98769-81-4

Basic information

• Product Name: Reboxetine
• Synonyms: REBOXETINE;(2R)-2-[(R)-(2-Ethoxyphenoxy)phenylmethyl]morpholine
• CAS NO: 98769-81-4
• Molecular Formula: C₁₉H₂₃NO₃
• Molecular Weight: 313.39
• Product Categories: Inhibitor
• Mol File: 98769-81-4.mol
• Article Data: 20

Chemical Properties

• Melting Point: 170-171°
• Boiling Point: 443.7°C at 760 mmHg
• Flash Point: 188.2°C
• Appearance: /
• Vapor Pressure: 4.54E-08mmHg at 25°C
• CAS DataBase Reference: Reboxetine(CAS DataBase Reference)
• NIST Chemistry Reference: Reboxetine(98769-81-4)
• EPA Substance Registry System: Reboxetine(98769-81-4)

Safety Data

• Hazardous Substances Data: 98769-81-4(Hazardous Substances Data)

Usage

Description

Reboxetine is a pure noradrenaline reuptake inhibitor (NRI) that is licensed as an antidepressant in the United Kingdom. It is known for its established efficacy in both short-term and long-term placebo-controlled studies. Unlike previous noradrenaline reuptake inhibitors such as desipramine, nortriptyline, and maprotiline, Reboxetine offers higher selectivity for noradrenaline without significant affinities for α1, muscarinic, and histaminergic receptors. This increased selectivity may contribute to a lower risk of cardiotoxicity compared to tricyclic antidepressants (TCAs), making Reboxetine a more suitable candidate for investigation of potential adjunctive treatments with selective serotonin reuptake inhibitors (SSRIs).
Used in Pharmaceutical Industry:
Reboxetine is used as an antidepressant medication for the treatment of severe depression. It is considered superior to fluoxetine in this context and is marketed in Europe. The drug's mechanism of action involves the inhibition of noradrenaline reuptake, leading to increased levels of noradrenaline in the synaptic cleft and enhancing noradrenergic neurotransmission. This results in improved mood and alleviation of depressive symptoms.
Reboxetine is also used as a research tool for investigating the role of noradrenaline in various psychiatric and neurological disorders. Its high selectivity for noradrenaline reuptake inhibition makes it a valuable compound for studying the effects of noradrenaline modulation on mood, cognition, and other central nervous system functions.
Furthermore, Reboxetine's potential as an adjunctive treatment with SSRIs is being explored. The combination of Reboxetine with SSRIs may provide enhanced therapeutic effects in the treatment of depression, particularly in cases where monotherapy with either drug has been insufficient. This approach could lead to the development of more effective treatment strategies for patients with severe depression who do not respond well to traditional antidepressant medications.

Clinical Use

Reboxetine is a nontricyclic SNRI in which the propylamine side chain of the TCAs is constrained into a morpholine ring. It is a potent and selective ligand for the NET, with a mechanism of action is similar to that of desipramine. Reboxetine is used for the treatment of major depressive disorders. It is a chiral compound that is marketed as a racemic mixture of R,R- and S,S-reboxetine. The antidepressant activity for reboxetine appears to reside with the S,S-(+)-enantiomer, which has approximately twofold the inhibition potency of the R,R-enantiomer. It is well tolerated, with different adverse-event profiles, and it appears to be at least as effective as the SSRIs in the treatment of depressive illness. Currently, it is available only in Europe and is under U.S. FDA review. It preferentially inhibits the reuptake of NE (5-HT :NE ratio, 8). Reboxetine is not metabolized by the polymorphic isoforms, CYP2D6 or CYP2C19, and may offer a valuable alternative to the secondary amine TCAs in the treatment of major depression. Reboxetine is likely to become a promising alternative for patients who have failed treatment with or do not tolerate serotonergic antidepressants.

