- 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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- 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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- 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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- 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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- 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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- Method for the preparation of aryl ethers
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The invention relates to a method for preparing aryl ethers that are useful as antidepressants. The invention also relates to intermediates useful in the method and to methods for preparing such intermediates.
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- Potential antidepressant agents. α-Aryloxy-benzyl derivatives of ethanolamine and morpholine
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Various α-aryloxy-benzyl derivatives of ethanolamine and morpholine were synthesized and tested as potential antidepressant agents. A morpholine derivative, the 2-[α-(2-ethoxy-phenoxy) benzyl]morpholine, showed outstanding activity in the antireserpine te
- Melloni,Carniel,Della Torre,et al.
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p. 235 - 242
(2007/10/02)
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