98769-81-4

Usage

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 
• 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 
• 93886-32-9 (2RS,3SR)-6-<α-(2-ethoxyphenoxy)benzyl>morpholin-3-one 
• 93886-32-9 (-)-(2S,3S)-6-<α-(2-ethoxyphenoxy)benzyl>morpholin-3-one 
• 71620-89-8 reboxetine 
• 4392-24-9 Cinnamyl bromide 
• 847805-33-8 (+)-(2S,3R)-2-[α-hydroxy(phenyl)methyl]morpholine-4-carboxylic acid tert-butyl ester 
• 132073-83-7 (S)-morpholin-2-ylmethanol 
• 135065-76-8 tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate 
• 98769-71-2 (+)-(2R,3S)-3-(2-ethoxyphenoxy)-2-mesyloxy-1-(4-nitrobenzoyloxy)-3-phenylpropane 
• 98819-74-0 N-[(2S,3S)-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropyl]-2-chloroacetamide 

Downstream Products

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

Relevant academic research and scientific papers

Sulfoxide ligand metal catalyzed oxidation of olefins

The enantioselective synthesis of isochroman motifs has been accomplished via Pd(II)-catalyzed allylic C—H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C—H oxidation reaction proceeds with the broadest scope and highest levels asymmetric induction reported to date (avg. 92% ee, 13 examples ≥90% ee). Additionally, C(sp3)-N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/sulfoxide (SOX) catalyzed intermolecular allylic C—H amination is disclosed. A range of 52 allylic amines are furnished in good yields (avg. 76%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stiochiometries for intermolecular C—H amination reactions.

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.

Stereodivergent synthesis of all the four stereoisomers of antidepressant reboxetine

Chiral amino alcohol-copper(ii) catalysts Cu-L1c and Cu-ent-L1c were utilized to promote the diastereoselective nitroaldol reactions of chiral aldehydes (S)-3 or (R)-3 with nitromethane, which respectively led to the preferential formation of certain stereoisomer for nitro diol derivatives 4. Using this catalytic protocol, all the four stereoisomers of the antidepressant reboxetine were divergently prepared. The highest overall yield of this synthetic route reached up to 30.5% from aldehyde (S)-3.

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.

Dynamic kinetic resolution-based asymmetric transfer hydrogenation of 2-benzoylmorpholinones and its use in concise stereoselective synthesis of all four stereoisomers of the antidepressant reboxetine

Dynamic kinetic resolution-driven, asymmetric transfer hydrogenation reaction of 2-benzoylmorpholin-3-ones (4) proceeds efficiently to give the corresponding (2R,3S)- or (2S,3R)-2-(hydroxyphenylmethyl)morpholin-3-ones (6) with an excellent level of diastereo- and enantioselectivity and simultaneous control of two contiguous stereogenic centers in a single step. This process is employed to prepare all four stereoisomers of the antidepressant reboxetine.

The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate

The Pfizer Green Chemistry metrics program is described and exemplified with a case history involving the synthesis of (S,S)-reboxetine succinate. The initial route used a classical resolution approach and generated high levels of waste. This route was replaced by an enantiospecific synthesis which used Sharpless epoxidation chemistry, an enzymatic process to selectively protect a primary alcohol and a new efficient method of chiral morpholine construction as key steps. These improvements reduced the levels of waste produced by the synthesis by more than 90%. Detailed metrics starting from a common starting material (trans-cinnamyl alcohol) for all routes of synthesis are presented.

Commercial synthesis of (S,S)-reboxetine succinate: A journey to find the cheapest commercial chemistry for manufacture

The development of a synthetic process for (S,S)-reboxetine succinate, a candidate for the treatment of fibromylagia, is disclosed from initial scale-up to deliver material for registrational stability testing through to commercial route evaluation and subsequent nomination. This entailed evaluation of several alternative routes to result in what would have been a commercially attractive process for launch of the compound.

Catalyst-controlled diastereoselection in the hydrogenation of heterocycloalkyl ketones

α-Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2-(4-benzoylmorpholinyl) phenyl ketone and 3-(1-tert-butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri-sec-butylborohydride as reducing agents affords the syn- and anti-alcohols in a lower than 80:20 ratio. Hydrogenation of these ketones with a catalyst system of RuCl 2(BIPHEP)(DMEN) and potassium tert-butoxide in 2-propanol results in the syn-alcohols with ≥ 99:1 selectivity [BIPHEP=2,2′- bis(diphenylphosphino)biphenyl, DMEN=N,N-dimethylethylenediamine]. The marked difference in the diastereoselectivity suggests that the stereoselection in this hydrogenation is primarily regulated by the structure of the catalyst's reaction field ("catalyst-controlled diastereoselection") but not the internal stereocontrol of the substrates. This chemistry is applied to the asymmetric hydrogenation through dynamic kinetic resolution with a RuCl 2[(S)-BINAP][(R)-DMAPEN]/potassium tert-butoxide catalyst [BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, DMAPEN=2-dimethylamino-1-phenylethylamine]. A series of aryl heterocycloalkyl ketones has been converted to the alcohols in excellent diastereo- and enantioselectivities. The modes of catalyst-controlled diastereoselection and enantioselection are interpreted by using transition-state molecular models. (S,S)-Reboxetine, a selective norepinephrine uptake inhibitor, was synthesized from one of product alcohols. Copyright

Application of a process friendly morpholine synthesis to (S,S)-Reboxetine

We report our results on the construction of a morpholine ring system from the corresponding epoxide and amino alcohol. From this study, we were able to convert a previous four-step synthesis into a more efficient two-step process.