A New and Simplified Process for Preparing N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine and a Telescoped Process for the Synthesis of (1S-cis)-4-(3,4-Dichlorophenol)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine Mandelate:  Key Intermediates in the Synthesis of Sertraline Hydrochloride

Taber, Geraldine P.; Pfisterer, David; Colberg, Juan

doi:10.1021/op0341465

Cited by 93 publications

(50 citation statements)

References 4 publications

(8 reference statements)

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“…A well-documented achievement in this context pertains to the redesigned preparation of sertraline ( Fig. 1.4) [53]. The discovery of sertraline (the active ingredient responsible for the antidepressant function of Zoloft ® ) dates back to the early 1970s [54,55].…”

Section: Pfizer's Sertraline Process: a Perspective On Overall Procesmentioning

confidence: 99%

Green Chemistry and Associated Metrics

Dicks

Hent

2014

SpringerBriefs in Molecular Science

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This chapter provides an overview of green metrics and their historical role in promoting the development of green chemistry. Starting with the history of the field, the Twelve Principles of Green Chemistry are introduced and discussed in conjunction with a "green-by-design" approach recently applied to the synthesis of Lipitor ® . Various perspectives on synthetic efficiency are briefly outlined with reference to atom economy and E factor. These ideas are further explored in the context of three industrial processes which have received Presidential Green Chemistry Challenge Awards. The synthesis of ibuprofen is examined from the point of view of intrinsic efficiency. Using the BHC process as an example, several benefits associated with the use of catalysis are discussed, with an emphasis placed on designing atom-efficient reactions. A global perspective centered around the production of chemical waste is also outlined with reference to Merck's commercial synthesis of Januvia ® , a medication for the treatment of type II diabetes. Finally, Pfizer's new sertraline process is used to describe ways of improving both quantitative as well as qualitative aspects of an industrial synthesis. The chapter concludes with a brief outline of the future directions of green metrics.

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Section: Pfizer's Sertraline Process: a Perspective On Overall Procesmentioning

confidence: 99%

Green Chemistry and Associated Metrics

Dicks

Hent

2014

SpringerBriefs in Molecular Science

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“…Subsequently, the syrup was diluted with n-heptane (20 mol) at 25Á358C and stirred for 2.0Á 2.5 h followed by the filtration to afford (9) trans-2 as off-white solid in 65% (6.12 g) yields and 95% HPLC purity. 1 …”

Section: -Benzyl-3-(4-fluoro-phenyl)-morpholin-2-ol [(9)-trans-2] Anmentioning

confidence: 99%

“…Subsequently, the distillation of toluene layer under vacuum afforded 10 as a thick syrup and it was purified by column chromatography (silica gel, cyclohexane) to give colorless liquid with 86% yield and 99.5% G.C purity. 1 …”

Section: Synthesis Of 10mentioning

confidence: 99%

Recycling of undesired isomers of key intermediate for aprepitant

Gangula¹,

Elati²,

Nardela³

et al. 2009

Green Chemistry Letters and Reviews

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“…[14,15] Today Zoloft is manufactured in relatively few steps by first reacting 1-naphthol, 3, and 1,2-dichlorobenzene, 4, with aluminium chloride to provide the racemic intermediate ketone. Simulated moving bed (SMB) chromatography is then used to separate efficiently the (4S)-and (4R)-enantiomers.…”

Section: Introductionmentioning

confidence: 99%

“…In their current process, Pfizer use a Pd/CaCO 3 catalyst which provides excellent diastereoselectivity (cis:trans ratio of 95:5) and < 1.0 % dechlorinated by-products. [15] The limited solubility of H 2 in conventional liquid phase hydrogenation reactions can be rate limiting. Therefore, large presures of H 2 and long reaction times are often required to achieve high levels of conversion.…”

mentioning

confidence: 99%

Continuous Flow Hydrogenation of a Pharmaceutical Intermediate, [4‐(3,4‐Dichlorophenyl)‐3,4‐dihydro‐2H‐naphthalenyidene]methylamine, in Supercritical Carbon Dioxide

2007

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Abstract:The hydrogenation of complex pharmaceutical intermediate, rac-sertraline imine has been optimized as a continuous flow process utilizing a palladium/calcium carbonate (Pd/CaCO 3 ) catalyst and hydrogen in supercritical carbon dioxide (scCO 2 ). Superior levels of selectivity were obtained in the flow system possibly attributable to the heat transfer properties of scCO 2 which help to remove excess heat from the catalyst surface.Keywords: carbon dioxide; diastereoselectivity; hydrogenation; sertraline; supercritical fluidsThe excessive use of organic solvents in synthesis, purification and cleaning is the largest single contributor to overall chemical waste in the pharmaceutical industry. Therefore, a new technology that minimizes the use of organic solvents will help make pharmaceutical and fine chemical synthesis more sustainable. Supercritical fluids (SCFs) and, in particular, supercritical CO 2 (scCO 2 ), have emerged as alternative green solvents which can help the pharmaceutical industry attain this goal. [1,2] For instance, SCF chromatography [3,4] and SCF extraction [5,6] have proved to be powerful tools for the separation of active pharmaceutical ingredients (APIs) from complex mixtures. scCO 2 has also more recently been applied to anti-solvent precipitation of drug particles from solution.[7-10] scCO 2 is highly suitable for pharmaceutical processing because it is non-toxic and has relatively mild critical parameters (T c = 31 8C, P c = 74 bar) so that the advantages of near-critical and scCO 2 can be achieved, whilst operating at relatively low temperatures where degradation of sensitive molecules is unlikely.The application of scCO 2 as a solvent for the synthesis of pharmaceuticals has not yet been fully realized. This is because synthetic research in scCO 2 has focused largely on model substrates and compounds relevent to the bulk and fine chemicals industry. [11][12][13] This article explores the use of scCO 2 as a solvent for the hydrogenation of a complex pharmaceutical intermediate, [4-(3,4-dichlorophenyl)-3,4-dihydro-2H-naphthalenyidene]methylamine, also known as racsertraline imine 1.(4S)-Sertraline imine 1a is an intermediate in the synthesis of cis-(1S,4S)-sertraline hydrochloride 2, marketed under the name, Zoloft (Scheme 1), a multi-billion dollar drug developed originally by Pfizer for the treatment of depression and other anxiety related disorders. [14,15] Today Zoloft is manufactured in relatively few steps by first reacting 1-naphthol, 3, and 1,2-dichlorobenzene, 4, with aluminium chloride to provide the racemic intermediate ketone. Simulated moving bed (SMB) chromatography is then used to separate efficiently the (4S)-and (4R)-enantiomers. Enantiomerically pure (4S)-ketone is then reacted with methylamine to afford the imine 1a. Diastereoselective hydrogenation puts in the second chiral centre to afford (4S)-sertraline before conversion to the hydrochloride salt 2 (Scheme 1).We chose to study the hydrogenation of imine 1a in scCO 2 for a number of reasons. It has both regio-a...

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Cited by 93 publications

References 4 publications

Green Chemistry and Associated Metrics

Green Chemistry and Associated Metrics

Recycling of undesired isomers of key intermediate for aprepitant

Continuous Flow Hydrogenation of a Pharmaceutical Intermediate, [4‐(3,4‐Dichlorophenyl)‐3,4‐dihydro‐2H‐naphthalenyidene]methylamine, in Supercritical Carbon Dioxide

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