Ethacrynic acid CAS 58-54-8
Introduction：Basic information about Ethacrynic acid CAS 58-54-8, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Ethacrynic acid Basic information
| Product Name: | Ethacrynic acid |
| Synonyms: | crinuryl;edecril;edecrin;edecrina;endecril;etacrinicacid;etakrinicacid;hidromedin |
| 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 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 |
| pka | 3.50(at 25℃) |
| form | powder |
| color | white to beige |
| Water Solubility | Soluble in ethanol, chloroform, ether, ammonia, carbonates, and methanol. Insoluble in water. |
| Merck | 3717 |
| InChI | 1S/C13H12Cl2O4/c1-3-7(2)13(18)8-4-5-9(12(15)11(8)14)19-6-10(16)17/h4-5H,2-3,6H2,1H3,(H,16,17) |
| InChIKey | AVOLMBLBETYQHX-UHFFFAOYSA-N |
| SMILES | ClC1=C(Cl)C(C(C(CC)=C)=O)=CC=C1OCC(O)=O |
| CAS DataBase Reference | 58-54-8(CAS DataBase Reference) |
| EPA Substance Registry System | Ethacrynic 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 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Acute Tox. 4 Oral |
| Hazardous Substances Data | 58-54-8(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): 176 i.v.; 627 orally (Peck) |
| Description | Ethacrynic 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 Properties | White Solid |
| Originator | Hydromedin,MSD,W. Germany,1966 |
| Uses | A diuretic used to treat high blood pressure and swelling caused by congestive heart failure, liver failure and kidney failure. |
| Uses | Ethacrynic 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 andlungs. |
| Uses | Ethacrynic 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. |
| Definition | ChEBI: 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 suchas congestive heart failure, liver failure, and kidney failure. It is also a glutathione S-transferase (EC 2.5.1.18) inhibitor. |
| Manufacturing Process | Step A: Preparation of 2,3-Dichloro-4-Butyrylphenoxy Acid - The product isprepared using the following ingredients: 22.1 grams (0.1 mol) 2,3-dichlorophenoxyacetic acid; 21.3 grams (0.2 mol) n-butyryl chloride; and 53.3grams (0.4 mol) powdered aluminum chloride. The 2,3-dichlorophenoxyacetic acid and n-butyryl chloride are placed in thereaction vessel and stirred while the aluminum chloride is added portionwiseover a 45-minute period. The mixture then is heated on the steam bath for 3hours and allowed to cool to room temperature. The gummy product obtainedis added to a mixture of 300 ml of crushed ice and 30 ml concentratedhydrochloric acid. The resulting mixture is extracted with ether and the extractevaporated at reduced pressure. The residue is suspended in boiling waterand dissolved by addition of a minimum quantity of 40% sodium hydroxide.After treatment with decolorizing charcoal and filtering, the hot filtrate ismade acid to Congo red paper and chilled in ice. The oil that separates is extracted with ether, the extract dried overanhydrous sodium sulfate and then evaporated at reduced pressure. Theresidue is dissolved in boiling benzene (75 ml) treated with decolorizingcharcoal, filtered, treated with boiling cyclohexane (275 milliliters) and cooledto give 22.3 grams of 2,3-dichloro-4-butyrylphenoxyacetic acid. After severalrecrystallizations from a mixture of benzene and cyclohexane, then frommethyl cyclohexane, next from a mixture of acetic acid and water, and finallyfrom 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 equippedwith an outlet tube suitable for application of intermittent suction, an intimatemixture 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) drydimethylamine 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 1minute intervals five or six times. Upon cooling, a solid is obtained, The crudereaction product is triturated with ether to give 5.8 grams (85%) of 2.3-dichloro-4-[2-dimethylaminomethyl)butyryl]phenoxyacetic acid hydrochloridein the form of a white solid. After two recrystallizations from a mixture ofmethanol and ether, the product melts at 165° to 167°C. Step C: Preparation of 2,3-Dichloro-4-(2-Methylenebutyryl) PhenoxyaceticAcid - The Mannich compound obtained as described above is treated withaqueous sodium bicarbonate to form 2,3-dichloro-4-(2-methylenebutyryl)phenoxyacetic acid, MP 115° to 118°C. Tworecrystallizations from a mixture of benzene and cyclohexane give white solidmaterial melting at 118.5° to 120.5°C. |
