Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs

Fish, Paul V.; MacKenny, Malcolm; Bish, Gerwyn; Buxton, Timothy; Cave, Russell; Drouard, David; Hoople, David W. T.; Jessiman, Alan S.; Miller, D. Craig; Pasquinet, Christelle; Patel, Bhairavi; Reeves, Keith A.; Ryckmans, Thomas; Skerten, Melanie; Wakenhut, Florian

doi:10.1016/j.tetlet.2008.11.025

Cited by 10 publications

(7 citation statements)

References 9 publications

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“…Esreboxetine is a highly selective norepinephrine reuptake inhibitor [19]. A prospective, randomized, placebo-controlled 14-week double blind multiple dose trial with approximately 280 subjects in each group has been completed (NCT00612170).…”

Section: Esreboxetinementioning

confidence: 99%

Recent strategies for drug development in fibromyalgia syndrome

Blumenthal

Malemud

2016

Expert Review of Neurotherapeutics

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The US Federal Drug Administration (FDA) approved 3 medications for treating fibromyalgia syndrome (FMS). There have been no additional FDA approvals since January 2009 and the efficacy of the FDA-approved medications for FMS has been questioned. Areas covered: The "search for studies" tool using clinicaltrials.gov and PubMed were employed. The term, "fibromyalgia" was used for clinicaltrials.gov. The terms employed for PubMed were "Name-of-Drug Fibromyalgia", "Fibromyalgia Treatment" or "Fibromyalgia Drug Treatment." Clinical trials were reviewed if they were prospective and blinded, and if they employed a comparator, either placebo or another pharmaceutical. Expert commentary: Progress toward standardizing the outcome measures for FMS clinical trials have been made but challenges remain. Several pharmaceutical candidates for FMS have been tested since 2009. The results of these studies with potential novel targets for drug development for FMS were reviewed including the results of trials with sodium oxybate, quetiapine, esreboxetine, nabilone, memantine, naltrexone, and melatonin.

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Section: Esreboxetinementioning

confidence: 99%

Recent strategies for drug development in fibromyalgia syndrome

Blumenthal

Malemud

2016

Expert Review of Neurotherapeutics

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“…The synthesis starts with the combination of n -Bu ester 149a with C. rugosa lipase in the presence of t -BuOMe/H 2 O, with the enzyme catalyzing the hydrolysis of the ( S )-ester 149a to afford ( S )-acid 150 while leaving the ( R )-ester 151 untouched. , Upon scale-up, resolution of 149a gives ester 151 in 94% yield with >99% ee and acid 150 in 97% yield with >99% ee after the separation of 151 from the organic layer during extraction and 150 from the aqueous layer. Both then are subjected to protection, and subsequent basic hydrolysis affords the ( R )- and ( S )-morpholine acids 154 and 152 , respectively (Scheme ).…”

Section: Synthetic Developments For Achieving Better Analogues Of Reb...mentioning

confidence: 99%

“…Along this line, activation of 154 with 1-propylphosphonic anhydride (T3P) and subsequent treatment with HN(Me)OMe furnishes Weinreb amide 155 in excellent yield (85%), and then reaction of 155 with the Grignard reagent phenylmagnesium bromide delivers phenyl ketone 156 with no noticeable loss in ee . Zinc-mediated hydride reduction generates ( S , R )-alcohol 157 along with the formation of the second stereogenic center with satisfactory diastereoselectivity ( S , R : R , R = 16:1). , The insertion of the aryl ether is most competently attained from 157 with a two-step course of mesylation and displacement. Reaction of 157 with methanesulfonyl chloride (MeSO 2 Cl) provides mesylate 158 , and displacement of the MsO entity of 158 with 4-chloro-2-methoxyphenol in the presence of Cs 2 CO 3 in dioxane delivers the corresponding ( R , R )-aryloxy ether 159 in excellent yield (95%) with complete inversion of the benzylic stereochemistry and no noticeable loss in ee (Scheme ).…”

Section: Synthetic Developments For Achieving Better Analogues Of Reb...mentioning

confidence: 99%

Synthetic Story of a Blockbuster Drug: Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

Shahzad

Faisal

Huang

2017

Org. Process Res. Dev.

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α-Aryloxybenzyl analogues of morpholine are a significant class of compounds because of their influence on the central nervous system (CNS), with particular concentration on their antidepressant potency. (±)-Reboxetine, an example of such α-aryloxybenzyl analogues, is an orally active and selective noradrenaline reuptake inhibitor that is presently recognized as a prescription drug in over 60 countries for depressive sickness and has been spaciously studied for its pharmacological characteristics. (+)-(S,S)-Reboxetine is presently undergoing advanced clinical evaluation as a potential treatment for neuropathic and fibromyalgia pain. Scheming well-organized approaches to access reboxetine and its derivatives represents a significant endeavor not only for developing antidepressant drugs but also advancing medical studies by radiolabeling of reboxetine derivatives with 11C, 18F, or 123I as potential positron emission tomography radioligands for imaging the brain norepinephrine transporter system. Therefore, to fulfill the challenge of creating the reboxetine architecture by improved synthetic routes, the review combines all of the literature synthetic processes for reboxetine and its derivatives on one platform. Cons and pros of each synthetic method are discussed in this review, which will be very fruitful for the synthetic and medical communities to increase the diversity of synthetic procedures and to develop new concepts and perceptions.

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“…Enantiopure alcohols, amines, and carboxylic acids are key compounds for the synthesis of many fine‐chemistry derivatives, such as pharmaceuticals, agrochemicals, and pheromones . In particular, steriochemically pure carboxylic acids are extremely useful building blocks, being easily converted into many of the other functional groups.…”

Section: Introductionmentioning

confidence: 99%

“…Given their high specificity, commercial availability, and versatility to catalyze a wide range of different reactions (such as esterification, transesterification, and interesterification), they became the most explored class of enzymes in organic synthesis. 1 Enantiopure alcohols, 2-4 amines, 5,6 and carboxylic acids [7][8][9] are key compounds for the synthesis of many fine-chemistry derivatives, such as pharmaceuticals, agrochemicals, and pheromones. 9 In particular, steriochemically pure carboxylic acids are extremely useful building blocks, being easily converted into many of the other functional groups.…”

Section: Introductionmentioning

confidence: 99%

Convenient enzymatic resolution of (R,S)‐2‐methylbutyric acid catalyzed by immobilized lipases

et al. 2017

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The application of several immobilized lipases has been explored in the enantioselective esterification of (R,S)-2-methylbutyric acid, an insect pheromone precursor. With the use of Candida antarctica B, using hexane as solvent, (R)-pentyl 2-methylbutyrate was prepared in 2 h with c 40%, ee p 90%, and E = 35, while Thermomyces lanuginosus leads to c 18%, ee p 91%, and E = 26.The (S)-enantiomer was obtained by the use of Candida rugosa or Rhizopus oryzae (2-h reaction, c 34% and 35%, ee p 75 and 49%, and E = 10 and 4, respectively). Under optimal conditions, the effect of the solvent, the molar ratio, and the nucleophile were evaluated.

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Enantioselective synthesis of (R)- and (S)-N-Boc-morpholine-2-carboxylic acids by enzyme-catalyzed kinetic resolution: application to the synthesis of reboxetine analogs

Cited by 10 publications

References 9 publications

Recent strategies for drug development in fibromyalgia syndrome

Recent strategies for drug development in fibromyalgia syndrome

Synthetic Story of a Blockbuster Drug: Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

Convenient enzymatic resolution of (R,S)‐2‐methylbutyric acid catalyzed by immobilized lipases

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