Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

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Synthetic story of a blockbuster drug; Reboxetine: a potent selective norepinephrine reuptake inhibitor Danish Shahzad, Muhammad Faisal, Ameema Rauf, and Jian-hua Huang Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00265 • Publication Date (Web): 02 Oct 2017 Downloaded from http://pubs.acs.org on October 2, 2017

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Organic Process Research & Development

Synthetic story of a blockbuster drug; Reboxetine: a potent selective norepinephrine reuptake inhibitor Danish Shahzad*a, Muhammad Faisal*a, Ameema Raufb, Jian-hua Huangc a

Department of Chemistry, Quaid-i-Azam University-45320, Islamabad, Pakistan.

b

c

Department of Chemistry, University of Wah, Wah Cantt, Pakistan.

School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.

*Email: [email protected], [email protected] Tel +92-313-5997725

ACS Paragon Plus Environment


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Graphical Abstract


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Abstract α-Aryloxybenzyl analogues of morpholine are a significant class of compounds attributed to their influence on the central nervous system (CNS), with particular concentration to their anti-depressant potency. (±)-Reboxetine, example of such α-aryloxybenzyl analogues, is an orally active, selective noradrenaline reuptake inhibitor (NRI) presently recognized as a prescription drug in over sixty countries for depressive sickness and is spaciously studied for its pharmacological characteristics. The (+)-(S,S)-reboxetine is presently undergoing advanced clinical evaluation as a potential treatment of neuropathic and fibromyalgia pain. Scheming well-organized approaches to access the 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 (PET) radioligands for imaging the brain norepinephrine transporter (NET) system. Therefore, to fulfil the challenge of creating the reboxetine architecture by improved synthetic routes, the review combines all the literature synthetic processes of reboxetine and its derivatives at one platform. Cons and pros of each synthetic method have been discussed in this review, which would be very fruitful for synthetic and medical community to increase the diversity of synthetic procedures and to develop new concepts and perceptions. Keywords: Reboxetine; noradrenaline reuptake inhibitor; anti-depressant; central nervous system; succinate; mesylate.



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1. Introduction The central nervous system (abbreviated as CNS) controls much of the body, including significant activities such as keeping the heart beating and breathing.1,2 Depression defines uncommonly low activity in the CNS.3,4 Depression is a common psychiatric illness and in the world it is one of the most frequent diseases, affecting women and men of all ages and backgrounds.5,6 The phenylpropylamino unit, having aryloxy substituents on position of benzylic carbon 1 (Fig. 1), is a frequent structural entity in many organic compounds acting on the CNS, as well as potential treatments for attention deficit hyperactivity disorder (abbreviated as ADHD) and depression illness.7,8 Examples include fluoxetine 4 (brand names: ProzacTM and SarafemTM), atomoxetine 5 (originally named tomoxetine, brand name: StratteraTM), nisoxetine 6, and reboxetine 7 and 8 (Fig. 2).9,10 Reboxetine mesylate 2 (Fig. 1) is an orally active, selective norepinephrine reuptake inhibitor (abbreviated as NRI), presently recognized in over sixty countries as an anti-depressant and broadly studied for its pharmacological characteristics.11 It is advertised under the trade names EdronaxTM, NoreboxTM, ProliftTM, VestraTM, and IntegrexTM in Europe and Latin America.12 It is sold as a racemic form i.e. mixture of the (S,S)- and (R,R)-enantiomers 7 and 8, namely (2S,3S)- and (2R,3R)-2-[R-(2-ethoxyphenoxy)phenylmethyl]-morpholine (Fig. 2).13 However, (S,S)enantiomer of reboxetine (7, Fig. 2) is almost 24-fold more effective than the (R,R)enantiomer of reboxetine 8,14 and demonstrates the best selectivity and affinity for norepinephrine transporter (abbreviated as NET).15 (S,S)-reboxetine succinate 3 has been under late stage development at PfizerTM for the medication of neuropathic and fibromyalgia pain (Fig. 1).16 Reboxetine mesylate 2 has almost equivalent effectiveness to that of fluoxetine 4 (Fig. 2), imipramine 9 (Fig. 3) and desipramine 10 (Fig. 3) and has better sideeffect profile.17 Owing to its high selectivity of reboxetine mesylate 2, it is operative at very


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low dosages i.e. 4-8 mg per day and causes significantly less side-effects in comparison to conventional tricyclic anti-depressant drugs.18 However, it has a inferior incidence of convulsions and cholinergic side-effects19; the inferior incidence of orthostatic hypotension can be due to the low interaction with beta-2- and alpha-2 adrenergic receptors, while the minor symptoms of dry mouth and tremors can be attributed to low interaction with muscarinic receptors (abbreviated AChR).20 Additionally, reboxetine mesylate 2 does not impair psychomotor function.21 The most common side-effects of reboxetine mesylate 2 are insomnia, tachycardia and stypsis, which only infrequently require suspension of the treatment.22 It is estimated that the efficiency of reboxetine mesylate 2 is almost23 to that of fluoxetine 4, anti-depressant of the selective serotonin re-uptake inhibitor (abbreviated as SSRI) class; however the differences between 2 and 4 have been found in particular populations. For instance, reboxetine mesylate 2 looks to be more active than fluoxetine 4 on lack of motivation and self-confidence, and this too can be due to the respective selectivity of the two drugs.24,25 Modulating central norepinephrine (abbreviated as NE) levels through its re-uptake transporter has been displayed to be an impressive pharmacotherapy strategy for medicating a diversity of diseases including attention deficit hyperactivity disorder (abbreviated as ADHD),26-29 depressive disorder or clinical depression,30 fibromyalgia syndrome (abbreviated as FMS),31 peripheral neuropathy (abbreviated as PN, also called distal polyneuropathy and diabetic nerve pain), and other kinds of pain (e.g. back pain, headaches and migraines, neck pain and shoulder pain).32 Recently reboxetine mesylate 2, due to its potent selective norepinephrine reuptake inhabitancy, has been extensively selected as a molecular model for the design of NET radioligands (radioactive biochemical substances) and various 11C-, 18F- or 123

I-labeled analogues of reboxetine mesylate 2 have been constructed and investigated as

putative positron emission tomography (abbreviated as PET) or single photon emission



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computed tomography (abbreviated as SPECT) imaging agents for the NET.33-41 These radioactive biochemical substances, including o-Me ((S,S)-[11C]-MeNER) 11,34-36 ofluoromethyl ((S,S)-[18F]FMeNERD2) 12,37,38 and 2-I ((S,S)-[123I]IPBM) 1339,40 derivatives (Fig. 4), exhibited many desired in vivo characteristics for imaging non-human primates (abbreviated as NHPs) that have not been detected with any other NET radioligands. o-Me (S,S)-[11C]MeNER 11 and o-fluoromethyl (S,S)-[18F]FMeNER-D2 12 are perhaps the most potent candidates disclosed so far for imaging NET by PET with the highest thalamus-tostriatum ratio of 1.5 in cynomolgus monkey.42-43 The above story throws light on the fact that the reboxetine 2 is a unique, superlative, outstanding, imperative and blockbuster drug hence, to make this drug more common, useful and cheap, its production at large scale required special attention. To achieve this goal, environmentally benign, low-cost, atom- and step-economical and convenient synthetic route is required. The present synthetic industrial technique of reboxetine synthesis suffers from low yields and complex processing which results in poor process throughput.43,44 Synthetic pathway which is commercially used to obtain reboxetine requires to meet many criteria in terms of safety, the environment, throughput, control and legality. Furthermore, a suitable pathway for the synthesis of a diversity of reboxetine analogues would be valuable for producing targets that are presently the object of intense development efforts to new and more potent NRIs. This review collect and debate on the cons and pros of all synthetic routes of reboxetine and its derivative in well-ordered, methodical, efficient and systemic manner. To resolve current synthetic problems, the discussion and deliberation in review provides key solutions. Furthermore, the review provides informative material which would be helpful to design new synthetic schemes, to study and determine best synthetic routes, to resolve synthetic problems towards synthesis of reboxetine and its derivative. Moreover, all synthetic schemes all one platform also provides knowledge about current synthetic progress in the


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field of reboxetine and its derivative, and from that knowledge it would be possible to develop new concepts and increase the diversity of reboxetine synthetic processes.

Figure 1. Structure of reboxetine mesylate and reboxetine succinate.

Figure 2. Potent phenylpropylamino group containing anti-depressant.

Figure 3. Structure of imipramine and desipramine.



