Ethacrynic acid

Ethacrynic acid Basic information
Product Name:Ethacrynic acid
Synonyms:crinuryl;edecril;edecrina;endecril;etacrinicacid;etakrinicacid;hidromedin;hydromedin
CAS:58-54-8
MF:C13H12Cl2O4
MW:303.14
EINECS:200-384-1
Product Categories:EDECRIN;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals
Mol File:58-54-8.mol
Ethacrynic acid Structure
Ethacrynic acid Chemical Properties
Melting point 125 °C
Boiling point 480.0±45.0 °C(Predicted)
density 1.3562 (estimate)
storage temp. 2-8°C
solubility DMSO: soluble20mg/mL, clear
form powder
pka3.50(at 25℃)
color white to beige
Water Solubility Soluble in ethanol, chloroform, ether, ammonia, carbonates, and methanol. Insoluble in water.
Merck 3717
CAS DataBase Reference58-54-8(CAS DataBase Reference)
EPA Substance Registry SystemEthacrynic acid (58-54-8)
Safety Information
Hazard Codes Xn
Risk Statements 20/21/22-36/37/38
Safety Statements 26-36
WGK Germany 3
RTECS AG6600000
HS Code 2918992090
Hazardous Substances Data58-54-8(Hazardous Substances Data)
ToxicityLD50 in mice (mg/kg): 176 i.v.; 627 orally (Peck)
MSDS Information
Ethacrynic acid Usage And Synthesis
DescriptionEthacrynic acid is a loop diuretic with anticancer activity., It inhibits the Na-K-2Cl (NKCC) cotransporter in duck erythrocytes (IC50 = 0.18 mM) and ATP-dependent chloride uptake in rat renal plasma membrane vesicles when used at a concentration of 0.3 mM., Ethacrynic acid also inhibits glutathione S-transferase P1-1 (GSTP1-1) and GSTA3-3 (IC50s = 4.9 and ~0.4 μM, respectively), and inhibits Wnt/β-catenin signaling in a cell-based reporter assay. It is cytotoxic to primary chronic lymphocytic leukemia cells (IC50 = 8.56 μM), as well as MCF-7, MDA-MB-231, and 4T1 cancer cells (IC50s = 45.53, 39.64, and 25.23 μM, respectively). Ethacrynic acid (250 μg per day) increases tumor growth reduction induced by the EGFR family inhibitors afatinib (Item Nos. 11492 | 21567) or neratinib in a 4T1 murine breast cancer model. Formulations containing ethacrynic acid have been used in the treatment of edema.
Chemical PropertiesWhite Solid
OriginatorHydromedin,MSD,W. Germany,1966
UsesEthacrynic acid is a powerful diuretic prescribed for edema associated with cardiac insufficiency, renal edema that does not respond to other diuretics, and edema of the brain and lungs.
UsesA diuretic used to treat high blood pressure and swelling caused by congestive heart failure, liver failure and kidney failure.
UsesEthacrynic acid is used to inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. This compound has been classified as a loop or high ceiling diuretic.
DefinitionChEBI: An aromatic ether that is phenoxyacetic acid in which the phenyl ring is substituted by chlorines at positions 2 and 3, and by a 2-methylidenebutanoyl group at position 4. It is a loop diuretic used to treat high blood pressure resulting from diseases such as congestive heart failure, liver failure, and kidney failure. It is also a glutathione S-transferase (EC 2.5.1.18) inhibitor.
Manufacturing ProcessStep A: Preparation of 2,3-Dichloro-4-Butyrylphenoxy Acid - The product is prepared using the following ingredients: 22.1 grams (0.1 mol) 2,3- dichlorophenoxyacetic acid; 21.3 grams (0.2 mol) n-butyryl chloride; and 53.3 grams (0.4 mol) powdered aluminum chloride.
The 2,3-dichlorophenoxyacetic acid and n-butyryl chloride are placed in the reaction vessel and stirred while the aluminum chloride is added portionwise over a 45-minute period. The mixture then is heated on the steam bath for 3 hours and allowed to cool to room temperature. The gummy product obtained is added to a mixture of 300 ml of crushed ice and 30 ml concentrated hydrochloric acid. The resulting mixture is extracted with ether and the extract evaporated at reduced pressure. The residue is suspended in boiling water and dissolved by addition of a minimum quantity of 40% sodium hydroxide. After treatment with decolorizing charcoal and filtering, the hot filtrate is made acid to Congo red paper and chilled in ice.
The oil that separates is extracted with ether, the extract dried over anhydrous sodium sulfate and then evaporated at reduced pressure. The residue is dissolved in boiling benzene (75 ml) treated with decolorizing charcoal, filtered, treated with boiling cyclohexane (275 milliliters) and cooled to give 22.3 grams of 2,3-dichloro-4-butyrylphenoxyacetic acid. After several recrystallizations from a mixture of benzene and cyclohexane, then from methyl cyclohexane, next from a mixture of acetic acid and water, and finally from methylcyclohexane, the product melts at 110° to 111°C (corr).
Step B: Preparation of 2,3-Dichloro-4-[2-(Dimethylaminomethyl) Butyryl]Phenoxyacetic Acid Hydrochloride - In a 100 ml round flask equipped with an outlet tube suitable for application of intermittent suction, an intimate mixture of 5.20 grams (0.0179 mol) 2,3-dichloro-4-butyrylphenoxyacetic acid; 0.63 gram (0.0209 mol) paraformaldehyde; 1.59 grams (0.0195 mol) dry dimethylamine hydrochloride; and 4 drops acetic acid is heated on the steam bath for about 1.5 hours during which period suction is applied for about 1 minute intervals five or six times. Upon cooling, a solid is obtained, The crude reaction product is triturated with ether to give 5.8 grams (85%) of 2.3- dichloro-4-[2-dimethylaminomethyl)butyryl]phenoxyacetic acid hydrochloride in the form of a white solid. After two recrystallizations from a mixture of methanol and ether, the product melts at 165° to 167°C.
Step C: Preparation of 2,3-Dichloro-4-(2-Methylenebutyryl) Phenoxyacetic Acid - The Mannich compound obtained as described above is treated with aqueous sodium bicarbonate to form 2,3-dichloro-4-(2- methylenebutyryl)phenoxyacetic acid, MP 115° to 118°C. Two recrystallizations from a mixture of benzene and cyclohexane give white solid material melting at 118.5° to 120.5°C.



