94-20-2

Basic information

• Product Name: CHLORPROPAMIDE
• Synonyms: Chloropropamide USP;CHLORPROPAMIDE USP;1-(p-chlorobenzenesulfonyl)-3-propylure;CHLORPROPRAMIDE;4-chloro-N-(propylcarbamoyl)benzenesulfonamide;Chlorpropamide (200 mg);ChlorproMaMide;1-(4-Chlorophenylsulfonyl)-3-propylurea , 99.0%(T)
• CAS NO: 94-20-2
• Molecular Formula: C₁₀H₁₃ClN₂O₃S
• Molecular Weight: 276.74
• EINECS: 202-314-5
• Product Categories: Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;DIABINESE
• Mol File: 94-20-2.mol
• Article Data: 6

Chemical Properties

• Melting Point: 128 °C
• Boiling Point: 302°C (rough estimate)
• Appearance: white crystalline powder
• Density: 1.3046 (rough estimate)
• Refractive Index: 1.6300 (estimate)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Sparingly), Methanol (Slightly)
• PKA: pKa 4.8 (Uncertain)
• Water Solubility: Soluble in ethanol (1:12), acetone (1:5), chloroform (1:9) and solutions of alkali hydroxides. Does not mix well with water.
• Stability: Stable. Combustible.
• Merck: 14,2186
• CAS DataBase Reference: CHLORPROPAMIDE(CAS DataBase Reference)
• NIST Chemistry Reference: CHLORPROPAMIDE(94-20-2)
• EPA Substance Registry System: CHLORPROPAMIDE(94-20-2)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-40
• Safety Statements: 22-36
• WGK Germany: 3
• RTECS: YS6650000
• Hazardous Substances Data: 94-20-2(Hazardous Substances Data)

Usage

Chemical Properties

white crystalline powder

Originator

Diabinese ,Pfizer, US,1958

Uses

Different sources of media describe the Uses of 94-20-2 differently. You can refer to the following data:
1. Chlorpropamide is a sulfonylurea derivative. Chlorpropamide is a long acting hyopglycemic agent. Chlorpropamide is used in the treatment of diabetes metilus type 2. Chlorpropamide acts to increase the secretion of insulin and is not effective in patients who do not have pancreatic beta cell function.
2. For treatment of NIDDM in conjunction with diet and exercise.

Definition

ChEBI: An N-sulfonylurea that is urea in which a hydrogen attached to one of the nitrogens is substituted by 4-chlorobenzenesulfonyl group and a hydrogen attached to the other nitrogen is substituted by propyl group. Chlorpropamide is a hypogly aemic agent used in the treatment of type 2 (non-insulin-dependent) diabetes mellitus not responding to dietary modification.

Manufacturing Process

A solution of 54 g (0.64 mol) of propyl isocyanate in 60 ml of anhydrousdimethylformamide was added to a cold, well-stirred suspension of 81 g (0.42 mol) of dry p-chlorobenzenesulfonamide in 210 ml of anhydrous triethylamine during the course of 20 to 30 minutes. The mildly exothermic reaction was completed by allowing it to stand at room temperature for about 5 hours. The reaction mixture was then slowly added to 3 liters of cold 20% acetic acid during the course of about one hour, constant agitation being maintained throughout the addition. After the addition was complete, the desired product, which had crystallized out, was filtered and washed well with about 2 liters of cold water. The crude material was then dissolved in 1 liter of cold 5% sodium carbonate and the resulting solution was immediately filtered from an insoluble gum. The product was then reprecipitated, by slowly adding the filtrate to 3 liters of 20% acetic acid. The precipitate, which is very nearly pure N-(p-chlorobenzenesulfonyl)- N'-propylurea, was then dried and subsequently recrystallized from about 800 ml of benzene to give a 59% yield of pure product, MP 129.2 to 129.8°C.

Brand name

Diabinese (Pfizer); Glucamide (Teva).