| Brand name | Edecrin (Merck). |
| Therapeutic Function | Diuretic, Cardiotonic, Smooth muscle relaxant, Respiratory stimulant |
| General Description | White solid. |
| Air & Water Reactions | Insoluble in water. |
| Reactivity Profile | Ethacrynic 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 Hazard | Ethacrynic acid is probably combustible. |
| Biochem/physiol Actions | Ethacrynic 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 action | The mechanism of action of ethacrynic acid appears to be more complex than the simple addition of sulfhydryl groups of the enzyme tothe drug molecule. When the double bond of ethacrynic acid is reduced, the resultant compound is still active, although the diuretic activity is diminished. The sulfhydrylgroups 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 beeasily 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 unsubstitutedaminomethyl 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 addthe sulfhydryl groups of the kidney enzymes. The complete mechanism of action of these compounds remains in doubt. |
| Synthesis | Ethacrynic acid?a[2,3-dichloro-4-(2-methylenbutyryl)phenoxy]aceticacid (21.4.9), is synthesized from 2,3-dichlorophenoxyacetic acid. This is acylated with butyroylchloride, forming 4-butyroyl-2,3-dichlorophenoxyacetic acid (21.4.7), which is furtheraminomethylated under Mannich reaction conditions using dimethylamine and formaldehyde.The resulting product (21.4.8) undergoes further thermal degredation, forming anunsaturated ketone?aethacrynic acid (21.4.9). |
| Veterinary Drugs and Treatments | Ethacrynic acid is a loop diuretic that shares the same indicationsas furosemide (congestive cardiomyopathy, pulmonary edema, hypercalcuricnephropathy, uremia, as adjunctive therapy in hyperkalemiaand, occasionally, as an antihypertensive agent). Its use hasbeen largely supplanted in the armamentarium by furosemide forthese indications. Ethacrynic acid may be useful in the treatment of nephrogenicdiabetes insipidus as it may cause a paradoxical decrease in urinevolume. Other uses include the adjunctive treatment of hypercalcemiaand to increase the excretion of bromide in the treatment ofbromide toxicity. |
| References | [1] YUKIKO KUNUGI . Ethacrynic Acid-Sensitive and ATP-Dependent Cl- Transport in the Rat Kidney[J]. Japanese journal of pharmacology, 1991, 57 2: Pages 167-174. DOI: 10.1254/jjp.57.167 [2] V MORRA. Fast gas chromatographic/mass spectrometric determination of diuretics and masking agents in human urine: Development and validation of a productive screening protocol for antidoping analysis.[J]. Journal of Chromatography A, 2006, 1135 2: 219-229. DOI: 10.1016/j.chroma.2006.09.034 [3] H W HAGEDORN R S. Detection of diuretics in horse urine by GC/MS.[J]. Journal of analytical toxicology, 1992, 16 3: 194-198. DOI: 10.1093/jat/16.3.194 [4] H C PALFREY S L. Inhibition of Na-K-2Cl cotransport and bumetanide binding by ethacrynic acid, its analogues, and adducts.[J]. American Journal of Physiology, 1993, 264 5 Pt 1: C1270-7. DOI: 10.1152/ajpcell.1993.264.5.c1270 [5] DESHENG LU. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.[J]. PLoS ONE, 2009, 4 12: e8294. DOI: 10.1371/journal.pone.0008294 [6] BING LIU. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.[J]. Oncotarget, 2016: 58038-58050. DOI: 10.18632/oncotarget.10846 [7] YAMAN MUSDAL . FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-1[J]. Chemico-Biological Interactions, 2013, 205 1: Pages 53-62. DOI: 10.1016/j.cbi.2013.06.003 |
Ethacrynic acid Preparation Products And Raw materials
| Raw materials | Sodium hydroxide-->Hydrochloric acid-->Methanol-->Diethyl ether-->Sulfuric acid-->Acetic acid-->Sodium sulfate-->Sodium bicarbonate-->Benzene-->Aluminum chloride-->Sodium acetate-->Carbon disulfide-->Paraformaldehyde-->Chloroacetic acid-->Cyclohexane-->Ethyl bromoacetate-->Heptane-->Butyryl chloride-->Carbon-->Dimethylamine hydrochloride-->Methylcyclohexane-->2,3-Dichlorophenol-->2,6-Dichloroanisole-->Butyrophenone-->Ethyl phenoxyacetate-->2,3-DICHLOROPHENOXYACETIC ACID |