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Figure 4. Reboxetine based radioligands. 2. Synthetic developments for reboxetine mesylate/succinate 2.1 (S,S)-Reboxetine mesylate synthesis through symmetric epoxidation The very first attempt towards reboxetine mesylate 2 in a racemic form is carried out by Meloni and co-workers. Cinnamyl alcohol 14 is oxidized under Prilezhaev epoxidation reaction conditions resulted in racemic phenylglycidol 15. Selective addition of oethoxyphenol to the hindered face of the oxiran to break its one of the C-O bonds afforded the diol 16 (Scheme 1). The stereospecificity is proved by the fact that only one diastereoisomer is obtained exclusively; as the 2-ethoxyphenate ion is necessary for the reaction, this strongly supports an SN2 mechanism and makes a syn-addition anchimerically assisted by the phenyl ring extremely improbable. The 1o alcohol of the diol 16 is protected with the assistance of p-nitrobenzoyl chloride in pyridine. The 2o alcohol of obtained ester 17 is then mesylated in situ to afford 18. Reaction of 18 with base NaOH in dioxane perform hydrolysis to give epoxide 19 (Scheme 1). Treatment of the epoxide 19 with NH3 followed by methanesulfonic acid afforded methanesulfonate salt of amino alcohol 20. At this stage, 3step process is done to construct the morpholine unit from prerequisite important entity 20. Conversion of the 20 to reboxetine is accomplished by reaction with chloroacetyl chloride in Et3N to give 21 followed by treatment with t-BuOK to yield the lactam 22, and lastly reduction with a versatile hydride reducing agent “Vitride” (also known as Red-Al; NaAlH2(OCH2-CH2OCH3)2,) resulted in (±)-reboxetine 7 and its salt formation yielded (±)reboxetine methanesulfonate 2 with 12% overall yield. Interestingly, during the reduction process the generation of structure like 23 2-3%, a fused cyclic product, is inevitable along with the desired product 7 (Scheme 1). It is hard to remove this impurity and substantially reduced the overall yield. Overall, this procedure suffered from low yields and complex processing which leaded to minor process throughput. The main limitations of this method


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are (i) p-nitrobenzoate group is used to protect the 1o alcohol of 16. Selectivity for this protection is very poor, and in this reaction 2o monobenzoate (diastereomer), up to 13%, is formed, which makes purification complicated and resulted in loss of yield, (ii) owing to involvement of large number of steps, the amount of waste product and manufacturing costs increases and (iii) the chlorinated intermediate 21 is formed during the process which have level of toxicity that may also influence worker’s health and safety.45

Scheme 1. The first attempt towards the (±)-reboxetine methanesulfonate. 2.2 Modified (S,S)-reboxetine mesylate synthesis via symmetric epoxidation



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An enhanced and well-organized process for the reboxetine mesylate 2 synthesis starting from cinnamyl alcohol 14 (also known as 3-Phenyl-2-propen-1-ol) is improved by Henager and co-workers as depicted in scheme 2. The improved procedure reduces impurity formation and is appropriate for the effective synthesis of multiton quantities of reboxetine mesylate 2. Cinnamyl alcohol 14 is epoxidized with 40% peroxyacetic acid (abbreviated as PAA), a quite strong oxidizing agent, proceeded smoothly in DCM in the presence of Na2CO3 afforded oxirane 15. Whereas, epoxidation with monoperoxyphthalic acid associated with various troubles i.e. synthesis of the reagent from 2-benzofuran-1,3-dione and H2O2 is timeconsuming, and a large quantity of 1,2-benzenedicarboxylic acid is developed as a byproduct, hence creating a disposal subject.46 Next, the process of epoxide opening is operated under controlled condition which not only eliminated the formation of 15 to an oil but gave in increment in yield (Scheme 2). The solution of 15 in DCM is reacted with o-ethoxyphenol and sodium hydroxide in the existence of PTC Bu3MeNCl to afford the diol 16 at 60 oC which is later crystallized by MTBE. Moreover, for the crystallization of methyl tert-butyl ether (MTBE), the toluene is investigated to be preferable, ended with improved recovery of product and superior filtering solids. In 16, selective protection of the 1o alcohol is very important to produce the accurate diastereomer, so along this line, it is found that 1o alcohol in 16 could be protected expeditiously with very excellent regioselectivity to give mono silyl ether 24 using an inexpensive protecting agent, trimethylsilyl chloride and triethyl amine at low temperature. At the same time, in situ mesylation of the secondary hydroxyl group in 24 yielded silyl ether-mesylate 25, which is in turn quenched with HCl for the cleavage of TMSether linkage delivering intermediate 26 in about 30 min. Under phase transfer condition, 26 is converted into epoxide 19 in the presence of toluene as solvent and aqueous sodium hydroxide as the base. The reaction is essentially quantitative and rapid. These conditions eliminate dioxane from the process. In the above synthetic methodology (Scheme 1), dioxane


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was used for the formation of 19. That reaction (conversion from 18 to 19) was very slow (17-19 h), and attributed to the high freezing and high boiling points of dioxane (10-12 °C and 100- 102 °C, respectively), removal of the solvent was both time consuming and a safety concern i.e. dioxane can freeze and damage the condenser if the jacket temperature is too cold.46 Reaction of the epoxide 19 with NH3 followed by methanesulfonic acid afforded the methanesulfonate salt of amino alcohol 20 (Scheme 2). Separation as the mesylate (CH3SO3‫־‬ anion) is more reliable and provided better-handling solids. Conversion of the 20 to 7 is accomplished by following number of steps such as i.e. chloroacetylation in dimethyl carbonate at low temperature to form 21, followed by non-nucleophilic strong base addition of tert-butoxide causing very rapid cyclization to the lactam 22. Finally, reduction of oxo group in 22 with inverse addition of Vitride resulted in (±)-reboxetine 7 and its salt formation yielded (±)-reboxetine methanesulfonate 2 with 25% overall yield. Inverse addition of 5 equiv. organoaluminium reducing agent in the final stage gave very low yield of a dimeric impurity 23 up to 0.06%. All entities in two schemes are racemic. For clearness, only a single enantiomer is displayed. In this process, instead of using p-nitrobenzoate group for 1o alcohol protection of 16, TMS group are used for protection, which provides better selectivity in comparison to p-nitrobenzoate group. Key improvements minimize formation of impurity, resulting in higher yields and more effective processing relative to the previous process (Scheme 1). Overall yield is increased from around 12% yield (Scheme 1) to around 25% in the modified process (Scheme 2), significantly increasing throughput of process. This process is appropriate for the efficient preparation of multiton amounts of reboxetine. However, the main problem that is associated with this synthetic protocol is the formation of large amount of waste during lactamization to give 22. Moreover, the chlorinated intermediate 21 is formed during the process which have level of toxicity that may also influence worker’s health and safety.46



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Scheme 2. Modified synthesis of (S,S)-reboxetine mesylate via symmetric epoxidation. 2.3 Early non-classical approach for construction of (S,S)-reboxetine succinate The (S,S)-enantiomer of reboxetine 7 is more active than the racemate reboxetine 7 in a number of biological examines, and (S,S)-reboxetine succinate 3 has been under late stage construction at Pfizer for the fibromyalgia treatment.47 A super effective early resolution

approach method is quickly identified for the development of (S,S)-reboxetine succinate 3 starting from the racemic alcohol 20 (Scheme 3). (S)-camphanic acid is used as a resolving agent which formed an insoluble salt with the undesired enantiomer. After filtration of reaction mixture, the obtained toluene solution of the required camphanate salt 28 is the used to construct benzoate salt 29 entity which upgraded in chiral purity from 80% ee to 99% ee.


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To approach the targeted moiety, the rest of the chemical transformation from 29 to 3 remained the same (Scheme 3). Pronounced features of this resolution procedure are the application of a single organic solvent (i.e. toluene) all the way through the method and reduction of 22 VitrideTM is exchanged by the more atom-economical LiAlH4 (LAH). Moreover, the use of tert-butanol instead of IPA as a solvent for the ring closing step prevent formation of impurities i.e. generated from the isopropoxide displacement of the chloride. One main drawback of chiral resolution of racemates compared to direct asymmetric preparation of one of the enantiomers is that only 50% of a required enantiomer is attained. In this process, large amount of waste is produced and the chlorinated intermediate have level of toxicity.47



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Scheme 3. Early non-classical resolution approach towards reboxetine succinate. 2.4 (S,S)-Reboxetine succinate synthesis by Sharpless asymmetric epoxidation (SAE) Henager and Cebula, in 2007, disclosed better methodology for accessing the (S,S)reboxetine 7 via enantioselective synthetic pathway employing a key Sharpless asymmetric epoxidation (SAE) protocol which yielded 2 chiral carbon centers early in the synthetic strategy (Scheme 4).48 However, the cinnamyl alcohol 14 served again as starting material, which is desymmterized by exposing to epoxidation to furnish (R,R)-phenyl glycidol 15 with


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>98% enantiomeric excess and in 89% yield. In fact, 15 is attained as a solution in DCM which is treated with o-ethoxyphenol selectively activated by NaOH under phase transfer conditions to deliver diol 16. Following standard protection and deprotection manipulations then advanced 16 to 19. Opening of the ring through nucleophilic addition of ammonia to unhindered side of the oxiran afforded stereoselective formation of intermediate amino alcohol 30, which is crystallized in the state of free base rather than as the mesylate salt (Scheme 4). Thus, eliminating one chemical step. For morpholine heterocyclic ring synthesis, the three steps procedure is established for the transformation of 30 to 7 using toluene as the single solvent, knocking out dimethylcarbonate (DMC) and a library of solvent exchanges. Schotten-Baumann acylation of 30 is done with the assistance of chloroacetyl chloride and sodium carbonate. The main advantage of Schotten-Baumann acylation is that no clear impurities are formed during reaction i.e. the reaction results in the formation of colourless 21 in quantitative yield. Regrettably, Scheme 1, Scheme 2 and Scheme 3 are deprived of these associated benefits. Lactam formation of amide 21 and its subsequent reduction are both carried out in toluene resulting in (S,S)-reboxetine 7 as a free base (Scheme 4). The addition of succinic acid for the salt formation of 7 afforded (S,S)-reboxetine succinate 3 with high enantiomeric and chemical purity.48 By this process the (S,S)-reboxetine succinate 3 is obtained in 19% overall yield from 14. The asymmetric procedure described reduces waste generation and solvent use by about 50% compared to the resolution route (Scheme 3) to (S,S)-reboxetine.



