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 that is licensed as an antidepressant in the United Kingdom. Reboxetine has established efficacy based on placebo-controlled studies both in the short and the long term. Previous noradrenaline reuptake inhibitors, such as desipramine, nortriptyline, and maprotiline, have been relatively selective for noradrenaline compared with serotonin but have not avoided affinities with α1, muscarinic, and histaminergic receptors. The lack of selectivity of these drugs has the consequence that the levels of cardiotoxicity are those expected with TCAs. Reboxetine is the first pure noradrenaline reuptake inhibitor, and therefore it may also provide a more appropriate agent to consider for the investigation of possible adjunctive treatments with SSRIs.

General Description

Most of the activity of reboxetine resides in the S,S-isomer(The marketed compound is RR and SS.) It is claimed to besuperior to fluoxetine in severe depression. It is marketed inEurope. At least three tricyclic compounds, desipramine,nortriptyline, and the technically tetracyclic maprotiline areSNERIs. They, of course, have typical characteristic TCAside effects but lower anticholinergic and H1-antihistaminic(sedative) effects than dimethyl compounds. SNERIs areclinically effective antidepressants.It would be expected that in the case of SNERIs,α2presynaptic receptors would be desensitized, after whichsustained NE transmission would be via one or more postsynapticreceptors; α1, β1, and β2 receptors are possibilities.

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

• 847805-34-9 (+)-(2S,3S)-2-[α-(2-ethoxyphenoxy)phenylmethyl]morpholine-4-carboxylic acid tert-butyl ester 
• 847805-32-7 (+)-(2S,3S)-2-[α-hydroxy(phenyl)methyl]morpholine-4-carboxylic acid tert-butyl ester 
• 1072-53-3 ethyleneglycol sulfate 
• 98819-73-9 (+)-(2S,3S)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane 
• 1250978-78-9 C₁₉H₂₄ClNO₃ 
• 1250978-71-2 2-{[(2S,3S)-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropyl]amino}ethyl hydrogen sulfate 
• 93853-04-4 (2RS,3RS)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane methanesulfonate 
• 1340546-28-2 C₁₉H₂₂O₅ 
• 1356958-70-7 C₂₀H₂₄O₇S 
• 1026328-70-0 tert-Butyl-dimethyl-((4R,5R)-2-oxo-5-phenyl-2λ⁴-[1,3,2]dioxathiolan-4-ylmethoxy)-silane 
• 155930-88-4 (1R,2R)-1-<(tert-Butyldimethylsilyl)oxy>-1-phenylpropane-1,2-diol 
• 100009-29-8 (E)-1-tert-butyldimethylsilyloxy-3-phenyl-2-propene 
• 133187-21-0 Methyl (S)-(+)-α-<<(1,1-dimethylethyl)dimethylsilyl>oxy>-α-phenylacetate 

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 
• 104968-70-9 (S,S)-reboxetine (S)-mandelate 
• 635724-55-9 (2S,3S)-2-[α-(2-ethoxyphenoxy)benzyl]morpholine succinate 

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.