- Sulfoxide ligand metal catalyzed oxidation of olefins
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The enantioselective synthesis of isochroman motifs has been accomplished via Pd(II)-catalyzed allylic C—H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C—H oxidation reaction proceeds with the broadest scope and highest levels asymmetric induction reported to date (avg. 92% ee, 13 examples ≥90% ee). Additionally, C(sp3)-N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/sulfoxide (SOX) catalyzed intermolecular allylic C—H amination is disclosed. A range of 52 allylic amines are furnished in good yields (avg. 76%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stiochiometries for intermolecular C—H amination reactions.
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Page/Page column 171
(2019/05/09)
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- C-H to C-N Cross-Coupling of Sulfonamides with Olefins
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Cross-coupling of nitrogen with hydrocarbons under fragment coupling conditions stands to significantly impact chemical synthesis. Herein, we disclose a C(sp3)-N fragment coupling reaction between terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/SOX (sulfoxide-oxazoline) catalyzed intermolecular allylic C-H amination. A range of (56) allylic amines are furnished in good yields (avg. 75%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). Mechanistic studies reveal that the SOX ligand framework is effective at promoting functionalization by supporting cationic π-allyl Pd.
- Ma, Rulin,Christina White
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supporting information
p. 3202 - 3205
(2018/03/13)
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- Stereodivergent synthesis of all the four stereoisomers of antidepressant reboxetine
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Chiral amino alcohol-copper(ii) catalysts Cu-L1c and Cu-ent-L1c were utilized to promote the diastereoselective nitroaldol reactions of chiral aldehydes (S)-3 or (R)-3 with nitromethane, which respectively led to the preferential formation of certain stereoisomer for nitro diol derivatives 4. Using this catalytic protocol, all the four stereoisomers of the antidepressant reboxetine were divergently prepared. The highest overall yield of this synthetic route reached up to 30.5% from aldehyde (S)-3.
- Liu, Cheng,Lin, Zhi-Wei,Zhou, Zhao-Hui,Chen, Hong-Bin
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p. 5395 - 5401
(2017/07/10)
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- Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: Applications in the synthesis of reboxetine
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A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O- cyclohexylidene-d-glyceraldehyde in ～43% overall yields. The Royal Society of Chemistry.
- Dar, Abdul Rouf,Aga, Mushtaq A.,Kumar, Brijesh,Yousuf, Syed Khalid,Taneja, Subhash Chandra
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p. 6195 - 6207
(2013/09/12)
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- Dynamic kinetic resolution-based asymmetric transfer hydrogenation of 2-benzoylmorpholinones and its use in concise stereoselective synthesis of all four stereoisomers of the antidepressant reboxetine
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Dynamic kinetic resolution-driven, asymmetric transfer hydrogenation reaction of 2-benzoylmorpholin-3-ones (4) proceeds efficiently to give the corresponding (2R,3S)- or (2S,3R)-2-(hydroxyphenylmethyl)morpholin-3-ones (6) with an excellent level of diastereo- and enantioselectivity and simultaneous control of two contiguous stereogenic centers in a single step. This process is employed to prepare all four stereoisomers of the antidepressant reboxetine.
- Son, Se-Mi,Lee, Hyeon-Kyu
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p. 8396 - 8404
(2013/09/24)
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- The use of environmental metrics to evaluate green chemistry improvements to the synthesis of (S,S)-reboxetine succinate
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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.
- Assaf, Georges,Checksfield, Graham,Critcher, Doug,Dunn, Peter J.,Field, Stuart,Harris, Laurence J.,Howard, Roger M.,Scotney, Gemma,Scott, Adam,Mathew, Suju,Walker, Geoffrey M. H.,Wilder, Alexander
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p. 123 - 129
(2012/04/11)
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- Commercial synthesis of (S,S)-reboxetine succinate: A journey to find the cheapest commercial chemistry for manufacture
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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.
- Hayes, Stewart T.,Assaf, Georges,Checksfield, Graham,Cheung, Chi,Critcher, Doug,Harris, Laurence,Howard, Roger,Mathew, Suju,Regius, Christian,Scotney, Gemma,Scott, Adam
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p. 1305 - 1314
(2012/01/14)
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- Catalyst-controlled diastereoselection in the hydrogenation of heterocycloalkyl ketones
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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
- Akashi, Masaya,Arai, Noriyoshi,Inoue, Tsutomu,Ohkuma, Takeshi
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supporting information; experimental part
p. 1955 - 1960
(2011/10/12)
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- Application of a process friendly morpholine synthesis to (S,S)-Reboxetine
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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.
- Assaf, Georges,Cansell, Gemma,Critcher, Doug,Field, Stuart,Hayes, Stewart,Mathew, Suju,Pettman, Alan
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scheme or table
p. 5048 - 5051
(2011/01/12)
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- Co(iii)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: A concise enantioselective synthesis of (S,S)-reboxetine and (+)-epi-cytoxazone
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The HKR of racemic syn- or anti- alkoxy- and azido epoxides catalyzed by Co(salen) complex affords a practical access to a series of enantioenriched syn- or anti- alkoxy- and azido epoxides and the corresponding 1,2-diols. This strategy has been successfully employed in the concise, enantioselective synthesis of bioactive molecules such as (S,S)-reboxetine and (+)-epi-cytoxazone.