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Scheme 4. Process development for (2S,3S)-reboxetine succinate via SAE. 2.5 Pfizer synthesis (S,S)-reboxetine succinate via green approach Up to this end, we have seen that the introduction of chirality in cinnamyl alcohol 14 via Sharpless asymmetric epoxidation (SAE) affords the glycidal 15 and its subsequent nucleophilic based introduction of 2-ethoxy phenol subunit are proved to be the best methodologies (Scheme 5). Because, later chemical transformation delivered the enatioenriched diol (S,R)-11 in a good yield up to 60% with excellent enantiomeric excess.5052

But somewhat is still missing because above mentioned well-established procedures have

some draw backs towards the commercial scale manufacturing of (S,S)-reboxetine 7 with or without salt.

•

Due to involvement of large number of steps, the amount of waste product and manufacturing costs increases.


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•

Mesylate salt isolation is a difficult process and this process produces large amount of unrequired chemical waste.

•

In compound, differentiation of the two OH species

•

Protection and deprotection approach of 16 required which is sub-optimal, as the initial tetramethylsilane protection is poorly selective for the 1o alcohol.

•

The chlorinated intermediates are formed during the process which have level of toxicity that may also influence worker’s health and safety. Nevertheless, this produced intermediate 22 at the incorrect oxidation level so demanding a reduction reaction with a powerful metal hydride reagent (VitrideTM).

•

In the reduction step, the serious aluminium as waste is produced.

•

Step of resolution has a max 50% theoretical yield.

•

The overall yield is low (10–25%) from cinnamyl alcohol.

To meet clinical and long term demands, Synthetic chemists from the Pfizer marched towards to find the cheapest commercial chemistry for the manufacturing of 2.50-52 After evaluating several alternatives pathways one synthetic strategy was adopted which yielded 2 with excellent yield, minimal waste generation and high throughput. Besides, this selected route incorporated with six chemical transformation from cinnamyl alcohol 14 in a total of 2 synthetic pathways with only one isolated precursor (Scheme 5). With the enantio enriched diol (S,R)-16 in hand, in next step 1o alcohol required regioselective protection. Which is accomplished using commercially available biocatalyst Novozyme 435 (Candida antartica

lipase B) permitting the regioselective protection of the 1o alcohol as the corresponding acetate 31. The Novozyme 435 is removed from reaction mixture by simple filtration. The main process impurity noted in this conversion is the acetylated 2o alcohol 32. Temperature < 25 oC and reaction time 15 M base mediated EtOH, THF ring closur e 2) succinic acid EtOH

-O

OAc OMs

OEt

O

O

O

MsCl NEt3, PhMe

OH

OEt aq. NaOH, PhMe MeN(n-Bu)3Cl

OEt

OH 35 3 to 8%

OEt

SO3-

Controlled mode of addition of the reagents, cumulative addition time and reaction temperature can minimize the formation of dimer 35

O NH

CO2H

O 7

Scheme 5. Pfizer synthesis for (2S,3S)-reboxetine succinate intended for commercialisation. 3. Stereoselective approaches for the development of (S,S)-reboxetine and its diastereomers 3.1 NBS-induced electrophilic multi-component approach for (S,S)-reboxetine Professor’s Jing and Ying have evaluated N-bromosuccinimide-induced electrophilic multicomponent reaction approach to construct 2-substituted morpholine system 36



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enantioselectively.53 This functionalized scaffold is less reported and is proved to be an important and advanced intermediate for pharmaceutically important (S,S)-reboxetine 7. Therefore, towards the synthesis of 7 the MCR reaction of olefinic partner with (S)epichlorohydrin, N-bromosuccinimide (NBS), and nitrobenzenesulfonamide (NsNH2) at -30 °C to -25°C for 16h. Morpholine 36 with a DCM handle at the 2-position could be attained in 66% yield (Scheme 6). X-ray crystallographic studies are used to confirm the structure of 36. Chloride of 36 is replaced with OAc by assistance of substitution reaction and then OAc of obtained entity is hydrolysed to afford morpholine 37. Hydroxyl morpholine 38, which is important intermediate in reboxetine 7 synthesis, is obtained in next step from conventional protecting group manipulation.53 Treatment of 38 with trichloroisocyanuric acid (TCIA) in the presence of TEMPO and NaHCO3 in solvent EtOAc at -5oC afforded aldehyde 79 in 89% yield.59 The existence of NaHCO3 is valuable for neutralization of hydrochloric acid which is formed during the reduction of trichloroisocyanuric acid, thus avoiding Boc group partial loss (Scheme 6). The conversion is carried out effectively by union of 79 with excess diphenylzinc (Ph2Zn). The finest transformation is attained by addition of 79 to diphenylzinc (Ph2Zn) in solvent THF at -10 °C, produced in situ from phenylmagnesium bromide (PhMgBr) in solvent THF and anhydrous Zinc bromide (ZnBr2). Flash chromatography on silica gel are used to separate the resulting mixture of diastereomers of (2S,3S)-80a and (2S,3R)-80b to furnish 60% and 19% yields, respectively (Scheme 6). The chief challenge in this work is the transforming the key isomer (2S,3S)-80a to ether 81 without affecting the stereochemistry. For this purpose, aromatic nucleophilic substitution is the most suitable way. 59

Sodium alkoxide of (2S,3S)-80a in solvent DMF treated with chromium complex of 2-

ethoxy fluorobenzene 138 (which in turn prepared from refluxing 2-flourophenol and Cr(CO)6 together) to deliver two complexes of chromium, which led to 81 in almost 95% yield after oxidative dechromination (process of removing residual chlorine through


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oxidation) with iodine (I2). Lastly, reaction of Boc amide 81 with excess trifluoroacetic acid (TFA) furnished (2S,3S)-reboxetine 7 in 98% yield and in 19.77% overall yield with 99% ee. This method delivers the desired product 7 with very low overall yield. However, on the good side, by application of (R)-epichlorohydrin, one can approach reboxetine 7 other enantiomers efficiently (Scheme 6). This method not only delivers a well-organized protocol toward biologically relevant 2-subsituted morpholine units, but also offers flexibility in synthesis of drug analogues for more biological studies. Moreover, no aluminium as waste and chlorinated intermediates are produced in this process. This process also avoids the protection of alcohols through TMS or p-nitrobenzoate groups.53

Scheme 6. NBS-Induced electrophilic multicomponent reaction. 3.2 Chiral resolution technique for (S,S)-reboxetine synthesis



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Professor Jaya and co-workers has demonstrated a neat approach towards 7 via resolution with (+)-mandelic acid of very important scaffold 45. Epoxide 15 is obatined from trans cinnamoyl alcohol 14 and meta-chloroperoxybenzoic acid in excellent yield (Scheme 7). The ring opening reaction of epoxide 15 with 2-(methoxymethoxy)phenol in the presence of sodium hydroxide afforded 39. Protection of the 1o alcohol unit of 39 is attained selectively with nitrobenzoylchloride afforded compound 40.54 Treatment of precursor 40 with mesyl chloride (MsCl) in the presence of Et3N yielded ester 41 in almost quantitative yield. Reaction of entity 41 with sodium hydroxide delivered 42. The ring opening reaction of oxirane 42 is achieved with aqueous NH3 to provide 43 unit (Scheme 7).54 44 is obtained by treatment 43 unit with chloroacetyl chloride in the existence of Et3N followed treatment with

t-BuOH and t-BuOK to give the amide 44 in 64% yield over two steps. Amide 44 reduction is accomplished with Red-Al in toluene to deliver 45. (+)-Mandelic acid in absolute EtOH is used for the resolution of the amine 45. After two days, crystals are formed which are recrystallized from EtOH to afford pure mandalate salt in 73% yield. The mandalate salt is partitioned between EtOAc solvent and aqueous K2CO3 to give 46 in almost 70% overall yield (Scheme 7). Following deprotection and protection manipulations and standard protection manipulation then advanced 46 to amino alcohol 47. This precursor 47 is only two steps away from the two potential norepinephrine reuptake inhibitors viz. (S,S)-reboxetine 7 and its methyl analogue 48. The drawbacks of this strategy are the large number of steps are involved along with the maximum 50% theoretical yield of a resolution step. A disadvantage of resolution through S-mandelic acid is that the one enantiomer is not recoverable from the reaction mixture. However, the key feature of this synthesis is that this protocols allows the synthesis of (S,S)-reboxetine as well as its analogues. By applying this approach, one can synthesized different analogues of (S,S)-reboxetine.54


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mC P 80 BA %

Scheme 7. Synthesis of (2S,3S)-reboxetine via resolution approach method. 3.3 (S,S)-Reboxetine synthesis by β-amino alcohols stereospecific rearrangement The primary NH2 and OH units in 49 are benzoylated to deliver moiety 50 with a yield of 96%. On the benzylic alcohol, it is very necessary to accomplish a Mitsunobu reaction (Scheme 8). After treatment of 50 with an excess of o-ethoxyphenol, triphenylphosphane (PPh3) and diisopropyl azodicarboxylate (DIAD), the reaction mixture is stirred in THF for



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30-40 min at r.t to generate desired benzylic ether 51 as the major entity in 76% yield.55 Reduction of 51 is performed in next step by reaction with borane tetrahydrofuran complex solution (BH3.THF) in refluxing THF for 3 h to afford 2-(Benzylamino)ethanol 52 in 92% yield. Diol 53, the precursor used for stereospecific rearrangement of β-Amino Alcohols, is attained in 70% yield (2 steps from 52) by N-alkylation using methyl 2-bromoacetate which is subsequently reduced by LAH. The diol 53 is then subjected to the rearrangement reaction using trifluoroacetic acid in THF under microwave irradiation conditions (Scheme 8). The obtained amino alcohol 54 is isolated in only yield of 36%, possibly due to sensitivity of the ether functionality in acidic environments. Moreover, to attain the morpholine unit, a solution of aminodiol 54 is treated with TsCl. The reaction mixture is then treated with sodium hydroxide to provide 54a in 57% yield which can be transformed in to desired (S,S)reboxetine 7 up to 80-90% yield by utilizing simple deprotonation protocol.55 This is the first protocol to complete (S,S)-reboxetine 7 total synthesis in 8 steps with an enhanced overall yield i.e. 8.5%. However, the main disadvantage of this protocol is the low yield (36%) of amino alcohol rearrangement of N,N-dialkyl-β-amino alcohol 53 to 54.