Brand nameEdecrin (Merck).
Therapeutic FunctionDiuretic, Cardiotonic, Smooth muscle relaxant, Respiratory stimulant
General DescriptionWhite solid.
Air & Water ReactionsInsoluble in water.
Reactivity ProfileEthacrynic acid may react vigorously with strong oxidizing agents. Can react exothermically with reducing agents (such as alkali metals and hydrides) to release gaseous hydrogen. May react exothermically with acids. Reacts exothermically with all bases both organic (for example, the amines) and inorganic.
Fire HazardEthacrynic acid is probably combustible.
Biochem/physiol ActionsEthacrynic acid is non sulfonamide loop diuretic that is used to treat high blood pressure and the swelling caused by diseases like congestive heart failure. Ethacrynic acid blocks sodium-potassium-chloride cotransport. Also, Ethacrynic acid potently inhibits glutathione S-transferase family members. Studies show that ethacrynic acid potently inhibits Tgase-2 (transglutaminase-2) dependent metastasis of cancer cells including lung and pancreatic cancers.
Mechanism of actionThe mechanism of action of ethacrynic acid appears to be more complex than the simple addition of sulfhydryl groups of the enzyme to the drug molecule. When the double bond of ethacrynic acid is reduced, the resultant compound is still active, although the diuretic activity is diminished. The sulfhydryl groups of the enzyme would not be expected to add to the drug molecule in the absence of the α,β-unsaturated ketone.
These compounds are potent high-ceiling diuretics that resemble ethacrynic acid in their mechanism of action. The ethyl ester group represents a pro-drug that can be easily hydrolyzed to the free carboxyl group. As in ethacrynic acid, a 2,3-dichloro substitution is necessary. In addition, a para-hydroxyl group and an unsubstituted aminomethyl group on the benzene ring are highly beneficial. The carbonyl group can be replaced with an ether or sulfide group. These compounds have no ability to add the sulfhydryl groups of the kidney enzymes. The complete mechanism of action of these compounds remains in doubt.
SynthesisEthacrynic acid?a[2,3-dichloro-4-(2-methylenbutyryl)phenoxy]acetic acid (21.4.9), is synthesized from 2,3-dichlorophenoxyacetic acid. This is acylated with butyroyl chloride, forming 4-butyroyl-2,3-dichlorophenoxyacetic acid (21.4.7), which is further aminomethylated under Mannich reaction conditions using dimethylamine and formaldehyde. The resulting product (21.4.8) undergoes further thermal degredation, forming an unsaturated ketone?aethacrynic acid (21.4.9).

Synthesis_58-54-8

Veterinary Drugs and TreatmentsEthacrynic acid is a loop diuretic that shares the same indications as furosemide (congestive cardiomyopathy, pulmonary edema, hypercalcuric nephropathy, uremia, as adjunctive therapy in hyperkalemia and, occasionally, as an antihypertensive agent). Its use has been largely supplanted in the armamentarium by furosemide for these indications.
Ethacrynic acid may be useful in the treatment of nephrogenic diabetes insipidus as it may cause a paradoxical decrease in urine volume. Other uses include the adjunctive treatment of hypercalcemia and to increase the excretion of bromide in the treatment of bromide toxicity.
2-(3-CHLOROPHENOXY)ETHANOL Sodium dichloroacetate ETHACRYNIC ACID USP(CRM STANDARD) 2-Chloro-4-hydroxybenzaldehyde 2,3-DICHLOROPHENOXYACETIC ACID 2-Chlorophenoxyacetic acid 3-(2-Chlorophenyl)-2-methylprop-1-ene Ethyl 2-(Chlorosulfonyl)acetate Ascoric Acid 2,3-Dichloroacetophenone Dichloroacetic acid methyl ester 1-(3-CHLORO-4-HYDROXYPHENYL)-1-ETHANONE (4-PROPIONYL-PHENOXY)-ACETIC ACID Ethacrynic acid TICRYNAFEN 4-ethoxypropiophenone GST Inhibitor-2 (Ethacrynic acid)) ethacrynic acid, sodium salt

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