635724-55-9

Usage

Uses

Used in Pharmaceutical Industry:
Esreboxetine succinate is used as an antidepressant for the treatment of major depressive disorder. It is effective in alleviating depressive symptoms by increasing the availability of norepinephrine in the brain, thereby enhancing mood regulation.
Esreboxetine succinate is also used as an analgesic for the management of neuropathic pain. By inhibiting the reuptake of norepinephrine, it helps in reducing the perception of pain, providing relief to patients suffering from neuropathic conditions.
In the context of clinical trials, esreboxetine succinate has demonstrated promising results, positioning it as a valuable treatment option for both major depressive disorder and neuropathic pain, contributing to its significance in the pharmaceutical sector.

InChI:InChI=1/C19H23NO3.C4H6O4/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;5-3(6)1-2-4(7)8/h3-11,18-20H,2,12-14H2,1H3;1-2H2,(H,5,6)(H,7,8)/t18-,19-;/m0./s1

Upstream product

• 110-15-6 succinic acid 
• 104968-70-9 (S,S)-reboxetine (S)-mandelate 
• 98819-74-0 N-[(2S,3S)-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropyl]-2-chloroacetamide 
• 1340546-27-1 (2S,3S)-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropylamine benzoate 
• 1340546-28-2 C₁₉H₂₂O₅ 
• 1356958-70-7 C₂₀H₂₄O₇S 
• 93853-04-4 (2RS,3RS)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane methanesulfonate 
• 98819-77-3 (+)-(2S,3S)-2-<α-(2-ethoxyphenoxy)benzyl>morpholine methanesulfonate 
• 98769-72-3 (-)-(2S,3S)-3-(2-ethoxyphenoxy)-3-phenylpropene-1,2-epoxide 
• 93851-63-9 (2RS,3RS)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane 
• 98819-73-9 (+)-(2S,3S)-1-amino-3-(2-ethoxyphenoxy)-2-hydroxy-3-phenylpropane 
• 98819-70-6 (+)-(2R,3S)-3-(2-ethoxyphenoxy)-1,2-dihydro-3-phenylpropane 
• 93886-32-9 (-)-(2S,3S)-6-<α-(2-ethoxyphenoxy)benzyl>morpholin-3-one 
• 71620-89-8 (S,S)-reboxetine 

Relevant academic research and scientific papers

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.

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

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.

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.

Process development for (S,S)-reboxetine succinate via a sharpless asymmetric epoxidation

Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. (S,S)-Reboxetine has usually been prepared by resolution of the racemate as the (-)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol was developed. (R,R)-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of (R,S)-4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. (S,S)-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.

Method for the preparation of aryl ethers

The invention provides a method of preparing a compound of formula (I): wherein R, R1, n and m are as defined herein, or a pharmaceutically acceptable salt thereof.

PHARMACEUTICAL SALTS OF REBOXETINE

The present invention relates to novel crystalline, water-soluble salts of the 2S,3S enantiomer of reboxetine, which are the fumarate and succinate salts thereof, to a process for their preparation, to their utility in therapy and to pharmaceutical compos