General Description

Different sources of media describe the General Description of 94-20-2 differently. You can refer to the following data:
1. Chlorpropamide is 4-chloro-N-[(propylamino)carbonyl]benzenesulfonamide; or 1-[(p-chlorophenyl)sulfonyl]-3-propylurea; or 1-(p-chlorobenzenesulfonyl)-3-propylurea(Diabinese, generic). The p-chlorophenyl moiety is quite resistantto P450-mediated hydroxylations; hence, blood levelsof the drug are sustained for a markedly long length of time,as aliphatic hydroxylation constitutes most of the clearance,and this happens relatively slowly. Although the -hydroxyland (ω–1)-hydroxyl metabolites (the latter formed in muchgreater portion) exert hypoglycemic potencies not much lessthan does the parent drug, elimination of these by conversion to the corresponding glucuronides occurs more rapidly thanhydroxylation of chlorpropamide, so blood levels of thesemetabolites remain low, and thus they probably do not makean appreciable contribution to the hypoglycemic action ofthis drug in clinical application. Removal of the entire propylside chain (oxidative N-dealkylation) also occurs to a significantextent (up to 20% of an orally administered dose), creatingthe inactive metabolite p-chlorobenzenesulfonylurea,about 10% of which degrades to the corresponding benzenesulfonamide.
2. Chlorpropamide, 1-[(p-chlorophenyl)-sulfonyl]-3-propylurea (Diabinese), is a white, crys-talline powder, practically insoluble in water, soluble in alcohol,and sparingly soluble in chloroform. It will form watersolublesalts in basic solutions. This drug is more resistant toconversion to inactive metabolites than is tolbutamide and, asa result, has a much longer duration of action. One studyshowed that about half of the drug is excreted as metabolites,with the principal one being hydroxylated in the 2-position ofthe propyl side chain.After control of the blood sugar level,the maintenance dose is usually on a once-a-day schedule.
3. White crystalline powder with a slight odor.

Air & Water Reactions

Insoluble in water.

Fire Hazard

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

Veterinary Drugs and Treatments

While chlorpropamide could potentially be of benefit in the adjunctive treatment of diabetes mellitus in small animals, its use has been primarily for adjunctive therapy in diabetes insipidus in dogs and cats.

Purification Methods

Crystallise the urea from aqueous EtOH. [Beilstein 11 IV 119.]

InChI:InChI=1/C10H13ClN2O3S/c1-2-7-12-10(14)13-17(15,16)9-5-3-8(11)4-6-9/h3-6H,2,7H2,1H3,(H2,12,13,14)

Synthetic route

Propyl isocyanate (110-78-1) + 4-Chlorobenzenesulfonamide (98-64-6) → chlorpropamide (94-20-2)

Conditions	Yield
With copper(l) chloride In nitromethane at 20℃; for 2h; Milling;	92%
With boron trifluoride diethyl etherate In diethyl ether Ambient temperature;	67%

4-Chlorobenzenesulfonamide (98-64-6) + phenyl N-(n-propyl)carbamate (14549-38-3) → chlorpropamide (94-20-2)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile Reflux; Green chemistry;	85%

4-Chlorobenzenesulfonamide (98-64-6) + S-Methyl N-propyl(thiocarbamate) (39078-44-9) → chlorpropamide (94-20-2)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 110℃; for 4h; Substitution;	75%

2-chlorobenzene sulphonamide + (2-hydroxy-ethyl)-carbamic acid propyl ester (6948-23-8) → chlorpropamide (94-20-2)

Conditions	Yield
In water; N,N-dimethyl-formamide	46%

[1,3]-dioxolan-2-one (96-49-1) + 4-Chlorobenzenesulfonamide (98-64-6) → chlorpropamide (94-20-2)

Conditions	Yield
With propylamine In water; N,N-dimethyl-formamide

chlorpropamide (94-20-2) → C10H12(2)HClN2O3S

Conditions	Yield
With Kerr's catalyst; deuterium In chlorobenzene at 120℃; for 1h; Reagent/catalyst; Temperature;	96%

chlorpropamide (94-20-2) + trifluoroacetic anhydride (407-25-0) → 4-Chloro-N-(2,2,2-trifluoro-acetyl)-benzenesulfonamide (98922-57-7)

Conditions	Yield
In chloroform for 1.5h;	94%

chlorpropamide (94-20-2) + acetic anhydride (108-24-7) → n-propylacetamide (5331-48-6) + N-((4-chlorophenyl)sulfonyl)acetamide (55379-05-0)

