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Metolazone

Product Name
Metolazone
CAS No.
17560-51-9
Chemical Name
Metolazone
Synonyms
DIULO;MYKROX;Zaroxolyn;Xuret;OLDREN;microx;s720-22;METENIX;Normelan;fonamide
CBNumber
CB4725936
Molecular Formula
C16H16ClN3O3S
Formula Weight
365.83
MOL File
17560-51-9.mol
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Metolazone Property

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
pka
pKa 9.7 (Uncertain)
form 
solid
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.
InChIKey
AQCHWTWZEMGIFD-UHFFFAOYSA-N
CAS DataBase Reference
17560-51-9(CAS DataBase Reference)
NIST Chemistry Reference
Metolazone(17560-51-9)
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Safety

WGK Germany 
2
RTECS 
VA1700000
HS Code 
2935904000
Hazardous Substances Data
17560-51-9(Hazardous Substances Data)
Toxicity
LD50 in mice (mg/kg): >5000 orally; >1500 i.p. (Shetty, 1967)
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P362Take off contaminated clothing and wash before reuse.

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N-Bromosuccinimide Price

Sigma-Aldrich
Product number
M1195
Product name
Metolazone
Purity
≥98% (HPLC), solid
Packaging
5mg
Price
$163
Updated
2024/03/01
Sigma-Aldrich
Product number
1441200
Product name
Metolazone
Purity
United States Pharmacopeia (USP) Reference Standard
Packaging
200mg
Price
$261.6
Updated
2024/03/01
Alfa Aesar
Product number
H37934
Product name
Metolazone
Purity
97%
Packaging
5g
Price
$270
Updated
2021/12/16
Alfa Aesar
Product number
H37934
Product name
Metolazone
Purity
97%
Packaging
1g
Price
$95
Updated
2021/12/16
Cayman Chemical
Product number
15987
Product name
Metolazone
Purity
≥98%
Packaging
10mg
Price
$32
Updated
2024/03/01
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Metolazone Chemical Properties,Usage,Production

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 insufficiency and 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: To a well-stirred mixture of 1,270 g (9 mols) of 5-chloro-2-methylaniline in 7.5 liters of water at 34°C was added all at once 1,710 ml (18 mols) of acetic anhydride. A solution was obtained and then almost immediately the product started to crystallize. The temperature rose to 60°C. The mixture was stirred until the temperature dropped to 30°C. The product was filtered and washed well with water. Yield 97% (1,640 g), MP 134° to 138°C. Product was air dried and 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 and thermometer 540 ml of chlorosulfonic acid were placed and cooled in an ice bath to 20°C. 300 g of the acetanilide were added portionwise while stirring and maintaining temperature at 20°C. This addition takes approximately 20 minutes. Remove the ice bath and add 88 g of sodium chloride portionwise (approximately 1 tsp every 10 minutes), This addition takes approximately 1 hour. Some foaming takes place. Using heating mantle bring temperature up slowly (approximately ? hour) to 75°C. Considerable foaming takes place and heating is continued another ? hour until 92°C is reached. Foaming can be controlled by shutting off heat and with good stirring. Once the temperature of 92°C has been reached and foaming has subsided reaction can be left unattended. 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 stir the ice mixture. What remains in the flask can be worked up by adding ice to it and swirling the contents. After approximately 3/4 of an hour, the solid is filtered and washed with approximately 600 ml water.
Break up cake into small pieces and add to 2.5 liters concentrated NH4OH in 4 liter beaker. Stir. Solid goes into solution and then the sulfonamide precipitates out. Heat to 50°C and then turn off heat. After ? hour cool in ice bath 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. While cooling filtrate add concentrated HCl until mixture is acid. Filter and wash cake until filtrate is neutral. Suck cake as dry as possible then air dry. Yield approximately 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) of magnesium sulfate (Epsom salts) in 2.8 liters of water was added 130 g (0.495 mol) of powdered 5-chloro-2-methyl-4-sulfamylacetanilide. With stirring and maintaining the temperature at 83°C, 234 g (1.482 mols) of potassium permanganate was added portionwise over a period of 2 hours. The mixture 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 carbonate monohydrate was added. The warm reaction mixture was filtered and the cake washed with water. The filtrate was then slowly treated with concentrated hydrochloric acid until mixture tested acid. Product was then filtered, washed with 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 a stirrer, 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 period of 15 minutes, 21.7 ml (34.1 g) (0.248 mol) of phosphorus trichloride. The mixture was then refluxed for 10 hours. The solid turned somewhat gummy towards the latter part of the first hour. The mixture then became more free flowing as heating was continued. Let stand overnight. The yellow solid was filtered, 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 yielded 11.5 g of the starting acid. The damp product was dissolved in 4.5 liters of 95% ethanol and the solution treated with charcoal and filtered. On cooling filtrate 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 was added 5.34 g (0.04 mol) of aluminum chloride, while stirring. To the resulting solution 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 sodium borohydride in 1 liter of dry diglyme was added portionwise over a period of 1 hour while stirring the mixture. The mixture was then heated at 85°C, with stirring, for 1 hour.
After cooling the reaction mixture to 25°C in an ice bath 600 ml of water was added and then enough dilute hydrochloric acid (approximately 100 ml) to make the solution acid. The solvent was then removed under reduced pressure at 60° to 70°C. The very viscid residue solidified when triturated with water. The solid was filtered and washed with water. The solid was dissolved in approximately 400 ml 95% ethanol and the solution filtered through 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, MP 253° to 259°C.
The above product was then recrystallized from 900 ml of 95% ethanol after filtering the hot solution through Celite. Crystallization was initiated and the mixture agitated occasionally while being cooled in the refrigerator. Yield of product 29 g, MP 253° to 259°C. Concentration of the filtrate to 125 ml yielded another 7.5 g of product, MP 253° to 259°C. The product was recrystallized another time in the manner described above. Total yield, first and second crops, 28.8 g (66%), MP 250° to 255°C. Product was dried at 80°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 group is acylated by ethyl chloroformate, forming 5-chloro-N-ethoxycarbonyl-2-methylaniline (21.3.15). The product, upon subsequent reaction with chlorosulfonic acid and ammonia, is transformed 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 treating this with thionyl chloride it cycles into the corresponding anhydride (21.3.18). This reacts with o-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

Ito et al. (2021), Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans; Biogerontology, 22 119 Beaumont et al. (1988), Thiazide diuretic drug receptors in rat kidney: identification with [3H] metolazone; Proc. Natl. Acad. Sci. USA, 85 2311 Moreno et al. (2006), Affinity-defining domains in the Na-Cl cotransporter: a different location for Cl- and thiazide binding; J. Biol. Chem., 281 17266 Temperini et al. (2008), Carbonic anhydrase inhibitors. Interaction of indapamide and related diuretics with 12 mammalian isozymes and X-ray crystallographic studies for the indapamide-isozyme II adduct; Bioorg. Med. Chem. Lett., 18 2567

Metolazone Preparation Products And Raw materials

Raw materials

Preparation Products

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Metolazone Suppliers

Energy Chemical
Tel
021-021-58432009 400-005-6266
Fax
021-58436166
Email
sales8178@energy-chemical.com
Country
China
ProdList
44751
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61
Jia Xing Isenchem Co.,Ltd
Tel
0573-85285100 18627885956
Fax
0573-85285100
Email
isenchem@163.com
Country
China
ProdList
9555
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66
Pure Chemistry Scientific Inc.
Tel
001-857-928-2050 or 1-888-588-9418
Fax
001-617-206-9595
Email
sales@chemreagents.com
Country
United States
ProdList
10194
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62
Chemsky(shanghai)International Co.,Ltd.
Tel
021-50135380
Email
shchemsky@sina.com
Country
China
ProdList
32344
Advantage
50
Sinopharm Chemical Reagent Co,Ltd.
Tel
86-21-63210123
Fax
86-21-63290778 86-21-63218885
Email
sj_scrc@sinopharm.com
Country
China
ProdList
9823
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79
Suzhou Sibian Chemical Technology Co.,Ltd.
Tel
0512-65617459 18915409046
Fax
0512-65617459
Email
sales@sibian-chem.com
Country
China
ProdList
1927
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55
Beijing HuaMeiHuLiBiological Chemical
Tel
010-56205725
Fax
010-65763397
Email
waley188@sohu.com
Country
China
ProdList
12338
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Haoyuan Chemexpress Co., Ltd.
Tel
021-58950125
Fax
(86) 21-58955996
Email
info@chemexpress.com
Country
China
ProdList
7553
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61
Shanghai Aladdin Bio-Chem Technology Co.,LTD
Tel
400-6206333 18521732826;
Fax
021-50323701
Email
market@aladdin-e.com
Country
China
ProdList
24835
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MedChemexpress LLC
Tel
021-58955995
Fax
609-228-5909
Email
sales@medchemexpress.cn
Country
United States
ProdList
4863
Advantage
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View Lastest Price from Metolazone manufacturers

Zhuozhou Wenxi import and Export Co., Ltd
Product
Metolazone 17560-51-9
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-10
Zhuozhou Wenxi import and Export Co., Ltd
Product
Metolazone 17560-51-9
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-08
Career Henan Chemical Co
Product
Metolazone 17560-51-9
Price
US $1.00/KG
Min. Order
1KG
Purity
98% HPLC
Supply Ability
10 tons/month
Release date
2020-01-08

17560-51-9, MetolazoneRelated Search:


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