118457-14-0

Basic information

• Product Name: Nebivolol
• Synonyms: NEBIVOLOL;dl-Nebivolol;[2R*[R*[R*(S*)]]]-alpha,alpha'-[Iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol;Unii-030Y90569u;(1S)-1-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-[[(2S)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]amino]ethanol
• CAS NO: 118457-14-0
• Molecular Formula: C8H11NO4
• Molecular Weight: 185.178
• Product Categories: Nebivolol;Pharmaceuticals
• Mol File: 118457-14-0.mol
• Article Data: 25

Chemical Properties

• Boiling Point: 600.5°C at 760 mmHg
• Flash Point: 316.9°C
• Appearance: /
• Density: 1.309
• Vapor Pressure: 2.88E-15mmHg at 25°C
• Refractive Index: 1.58
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: pKa 8.22(H2O,t =25±1,Iundefined,Ar) (Uncertain)
• CAS DataBase Reference: Nebivolol(CAS DataBase Reference)
• NIST Chemistry Reference: Nebivolol(118457-14-0)
• EPA Substance Registry System: Nebivolol(118457-14-0)

Safety Data

• Hazardous Substances Data: 118457-14-0(Hazardous Substances Data)

Usage

Description

Nebivolol is a cardioselective beta-1 receptor blocking agent, primarily used as an antihypertensive medication. It is a third-generation beta-blocker with vasodilating properties, which makes it distinct from traditional beta-blockers. Nebivolol selectively targets the beta-1 receptors in the heart, leading to a reduction in heart rate and blood pressure without significantly affecting the beta-2 receptors in the lungs. This selective action results in fewer side effects, such as bronchoconstriction, which is common with non-selective beta-blockers.

Uses

Used in Pharmaceutical Industry:
Nebivolol is used as an antihypertensive agent for the treatment of hypertension. Its cardioselective action allows it to effectively lower blood pressure without causing significant side effects on the respiratory system. This makes it a preferred choice for patients with hypertension who may also have respiratory issues.
Used in Cardiovascular Applications:
Nebivolol is used as a beta-1 receptor blocking agent for the management of various cardiovascular conditions, such as angina pectoris, arrhythmias, and heart failure. Its vasodilating properties help improve blood flow and reduce the workload on the heart, making it a valuable addition to the treatment of these conditions.
Used in Research and Development:
Nebivolol is also used in the research and development of new pharmaceuticals and therapies. Its unique properties as a selective beta-1 receptor blocker with vasodilating effects make it an interesting compound for studying the mechanisms of cardiovascular diseases and developing targeted treatments.

Clinical Use

Beta-adrenoceptor blocker: Essential hypertension Adjunct in heart failure

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: NSAIDs antagonise hypotensive effect. Anti-arrhythmics: increased risk of myocardial depression and bradycardia; increased risk of bradycardia, myocardial depression and AV block with amiodarone; increased risk of myocardial depression and bradycardia with flecainide. Antidepressants: enhanced hypotensive effect with MAOIs. Antihypertensives; enhanced hypotensive effect; increased risk of withdrawal hypertension with clonidine; increased risk of first dose hypotensive effect with post-synaptic alpha-blockers such as prazosin. Antimalarials: increased risk of bradycardia with mefloquine. Antipsychotics enhanced hypotensive effect with phenothiazines. Calcium-channel blockers: increased risk of bradycardia and AV block with diltiazem; hypotension and heart failure possible with nifedipine and nisoldipine; asystole, severe hypotension and heart failure with verapamil. Cytotoxics: possible increased risk of bradycardia with crizotinib. Diuretics: enhanced hypotensive effect. Fingolimod: possibly increased risk of bradycardia. Moxisylyte: possible severe postural hypotension. Sympathomimetics: severe hypertension with adrenaline and noradrenaline and possibly with dobutamine.

Metabolism

Nebivolol is extensively metabolised in the liver by acyclic and aromatic hydroxylation, N-dealkylation, and glucuronidation. Hydroxylation is by cytochrome P450 isoenzyme CYP2D6, partly to active hydroxy-metabolites. It is excreted in the urine and faeces, almost entirely as metabolites.

InChI:InChI=1/C22H25F2NO4/c23-15-3-7-19-13(9-15)1-5-21(28-19)17(26)11-25-12-18(27)22-6-2-14-10-16(24)4-8-20(14)29-22/h3-4,7-10,17-18,21-22,25-27H,1-2,5-6,11-12H2

