Determination of theoretical purge factors for the evaluation of risk of carryover of potential mutagenic impurities (MIs) into the final active pharmaceutical ingredient (API) has been discussed as a possible approach to demonstrate efficient purification of potential MIs (Substances I, II, III and IV) in the synthesis of the vortioxetine drug substance. Theoretical purge factors for the four potential MIs were determined based on the physicochemical properties of an MI in relation to processing conditions. Compared to depletion studies of I and III, the calculated purge factors were very conservative in predicting impurities reduction.However, even a conservatively calculated purge factor correctly predicted high purging capability of the process to eliminate substance I. This novel approach could help pharmaceutical companies to focus on those impurities that are more likely to be carried over into the final API thus obviating the use of analytical testing where not necessary.

A series of R-SMS-Phos ligands was evaluated in the Rh(I)-catalyzed hydrogenation of a set of olefins showing a marked influence of the cyclic nature and structure of the R groups. Overall, cPen- and Cy-SMS-Phos performed efficiently, while Ph- and Bn-SMS-Phos exhibited slower kinetics and furnished lower ee's also compared with C(6)F(5)CH(2)-SMS-Phos. The Rh(I)-(Cy-SMS-Phos) catalyst was screened under mild conditions displaying excellent enantioselectivities and high TOFs. Cases of catalysis under catalyst or substrate control were identified.

A diversified family of enantiopure P-stereogenic "R-SMS-Phos" {R-SMS-Phos = 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane} ligands wherein R = branched or heteroatom-substituted alkyl, aralkyl, silyl, acyl, sulfonyl, etc. was screened for the Rh(I)-catalyzed hydrogenation of a representative set of olefinic substrates. This systematic and detailed investigation revealed a marked beneficial impact on enantioselectivity and catalyst activity in comparison to Knowles' ultimate DiPAMP {DiPAMP = 1,2-bis[(o-anisyl)(phenyl)phosphino]ethane} design. Mutant ligands with highly enhanced properties possessing particular features wherein the DiPAMP structure is found embedded were identified.

A series of enantiopure P-stereogenic 1,2-bis[(o-RO-phenyl)(phenyl)phosphino]ethane (R-SMS-Phos) ligands wherein R = i-Pr, i-Bu, t-Bu, 3-Pen, and CH(2)TMS was assessed in the Rh(I)-catalyzed hydrogenation of an indicative set of olefins. The best performing t-Bu-SMS-Phos ligand was screened against a wide range of representative classes of standard and new olefinic substrates such as dehydroamido esters, dehydro-alpha-amido-phosphonates, enamides, itaconates, acrylates, enol acetates, alpha-phosphonovinyl benzoates, alpha-(2-pyridyl N-oxide)styrenes, and alpha-(1-hydroxyliminoethyl)styrenes. Excellent enantioselectivities and high TOFs were attained under mild conditions.

phosphino]ethane (DiPAMP) as a P-stereogenic ligand for rhodium(I)-catalyzed hydrogenation by Knowles et al. came after their evaluation of several diphosphines. However, no in-depth study was carried out on incorporating various substituents on its P-o-anisyl groups. In this work, we have prepared a large series of enantiopure and closely related DiPAMP analogues possessing various substituents (MeO, TMS, t-Bu, Ph, fused benzene ring) on the oanisyl rings. The new ligands were evaluated in rhodium-catalyzed hydrogenation of several model substrates: methyl a-acetamidoacrylate, methyl (Z)-aacetamidocinnamate, methyl (Z)-b-acetamidocrotonate, dimethyl itaconate, and atropic acid. They displayed enhanced activities and increased enantioselectivities, particularly the P-(2,3,4,5-tetra-MeO-C 6 H)-substituted ligand (4MeBigFUS). Interestingly enough, 88% ee was obtained in the hydrogenation of atropic acid using the Rh-(4MeBigFUS) catalyst under mild conditions (10 bar H 2 , room temperature) versus 7% ee using Rh-DiPAMP. Conversely, the ligand possessing P-(2,6-di-MeO-C 6 H 3 ) groups proved to slow down considerably the hydrogenation. X-Ray structures of their corresponding Rh complexes are presented and discussed.

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The nature of the starting material (SM) and the presence of (potentially) mutagenic impurities (PMIs) can correlate strongly, since many syntheses involve the use of potentially mutagenic electrophilic (alkylating) agents as SMs. Since the regulatory guidelines are far from clear and straightforward, selection of the appropriate SMs is a very challenging task for pharmaceutical companies. Here, the principal criteria for the selection of SMs have been identified based on the existing guidelines. Three SMs in the synthesis of vortioxetine drug substance were selected and justified on the basis of their incorporation into the structure of the API, on whether they have defined chemical properties and structure or not, on the number of synthetic steps between the SM and the API, on commercial availability and formation of impurities, and their control. Determination of a theoretical purge factor (TPF) was successful in evaluating the risk of using potentially mutagenic SM 1 and SM 3, with their related impurities, and the effect of a nonmutagenic SM 2 on the quality and safety of the API. This approach enables the use of selected SMs to be justified.