Conditions	Yield
With pyridine for 0.0833333h;	A 27% B 83%

chlorpropamide (94-20-2) → N,N'-Bis-(4-chlorphenylsulfonyl)-N''-n-propylguanidin

Conditions	Yield
With pyridine; p-toluenesulfonyl chloride Heating;	81%

chlorpropamide (94-20-2) + mercury(II) diacetate (1600-27-7) → mercury bis{N-((propylamino)carbonyl)-4-chlorobenzenesulfonamide}

Conditions	Yield
With KOH In ethanol byproducts: CH3COO(1-), H2O; addn. of suspension of Hg(CH3CO2)2 in ethanol to soln. of ligand and KOH, mixt.stirred for 20 min; pptn. on cooling to -10°C, filtered, washed (EtOH, Et2O), dried in vac., elem. anal.;	70%

chlorpropamide (94-20-2) + cadmium(II) acetate (543-90-8) → potassium tris{N-((propylamino)carbonyl)-4-chlorobenzenesulfonamido}cadmate

Conditions	Yield
With KOH In ethanol byproducts: CH3COOK, H2O; addn. of suspension of Cd(CH3CO2)2 in EtOH to ligand and KOH in EtOH, mixt. stirred for 3h, pptn.; concd., cooled to -10°C, crystn., filtered, washed (EtOH, Et2O), dried in vac., elem. anal.;	60%

chlorpropamide (94-20-2) + acetic anhydride (108-24-7) → N-((4-chlorophenyl)sulfonyl)acetamide (55379-05-0)

Conditions	Yield
With pyridine Ambient temperature;	54.8%

chlorpropamide (94-20-2) → 4-Chlorobenzenesulfonamide (98-64-6) + N,N'-Bis-propylcarbamoyl-biphenyl-disulfonamid-(4,4') (99996-79-9) + N-(p-chlorophenylsulfonyl)formamide (98273-82-6)

Conditions	Yield
In methanol at 20℃; for 8h; Irradiation;	A 13% B 53% C 34%
In methanol at 20℃; for 8h; Mechanism; Irradiation; in vitro phototoxicity;	A 13% B 53% C 34%

succinic acid anhydride (108-30-5) + chlorpropamide (94-20-2) → N-4-Chlorphenylsulfonyl-N'-n-propyl-bernsteinsaeurediamid

Conditions	Yield
With pyridine; dmap	52%

chlorpropamide (94-20-2) + silver nitrate → potassium bis{N-((propylamino)carbonyl)-4-chlorobenzenesulfonamido}argentate

Conditions	Yield
With KOH In ethanol; water addn. of EtOH/H2O (80:20) soln. of AgNO3 to soln. of ligand and KOH in EtOH, mixt. stirred for 30 min, pptn.; concd., cooled to 0°C, pptn., filtered, washed (EtOH/H2O and ether), dried in vac., elem. anal.;	45%

chlorpropamide (94-20-2) + acetic anhydride (108-24-7) → N-acetyl-N-ethyl-4-chlorobenzenesulfonamide

Conditions	Yield
With triethylamine at 130℃; for 20h;	40%

chlorpropamide (94-20-2) + diisopropyl-carbodiimide (693-13-0) → N-(bis(isopropylamino)methylene)-4-chlorobenzenesulfonamide

Conditions	Yield
With pyridine Heating;	35%

chlorpropamide (94-20-2) → n-propylurea (627-06-5) + 4-chloromethoxybenzene (623-12-1) + 4,4'-dichlorobiphenyl (2050-68-2) + chlorobenzene (108-90-7) + 4'-biphenyl chloride (2051-62-9) + benzene (71-43-2)

Conditions	Yield
In methanol for 76h; Product distribution; Mechanism; Irradiation; λ=254 nm;	A 21.8% B n/a C 3.1% D 32.8% E n/a F n/a

chlorpropamide (94-20-2) + 3-methyl-4-nitro-1-(trifluoromethoxy)-6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-3-ium trifluoromethanesulfonate → 4-chloro-N-(propylcarbamoyl)-3-(trifluoromethoxy)benzenesulfonamide