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Scheme 8. (2S,3S)-Reboxetine through catalytic stereospecific rearrangement. 3.4 Jacobson’s HKR method for reboxetine development Santhosh Reddy reported Co(III)(salen)-catalyzed 56 Jacobsen's hydrolytic kinetic resolution focused approach towards (S,S)-reboxetine 7 (Scheme 9). Route for 7 commenced with the conversion of racemic syn-benzyloxy epoxide 55, which in turned efficiently derived in excellent diastereoselective way from the E-allylic alcohol, catalysed by Co(III)(salen)catalyzed HKR 56 to the corresponding chiral epoxide 58 and diol 57 that are isolated in excellent optical purity and yields.56 Chiral epoxide 58 regiospecific opening with aqueous NH4OH afforded amino alcohol 59 in almost 83% yield, which is reacted with chloroacetyl chloride in the existence of Et3N followed treatment with t-BuOK and t-BuOH to give imide 60 in 72% yield (Scheme 9). Alcohol 61 is prepared from 60 in 75% overall yield via following three steps reaction sequences i) carbonyl reduction with Red-Al in the presence of



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NaOH in dry toluene, ii) protecting NH of 60 with Boc group using (Boc)2O in presence of Et3N in DCM and iii) deprotecting benzyl ether (Bn) protecting group with palladium on carbon. The treatment of 61 with tetrabromomethane in the presence of triphenylphosphine in DCM followed by reaction with 2-ethoxyphenol in presence of NaH in DMF furnished (S,S)reboxetine 7 in 98% ee after TFA in DCM treatment. This approach is highly useful and practical for constructing reboxetine 7. In a single step, the Co(III)(salen)-catalyzed hydrolytic kinetic resolution of racemic alkoxy- and azido epoxides offers a highly practical pathway to enantiopure anti- or syn-alkoxy- and azido epoxides and the corresponding 1,2diols. This procedure is suitable to carry out under mild conditions demonstrating a spacious range of substrate scope. Moreover, the valuable features of this synthetic approach are rapid approachability of catalyst 56 in both enantiomeric forms.56


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Scheme 9. (2S,3S)-Reboxetine synthesis through Co-catalyzed HKR of syn-benzyloxy epoxide. 3.5 Sugar based chiral pool synthon protocol to obtain (2R,3S)- and (2S,3S)-reboxetine Abdul Rauf et al. demonstrated a novel methodology which is effectively applied in the synthesis of (2S,3S)- and (2R,3S)-reboxetine 7 and 67. High yielding regioselective construction of chlorohydrin and its indirect access to epoxide with retention of configurations against in usual Mitsunobu reaction is a vital characteristic of this versatile approach (Scheme 10). The procedure utilized the precursor (R)-2,3-o-cyclohexylidene-Dglyceraldehyde 62, which can be simply attained from D-mannitol. Grignard reaction of 62 with phenylmagnesium bromide delivered diastereomers (2R,3R)- and (2R,3S)-63 in a 1:1



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ratio, which are easily separable by column chromatography.57 The (2R,3R)-63 was subjected to Mitsunobu conditions with o-ethoxyphenol to give (2R,3S)-64, which is then deprotected using p-toluenesulfonic acid in MeOH to afford (2R,3S)-diol 16. The obtained 16 is transformed to synthon (2S,3S)-65 by Mitsunobu chloride substitution with diisopropyl azodiformate in the presence of triphenylphosphine and trimethylsilyl chloride. Reaction of (2S,3S)-65 with DBU in DCM afforded (2R,3S)-epoxide 66 in 98% yield and the retention of configuration is observed in this reaction (Scheme 10). The (2R,3S)-reboxetine 67 is obtained in 43% overall yield through epoxide ring opening of 66 with sulfuric acid mono 2aminoethylester in the presence of DBU in THF and subsequent cyclization with NaOH in THF. For the preparation of (2S,3S)-reboxetine 7, the (2R,3S)-diol 16 is transformed to (2S,3S)-epoxide 19 in the presence of Mitsunobu reaction conditions followed by epoxide ring opening with the same bifunctional subunit sulfuric acid mono 2-aminoethylester and cyclization under basic conditions (NaOH in THF) in good yields. The procedure of chlorohydrin construction may also be used for the synthesis of epoxides in excellent yields with the retention of configuration.57


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Scheme 10. Synthesis of (2S,3S)- and (2R,3S)-reboxetine using the precursor (R)-2,3-ocyclohexylidene-D-glyceraldehyde. 3.6 Asymmetric dihydroxylation methodology to construct (S,S)-reboxetine framework



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Siddiqui et al. disclosed a new and enantioselective synthesis of (2S,3S)-reboxetine 7 in nine linear steps with an overall yield of 21% from commercially available t-cinnamyl bromide 68.58 The synthesis of (2S,3S)-reboxetine 7 is effected through the synthetic pathway as displayed in Scheme 11. Sharpless asymmetric dihydroxylation condition i.e. osmium tetroxide (OsO4) and potassium ferricyanide (K3Fe(CN)6) as co-oxidant in the presence of the chiral ligand hydroquinidine 1,4-phthalazinediyl diether ((DHQ)2PHAL) and sodium bicarbonate (NaHCO3) as a buffering agent transform t-cinnamyl bromide 68 to diol 69 in 84% yield with 96% ee. Nucleophilic displacement of the bromo moiety in 69 with sodium azide (NaN3) afforded the azido-alcohol 70 in 80% yield.58 The azide moiety is then reduced to amine moiety using 10% Pd/C (Scheme 11). The obtained free amine 71 (in 90% yield) is then reacted with chloroacetyl chloride to obtain amide 72a in 70% yield, which is easily cyclized to entity 73 in the presence of strong basic condition. This cyclized amide 73 is then reduced by application of Vitride in THF at 0 °C, which afforded the morpholine precusor 74 in 83% yield. The 2o amine is protected with t-butoxycarbonyl (Boc) moiety to furnish 75 in 83% yield.58 The free OH unit in 75 is reacted with chromium complex of 2-ethoxy fluorobenzene 138 followed by deprotection by trifluoroacetic acid (TFA) to furnish the (2S,3S)-reboxetine 7 in 88% yield (Scheme 11). The vital feature of this approach towards (2S,3S)-reboxetine 7 is the application of Sharpless asymmetric dihydroxylation, which are used as a source of chirality into nonchiral reactant 68. Sharpless asymmetric dihydroxylation is a powerful, important, significant and unique tool, which provides high yield and excellent enantioselectivity. However, since osmium tetroxide is expensive and very toxic, it has become favourable to make catalytic variants of this reaction.


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Scheme 11. Enantioselective synthesis of (2S,3S)-reboxetine. 3.7 Synthesising (S,S)-reboxetine from chiral amino diol Tamagnan and co-workers reported an effective stereospecific synthesis leading directly to (2S,3S)-reboxetine 7. This work also represented a convenient pathway to an extensive range of chiral α-aryloxybenzyl analogous of morpholine. Commercially available (S)-3-amino-1,2propanediol 76 is used as a starting material.59 Treatment of 76 with chloroacetyl chloride in the presence of acetonitrile and methanol furnished 77-amide in almost 94% yield. Without protection of the 1o alcohol, transformation to morpholinone 78 is successfully accomplished directly by addition of 77 to a solution of t-AmOH and t-BuOK, affording entirely 78 with no detectable trace of 7-membered cyclization product.59 Hydride reduction using vitirde of 78 furnished 78a in almost 85% yield. Treatment of 78a with (Boc)2O and subsequent reaction with trichloroisocyanuric acid (TCIA) in the presence of TEMPO and NaHCO3 in solvent EtOAc at -5oC afforded aldehyde 79 in 89% yield.59 The existence of NaHCO3 is valuable for neutralization

of

hydrochloric

acid

which

is formed during

the

reduction

of

trichloroisocyanuric acid, thus avoiding Boc group partial loss (Scheme 12). By avoiding



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development of chlorination as side products, application of solvent ethyl acetate instead of DCM significantly improved the reaction yields. The conversion is carried out effectively by union of 79 with excess diphenylzinc (Ph2Zn). The finest transformation is attained by addition of 79 to diphenylzinc (Ph2Zn) in solvent THF at -10 °C, produced in situ from phenylmagnesium bromide (PhMgBr) in solvent THF and anhydrous Zinc bromide (ZnBr2). Flash chromatography on silica gel are used to separate the resulting mixture of diastereomers of (2S,3S)-80a and (2S,3R)-80b to furnish 60% and 19% yields, respectively (Scheme 12). The chief challenge in this work is the transforming the key isomer (2S,3S)-80a to ether 81 without affecting the stereochemistry. For this purpose, aromatic nucleophilic substitution is the most suitable way.59 Sodium alkoxide of (2S,3S)-80a in solvent DMF treated with chromium complex of 2-ethoxy fluorobenzene 138 (which in turn prepared from refluxing 2-flourophenol and Cr(CO)6 together) to deliver two complexes of chromium, which led to 81 in almost 95% yield after oxidative dechromination (process of removing residual chlorine through oxidation) with iodine (I2). Lastly, reaction of Boc amide 81 with excess trifluoroacetic acid (TFA) furnished (2S,3S)-reboxetine 7 in 98% yield and in 30% overall yield with 99% ee in eight steps. The key approaches in this synthetic protocol are selective oxidation of an N-protected hydroxymethylmorpholine and aryl-chromium-based nucleophilic aromatic substitution. These key approaches play vital role in providing 7 in 30% overall yield with 99% ee.


