The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin

Abstract

The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4-dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3,4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl]2-(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1–2 equiv of H3PO4, 60 °C, 20 bar H2, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).

Asymmetric Transfer Hydrogenation of 1‐Aryl‐3,4‐Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex

“…orthophosphoric acid - Table S2, entries 5-15), the 85 % aq. Therefore, orthophosphoric acid was investigated further, including the anhydrous phosphoric acid (APA) [11] prepared by mixing the 85 % H 3 PO 4 with stoichiometric amounts of phosphorus pentoxide (Table S2, entries [16][17][18][19][20][21][22][23][24][25][26][27][28]. Therefore, orthophosphoric acid was investigated further, including the anhydrous phosphoric acid (APA) [11] prepared by mixing the 85 % H 3 PO 4 with stoichiometric amounts of phosphorus pentoxide (Table S2, entries [16][17][18][19][20][21][22][23][24][25][26][27][28].…”

“…[11,[13][14][15][16] However, the corresponding ligands are oxygen sensitive and the complexes may not be readily available. [11,[13][14][15][16] However, the corresponding ligands are oxygen sensitive and the complexes may not be readily available.…”

Hydrogen

“…Another example of an optimized imine hydrogenation, performed on a several hundred gram scale, occurs during the production of the urinary antispasmodic solifenacin (eq 36). 93 Imine hydrogenation catalyzed by iridium or rhodium to give a primary amine was evaluated during the enantioselective synthesis of a hepatitis C NS5A antagonist, but due to challenges with imine hydrolysis, transfer hydrogenation using tethered Ru catalysts proven superior. 94 Phosphine-free asymmetric imine reductions have also been reported.…”

Immobilization of γ‐Glutamyl Transpeptidase from Equine Kidney for the Synthesis of kokumi Compounds

“…Moreover, once the biocatalyst is bound to the support, it becomes a heterogenous catalyst, thus facilitating its separation from the reaction mixture and minimizing the risk of product contamination. Protein impurities associated with molecules synthesized by biocatalysis represent an issue in food and pharmaceutical processes . Many immobilization techniques have been developed, including absorption, entrapment, encapsulation, cross‐linking and covalent binding.…”