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Amiloride hydrochloride

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Amiloride hydrochloride Basic information

Product Name:
Amiloride hydrochloride
Synonyms:
  • amiloridechloride
  • amiprazidine
  • n-amidino-3,5-diamino-6-chloro-pyrazinecarboxamidmonohydrochloride
  • 3,5-DIAMINO-N-(AMINOMETHYL)-6-CHLOROPYRAZINE CARBOXAMIDE HYDROCHLORIDE
  • HCL AMILORIDE HCL
  • N-amidino-3,5-diamino-6-chloropyrazinecarboxamide monohydrochloride
  • Amipramidin hydrochloride
  • Amipramizide hydrochloride
CAS:
2016-88-8
MF:
C6H8ClN7O.ClH
MW:
266.09
EINECS:
217-958-2
Product Categories:
  • MIDAMOR
  • Active Pharmaceutical Ingredients
  • Ion transporter and other ion channel
  • Ion Channels
  • Amines
  • Bases & Related Reagents
  • Heterocycles
  • Intermediates & Fine Chemicals
  • Nucleotides
  • Pharmaceuticals
Mol File:
2016-88-8.mol
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Amiloride hydrochloride Chemical Properties

Melting point:
293-294°C
storage temp. 
Store at RT
solubility 
H2O: 50 mg/mL, clear, yellow-green
form 
powder
color 
yellow
Water Solubility 
<0.1 g/100 mL at 19.5 ºC
CAS DataBase Reference
2016-88-8(CAS DataBase Reference)
EPA Substance Registry System
Amiloride hydrochloride (2016-88-8)
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Safety Information

Hazard Codes 
T,Xi
Risk Statements 
25-36/37/38
Safety Statements 
36-45-26
RIDADR 
UN 2811 6.1/PG 3
WGK Germany 
3
RTECS 
UQ2275500
HazardClass 
6.1(a)
PackingGroup 
II
HS Code 
29339980

MSDS

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Amiloride hydrochloride Usage And Synthesis

Chemical Properties

Pale Yellow Solid

Originator

Midamor,Merck,UK,1971

Uses

Sodium channel blocker. Diuretic.

Uses

Na+ channel inhibitor, diuretic

Uses

A calcium channel andsodium channel protein inhibitor

Definition

ChEBI: A hydrochloride obtained by combining amiloride with one molar equivalent of hydrochloric acid.