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Scheme 12. (2S,3S)-Reboxetine synthesis through (S)-2-(hydroxymethyl) morpholine preparation. 3.8 Utilization nitroaldol adducts for the synthesis of (S,S)-, (R,R)-, (S,R)- and (R,S)reboxetine Liu et al. employed chiral amino alcohol-copper catalysts viz. Cu-ent-L1c and Cu-L1c on a 30.0 mole scale to catalyze the key diastereoselective Henry nitro-aldol reactions of chiral aldehydes (R)-82 or (S)-82 with nitro-methane, which results in the preferential formation of corresponding stereoisomers of nitro-diol 83 (Scheme 13). In organic synthesis, the catalytic asymmetric Henry reaction, for the establishment of C-C bond, is a powerful and atomeconomical methodology on account of the resulting β-nitro alcohols can be easily transformed into β-amino alcohols and other important precursors, which are beneficial for the synthesis of complex bioactive entities.60



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OTBS R NO2 S OH

OTBS S NO2 S OH OTBS O

L1c (5%) (1S,2S)-83a MeNO2 syn/anti=10.4:1 86% . CuOAc H2O (5%) rt, 3d

(S)-82 Henry reaction

CuOAc.H2O (5%) rt, 3d

(1S,2R)-83d syn/anti=1:8.4 68%

rt, 3d OTBS CuOAc.H2O (5%) O

rt, 3d CuOAc.H2O (5%)

OTBS R NO2 R OH

ent-L1c MeNO2

MeNO2 L1c (5%)

(R)-82

MeNO2 ent-L1c

OTBS S NO2 R OH (1R,2S)-83b syn/anti=1:9.5 64%

(1R,2R)-83c syn/anti=10.9:1 87% N (CH2)5

OH L1c

N (CH2)5

OH ent-L1c

Scheme 13. Copper catalysed Henry nitro-aldol reactions. For the synthesis of (2S,3S)-reboxetine 7, a model reactant (1S,2S)-83 was selected (Scheme). Cleavage of silyl ether in aqueous hydrochloric acid in CH3OH furnished nitro-diol (1S,2S)84 in excellent yield (84%). Reduction of the nitro moiety of (1S,2S)-84 into the amino moiety using Pd/C-catalyzed hydrogenation followed by treatment with 2-chloroacetyl chloride in the presence of K2CO3 delivered chloroacetamide (2S,3S)-72a in 71% yield. After lactam ring formation, reduction and protection protocols advanced (2S,3S)-72a to (2S,3S)80a in 70% overall yield from 72a (Scheme 14). This methodology provides (2S,3S)-7 in 30% overall yield from (S)-82. Using the same protocol (2S,3R)-, (2R,3R)- and (2R,3S)reboxetines are also synthesized from their corresponding nitro-aldol adducts 83. Using this novel catalytic methodology, all 4 isomers of the reboxetine are divergently synthesized. The key feature of this synthetic protocol is that the structurally diverse reboxetine derivatives can be conveniently synthesized because phenols are commercially available and plentiful.60


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Scheme 14. Utilization of nitro-aldol adducts for synthesis of reboxetine. 3.9 (2S,3R)- and (2R,3S)-Reboxetine synthesis via amide-stabilized sulfur ylide Aparicio et al. reported a straight-forward and stereo-divergent access to (2S,3R)- and (2R,3S)-reboxetine diastereoisomers (88 and 67) by application of chiral amide-stabilized sulfur ylide 85, which is derived from N-ethylaniline in quantitative yield (Scheme 15). Condensation reaction of 85 with benzaldehyde in the presence of base t-BuOK and THF, leads to development of a 73/27 diastereoisomeric mixture of trans epoxides 86a and 86b in the quantitative yield.61 The nucleophilic opening of epoxides 86a and 86b by addition of 20 mol % of ether 18-crown-6 resulted in the diastereoisomeric mixture of compounds 87a+87b in 95% yield. The diastereoisomers are simply separated by column chromatography. 87a is the minor diastereoisomer (25% yield) while 87b is the major diastereoisomer (69% yield). The reduction of 87b using borane dimethyl sulfide complex (BH3.Me2S) generate 89, in almost 75% yield. The morpholine 90 is prepared from 89 in 83% overall yield via following



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three steps reaction sequences i) amidification of 89 with 2-bromoacetyl bromide, ii) treatment with t-BuOK and iii) reduction manipulation with BH3.Me2S. The final reaction is chemoselective hydrogenolysis (reaction in which hydrogen is added to an entity and breaks its the carbon-carbon or carbon-heteroatom single bond) of 90 under hydrogenation conditions to furnish the required (2R,3S)-reboxetine 67 in 80% yield.61 The (2S,3R)reboxetine 88 is also attained using the same technique of diastereomer 87b. In brief, using only 6-steps, (2R,3S)-reboxetine 67 is attained in 36% overall yield whereas (2S,3R)reboxetine 88 is attained in 14% yield from the synthon 85. This versatile strategy provided scalable access to both enantiomers. In this approach the reduction of amides (87a and 87b) are successfully accomplished through borane dimethylsulfide (BH3.Me2S), which does not degrade amides and demonstrate better solubility and stability in organic media.


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Scheme 15. (2S,3R)- and (2R,3S)-Reboxetine synthesis via amide-stabilized sulfur ylide. 3.10 Obtaining (2R,3S)-reboxetine from tandem cyclic sulfate rearrangement-opening Soo et al. pursued the novel method for the synthesis of diastereoisomers (2R,3S)-reboxetine 67. Starting from t-cinnamyl alcohol 14, within nine steps the desired moiety is achieved in 43% overall yield (Scheme 16).62 The synthesis is commenced with TBDMS-protection of 14 to generate 91 followed by Sharpless asymmetric dihydroxylation (AD) (AD-mix-α 92, 95%) to produce 92 which is then subjected to cyclic sulfate formation (thionyl chloride (SOCl2); sodium Periodate/ruthenium(III) chloride (NaIO4-RuCl3) to access 93, 100%).61 This envisioned an efficient dihyroxyaltion (AD), wherein the desired activation at carbon-1 and carbon-3 of 93 (for the insertion of azide-functionality at carbon-3, and the aryloxy moiety at



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carbon-1) would be accomplished in a one-pot single reaction step utilizing cyclic sulfate formation and following rearrangement process. In fact, this protocol is initially established to address the limitation of the asymmetric dihyroxylation methodology, i.e., its incapability to produce anti-diols directly since (Z)-alkenes are not fine substrates for the asymmetric dihyroxylation. However, desilylation (tetra-n-butylammonium fluoride; TBAF) prompted a rearrangement to the terminal epoxide 95, which is then opened by azide anion (N3‫ )־‬after the cyclic sulfate rearrangement-opening stage and following reaction of crude azide anion (N3‫)־‬opened product 96 with o-ethoxyphenol in sodium hydroxide.62 The diol 94 is attained in 84% yield from the cyclic sulfate 93 (Scheme 16). Azido functionality reduction (with hydrogen in presence Pd/C, 88%), amidation (formation of an amide) of 97 to 98 (with the assistance of chloroacetyl chloride, 84%), cyclization of 98 to 99 (using potassium t-butoxide (t-BuOK), 99%), and reduction of the lactam function of 99 to 67 (with borane methyl sulfide complex (BH3.Me2S), 73%) all ensued smoothly to afford (2R,3S)-reboxetine 67.62


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Scheme 16. (2R,3S)-Reboxetine synthetic via tandem cyclic sulfate rearrangement-opening. 3.11 (S,S)-, (R,R)-, (S,R)- and (R,S)-Reboxetine synthesis via asymmetric transfer hydrogenation Professor Se-Mi and Hyeon-Kyu reported the dynamic kinetic resolution (DKR; also called second order asymmertic transformations)-driven chiral Ruthenium-catalyzed asymmetric transfer hydrogenation (ATH) approach for asymmetric reduction of racemic 100, which yielded the corresponding (2R,3S)- and (2S,3R)-2-(hydroxyphenylmethyl)-morpholin-3-ones 102.63 The resulted chiral alcohols are utilized then to synthesize all 4 stereoisomers of the anti-depressant reboxetine. The methodology commenced (Scheme 17) with asymmetric