Side effects

Reboxetine is relatively well tolerated, with insomnia, sweating, constipation, and dry mouth being commonly reported adverse events. Hypotension and urinary hesitancy occur at lower rates than with the TCAs. When compared with the SSRIs, reboxetine is associated with lower rates of nausea, somnolence, and diarrhea.

Drug interactions

Reboxetine seems to be an antidepressant that has negligible interference with the pharmacokinetics of other drugs; thus, fewer drug–drug interactions are expected. It also may be possible to use reboxetine in combination with MAOIs, because it has no inhibitory effect on this enzyme, which would avoid tyramineinduced hypertensive reactions.

Metabolism

Reboxetine is predominantly metabolised in vitro via cytochrome P4503A (CYP3A4); the main metabolic pathways identified are dealkylation, hydroxylation, and oxidation followed by glucuronide or sulfate conjugation. Elimination is mainly via urine (78%) with 10% excreted as unchanged drug.

InChI:InChI=1/C19H23NO3.CH4O3S/c1-2-21-16-10-6-7-11-17(16)23-19(15-8-4-3-5-9-15)18-14-20-12-13-22-18;1-5(2,3)4/h3-11,18-20H,2,12-14H2,1H3;1H3,(H,2,3,4)

Upstream product

• 93886-32-9 (2RS,3RS)-6-<α-(2-ethoxyphenoxy)benzyl>morpholin-3-one 
• 94-71-3 2-Ethoxyphenol 
• 100-52-7 benzaldehyde 
• 40641-81-4 trans-2,3-epoxy-3-phenylpropan-1-ol 
• 98769-72-3 (2RS,3RS)-3-(2-ethoxyphenoxy)-3-phenylpropene-1,2-epoxide 
• 93851-63-9 (2RS,3RS)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane 
• 98769-69-8 (2RS,3SR)-3-(2-ethoxyphenoxy)-1,2-dihydroxy-3-phenylpropane 
• 98769-70-1 (2RS,3SR)-3-(2-ethoxyphenoxy)-2-hydroxy-1-(4-nitrobenzoyloxy)-3-phenylpropane 
• 98769-71-2 (2RS,3SR)-3-(2-ethoxyphenoxy)-2-mesyloxy-1-(4-nitrobenzoyloxy)-3-phenylpropane 
• 4407-36-7 (2E)-3-phenyl-2-propen-1-ol 
• 104-54-1 3-Phenylpropenol 
• 93853-04-4 (2RS,3RS)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane methanesulfonate 

Downstream Products

• 93851-87-7 Reboxetine mesylate 
• 93851-87-7 (2RS,3SR)-2-<α-(2-ethoxyphenoxy)benzyl>morpholine methanesulfonate 
• 98819-77-3 (+)-(2S,3S)-2-<α-(2-ethoxyphenoxy)benzyl>morpholine methanesulfonate 
• 71620-89-8 (S,S)-reboxetine 
• 105017-38-7 (2R,3R)-reboxetine 
• 635724-54-8 2S,3S-2-[α-(2-ethoxyphenoxy)benzyl]morpholine fumarate 
• 635724-55-9 (2S,3S)-2-[α-(2-ethoxyphenoxy)benzyl]morpholine succinate 
• 104968-70-9 (S,S)-reboxetine (S)-mandelate 

Relevant articles and documents

Synthesis of (S,S)-Reboxetine

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C-H to C-N Cross-Coupling of Sulfonamides with Olefins

Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp3)-N fragment coupling reaction between terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/SOX (sulfoxide-oxazoline) catalyzed intermolecular allylic C-H amination. A range of (56) allylic amines are furnished in good yields (avg. 75%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). Mechanistic studies reveal that the SOX ligand framework is effective at promoting functionalization by supporting cationic π-allyl Pd.

Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: Applications in the synthesis of reboxetine

A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O- cyclohexylidene-d-glyceraldehyde in ～43% overall yields. The Royal Society of Chemistry.