Labetalol

Labetalol Basic information
Use advice
Product Name:Labetalol
Synonyms:5-[1-HYDROXY-2-[(1-METHYL-3-PHENYLPROPYLAMINO)ETHYL]]SALICYLAMIDE;LABETALOL;LABETOLOL;5-[1-hydroxy-2-[(1-methyl-3-phenylpropylamino)ethyl]saicylamide;Labetalol (base and/or unspecified salts);SeH-15719W;2-hydroxy-5-[(1S)-1-hydroxy-2-{[(2R)-4-phenylbutan-2-yl]aMino}ethyl]benzaMide;Laβlol
CAS:36894-69-6
MF:C19H24N2O3
MW:328.41
EINECS:253-258-3
Product Categories:API's
Mol File:36894-69-6.mol
Labetalol Structure
Labetalol Chemical Properties
Melting point 188 °C
Boiling point 552.7±50.0 °C(Predicted)
density 1.200±0.06 g/cm3(Predicted)
storage temp. Store at -20°C
solubility DMSO : 125 mg/mL (380.62 mM; Need ultrasonic)
pkapKa 7.41 ± 0.01;9.36± 0.01(H2O,t =25,I=0.15(KCl),Ar)(Approximate)
form Solid
color White to Pale Orange
Stability:Hygroscopic
CAS DataBase Reference36894-69-6(CAS DataBase Reference)
NIST Chemistry ReferenceBenzamide, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]-(36894-69-6)
Safety Information
Hazardous Substances Data36894-69-6(Hazardous Substances Data)
MSDS Information
Labetalol Usage And Synthesis
Use adviceLabetalol is a competitive α1- and β-antagonist which is more active at β- than at α-receptors (1 : 3–1 : 7, depending on route). It may be administered orally or i.v. Intravenous bolus doses range from 50–200mg, with infusion rates between 5–150mgh –1, titrated to effect.
DescriptionLabetalol is an α-adrenergic and α-1 blocking agent which caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.
OriginatorTrandate,Allen and Hanburys,UK,1977
UsesLabetalol is used to treat essential hypertension.
UsesAnti-adrenergic (α-receptor); anti-adrenergic (β-receptor).
DefinitionChEBI: A secondary amino compound formally derived from ammonia by replacing two of the hydrogens by 2-(3-carbamoyl-4-hydroxyphenyl)-2-hydroxyethyl and 4-phenylbutan-2-yl groups. It is an adrenergic antagonist used to treat high blood pressure.
Manufacturing Process(a) 5-Bromoacetylsalicylamide (2.6 g), N-benzyl-N-(1-methyl-3-phenylpropyl) amine (4.8 g) and methyl ethyl ketone (50 ml) were heated at reflux for 40 minutes. The solvent was removed and the residue was treated with benzene. The secondary amine hydrobromide was filtered off and discarded, and the filtrate was evaporated to dryness. The residue was treated with an excess of ethanolic hydrogen chloride when 5-[N-benzyl-N-(1-methyl-3-phenylpropyl)- glycyl]-salicylamide hydrochloride (1.15 g) crystallized out, MP 139°C to 141°C.
(b) 5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]-salicylamide hydrochloride (0.75 g), 10% mixture of PdO and PtO on carbon catalyst (0.1 g) and ethanol (20 ml) were shaken at room temperature and pressure with hydrogen until uptake ceased. The catalyst was filtered off and the filtrate evaporated to dryness. The residue was crystallized from ethanol to give 5-[1- hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl]salicylamide hydrochloride as a white solid (0.40 g), MP 188°C.
Brand nameNormodyne (Schering); Trandate (Promethus).
Therapeutic FunctionAlpha-adrenergic blocker, Beta-adrenergic blocker
Biological FunctionsLabetalol (Normodyne, Trandate) possesses both - blocking and β-blocking activity and is approximately one-third as potent as propranolol as a -blocker and one-tenth as potent as phentolamine as an -blocker. The ratio of β- to α-activity is about 3:1 when labetalol is administered orally and about 7: 1 when it is administered intravenously. Thus the drug can be most conveniently thought of as a β -blocker with some -blocking properties.
General DescriptionLabetalol is a phenylethanolamine derivative, is representative of a classof drugs that act as competitive blockers at α1-, β1-, andβ2-receptors. It is a more potent β-blocker than α-blocker.Because it has two asymmetric carbon atoms (1 and 1' ), it existsas a mixture of four isomers. It is this mixture that is usedclinically in treating hypertension. The different isomers,however, possess different α- and β-blocking activities. The -blocking activity resides solely in the (1R,1 'R) isomer,whereas the 1-blocking activity is seen in the (1S,1 R) and(1S,1'S) isomers, with the (1S,1'R) isomer possessing thegreater therapeutic activity.
Contact allergensThis beta-adrenergic and alpha-1 blocking agent caused contact dermatitis and a contact anaphylactoid reaction during patch testing in a nurse.
Mechanism of actionLabetalol produces equilibrium-competitive antagonism at β-receptors but does not exhibit selectivity for β1- or β2-receptors. Like certain other β-blockers (e.g., pindolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial agonism, especially at β2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other β-blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic.
Labetalol appears to produce relaxation of vascular smooth muscle not only by α-blockade but also by a partial agonist effect at β2-receptors. In addition, labetalol may produce vascular relaxation by a direct non–receptor-mediated effect. Labetalol can block the neuronal uptake of norepinephrine and other catecholamines. This action, plus its slight intrinsic activity at α-receptors, may account for the seemingly paradoxical, although infrequent, increase in blood pressure seen on its initial administration.
PharmacokineticsLabetalol is almost completely absorbed from the gastrointestinal tract. However, it is subject to considerable first-pass metabolism, which occurs in both the gastrointestinal tract and the liver, so that only about 25% of an administered dose reaches the systemic circulation. While traces of unchanged labetalol are recovered in the urine, most of the drug is metabolized to inactive glucuronide conjugates.The plasma half-life of labetalol is 6 to 8 hours, and the elimination kinetics are essentially unchanged in patients with impaired renal failure.
Clinical UseLabetalol is a clinically usefulantihypertensive agent. The rationale for its use in themanagement of hypertension is that its α-receptor–blockingeffects produce vasodilation and its β-receptor–blockingeffects prevent the reflex tachycardia usually associated withvasodilation. Although labetalol is very well absorbed, it undergoesextensive first-pass metabolism.
Side effectsThere have been reports of excessive hypotension and paradoxical pressor effects following intravenous administration of labetalol. These latter effects may be due to a labetalol-induced blockade of neuronal amine uptake, which increases the concentrations of norepinephrine in the vicinity of its receptors.
Approximately 5% of the patients who receive labetalol complain of side effects typical of noradrenergic nervous system suppression. These include postural hypotension, gastrointestinal distress, tiredness, sexual dysfunction, and tingling of the scalp. Most of these effects are related to α-blockade, although the tingling of the scalp may be due to the drug’s intrinsic activity at α-receptors. Side effects associated with β-blockade, such as induction of bronchospasm and congestive heart failure, may also occur, but generally at a lower frequency than -receptor–associated effects.
Skin rashes have been reported, as has an increase in the titer of antinuclear antibodies. Despite the latter observation, the appearance of a systemic lupus syndrome is rare. Labetalol also has been reported to interfere with chemical measurements of catecholamines and metabolites.

