64-77-7 Usage
Chemical Properties
White or almost white, crystalline powder.
Originator
Dolipol,Hoechst,France,1956
Uses
Different sources of media describe the Uses of 64-77-7 differently. You can refer to the following data:
1. It is used for type II diabetes mellitus of medium severity with no
expressed microvascular complications.
2. Tolbutamide, have been used in a cDNA microarray assay to probe changes in gene expression in HepG2 cells upon their administration. It has been utilized to counteract insulin activity in a patch-clamp investigation of ATP sensitive K+ channels in mouse pancreatic β-cells. The activity of various biotransformation enzymes in cultured primary rat proximal tubular cells in the presence of tolbutamide and other compounds has been studied.
3. An antidiabetic, used as a hypoglycemic agent in veterinary medicine.
Definition
ChEBI: An N-sulfonylurea that consists of 1-butylurea having a tosyl group attached at the 3-position.
Manufacturing Process
50 grams of n-butyl isocyanate are stirred at room temperature into a
suspension of 96 grams of sodium 4-methyl-benzenesulfonamide in 120 cc of
dry nitrobenzene and the whole is then heated for 7 hours at 100°C. After
being cooled, the reaction mixture, which is a thick magma, is diluted with
methylene chloride or ethyl acetate and the sodium salt of the sulfonylurea
formed is separated by centrifuging. The centrifuged crystalline residue freed
from organic solvents is dissolved in 500 to 600 cc of water heated at 50°C
and decolorized with animal charcoal.
The precipitate obtained by acidification with dilute hydrochloric acid is
dissolved in an equivalent quantity of dilute ammonia solution (about 1:20),
again treated with animal charcoal and reprecipitated with dilute hydrochloric
acid. In this manner N-4-methylbenzenesulfonyl-N'-n-butyl-urea is obtained in
analytically pure form in a yield of 70 to 80% of theory. It melts at 125° to
127°C (with decomposition).
Therapeutic Function
Oral hypoglycemic
General Description
Different sources of media describe the General Description of 64-77-7 differently. You can refer to the following data:
1. Tolbutamide is N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide;or 1-butyl-3-(p-tolylsulfonyl)urea (Orinase,generic). Orinase Diagnostic was the sodium salt, which isfreely soluble in water for injection, but this product was discontinuedc. 2000.
2. Tolbutamide, 1-butyl-3-(p-tolylsulfonyl)urea (Orinase), occurs as a white, crystalline powderthat is insoluble in water and soluble in alcohol or aqueousalkali. It is stable in air.Tolbutamide is absorbed rapidly in responsive diabetic patients.The blood sugar level reaches a minimum after 5 to8 hours. It is oxidized rapidly in vivo to 1-butyl-3-(p-carboxyphenyl)sulfonylurea, which is inactive. The metabolite isfreely soluble at urinary pH; if the urine is strongly acidified,however, as in the use of sulfosalicylic acid as a protein precipitant,a white precipitate of the free acid may be formed.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
TOLBUTAMIDE is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). TOLBUTAMIDE is incompatible with acids. .
Fire Hazard
Flash point data for TOLBUTAMIDE are not available. TOLBUTAMIDE is probably combustible.
Biological Activity
tolbutamide is a potent inhibitor of camp with an ic50 value of 4mm [1].tolbutamide has been reported to inhibit both the basal and the cyclic amp-stimulated protein kinase activites with an ic50 value of 4mm for cyclic amp-dependent kinase activity. in addition, tolbutamide has been revealed to inhibit both soluble and membrane-bound protein kinase from canine heart. moreover, the tolbutamide inhibition of adipose tissue cyclic amp- dependent protein kinase is explanation for antilipolytic effects [1]. besides, tolbutamide and dbcamp has been exhibited to increase about four-fold levels of cx43 mrna and decrease about 80% the expression of ki-67 [2].
Mechanism of action
Tolbutamide is one of the most widely used antidiabetic agents. Its action is preferably
connected with stimulatory action of β-cells in the pancreas, which results in intensive
insulin secretion.
Clinical Use
Tolbutamide should be used only when the diabetic patientis an adult or shows adult-onset diabetes, and the patientshould adhere to dietary restrictions.
Safety Profile
Moderately toxic by
ingestion and several other routes. A human
teratogen. Human reproductive effects by
ingestion and possibly other routes:
stillbirth, developmental abnormalities of
the cardlovascular (circulatory) system and
urogenital system, and unspecified neonatal
effects. Human systemic effects by
ingestion: nausea or vomiting, hypoglycemia.