Upstream product

• 303176-42-3 (R)-2-amino-1-[(S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]ethanol 
• 303176-46-7 (R)-2-[(R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl-4-methylbenzenesulfonate 
• 129050-23-3 (2S)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene 
• 905454-41-3 2-amino-1-[6-fluoro-(2R)-3H,4H-2-chromenyl]-(1S)-ethan-1-ol 
• 409346-73-2 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde 
• 129050-27-7 (R*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol 
• 99199-60-7 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid 
• 99199-62-9 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol 
• 929706-85-4 (+/-)-[2R*[1S*,5S*(S*)]]-α,α-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] 
• 129050-27-7 (S*,R*)-(±)-α-[(benzylamino)methyl](6-fluoro-2-chromanyl)methanol 
• 929706-85-4 α,α'-[[(phenylmethyl)imino]bismethylene]bis-[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] 
• 197706-50-6 6-fluoro-(2R)-2-[(2R)-2-oxiranyl]-3,4-dihydrobenzopyran 
• 129050-26-6 (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene 
• 99199-90-3 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran 

Downstream Products

• 152520-56-4 DL-nebivolol hydrochloride 
• 169293-50-9 nebivolol hydrochloride 
• 152520-56-4 nebivolol hydrochloride 
• 9920-09-6 α,α'-iminobis(methylene)bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride 
• 920299-33-8 (R)-1-((R)-6-Fluoro-chroman-2-yl)-2-[(S)-2-((R)-6-fluoro-chroman-2-yl)-2-hydroxy-ethylamino]-ethanol; hydrochloride 

Relevant articles and documents

X-ray investigations of nebivolol and its isomers

The molecular and crystal structures of the hydrochlorides of d-nebivolol, dl-nebivolol, and seven nebivolol isomers have been determined by X-ray structure analysis. The absolute configuration of all the compounds could be determined unambiguously using anomal dispersion effects. Two compounds, dl-nebivolol (NEB-1d,l) and the (S,R,S,R) nebivolol isomer (NEB-6), crystallize as racemic mixtures in the centrosymmetric space group P-1. d-Nebivolol and six nebivolol isomers crystallize in space group P212121. The d- and l-nebivolol molecules in NEB-1d and NEB-1d,l adopt a conformation which is significantly different compared with that of all nebivolol isomers. With the exception of dl-nebivolol (NEB-1d,l) numerous intermolecular hydrogen bonds connect the molecules forming molecular layers.

Synthesis of intermediate compound and [...] (by machine translation)

Synthesis of intermediate compounds [a] and [...]. [Solution] a [...], asymmetric epoxidation, sulfonyl halide in the presence of base catalyst by sulfonation, alkylation of amines, such as synthesized by a series of cross-coupling reaction. [Effect] [...] important from the viewpoint of pharmacological value, high efficiency, low cost, and which meets the requirements of industrial, optical isomers may be prepared [...] and develop a method, which is very economical in social benefit. [Drawing] no (by machine translation)

A process for the preparation of nebivolol and wherein the intermediate compound

The invention discloses a preparation method of nebivolol used for preparing medicines for treating hypertension of slight or medium degrees, and an intermediate compound. The preparation method comprises the following steps: taking 6-fluoro-2-(1-hydroxy-2-paratoluensulfonyl oxygroup-ethyl)-3,4-dihydrobenzopyrans as an initial raw material, introducing amino, then coupling with 6- fluoro-3,4-dihydro-2-epoxy ethyl-2H-1-benzopyran, and preparing (S,R,R,R) and (R,S,S,S)-nebivolol. Compared with a prior art, the preparation method has the advantages of novel design, simple operation and high yield, the usage of hazardous reagent such as ssodium azide and sodium hydride can be avoided, a column chromatography purifying method is avoided, so that the preparation method conforms to industrial production.

METHOD FOR PRODUCING NEBIVOLOL

The present invention relates to a method for producing racemic nebivolol represented by general formula (I) from the enantiomerically-pure compounds represented by formula (IVa) and (IVb); whereby racemic nebivolol is obtained through mixing enantiomerically-pure d-nebivolol and l-nebivolol which are synthesised independent of each other as enantiomerically-pure compounds through individual coupling of the 4 enantiomerically-pure key intermediates represented by formula (IIa-d) to the corresponding precursors represented by formula (IIIa-d); whereby d-nebivolol (Ia) is obtained through coupling (IIa) to (IIIb) or (IIb) to (IIIa) and l-nebivolol (Ib) is obtained through coupling (IIc) to (IIId) or (IId) to (IIIc), and PG in the intermediates represented by formula (IIa-d) is a hydrogen atom or an amine protection group, and X in the precursors represented by formula (IIIa-d) is a halogen atom, a hydroxyl group, an acyl group, an alkylsulfonyloxy group or an arylsulfonyloxy group, whereby intermediate (IIa) is formed from (IIIa), intermediate (IIb) is formed from (IIIb), intermediate (IIc) is formed from (IIIc), and intermediate (IId) is formed from (IIId), whereby the precursors represented by formula (IIIa) and (IIId) originate from the ketone precursor represented by formula (IVa), and the precursors represented by formula (IIIb) and (IIIc) originate from the ketone precursor represented by formula (IVb), and Z in the ketone precursors (IVa,b) is a halogen atom, a hydroxyl function, an acyl group, an alkylsulfonyloxy group or an arylsulfonyloxy group.