Metolazone CAS 17560-51-9
Introduction：Basic information about Metolazone CAS 17560-51-9, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Metolazone Basic information
| Product Name: | Metolazone |
| Synonyms: | s720-22;Zaroxolyn;7-Chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, SR-720-22, Diulo, Metenix, Mykrox, Oldren,;6-Quinazolinesulfonamide, 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo- (9CI);6-Quinazolinesulfonamide, 7-chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl- (8CI);Normelan;Xuret;6-Quinazolinesulfonamide, 7-chloro-1,2,3,4-tetrahydro- 2-methyl-3-(2-methylphenyl)-4-oxo- |
| CAS: | 17560-51-9 |
| MF: | C16H16ClN3O3S |
| MW: | 365.83 |
| EINECS: | 241-539-3 |
| Product Categories: | ZAROXOLYN;Other APIs;Organics;Amines;Aromatics;Heterocycles;Sulfur & Selenium Compounds;Intermediates & Fine Chemicals;Pharmaceuticals |
| Mol File: | 17560-51-9.mol |
Metolazone Chemical Properties
| Melting point | 252-254°C |
| Boiling point | 613.6±65.0 °C(Predicted) |
| density | 1.2895 (rough estimate) |
| refractive index | 1.6100 (estimate) |
| storage temp. | 2-8°C |
| solubility | DMSO: >5mg/mL |
| form | solid |
| pka | pKa 9.7 (Uncertain) |
| color | white |
| Water Solubility | 60.3mg/L(25 ºC) |
| Stability: | Stable for 2 years as supplied. Solutions in DMSO may be stored desiccated at -20°C for up to 2 months. |
| Major Application | pharmaceutical (small molecule) |
| InChI | 1S/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23) |
| InChIKey | AQCHWTWZEMGIFD-UHFFFAOYSA-N |
| SMILES | CC1Nc2cc(Cl)c(cc2C(=O)N1c3ccccc3C)S(N)(=O)=O |
| CAS DataBase Reference | 17560-51-9(CAS DataBase Reference) |
| NIST Chemistry Reference | Metolazone(17560-51-9) |
Safety Information
| WGK Germany | 2 |
| RTECS | VA1700000 |
| HS Code | 2935904000 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 17560-51-9(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): >5000 orally; >1500 i.p. (Shetty, 1967) |
| Description | Metolazone (Item No. 26304) is an analytical reference standard categorized as a diuretic. It has been detected as an adverse analytical finding (AAF) during anti-doping testing. This product is intended for use in analytical forensic applications. This product is also available as a general research tool . |
| Chemical Properties | Crystalline Solid |
| Originator | Zaroxolyn,Pennwalt,UK,1973 |
| Uses | Metolazone acts on the distal tubules, thus increasing excretion of water and sodium,potassium, and chloride ions. It is used for treating edema caused by cardiac insufficiencyand adrenal irregularities, including nephrotic syndrome. |
| Uses | A diruetic. An antihypertensive |
| Uses | diuretic, antihypertensive |
| Definition | ChEBI: A quinazoline that consists of 1,2,3,4-tetrahydroquinazolin-4-one bearing additional methyl, 2-tolyl, sulfamyl and chloro substituents at positions 2, 3, 6 and 7 respectively. A quinazoline diuretic, with properties similar to thiazide diuretics. |
| Manufacturing Process | Preparation of Intermediate Compound N-Acetyl-5-Chloro-2-Methylaniline: Toa well-stirred mixture of 1,270 g (9 mols) of 5-chloro-2-methylaniline in 7.5liters of water at 34°C was added all at once 1,710 ml (18 mols) of aceticanhydride. A solution was obtained and then almost immediately the productstarted to crystallize. The temperature rose to 60°C. The mixture was stirreduntil the temperature dropped to 30°C. The product was filtered and washedwell with water. Yield 97% (1,640 g), MP 134° to 138°C. Product was air driedand then in vacuum over P2O5. Preparation of Intermediate Compound 5-Chloro-2-Methyl-4-Sulfamylacetanilide: Into a 3-necked 3-liter flask fitted with stirrer andthermometer 540 ml of chlorosulfonic acid were