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transfer hydrogenation reaction of 100 using the catalyst RuCl[(R,R)-TsDPEN](mesitylene) ((R,R)-101b), which possesses an η6-arene=mesitylene ligand, delivered alcohol (2R,3S)102a in the excellent yield i.e. >98% and in 99% enantiomeric excess. And asymmetric transfer hydrogenation reaction of 100 with the enantiomeric catalyst RuCl[(S,S)TsDPEN](mesitylene) ((S,S)-101a) affords the alcohol (2S,3R)-102b as the chief product with 99% enantiomeric excess).63 Both reaction utilized vary but suitable mixture of triethylamine (Et3N) and formic acid (HCOOH) as the hydrogen source (Scheme 17). The resultant morpholinone-alcohols 102a and 102b, could potentially serve as beneficial late stage synthons in pathways for the synthesis of all 4 stereoisomers of the reboxetine. The lactam unit in (2R,3S)-102a reduction with borane tetrahydrofuran complex solution (BH3·THF) efficiently affords the benzyl morpholine alcohol (2S,3S)-103a in 97% yield. Using triphenylphosphine dibromide (Ph3PBr2), this (2S,3S)-103a is transformed to the corresponding bromide morpholine (2S,3R)-104, inversion of configuration takes place in this procedure. Bromide displacement of (2S,3R)-104 with o-ethoxyphenol in the existence of potassium tert-butoxide (t-BuOK) delivers the N-benzyl-protected (2S,3S)-reboxetine (2S,3S)-106.63 Reaction of (2S,3S)-106 with 1-chloroethyl chloroformate (ACE-Cl) and subsequent methanolysis (alcoholysis reaction in which the solvent alcohol is methanol) of the precursor 1-chloroethyl carbamate promotes selective removal of the N-benzyl moiety and produces (2S,3S)-reboxetine 7 in a 4-step pathway from alcohol (2R,3S)-102a and without optical purity deterioration. Likewise, (2R,3R)-reboxetine 8 is also synthesized from optically pure (2S,3R)-102b using the same way as employed for the construction of (2S,3S)reboxetine 7.63 (2S,3R)-reboxetine 88 can be suitably synthesized from the same precursor (2S,3S)-103a which is used in the synthetic pathway of (2S,3S)-reboxetine 7 (Scheme 17). Therefore, treatment of (2S,3S)-103a with o-ethoxyphenol under Mitsunobu conditions furnishes (2S,3R)-106 with inversion of conformation at benzylic position. Following N-


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debenzylation of (2S,3R)-106 yields (2S,3R)-reboxetine 88. (2R,3S)-reboxetine 67 is also synthesized starting 103b using essentially the same way. This study has resulted in the construction of highly efficient and stereoselective routes for the synthesis of all four isomers of reboxetine from the common precursors. Following advantages are associated with this novel synthetic methodology i) in this methodology, the stereochemistry at two contiguous stereocenters is controlled simultaneously with outstanding levels of enantio- and diastereoselectivity and ii) asymmetric transfer hydrogenation (ATH) has significant advantage over conventional catalytic metal hydride reductions. It avoids the special handling techniques involved and the use of molecular hydrogen. However, in the case of reduction with BH3.THF, special techniques are required. Borane tetrahydrofuran (BH3.THF) solution is a valuable reagent for reduction but it suffers from the disadvantage in that the solutions are less soluble in organic media and are highly sensitive to air. Moreover, these solutions are unstable over a period of time and requires the use of air-free technique.63



EtO

EtO

O

H

S

S 7 (S,S)-Reboxetine 71% yield from 100

O

(i-Pr)NEt2 CH2Cl2, 86%

O

S

S N

106

OH KOt-Bu, t-BuOH 80 oC, 91%

R

S N 88 H (S,R)-Reboxetine 51% yield form 100

O

H

OEt

O

H

Cl

O

H3C

N H

EtO

O

Cl

O

EtO

O

O

N

Br R

H S

p De ro te

O

io ct

H

R

104

S

n

N

106

Ph3PBr2 CH2Cl2, 50 oC

OEt

95%

OH O S O N Ru N Cl H2

O

H

M co itsu nd no itio bu ns

OH S

R N

O

OH S

S

O

(R,R)-101b (0.5 mol%)

H

N

103a

BH3.THF, 60 oC 97%

HCO2H/Et3N (0.2:1) CH2Cl2, 35 oC

(2R,3S)-102a, 98%

EtO

(dr 99:1, 99% ee) O

O

N Bn

O

100 Racemic

O S O N Ru N Cl H2 (S,S)-101a (0.5 mol%)

O N

(2S,3R)-102b, 97% (dr 99:1, 99% ee)

H

O

H

OH R

R

R

R

employing same procedure as for the production of (S,S)-Reboxetine 1

O 102b

HCO2H/Et3N (5:2) CH2Cl2, 35 oC EtO

O

OH R S

H

O

N 8 H (R,R)-Reboxetine 64% yield from 100 st ep s

O

H

3

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N

103b

ps 2 ste

O S

R N 67 H (R,S)-Reboxetine 44% yield from 100

employing same procedure as for the production of (S,R)-Reboxetine

Scheme 17. (S,S)-,(R,R)-,(S,R)- and (R,S)-Reboxetine synthesis via DKR-based-ATH. 4. Synthetic developments for achieving better analogues of reboxetine 4.1 Developing (2S,3S/2R,3R)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholine series


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Javier and Carlos, in quest of exploration of new selective inhibitors of norepinephrine transporter (NET), targeted the highly efficient diastereoselective synthesis of family of compounds

(2R,3R/2S,3S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholine

113.64

The

series

featured the same 2,2’-anti stereochemistry as reboxetine, which played a pivotal role in inhibitory activity. Morpholine 109 with E stereochemistry attached with triflate group could serve as a key intermediate (Scheme 18 and Table 1). Under considerable reaction optimization, ketone 108 deprotonation with potassium tert-butoxide (t-BuOK), 18-crown-6,

N-phenyl-bis(trifluoromethanesulfonimide) (PhN(SO2CF3)2) and 0.5 equivalent of water in solvent THF at 0oC delivered the required E-enol-triflate 109 in 65-70% yield and 9:1 ratio of (E)- to (Z)-enol triflate. Following Pd-catalyzed coupling with o-substituted benzylzinc reagent 111 and final standard Pd-catalyzed hydrogenation then advanced intermediate 109 to final racemic product 113.64



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Scheme 18. Synthesis of (2R,3R/2S,3S)-2-[2-(2-aryl)-1-phenyl-ethyl]-morpholine series. Table 1. Yield of 112 and 113. R

112 (Yield %) 113 (Yield %)

OEt

80

80

OMe

85

81

Ph

88

80

i

Pr

88

82

OPh

87

85

OTBDMS

76

72


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4.2 Iodine substituted analogues of (2R,3S)- and (2S,3R)-reboxetine Jobson et al. reported the stereoselective synthesis of iodine analogues of (2R,3S)- and (2S,3R)-reboxetine (125 and 128) form the 4-bromobenzaldehyde 114 (Scheme 19 and 20).6567

The key steps involved in this strategy the same Sharpless asymmetric epoxidation (SAE)

as describes many times above for the establishment of stereogenic centres. The end game sequence a new methodology is utilized first time to insert the iodine entity via Cu-catalysed halogen exchange reaction (Scheme 19). The inception of the synthetic strategy began by subjecting 4-bromobenzaldehyde 114 in Horner-Wadsworth-Emmons under MasamuneRoush conditions to yield E-ester 115.65-67 Following DIBAL-H reduction and Sharpless asymmetric cascade with diisopropyl tartrate (DIPT; diester of tartaric acid) then advanced 115 to epoxide 117. Reaction of 117 with o-ethoxyphenol would furnish diol 118a and treatment of obtained diol 118a with p-toluenesulfonyl chloride (TsCl) in the presence of 4dimethylaminopyridine (DMAP) and base triethyl amine (Et3N) in solvent Et2O followed by reaction aqueous ammonia (NH3) in solvent acetonitrile delivered amino-alcohol 119a. The morpholine unit on 119a is constructed via following three steps reaction sequences i) treatment of 119a with chloroacetyl chloride to deliver 120a in 83% yield, ii) cyclisation reaction using sodium tert-butoxide in tert-Butyl alcohol to afford 121a in 79% yield and iii) reduction of carbonyl group of 121a with ammonia borane in THF to obtain 122a in 73% yield. Protection with Boc protecting group yielded 123a (75%). Cu-catalysed halogen exchange reaction under Klapars and Buchwald iodination condition furnished 124 in 49% yield. 124 is subjected to deprotection conditions (TFA in DCM) to create the target, (2R,3S)iodoreboxetine 125, in 57% yield (Scheme 19). In vitro testing of the compound 125 depicted significant potency.65-67



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Scheme 19. (2R,3S)-Iodoreboxetine synthesis. For the preparation of the (2S,3R)-stereoisomer 128 the inverse enantiomer DIPT is employed (Scheme 20).65-67 Treatment of (2E)-3-(4-bromophenyl)-2-propen-1-ol with (+)DIPT afforded 126 in 79% yield. Reaction of 126 with o-ethoxyphenol would furnish diol 118b and treatment of obtained diol 118b with p-toluenesulfonyl chloride (TsCl) in the presence of 4-dimethylaminopyridine (DMAP) and base triethyl amine (Et3N) in solvent Et2O followed by reaction aqueous ammonia (NH3) in solvent acetonitrile delivered amino-


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alcohol 119b.65-67 The morpholine unit on 119b is constructed via following three steps reaction sequences i) treatment of 119b with chloroacetyl chloride to deliver 120b in 84% yield, ii) cyclisation reaction using sodium tert-butoxide in tert-Butyl alcohol to afford 121b in 79% yield and iii) reduction of carbonyl group of 121b with ammonia borane in THF to obtain 122b in 73% yield. Protection with Boc protecting group yielded 123b (76%). Cucatalysed halogen exchange reaction under Klapars and Buchwald iodination condition furnished 127 in 49% yield. 127 is subjected to deprotection conditions (TFA in DCM) to create the target, (2S,3R)-iodoreboxetine 128, in 57% yield (Scheme 20).65-67 Br

