The tetrasubstituted pyrrolidine core of ABBV-3221 was synthesized by catalytic, enantioselective cycloaddition. A Cu­(I) catalyst system was identified as ideal for further development, which gave a 78% yield of 99% purity product after optimization. The processes of catalyst selection, optimization, and crystallization of the cycloaddition product are described herein.

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A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc...

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Foslevodopa (FLD, levodopa 4′-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4′-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson’s disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner–Wadsworth–Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki–Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

2-pyridone8a and 4-methyl-3-hydroxypyridine,8b respectively. The regiospecific formation of monobromo-and monoiodopyridones and hydroxypyridines underscores the advantage and complimentarity of this methodology visa-vis the electrophilic halogenation approach.9By analogy to the O-aryl carbamates,3 the metalated pyridyl carbamates lb, lc, and 2c underwent the anionic Fries rearrangement (-78 °C -*• room temperature/8 h) to give the isonicotinamide 3 and nicotinamides 4a and 4b, respectively (see Table I). In view of the well-known facile reductive conversion of hydroxypyridines to the corresponding pyridines via their chloro derivatives,10 2a-c and 3, 4 systems are, in principle, prototype precursors to diversified pyridines. As an illustrated of such a sequence, the substituted 4-pyridone 4, E = Me, prepared by anionicFries rearrangement of 2c, E = Me (2.1 equiv sec-BuLi/ TMEDA/THF/-78 °C -*• room temperature/8 h), was transformed into the 4-chloropyridine 5 (POCl3/reflux/10 min) and hydrogenolyzed (H2/Pd-BaS04/Et0H/16 h)10to afford the 5-methylnicotinamide 6 in 40% unoptimized yield.As initial tests of further directed metalation possibilities on the derived O-pyridyl carbamates, metalation and Me3SiCl quench sequences were carried out on 2b, E = Br,11 12b, E = CONEÍ2, and 2c, E = CONEt2. The isolated products, 7 (65%), 8 (66%), and 9 (68%), respectively, indicate that metalation occurs at the 5-position irrespective of the directing group.12,13 The propensity of pyridine tin derivatives to undergo electrophile-induced ipso destannylation,14 invited iodination and acylation experiments on 2b, E = SnMe3. In the event, treatment with I2 (CHCl3/room temperature/4 h) and MeCOCl (PhH/reflux/40 h) afforded the ipso-substituted products 10a (90%) and 10b (57%), respectively, thus offering an additional connecting link between the directed metalation tactic and electrophilic substitution chemistry.The directed ortho metalation chemistry of O-pyridyl carbamates la-c described herein provides efficient and (8) (a) mp 175-179 °C, lit. mp 181-187 °C, see ref 1, p 844. (b) mp 114-115 °C, lit. mp 117-119 °C, see ref 1, p 981.(9) Monohalogenation of these systems is difficult to achieve, see: