A nine-step convergent process was developed for the synthesis
of ABT-472, a benzimidazole PARP inhibitor. The identity and
origin of several impurities were determined, and the process
was modified to reduce or eliminate these impurities. A number
of safety and control issues were investigated. The original
synthesis was shortened to 9 steps and streamlined while
maintaining a convergent strategy. A stable salt was selected,
and control of the API solid form was established. The process
was successfully scaled up to provide 8.5 kg of final product of
>99% purity in 33% yield over 9 steps.
Dasabuvir
(1) is an HCV polymerase inhibitor which
has been developed as a part of a three-component direct-acting antiviral
combination therapy. During the course of the development of the synthetic
route, two novel coupling reactions were developed. First, the copper-catalyzed
coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed
sulfonamidation of aryl nonaflate 33 was developed, promoted
by electron-rich palladium complexes, including the novel phosphine
ligand, VincePhos (50). This made possible a convergent,
highly efficient synthesis of dasabuvir that significantly reduced
the mutagenic impurity burden of the process.
A novel method for the preparation of MOM-protected carbamates is described that avoids the use of MOM-Cl, a regulated carcinogen. The two-step, one-pot procedure generates a reactive N-chloromethyl carbamate that is quenched with methanol to afford MOM-protected carbamates. The process is tolerant of a variety of functionalities, including Boc, sulfonamide, and acetamide protecting groups. Mild conditions for the removal of the MOM group are also described; selective deprotection of the MOM group in the presence of a Boc group has been demonstrated.
A scalable process for the novel antidepressant ABT-200, starting with 5,6-methylenedioxy-1-tetralone, is described. The new process improves the scale-up and safety concerns associated with the previously employed route to ABT-200. The scalable process eliminates the potential for HCN exposure to employees and produces ABT-200 in a stereospecific fashion. (TMS)CN was replaced by nitromethane as a reagent to introduce the nitrogen in the ABT-200 molecule. This stereospecific process employs an epimerization procedure which takes advantage of a key difference in the solubility of the two diastereomers of the succinimide intermediate, 9a/b and 10a/ b. Balancing the rate of epimerization with the solubility of the diastereomers in the reaction medium was an essential factor in optimizing the yield and efficiency of this simple, one-pot reaction. The solubility-directed epimerization was demonstrated in both a predominantly aqueous and an organic solvent mixture. The succinimide derivative 10a/b was then converted to ABT-200. This improved procedure was used to prepare kilogram quantities of ABT-200.
The impact of entropic effects on the classical salt resolution of a 2-arylpyrrolidine is described. We have found that the crystallization of a racemic mixture of the base with tartaric acid led to a salt in which the undesired enantiomer is incorporated into the crystal lattice as a solid solution. The product enantiomer ratio was later determined to be at the thermodynamic well when the racemate is crystallized. In order to circumvent this effect, an efficient two-crystallization resolution was developed. The bulk of the undesired enantiomer is removed in the first crystallization so that the second crystallization can result in material of acceptable optical purity. † This paper is dedicated to the memory of Chris Schmid.
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