OEt Br OH

(+)-DIPT, Ti(Oi Pr)4, t-BuO2H 4 A mol. sieves, CH2Cl2

OH

Br O H

79% ee >98%

OH

H

116

126 Br

2) 25% NH3 (aq.) MeCN, 49%

OH

O OEt

Cl

Et3N, MeCN 84%

NH2

119b

O OEt

OH

Cl

N H

O

O

O

N H

122b

76%

O OEt 123b

N H

121b

Br

THF

OH

O

O

79% OEt

120b

O

I

(Boc)2O, DMAP Et3N, CH2Cl2 OEt

118b Br

, t-BuOH

Br

73%

OEt

O-Na+

O Cl

OH

O

Br

1) TsCl, DMAP Et2O, Et3N, 82%

BH3.NH3,

NaOH, 70 oC 66%

O

CuI (cat), NaI 1,3-diaminopropane 1,4-dioxane 49% O

N Boc

I

OEt 127

O N Boc

TFA,CH2Cl2 57%

O OEt

O N H

128

Scheme 20. (2S,3R)-Iodoreboxetine synthesis. Jobson et al. disclosed stereoselective synthesis of (2S,3S)-iodoreboxetine 140 and (2R,3R)iodoreboxetine 142. Both 140 and 142 analogues depicted potent binding affinity with



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nordrenaline transporter (NAT) versus the related serotonin reuptake transporter (SERT) and dopamine reuptake transporter (DAT). The inception of the synthetic strategy began by subjecting 4-iodobenzaldehyde 129 in Horner-Wadsworth-Emmons under Masamune-Roush conditions followed by DIBAL-H reduction to yield 130 in 96% overall yield.65-67 The only difference was utilization of Sharpless asymmetric dihydroxylation of allylic chloride moiety 131 rather than Sharpless asymmetric epoxidation (SAE) to originate the two stereogenic centers containing bishydroxylated specie 132a using AD-mix-α in 84% yield with an excellent 98% ee. Treatment of 132a with sodium hydroxide (NaOH) led to effective creation of epoxide 133a in 98% yield and subsequent reaction with aqueous NH3 solution to obtain the required amino alcohol 134a in 90% yield.65-67 Treatment of amino alcohol 134a with chloroacetyl chloride furnished amide 135a and ring closure is then effected by application of sodium tert-butoxide (NaOtBu) which afforded morpholinone 136a in 37% yield over the 2 steps (Scheme 21). Reduction of morpholinone and subsequent protection of the resulting morpholine yielded 137a. SNAr reaction of 138a with 137a in the presence of NaH furnished 139a. Lastly, protecting group removal using TFA gave (2S,3S)-iodoreboxetine 140a in 60% yield.65-67


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Scheme 21. (2S,3S)-Iodoreboxetine synthesis. The same methodology is applied for the (2R,3R)-iodoreboxetine 140b synthesis (Scheme 22). In this case, subjection of 1-[(1E)-3-chloro-1-propen-1-yl]-4-iodobenzene 131 to an asymmetric dihydroxylation via AD-mix-β, which delivered the corresponding diol 141 in good yield (62%). Treatment of 132b with sodium hydroxide (NaOH) led to effective creation of epoxide 133b in 99% yield and subsequent reaction with aqueous NH3 solution to obtain the required amino alcohol 134b in 90% yield.65-67 Treatment of amino alcohol 134b with chloroacetyl chloride furnished amide 135b and ring closure is then effected by application of sodium tert-butoxide (NaOtBu) which afforded morpholinone 136b in 37.7% yield over the 2 steps (Scheme 22). Reduction of morpholinone and subsequent protection of the resulting morpholine yielded 137b. SNAr reaction of 138b with 137b in the presence of NaH furnished 139b. Lastly, protecting group removal using TFA gave (2R,3R)iodoreboxetine 140b in 61% yield.65-67



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Scheme 22. (2R,3R)-Iodoreboxetine synthesis. 4.3 Flourine substituted analogues of (2S,3S)-reboxetine Xu and co-workers developed a way to access flourine substituted analogs of (S,S)reboxetine. Synthetic strategy is initiated from the hydroxymorpholine 143 (Scheme 23). Oxidation of hydroxymorpholine 143 with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) in the presence of sodium hypochlorite, potassium bromide and tetrabutylammonium chloride followed by treatment with phenyl lithium 141 afforded 145 in 63.7% overall yield from 143. The reduction of 145 is accomplished with hydrogen in the presence of Ru-complex containing R-Xyl-BINAP/R-DPEN (Scheme 23). After establishing the desired stereocenters, Mitsunobu reaction of selected substituted phenols 142 with the 2o alcohol 146 proceeded, delivering the protected ethers 147. Subsequent deprotection with hydrochloric acid in dioxane generates the morpholine product 148 in excellent yields (Table 2). This chemical synthesis protocol allows to synthesize a library of reboxetine analogues.68


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Scheme 23. Flourine substituted analogues of (2S,3S)-reboxetine. Table 2. Scope of R1. R1

Yield %

4-F

82

3-F

84

2-F

88

2-Cyano

90

2-Methylsulfonyl

80

4.4 3-Methy-4-chloro analogues of (2S,3S)- and (2R,3R)-reboxetine Fish et al. demonstrated the stereoselective synthesis of analogs of reboxetine 153 and 160 by using a extremely selective kinetic resolution of racemic 149a catalysed by enzyme (lipase

cadida rugosa) as the main step, which in turn obtained from N-benzylethanolamine 149 using 3 steps i.e. (i) reaction with 2-chloroacrylonitrile in Et2O, (ii) treatment with potassium

tert-butoxide in DME and (iii) reaction with butanol in H2SO4 (Scheme 24). The synthesis started with the combination of the n-Bu ester 149a with lipase Candida rugosa in the presence of t-BuOMe-H2O, with the enzyme catalysing the hydrolysis of the (S)-ester 149a to afford (S)-acid 150 whilst leaving the (R)-ester 151 untouched.69,70 On scale-up, resolution of



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149a gave ester 151 (94%; >99% ee) and acid 150 (97%; >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 afforded the (R)- and (S)-morpholine acids 154 and 152, respectively (Scheme 24). The conversion of acid 154 to 160 is pursued by the introduction of the second stereocenter aided with diastereoselective reduction of ketone 156. Along this line, activation of 154 with 1-propylphosphonic anhydride (T3P), subsequent treatment with HN(Me)OMe furnished Weinreb amide 155 in excellent yield (85%) and then reaction of 155 with the Grignard reagent phenylmagnesium bromide (PhMgBr) delivered the phenyl-ketone 156 with no noticeable loss in ee. Zinc mediated hydride reduction generated the (S,R)-alcohol 157 along with the formation of the second stereogenic center with satisfactory diastereoselectivity (S,R:R,R 16:1).69,70 The insertion of the aryl ether is most competently attained from 157 with a two-step course of mesylation reaction and displacement reaction. Reaction of 157 with methanesulfonyl chloride (MeSO2Cl) provided mesylate 158, and displacement of the MsO entity of 158 with 4-chloro2-methoxyphenol in the presence of cesium carbonate (Cs2CO3) in dioxane delivered the corresponding (R,R)-aryloxy ether 159 in excellent yield (95%), with complete inversion of the benzylic stereochemistry and no noticeable loss of ee (Scheme 24). Finally, deprotection of 159 with HCl afforded the (R,R)-amine 160. Similalry, (S,S)-enantiomer 153 is synthesized by an identical order, but with the (S)-acid 152 as starting material. (S,S)-153 was found to be potent and selective against dual SNRI (Serotonin Noradrenaline Reuptake Inhibition) and can be put forward as a candidate for further pre-clinical evaluation.69,70


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O S

NH S

(S,S)-analog

O

153 MeO

HO

Cl

HN 149

O HO

1) CH2=C(Cl)CN, Et2O, 40oC, quant 2) t-BuOK, DME, reflux 65%;

n-BuO

N S

lipase Cadida rugosa t-BuOMe-H2O, rt

N O

HO

97% yield >99% ee

150 O

+

151 O

R

Boc

PhMgBr, THF rt, 98%

O 156

EtOH, reflux 2) LiOH N

R

O

1) 2,5-dihydrotoluene 10%-Pd/C, (Boc)2

O n-BuO

149a

N

O

152

O

3) n-BuOH, H2SO4, reflux, 85%

O

NBoc S

94% yield >99% ee

CH3 O N H3CO R O 155

N

O T3P, NH(Me)OMe LiO NEt3, CH2Cl2 R Boc then O aq K2CO3, 85% 154

Zn(BH4)2 Et2O, rt

NBoc

OH OMe O

O S R OH 157

N

87% yield with (SR):(RR) 16:1

Boc

MeSO2Cl, Et3N o

CH2Cl2, 0 C

R

O S R OMs

N 158

Boc

N R

Cl Cs2CO3, reflux in dioxane 95%

Boc

O MeO

Cl 159

HCl, dioxane CH2Cl2, 95% O R R

NH

O MeO

Cl 160

(R,R)-analog

Scheme 24. Synthesis of reboxetine analogues by enzyme catalyzed kinetic resolution. 4.5 2-Methyl-3-chloro analogue of (2R,3R)- and (2S,3S)-reboxetine



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Harding et al. disclosed the enantioselective pathway towards (2R,3R)- and (2S,3S)enantiomers of 168. 3-cholorocinnamyl alcohol 161 is used as a starting material of the synthetic strategy.71 Sharpless asymmetric epoxidation (SAE) of 161 with (-)-DET in the presence of cumene hydroperoxide as oxidant provided the key intermediate 162 with greater than 84% ee (Scheme 25). Regioselective cleavage of oxiran with Guaiacol (2-methoxy phenol) afforded the intermediate diol 163, which is advanced to epoxide 164 in 60% overall yield from 163 via 4-steps i.e. (i) selective protection of the primary alcohol functionality as the TMS ether, (ii) mesylation of secondary hydroxyl group, (iii) treatment with acid to break silyl ether bond to regenerate primary alcohol and (iv) conversion to mesylate precursors to epoxide 164 under PTC conditions in basic medium. Compound 165 is prepared by reaction of 164 with ethanol-amine in toluene (Scheme 25). Following protection of the 2o amine and ring closure reaction then advanced 165 to morpholine 167.71 Finally, NBoc deprotection in trifluoroacetic acid (TFA) delivered (2S,3S)-168 with 60% overall yield. Similarly, (2R,3R)168 is also synthesized from 161 via SAE (Sharpless asymmetric epoxidation (SAE) reaction using (+)-DET.