SynthesisLabetalol, 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropanol)amino)] ethyl] benzamide (12.1.12) is synthesized by the N-alkylation of N-benzyl-N(4-phenyl-2- butyl)amine 5-bromacetylsalicylamide and forming aminoketone (12.1.11), which is further debenzylated by hydrogen using a palladium¨Cplatinum on carbon catalyst into labetalol (12.1.12) [28¨C30].

Synthesis_36894-69-6

Labetalol Preparation Products And Raw materials
Raw materialsN,N-Dimethylformamide-->Potassium borohydride-->Salicylamide-->Hydrogen-->5-Bromoacetyl salicylamide
2-hydroxy-5-[[N-(1-methyl-3-phenylpropyl)amino]acetyl]benzamide hcl (intermediate of labetalol hcl) Chlorantraniliprole 5-[2-[[3-(1,3-benzodioxol-5-yl)-1-methylpropyl]amino]-1-hydroxyethyl]salicylamide Methyl p-(2-Methoxyethyl) phenol Labetalol Hydrochloride Injection USP N,N-DIBENZYL GLYCYL SALICYLAMIDE ( FOR LABETALOL) 3-Diethylaminophenol LABETALOL HCL USP(CRM STANDARD) Basic Violet 1 LABETALOL HYDROCHLORIDE EPL(CRM STANDARD) Kresoxim-methyl Labetalone hydrochloride LABETALOL HYDROCHLORIDE MM(CRM STANDARD) 5-bromoacetylsalicylamide (intermediate of labetalol) 5-(n,n-dibenzylamineacetyl) salicylamide (intermediate of labetalol) Labetalol Hydrochoride,LABETALOL HCL,LABETALOL HYDROCHLORIDE,Labetalol Hydrochloride(USP28/EP5/BP2003) CHLOROPHOSPHONAZO III

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