- Reddy, R. Santhosh,Chouthaiwale, Pandurang V.,Suryavanshi, Gurunath,Chavan, Vilas B.,Sudalai, Arumugam
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supporting information; experimental part
p. 5012 - 5014
(2010/08/07)
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- Syntheses of (S,S)-reboxetine via a catalytic stereospecific rearrangement of β-amino alcohols
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(Chemical Equation Presented) The formal total synthesis of (S,S)-reboxetine has been realized by two different approaches using a stereospecific rearrangement of β-amino alcohols catalyzed by (CF 3CO)2O.
- Metro, Thomas-Xavier,Pardo, Domingo Gomez,Cossy, Janine
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p. 707 - 710
(2008/09/17)
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- Process development for (S,S)-reboxetine succinate via a sharpless asymmetric epoxidation
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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.
- Henegar, Kevin E.,Cebula, Mateusz
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p. 354 - 358
(2012/12/31)
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- NOREPINEPHRINE TRANSPORTER RADIOTRACERS AND METHODS OF SYNTHESES THEREOF
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The present invention provides compounds and radiotracers thereof for locating, diagnosing, identifying, evaluating, detecting or quantitating NET by in vivo imaging. The invention also provides methods for locating, diagnosing, identifying, evaluating, detecting or quantitating NET, using radiotracers of high-affinity or labeled compounds of the invention, which exhibit low toxicity, can cross the blood-brain barrier and, preferably, distinguish among normal and abnormal brains. For example, a radiotracer of the invention can be administered to a patient in an amount suitable for in vivo imaging thereof. Preferably, radiotracers of the invention can also be used to locate, diagnosis, identify, evaluate, detect and quantitate NET in such diseases, disorders, conditions or maladies as, without limitation, depression, anxiety, ADHD and drug dependency.
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Page/Page column 61; 62
(2008/06/13)
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- Process development and scale-up for (±)-reboxetine mesylate
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Redevelopment of the commercial process for the synthesis of (±)-reboxetine methanesulfonate is described. An optimized and efficient process for the synthesis of (±)-reboxetine starting from cinnamyl alcohol was developed. The redeveloped process minimizes impurity formation and utilizes simplified processing to substantially improve process yield and throughput, and is suitable for the efficient synthesis of multiton quantities of reboxetine.
- Henegar, Kevin E.,Ball, Cynthia T.,Horvath, Carolyn M.,Maisto, Keith D.,Mancini, Sarah E.
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p. 346 - 353
(2012/12/31)
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- Enantioselective synthesis of (+)-(S,S)-reboxetine
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An efficient enantioselective synthesis leading directly to (+)-(S,S)-reboxetine has been described from commercially available trans-cinnammyl bromide using Sharpless asymmetric dihydroxylation as the key step. Georg Thieme Verlag Stuttgart.
- Siddiqui, Shafi A.,Narkhede, Umesh C.,Lahoti, Rajgopal J.,Srinivasan, Kumar V.
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p. 1771 - 1773
(2008/02/04)
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- Asymmetric synthesis of (+)-(S,S)-reboxetine via a new (S)-2- (hydroxymethyl)morpholine preparation
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(Chemical Equation Presented) (S,S)-Reboxetine was synthesized stereospecifically in 30% overall yield and 99% ee in eight steps. Key steps were selective oxidation of an N-protected hydroxymethylmorpholine and aryl-chromium-mediated aromatic nucleophilic substitution.
- Brenner, Eric,Baldwin, Ronald M.,Tamagnan, Gilles
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p. 937 - 939
(2007/10/03)
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- Method for the preparation of aryl ethers
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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.
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- Discovery and structure-activity relationships of novel selective norepinephrine and dual serotonin/norepinephrine reuptake inhibitors
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Novel arylthiomethyl morpholines are potent selective norepinephrine reuptake inhibitors (NERIs) and dual serotonin/norepinephrine reuptake inhibitors (SRI/NERIs). The target compounds were prepared using a stereochemically versatile synthesis featuring an aldol condensation as the key step. One enantiomer of the 2-methoxy-substituted analogue was found to be a potent and selective norepinephrine reuptake inhibitor, whereas the opposite enantiomer was a potent dual serotonin/norepinephrine reuptake inhibitor.
- Boot, John,Cases, Manuel,Clark, Barry P.,Findlay, Jeremy,Gallagher, Peter T.,Hayhurst, Lorna,Man, Teresa,Montalbetti, Christian,Rathmell, Richard E.,Rudyk, Helene,Walter, Magnus W.,Whatton, Maria,Wood, Virginia
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p. 699 - 703
(2007/10/03)
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