Manufacturing Process

Step A: Preparation of methyl 3-amino-5,6-dichloropyrazinoare: Methyl 3- aminopyrazinoate (765 g, 5 mols) is suspended in 5 liters of dry benzene. While stirring under anhydrous conditions sulfuryl chloride (1.99 liters, 3.318 g, 24.58 mols) is added over a period of 30 minutes and stirring is continued for 1 hour. During this period, the temperature rises to about 50°C and then begins to drop. The mixture is heated cautiously to reflux (60°C), refluxed for 5 hours and then stirred overnight at room temperature. The excess sulfuryl chloride is distilled off at atmospheric pressure (distillation is stopped when vapor temperature reaches 78%). The dark red mixture is chilled to 6°C. The crystals are filtered off, washed by displacement with two 100 ml portions of cold (8°C) benzene, then washed with 300 ml petroleum ether and dried in vacuum at room temperature, yielding 888 g (80%) of methyl 3-amino-5,6- dichloropyrazinoate in the form of red crystals, MP 228-230°C. The crude product is dissolved in 56 liters of boiling acetonitrile and passed through a heated (70-80°C) column of decolorizing charcoal (444 g). The column is washed with 25 liters of hot acetonitrile, the combined eluate concentrated in vacuum to about 6 liters and chilled to 5°C. The crystals that form are filtered, washed three times with cold acetonitrile, and air dried to constant weight, yielding 724 g (82% recovery, 66% overall) of methyl 3-amino-5,6- dichloropyrazinoate in the form of yellow crystals, MP 230-234°C. After additional recrystallizations from acetonitrile the product melts at 233-234°C.
Step B: Preparation of methyl-3,5diamino-6-chloropyrazinoete: In a 2-liter, 3-necked flask fitted with a a mechanical stirrer, thermometer and gas inlet tube is placed dry dimethyl sulfoxide (1 liter). Methyl 3-amino-5,6- dichloropyrazinoate (100 g, 0.45 mol) is added and the mixture stirred and heated at 65°C on a steam bath until solution is effected. A stream of dry ammonia gas is admitted to the solution with continuous stirring, over a period of 45 minutes while the temperature is maintained at 65-70°C. The solution is cooled to about 10°C with continuous stirring and ammonia gas is admitted for an additional 1 1/4 hours. The yellow reaction mixture is poured, with stirring, into cold water (2 liters) and the light yellow solid that separates is removed by filtration, thoroughly washed with water, and dried in a vacuum desiccator to give 82.5 g (91%) of methyl 3,5-diamino-6-chloropyrazinoate, MP 210-212°C. Recrystallization from acetonitrile gives material melting at 212-213°C.
Step C: Preparation of the base: A 300 ml one-necked, round-bottomed flask, equipped with a water-cooled condenser, calcium chloride tube and magnetic stirrer is charged with anhydrous methanol (150 ml) and sodium metal (5.75 g, 0.25 g atom). When the reaction is complete, the solution is treated with dry guanidine hydrochloride (26.3 g, 0.275 mol) and stirred for 10 minutes. The sodium chloride that forms is removed by filtration. The solution is concentrated in vacuum to a volume of 30 ml and the residue treated with the product of Step B, heated one minute on a steam bath and kept at 25°C for 1 hour. The product is filtered, washed well with water, dissolved in dilute hydrochloric acid and the free base precipitated by addition of sodium hydroxide to give the amiloride product base, a solid which melts at 240.5- 241.5°C.
To produce the hydrochloride, the base is suspended in water (70 ml) and treated with sufficient 6 N hydrochloric acid to dissolve the free base. The solution is filtered and treated with concentrated hydrochloric acid (5 ml). The hydrochloride salt (22 g, 97%) separates and is recrystallized from water (50 ml) containing concentrated hydrochloric acid (3 ml).

brand name

Midamor (Merck).

Therapeutic Function

Diuretic

General Description

Crystalline solid or very light yellow powder.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

A halogenated amine and amide, acidic salt. In aqueous solution, behaves as a weak acid. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides. Organic amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Health Hazard

SYMPTOMS: Symptoms of exposure to Amiloride hydrochloride include headache, weakness, fatigue, back, chest, neck, shoulder or extremity pain; nausea, anorexia, vomiting, abdominal pain, hyperkalemia, paresthesias, shock, dizziness, coughing, shortness of breath, depression, nervousness, flaccid paralysis of the extremities, bradycardia, flatulence, skin rash, gas pain, constipation and dyspnea.

Fire Hazard

Flash point data for Amiloride hydrochloride are not available; however, Amiloride hydrochloride is probably combustible.

Biological Activity

Na + channel blocker. Defines the I 2A -amiloride sensitive and I 2B -amiloride insensitive imidazoline binding sites. Also inhibits TRPP3 channels.

Biochem/physiol Actions

Selective T-type calcium channel blocker and blocker of epithelial sodium channel. Selective inhibitor of urokinase plasminogen activator (uPA).

Clinical Use


Oedema
Potassium conservation with thiazide and loop diuretics

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitor and angiotensin-II antagonists: increased risk of hyperkalaemia and hypotension.
Antibacterials: avoid concomitant use with lymecycline.
Antidepressants: increased risk of postural hypotension with tricyclics; enhanced hypotensive effect with MAOIs.
Antihypertensives: enhanced hypotensive effect.
Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity.
Cytotoxics: increased risk of nephrotoxicity and ototoxicity with platinum compounds.
Lithium excretion reduced
NSAIDS: increased risk of hyperkalaemia; increased risk of nephrotoxicity; antagonism of diuretic effect.
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia.

Metabolism

Amiloride is excreted unchanged in the urine. In two studies in which single doses of 14C-Amiloride were used, approximately 50% was recovered in urine and 40% in the faeces within 72 hours.

Amiloride hydrochloride Preparation Products And Raw materials

Raw materials

Amiloride hydrochlorideSupplier

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