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MeO

S

R Ti(i-OPr)4, D-DET

OH

O Cl

161

OH O R

OH

162

Cl CH2Cl2 , 4 A mol. seives

O R OH OH 163

Guaiacol NaOH, CH2Cl2

72% 85% ee

Cl 99%

1) TMSCl, Et3N,EtOAc 2) MsCl, Et3N, EtOAc 3) 2 M HCl, EtOAc 4) NaOH, toluene, MTBAC

O TsIm, NaH S S OH Cl

O

O NBoc

S

(Boc)2O

S

NH

Cl

OH 166 83%

H2N

S

OH

i-PrOH reflux

OH OH 165 70%

S Cl

O

164

60% from 163

MeO

MeO

O

O NBoc

S

TFA

S

61%

167

NH

O

O Cl

MeO

MeO

MeO

Cl

168

93% 60% overall yield

Scheme 25. 2-Methyl-3-chloro analogue of (2R,3R)- and (2S,3S)-reboxetine. 4.6 Methyl, thiomethyl, flouroalkyl, thioflouroalkyl, ester, thioester substituted analogues In an effort to find out more promising candidate associated with high potency for NET and selectively versus the DAT and SERT.72-74 Zeng et al. evaluated various derivatives of (2S,3S)- reboxetine, because the highest potency containing isomer of reboxetine always corresponds to the 2S,3S-reboxetine isomer, manipulating the key precursors 169 and 175 (Scheme 26 and Scheme 27). However, these intermediates have already been discussed in the syntheses of reboxetine enantioselectively reported by Tamagnan and colleagues (Scheme 26).72-74 Ligands 170 and 172 are synthesized in 29% and 44% yields over two steps by



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reacting 169 with 2-(methylsulfanyl)phenol and methyl 2-hydroxybenzoate under Mitsunobu conditions and subsequent deprotection with assistance of TFA. Whereas, flouroethyl 171 and flouropropyl 173 compounds are also achieved in good yields under similar reaction conditions, respectively. F O O

171

N H

F 1) DIAD, PPh3, THF 2) TFA, CH2Cl2 36%

OH CO2CH3 O

172

CO2CH3

SCH3

1)

1) O

OH DIAD, PPh3, THF

N H

2) TFA, CH2Cl2 44%

HO Ph

OH

OH DIAD, PPh3, THF

O 169

N Boc

2) TFA, CH2Cl2 29%

SCH3 O O

170

N H

F 1) DIAD, PPh3, THF 2) TFA, CH2Cl2 39% F O O

173

N H

Scheme 26. Stereoselective synthesis of 170, 171, 172 and 173. Similarly, 181 is synthesized by treating 2-methylbenzenethiol with 174, which in turn obtained through 175 with inversion of benzylic stereochemistry from S to R, in DMF using Cs2CO3 as base and subsequent deprotection with TFA (Scheme 27). By employing the similar reaction conditions, 180 and 178 are also prepared by reaction of 2methoxybenzenethiol and methyl thiosalicylate, respectively.72-74 Whereas, compounds 177


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and 179 are obtained through three steps in 36% and 53% yields, correspondingly. Following nucleophilic substitution of 175 with chromium tri carbonyl complex and deprotection afforded the 176 in 79% yield (Scheme 27).

Scheme 27. Stereoselective synthesis of 176, 177, 178, 179, 180 and 181. 5. Conclusions This review summarises all the synthetic techniques of reboxetine. The aim of this review is to point out recent advances in the field of synthesis of reboxetine and its analogous and to encourage the chemists to design and develop new bioactive reboxetine derivatives and to perform structural modifications intended to improve NRI selectivity or to decrease side



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effects. In here, we first give a smart summing-up for all the techniques. It has been investigated that, for (S,S)-reboxetine, the best overall yield (30%) is obtained from chiral amino diol protocol while the Pfizer synthesis technique produces more than 90% less waste than the original Pharmacia procedure. NBS-induced electrophilic multi-component approach for (S,S)-reboxetine is the most efficient approach because this approach offers highest flexibility in making drug analogues for further biological studies. Furthermore, to obtain (R,S)-reboxetine, amide-stabilized sulfur ylide approach and tandem cyclic sulfate rearrangement-opening protocol are the most effective procedures because the amidestabilized sulfur ylide approach, in only 6 steps, provides 35.6% overall yield; while the tandem cyclic sulfate rearrangement-opening protocol, in only 9 steps, provides 43% overall yield. Also, sugar based chiral pool synthon methodology allows the synthesis of (2S,3S)- and (2R,3S)-reboxetine, as well as the preparation of a chiral hydroxy-methyl morpholine analogue (also a precursor of (2R,3S)-reboxetine). Dynamic kinetic resolution asymmetric hydrogenation (DKR-ATH) route is worth mentioning which gives the best results so far for all four isomers of reboxetine; with excellent levels of diastereo- and enantioselectivity. However, to make DKR-ATH protocol more fruitful BH3.THF reducing agent may be replaced with some more stable and environmental begin reductant for instance BH3.(Me)2. The core steps in the synthesis of reboxetine are Sharpless asymmetric epoxidation (SAE), Sharpless asymmetric dihydroxylation (SAD), OH group protection, NH group protection, Mitsunobu reaction, amine reaction with chloroacetyl chloride and cyclization reaction for construction of morpholine ring. In order to achieve excellent yield, excellent diastereo- and stereoselectivity and minimum chemical waste, improvement and modification in these core steps are required. For this purpose, authors of the review made a number of suggestions, recommendations and implications for future research. Following are the recommended modifications in SAE which may provide more better yield (i) the catalyst is synthesized


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fresh and “aged” for 30 minutes and (ii) mesoporous silica support for heterogeneous catalysis (MCM-41) are recommended to perform SAE.75 To originate the two stereogenic centers for the synthesis of reboxetine, Sharpless asymmetric dihydroxylation (SAD) is better approach as compare to SAE. Olefin dihydroxylation using osmium tetroxide is a particularly valuable and well-established protocol for the functionalization of alkenes. However, since OsO4 is extremely toxic and expensive, it has become favourable and recommended to make catalytic variants of this reaction.76 For the protection of alcohol, attributed to excellent yield and selectivity, it is recommended to investigate triethylsilyl ether (TES)-, methoxypropyl acetal (MOP)-, triisopropylsilyl ether (TIPS)- and tert-Butyldimethylsilyl ether (TBS, TBDMS)-mediate protection protocols.77-80 Furthermore, make use of enzyme catalyzed protection of 1o alcohol which shows tremendous selectivity at room temperature. Thus, circumvents cryogenic TMS protective conditions. For amine protection, investigation on benzyloxy carbamate (CBz)-, 4-methoxybenzenesulfonamide-, trifluoroacetamide-based protection protocols are suggested.81-83 In Mitsunobu reaction, to avoid formation of so much chemical waste and simplify the separation of the product, numerous modifications to the original reagent combination have been established.84 Investigation on modified Mitsunobu reaction for reboxetine synthesis is highly recommended. For example, instead of DEAD, one variation of the Mitsunobu reaction uses resin-bound triphenylphosphane and uses di-tertbutyl azodicarboxylate. The oxidized triphenylphosphane resin can be removed through filtration, and the byproduct of di-tert-butyl azodicarboxylate is removed by reaction with TFA.84 Chung and co-workers disclosed an alternative to DEAD, di-(4-chlorobenzyl) azodicarboxylate (DCAD) where the hydrazine as byproduct can be removed easily through filtration and recycled back to DCAD.85 Further, it has been noticed in almost each section that heterocyclic morpholine core is synthesized by bifunctional toxic choloroactetyl chloride and on contact with protic amines or alcohols, as both functionalities are primarily present on



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intermediates, generates hydrochloric acid thus make it a lachrymator. Hence, to make this heterocyclic ring construction more effective electrophilic chloroacetyl chloride must be replaced with two carbon synthon reagent like ethanolamine-O-sulfate. The two carbon synthon may increase the final output of all synthetic procedures, because morpholinone is not generated in this case, hence its reduction is not required so avoids formation of dimer 23, which is an inevitable moiety generated upon reduction. Additionally, currently in all procedure for synthesis of reboxetine, large number of steps are involved. Due to involvement of large number of steps, the amount of waste product and manufacturing cost get increased. The present issue is to decrease the number of steps and to increase the yield of reaction steps that are involved in the reboxetine synthesis. To achieve the target focus on modern and green synthetic techniques are required. Researchers should also work on the ionic liquid catalyzed synthesis, microwave assisted synthesis, enzymecatalyzed synthesis and environmentally-benign (green) synthesis approaches because whole manuscript is deprived of these modern synthetic methodologies. To make better analogues of reboxetine it is essential to understand the structure-activity relationship.86,87 On the basis of structure-activity relationship, authors of the review conclude with the following implications for chemist (i) synthesis of thiophene-, furan-, pyrrole-, piperidine-, thiane-, oxadiazole- and thiadiazole-mediated analogues of reboxetine, (ii) synthesis of dimer of reboxetine and (iii) derivatization of reboxetine with biological active flavonoids, coumarins and saponins. The review is very helpful for further development of reboxetine synthetic methodologies and for medical chemistry.


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