metabolite. In patients with renal impairment excretion in the bile becomes more prominent.

InChI:InChI=1/C15H15ClN2O4S/c1-8-4-3-5-9(2)14(8)18-15(20)10-6-13(23(17,21)22)11(16)7-12(10)19/h3-7,19H,1-2H3,(H,18,20)(H2,17,21,22)

Relevant articles and documents

Structure activity relationship for derivatives of xipamide (4 chloro 5 sulfamoyl 2',6' salicyloxylidide)

The synthesis of various derivatives of 4 chlorosalicylic acid substituted in position 5 is described. The evaluation of their diuretic potency on the rat showed 4 chloro 5 sulfamoyl 2',6' salicyloxylidide (BE 1293, xipamide, 'Aquaphor') as the most effective. The normal urinary volume is increased 10 fold by an oral dose of 100 mg/kg body weight. All changes in the molecular structure of xipamide, even acetylation, the introduction of a second sulfamoyl group or the exchange of the sulfonic group for the carbonyl group lead to a decrease in activity.