Conditions	Yield
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate In acetonitrile at 23℃; for 16h; Sealed tube; Irradiation; regioselective reaction;	27%
With tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate In acetonitrile at 23℃; for 16h; Glovebox; Irradiation; Sealed tube; Inert atmosphere;	27%

chlorpropamide (94-20-2) + dicyclohexyl-carbodiimide (538-75-0) → N-(bis(cyclohexylamino)methylene)-4-chlorobenzenesulfonamide

Conditions	Yield
With pyridine Heating;	24%

chlorpropamide (94-20-2) → Propyl isocyanate (110-78-1)

Conditions	Yield
With COCl2 In chlorobenzene at 130℃;

chlorpropamide (94-20-2) → 4-Chlorophenylsulfonyl isocyanate (5769-15-3)

Conditions	Yield
With COCl2 In chlorobenzene at 130℃;

chlorpropamide (94-20-2) + allyl bromide (106-95-6) → 1-(3-propenyl)-1-[(4-chlorophenyl)sulfonyl]-3-n-propylurea

Conditions	Yield
With sodium hydride 1.) dimethylacetamide, 20 min, 2.) dimethylacetamide, 20 h; Yield given. Multistep reaction;

Upstream product

• 6948-23-8 (2-hydroxy-ethyl)-carbamic acid propyl ester 
• 107-10-8 propylamine 
• 98-64-6 4-Chlorobenzenesulfonamide 
• 1885-14-9 phenyl chloroformate 
• 14549-38-3 phenyl N-(n-propyl)carbamate 
• 96-49-1 [1,3]-dioxolan-2-one 
• 39078-44-9 S-Methyl N-propyl(thiocarbamate) 
• 110-78-1 Propyl isocyanate 

Downstream Products

• 98-64-6 4-Chlorobenzenesulfonamide 
• 99996-79-9 N,N'-Bis-propylcarbamoyl-biphenyl-disulfonamid-(4,4') 
• 98273-82-6 N-(p-chlorophenylsulfonyl)formamide 
• 98922-57-7 4-Chloro-N-(2,2,2-trifluoro-acetyl)-benzenesulfonamide 
• 55379-05-0 N-((4-chlorophenyl)sulfonyl)acetamide 
• 5331-48-6 n-propylacetamide 
• 627-06-5 n-propylurea 
• 623-12-1 4-chloromethoxybenzene 
• 2050-68-2 4,4'-dichlorobiphenyl 
• 108-90-7 chlorobenzene 
• 2051-62-9 4'-biphenyl chloride 
• 71-43-2 benzene 
• 5769-15-3 4-Chlorophenylsulfonyl isocyanate 

Relevant articles and documents

Rapid Multigram-Scale End-to-End Continuous-Flow Synthesis of Sulfonylurea Antidiabetes Drugs: Gliclazide, Chlorpropamide, and Tolbutamide

A multigram-scale robust, efficient, and safe end-to-end continuous-flow process for the diabetes sulfonylurea drugs gliclazide, chlorpropamide, and tolbutamide is reported. The drugs were prepared by the treatment of an amine with a haloformate affording carbamate, which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was obtained in 87% yield within 2.5 minutes total residence time with 26 g/h throughput; 0.2 kg of the drug was produced in 8 hours of running the system continuously. Chlorpropamide and tolbutamide were both obtained in 94% yield within 1 minute residence time with 184-188 g/h throughput; 1.4-1.5 kg of the drugs was produced in 8 hours of running the system continuously. N-Substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Mechanosynthesis of pharmaceutically relevant sulfonyl-(thio)ureas

We demonstrate the first application of mechanochemistry to conduct the synthesis of sulfonyl-(thio)ureas, including known anti-diabetic drugs tolbutamide, chlorpropamide and glibenclamide, in good to excellent isolated yields by either stoichiometric base-assisted or copper-catalysed coupling of sulfonamides and iso(thio)cyanates. the Partner Organisations 2014.

Lewis Acid Catalysed Preparation of some Carbamates and Sulphonylureas. Application to the Determination of Enantiomeric Purity of Chiral Alcohols

Lewis acids such as boron trifluoride-diethyl ether and aluminium chloride catalyze the reaction of alcohols and sulphonamides with isocyanates, affording carbamates and sulphonylureas, respectively, in acceptable yield.Applied to the formation of diastereoisomeric carbamates from chiral alcohols using Pirkle's reagents, , this technique provides a convenient method for determination of enantiomeric purity.