Other experimental teratogenic and
reproductive effects. Mutation data
reported. Implicated in aplastic anemia.
When heated to decomposition it emits very
toxic fumes of NO, and SOx.
Synthesis
Tolbutamide, 1-butyl-3-p-toluenesulfonylurea (26.2.2), is made in a single step
reaction by interaction of p-toluenesulfonylamide (in the form of sodium salt) with butylisocyanate.
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: effects enhanced by NSAIDs - avoid
with azapropazone.
Antibacterials: effects enhanced by chloramphenicol,
sulphonamides, tetracyclines and trimethoprim;
effect reduced by rifamycins.
Anticoagulants: effect possibly enhanced by
coumarins; also possibly changes to INR.
Antifungals: concentration increased by fluconazole
and miconazole, and possibly voriconazole.
Lipid-regulating drugs: possibly additive
hypoglycaemic effect with fibrates.
Sulfinpyrazone: enhanced effect of sulphonylureas.
Metabolism
Tolbutamide is metabolised in the liver by hydroxylation mediated by the cytochrome P450 isoenzyme CYP2C9. It is excreted in the urine chiefly as inactive metabolites.
references
[1] wray hl, harris aw. adenosine 3', 5'-monophosphate-dependent protein kinase in adipose tissue: inhibition by tolbutamide. biochem biophys res commun. 1973 jul 2;53(1):291-4.[2] sánchez-alvarez r1, paíno t, herrero-gonzález s, medina jm, tabernero a. tolbutamide reduces glioma cell proliferation by increasing connexin43, which promotes the up-regulation of p21 and p27 and subsequent changes in retinoblastoma phosphorylation. glia. 2006 aug 1;54(2):125-34.
Check Digit Verification of cas no
The CAS Registry Mumber 64-77-7 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 4 respectively; the second part has 2 digits, 7 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 64-77:
(4*6)+(3*4)+(2*7)+(1*7)=57
57 % 10 = 7
So 64-77-7 is a valid CAS Registry Number.
InChI:InChI=1/C12H18N2O3S/c1-3-4-9-13-12(15)14-18(16,17)11-7-5-10(2)6-8-11/h5-8H,3-4,9H2,1-2H3,(H2,13,14,15)
64-77-7Relevant articles and documents
Rapid Multigram-Scale End-to-End Continuous-Flow Synthesis of Sulfonylurea Antidiabetes Drugs: Gliclazide, Chlorpropamide, and Tolbutamide
Sagandira, Cloudius R.,Watts, Paul
supporting information, (2021/12/02)
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.
Product-Derived Bimetallic Palladium Complex Catalyzes Direct Carbonylation of Sulfonylazides
Zhao, Jin,Li, Zongyang,Song, Shaole,Wang, Ming-An,Fu, Bin,Zhang, Zhenhua
supporting information, p. 5545 - 5549 (2016/05/09)
A novel product-derived bimetallic palladium complex catalyzes a sulfonylazide-transfer reaction with the σ-donor/π-acceptor ligand CO, and is advantageous given its broad substrate scope, high efficiency, and mild reaction conditions (atmospheric pressure of CO at room temperature). This methodology provides a new approach to sulfonylureas, which are present in both pharmaceuticals and agrochemicals. The synthesis of Glibenclamide on a gram scale further revealed the practical utility of this procedure. Mechanistically, the generation of a bridged bimetallic palladium species derived from the product sulfonylurea is disclosed as the crucial step for this catalytic cycle.
Facile one-pot synthesis of carbamoylbenzotriazoles directly from CO Synthesis of tolbutamide
Hunter, Roger,Msutu, Athenkosi,Dwyer, Cathy L.,Emslie, Neville D.,Hunt, Raymond C.,Bezuidenhoudt, Barend C. B.
supporting information; experimental part, p. 2335 - 2338 (2011/11/01)
COgas trapped with a primary or secondary amine as a carbamate salt in the presence of DBU reacts with triphenylphosphine and 1-chlorobenzotriazole (BtCl) to form a carbamoylbenzotriazole urea, which reacts with para-toluenesulfonamide under solvent-free conditions to produce N-sulfonyl ureas such as tolbutamide. Georg Thieme Verlag Stuttgart - New York.
