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

Abstract

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...

Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen

“…Der Einsatz von scCO 2 beim kontinuierlichen Durchfluss hat sich nunmehr bei chemischen Verfahren wie Hydrierung, Hydroformylierung und Kondensation recht gut etabliert. [32][33][34] Leitner und Mitarbeiter demonstrierten kürzlich die enantioselektive kontinuierliche Durchflusshydrierung des Dimethylitaconats 16 über einen Rhodium-Komplex vom Schrock-Osborn-Typ mit überkritischem Kohlendioxid als mobile Phase (Schema 5a). [33] Der Hydrierkatalysator war in einer ionischen Flüssigkeit in einem Festbettreaktor (5 mL Volumen) gebunden.…”

“…[33] In ähnlicher Weise untersuchten Poliakoff und Mitarbeiter in Zusammenarbeit mit Forschern von AstraZeneca die Hydrierung von racemischem Sertralinimin (18)i ne inem Festbettreaktor unter Verwendung von scCO 2 als Lçsungsmittel (Schema 5b). [34] (4S)-Sertralinimin (18) [34] Mittlerweile stehen Reaktoren aus druck-und korrosionsbeständigem Rohrmaterial zur Verfügung,d ie bei Temperaturen weit über 300 8 8Cu nd Drücken bis zu 280 bar betrieben werden kçnnen und in denen Wasser im nah-oder überkritischen Zustand erzeugt werden kann. [35] …”

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

“…[11] Carbon dioxide reaches its supercritical state (scCO 2 )u nder relatively mild conditions (T c = 31.1 8 8C, 73.9 bar) and scCO 2 is,therefore,among the most frequently used supercritical fluids.T he application of scCO 2 in continuous flow is now reasonably established for reactions such as hydrogenations,h ydroformylations,a nd condensations. [32][33][34] Leitner and co-workersr ecently demonstrated the enantioselective continuous-flow hydrogenation of dimethylitaconate 16 over aS chrock-Osborn-type rhodium complex with supercritical carbon dioxide as the mobile phase (Scheme 5a). [33] Theh ydrogenation catalyst was supported in an ionic liquid phase in af ixed-bed reactor (5 mL volume).…”

Nanocatalysis in Flow

“…[22] Many studies have been carried out by using Pd/Ci mmobilizedi nr eplaceable, prepacked, stainless-steel cartridges and tested mostly in crosscoupling reactions, [23] and hydrogenations. [24] Another popular choice is represented by the commerciallya vailable polyureaencapsulated Pd(OAc) 2 developed by Ley et al (commonly known as Pd EnCat), [25] mostly employed for Suzuki-Miyaura cross-coupling reactions.…”