The Degradation Map Process - A Tool for Obtaining a Lean Stability Strategy in Drug Development.

Stability is fundamental when exploring a drug candidate's potential as a drug product. During the pharmaceutical industry drug development process information regarding stability and degradation are captured in different departments, e.g. from discovery to operations, and will be included in the overall control strategy. With a profound understanding of a drug candidate's degradation chemistry, a science and risk based approach in progressing a lean stability strategy is possible. This case study present a clear and visible concept to facilitate a lean stability strategy by the use of degradation maps and describes a process for how these can be used during drug development. The understanding of possible and/or observed degradation pathways will guide the design of the drug product and stability studies in development. A degradation map displays degradation pathways with short comments on the reaction/mechanism involved. The degradation map process starts with a theoretical degradation map. The map is updated as the drug project progresses, preferably after forced degradation experiments, after compatibility studies and finally when the late stage formulation is set. The degradation map should be used to capture information of intrinsic chemical properties of the active pharmaceutical ingredient (API) and can thereby be used to mitigate stability issues. The map is foremost a cross-functionally available tool collecting and visualizing stability information throughout the development process, and as such a valuable tool to efficiently develop a lean stability strategy.

Catalytic Iodination of the Aliphatic C-F Bond by YbI3(THF)3: Mechanistic Insight and Synthetic Utility.

A facile iodination protocol of unactivated alkyl fluorides using catalytic amounts of YbI3(THF)3 in the presence of iodotrimethylsilane as a stoichiometric fluoride trapping agent is presented. (1)H NMR spectroscopy demonstrates a two-step catalytic cycle where TMSI regenerates active YbI3(THF)3. Finally, the catalytic reaction is extended into a one-pot procedure to demonstrate a potential application of the method. Overall, the findings present a distinct strategy for C-F bond transformations in the presence of catalytic YbI3(THF)3.

Mild and selective activation and substitution of strong aliphatic C-F bonds.

A procedure for chemoselectively manipulating the strong aliphatic C-F bond with direct transformation into a C-N bond under mild conditions is reported. The activation and subsequent substitution of primary alkyl fluorides is mediated by La[N(SiMe3)2]3, and results in high to excellent yields of tertiary amines. The methodology displays high selectivity towards the C(sp(3))-F bond, and a variety of secondary amines are applicable as nucleophiles. Mechanistic investigations reveal a reaction that is first order with respect to [La[N(SiMe3)2]3], [R(1)R(2)NH], and [alkyl fluoride], and a 6-membered cyclic transition state is proposed. In addition, (1)H NMR spectroscopy shows that La[N(SiMe3)2]3 is the active species involved in the substitution and that protonolysis of the amine, yielding La[NR(1)R(2)]3, lowers the reactivity.

Solvent dependent reductive defluorination of aliphatic C-F bonds employing Sm(HMDS)2.

Sm(HMDS)(2) in n-hexane mediates fast cleavage of primary, secondary and tertiary alkyl fluorides in good to excellent yields. In n-hexane Sm(HMDS)(2) exhibits uniquely enhanced reductive ability towards the C-F bond compared to when using THF as solvent.

A chemoenzymatic dynamic kinetic resolution approach to enantiomerically pure (R)- and (S)-duloxetine.

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of ß-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded ß-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.

Enantioselective synthesis of syn- and anti-1,3-aminoalcohols via ß-aminoketones and subsequent reduction/dynamic kinetic asymmetric transformation.

ß-Aminoketones obtained from imines in an organocatalytic Mannich reaction were transformed to enantio- and diastereomerically pure 1,3-aminoalcohols with two stereogenic centers via a combined reduction/dynamic kinetic asymmetric transformation. Both syn and anti diastereomers were obtained in high yield, dr, and ee.

Highly efficient route for enantioselective preparation of chlorohydrins via dynamic kinetic resolution.

Dynamic kinetic resolution (DKR) of various aromatic chlorohydrins with the use of Pseudomonas cepacia lipase (PS-C "Amano" II) and ruthenium catalyst 1 afforded chlorohydrin acetates in high yields and high enantiomeric excesses. These optically pure chlorohydrin acetates are useful synthetic intermediates and can be transformed to a range of important chiral compounds.