placed and cooled in an icebath to 20°C. 300 g of the acetanilide were added portionwise while stirringand maintaining temperature at 20°C. This addition takes approximately 20minutes. Remove the ice bath and add 88 g of sodium chloride portionwise(approximately 1 tsp every 10 minutes), This addition takes approximately 1hour. Some foaming takes place. Using heating mantle bring temperature upslowly (approximately ? hour) to 75°C. Considerable foaming takes place andheating is continued another ? hour until 92°C is reached. Foaming can becontrolled by shutting off heat and with good stirring. Once the temperatureof 92°C has been reached and foaming has subsided reaction can be leftunattended. Keep reaction at 92°C for a total of 2? hours. Pour the hot reaction mixture onto 4 liters of crushed ice. Pour slowly and stirthe ice mixture. What remains in the flask can be worked up by adding ice toit and swirling the contents. After approximately 3/4 of an hour, the solid isfiltered and washed with approximately 600 ml water. Break up cake into small pieces and add to 2.5 liters concentrated NH4OH in 4liter beaker. Stir. Solid goes into solution and then the sulfonamideprecipitates out. Heat to 50°C and then turn off heat. After ? hour cool in icebath and filter. Wash cake with 600 ml water. Add cake to 2 liters 5% NaOH(130 ml 50% NaOH to 2 liters water). Filter and discard insolubles. Whilecooling filtrate add concentrated HCl until mixture is acid. Filter and wash cakeuntil filtrate is neutral. Suck cake as dry as possible then air dry. Yieldapproximately 200 g (45%), MP 255° to 260°C. Preparation of Intermediate Compound 4-Chloro-5-Sulfamyl-NAcetylanthranilic Acid: To a hot solution (80°C) of 366 g (1.482 mols) ofmagnesium sulfate (Epsom salts) in 2.8 liters of water was added 130 g(0.495 mol) of powdered 5-chloro-2-methyl-4-sulfamylacetanilide. Withstirring and maintaining the temperature at 83°C, 234 g (1.482 mols) ofpotassium permanganate was added portionwise over a period of 2 hours. Themixture was then kept at 85°C with stirring for an additional 3 hours. By thistime the pink color of the permanganate had been discharged. The mixture was cooled to 65°C and 250 g (2.0 mols) of sodium carbonatemonohydrate was added. The warm reaction mixture was filtered and the cakewashed with water. The filtrate was then slowly treated with concentratedhydrochloric acid until mixture tested acid. Product was then filtered, washedwith water and dried. Yield 103 g (71.0%), MP 245° to 249°C (dec.). Preparation of Intermediate Compound 2-Methyl-3-o-Tolyl-6-Sulfamyl-7-Chloro-4(3H)-Quinazolinone: Set up a 5-liter 3-necked flask fitted with astirrer, condenser and a drying tube. To a stirred mixture of 100 g (0.342 mol)of powdered 4-chloro-5-sulfamyl-N-acetylanthranilic acid, 40.2 g (0.376 mol)of o-toluidine and 2.0 liters of dry toluene was added dropwise, over a periodof 15 minutes, 21.7 ml (34.1 g) (0.248 mol) of phosphorus trichloride. Themixture was then refluxed for 10 hours. The solid turned somewhat gummytowards the latter part of the first hour. The mixture then became more freeflowing as heating was continued. Let stand overnight. The yellow solid wasfiltered, washed with toluene and dried. The toluene filtrate was discarded.The dried solid was triturated with 1.5 liters of 10% sodium bicarbonate,filtered and the cake washed with water. The filtrate on acidification yielded11.5 g of the starting acid. The damp product was dissolved in 4.5 liters of95% ethanol and the solution treated with charcoal and filtered. On coolingfiltrate yielded 69.5 g (55.5%) of the title compound, MP 271.5° to 274°C. Preparation of the Final Compound 2-Methyl-3-o-Tolyl-6-Sulfamyl-7-Chloro-1,2,3,4-Tetrahydro-4(3H)-Quinazolinone: To 4 liters of dry diglyme in a 12-liter 3-necked flask fitted with a stirrer, thermometer and drying tube wasadded 5.34 g (0.04 mol) of aluminum chloride, while stirring. To the resultingsolution was added 43.6 g (0.12 mol) of 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-4(3H)-quinazoline. A solution of 4.56 g (0.12 mol) of sodiumborohydride in 1 liter of dry diglyme was added portionwise over a period of 1hour while stirring the mixture. The mixture was then heated at 85°C, withstirring, for 1 hour. After cooling the reaction mixture to 25°C in an ice bath 600 ml of water wasadded and then enough dilute hydrochloric acid (approximately 100 ml) tomake the solution acid. The solvent was then removed under reducedpressure at 60° to 70°C. The very viscid residue solidified when trituratedwith water. The solid was filtered and washed with water. The solid wasdissolved in approximately 400 ml 95% ethanol and the solution filteredthrough Celite. On cooling the solution yielded 30 g of colorless solid, MP 253°to 259°C. The filtrate was concentrated to 200 ml to yield another 4.6 g, MP253° to 259°C. The above product was then recrystallized from 900 ml of 95% ethanol afterfiltering the hot solution through Celite. Crystallization was initiated and themixture agitated occasionally while being cooled in the refrigerator. Yield ofproduct 29 g, MP 253° to 259°C. Concentration of the filtrate to 125 mlyielded another 7.5 g of product, MP 253° to 259°C. The product wasrecrystallized another time in the manner described above. Total yield, firstand second crops, 28.8 g (66%), MP 250° to 255°C. Product was dried at80°C in a vacuum, according to US Patent 3,360,518. |
| Brand name | Diulo (Searle); Mykrox(UCB); Zaroxolyn(UCB). |
| Therapeutic Function | Diuretic |
| Biochem/physiol Actions | Inhibitor of thiazide-sensitive Na+-Cl- cotransporter; antihypertensive; moderate "loop" diuretic. |
| Synthesis | Metolazone, 7-chloro-1,2,3,4-tetrahydro-2-methyl-4-oxo-3-o-tolyl-6-quinazolinsulfonamide(21.3.20), is synthesized from 5-chloro-2-methylaniline. The amino groupis acylated by ethyl chloroformate, forming 5-chloro-N-ethoxycarbonyl-2-methylaniline(21.3.15). The product, upon subsequent reaction with chlorosulfonic acid and ammonia, istransformed in the usual manner into 4-sulfonamido-5-chloro-N-ethoxycarbonyl-2-methylaniline(21.3.16). The methyl group of this product is oxidized by potassium permanganate,giving 5-sulfonamido-4-chloro-N-ethoxycarbonyl anthranylic acid (21.3.17). Upon treatingthis with thionyl chloride it cycles into the corresponding anhydride (21.3.18). This reacts witho-toluidine, turning it into 2-amino-5-aminosulfonyl-4-chloro-o-toluolbenzamide (21.3.19).Finally, reacting this with dimethylacetal acetic acid gives metolazone (21.3.20). |
| References | [1] AI ITO. Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.[J]. Biogerontology, 2021: 119-131. DOI:10.1007/s10522-020-09907-6 [2] K BEAUMONT D D F D A Vaughn. Thiazide diuretic drug receptors in rat kidney: identification with [3H]metolazone.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1988, 85 7: 2311-2314. DOI:10.1073/pnas.85.7.2311 [3] ERIKA MORENO. Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding.[J]. The Journal of Biological Chemistry, 2006, 281 25: 17266-17275. DOI:10.1074/jbc.m602614200 [4] CLAUDIA TEMPERINI. Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with 12 mammalian isozymes and X-ray crystallographic studies for the indapamide–isozyme II adduct[J]. Bioorganic & Medicinal Chemistry Letters, 2008, 18 8: Pages 2567-2573. DOI:10.1016/j.bmcl.2008.03.051 |
Metolazone Preparation Products And Raw materials
| Raw materials | Phosphorus trichloride |
