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The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with99% area purity.

Thermal hazard analyses of two reactions, one with DMSO as the solvent and a reactant and one with DMSO as the solvent and a byproduct, identified low-probability but severe consequence process risks associated with violent decomposition of DMSO during heating control failure or external heating. Although DMSO cannot be totally eliminated from these reactions, using an alternative solvent to replace DMSO proved to be an effective measure in reducing the thermal hazards to allow safe scale-up.

A facile and scaleable synthesis of potent and selective histamine H3 receptor antagonist 1 is described, starting from commercially available 6-bromo-naphthalene-2-carboxylic acid methyl ester 3a. The key intermediate, 2-(6-bromonaphthalen-2-yl)ethanol 5 was prepared in good yield (78%) and purity (99%) via a one-carbon homologation of 3a. The coupling of 5 with pyridazinone 12 was accomplished effectively by a copper-catalyzed cross-coupling reaction. Activation of the hydroxyl group of 4, followed by displacement reaction with 2(R)-methylpyrrolidine 13, afforded the free base of 1, which was subsequently converted to its corresponding salt. The new process consisted of eight chemical steps and one salt formation step and required no chromatographic purification throughout the synthesis. It has been successfully implemented on pilot plant scale to prepare over 10 kg quantities of the target compound 1 in 43% overall yield in high purity (99%) and with the desired physical properties.

A stereoselective synthesis of the hydroxyethylene dipeptide isostere 1 is described. The route employs a substrate-directed kinetic protonation of an alpha/gamma-substituted lactone to afford the desired stereochemistry. A method for converting the diastereomerically enriched intermediate lactone to the ring-open form with retention of stereochemistry is demonstrated. A novel procedure for utilizing N,N-dibromo-5,5-dimethylhydantoin in Hofmann rearrangements is disclosed. This route was used to prepare amino alcohol 1, the core portion of the HIV protease inhibitor A-792611, in 46% yield from phenylalanine-derived epoxide 2.

A facile and scaleable synthesis of a potent and selective histamine H3 receptor antagonist, ABT-239 (1), was developed starting from commercially available 4‘-hydroxy-biphenyl-4-carbonitrile (2). The synthesis comprised four chemical steps and a salt formation step with an overall yield of 40%. A highly selective monoiodination of a phenol was developed and used to prepare iodophenol (3b) in near quantitative yield using NIS in AcOH in the presence of a small amount of H2SO4. A Pd-catalyzed cross coupling reaction of the iodophenols (3b) with butyn-3-ol (4a) provided benzofuran (5) in one step in >80% yield, en route to 1. The new process required no chromatographic purification throughout the synthesis and was successfully demonstrated on scale-up to prepare 1.7 kg of the target ABT-239 (1).

The carbonyl groups in several artemisinin derivatives were converted into geminal difluorinated compounds on treatment with diethylaminosulfur trifluoride. A number of other mono- and polyfluorinated artemisinin derivatives were prepared. Their in vitro antimalarial activities were all equal to or greater than the nonfluorinated analogs or precursors.

The magnitude and sign of the characteristic circular dichroism spectrum of bilirubin bound to human serum albumin are highly sensitive to the presence of trace amounts of dissolved chloroform. The presence of b-40 mM chloroform in an aqueous solution containing 0.25 mM bilirubin and 0.44 mM albumin is sufficient to cause complete inversion of the circular dichroism curve obtained without chloroform. Addition of chloroform to the albumin solution before or after the bilirubin has the same effect. The sign inversion is not due to a chemical reaction because it was reversed completely on removal of chloroform, regenerating curves characteristic of chloroform-free solutions

Iodoacetylene 1 was prepared in situ from the reactions of ethynylmagnesium bromide or tributyl(ethynyl)tin with iodine. It was used as a dipolarphile in the [2 + 3] cyclization reaction with 1,3-dipolar nitrile oxide derivatives to produce 2-(5-iodoisoxazol-3-yl)pyridine 2 and 3-(4-fluorophenyl)-5-iodoisoxazole 8 in good yield (70-90%). Subsequently, several 5-substituted isoxazole derivatives 3 were obtained by Pd-catalyzed reactions. [reaction: see text]

(4Z,15Z)-Bilirubin IXα, the cytotoxic yellow tetrapyrrole pigment of jaundice, readily adopts either of two interconverting, enantiomeric conformations, which are stabilized through complementary intramolecular hydrogen bonding between the pyrrole and lactam N-H and C=O residues of one dipyrrinone moiety and the CO 2 H group of propionic acid side chains on the second dipyrrinone. One conformational enantiomer can be destabilized relative to the other through allosteric action by judicious placement of methyl groups in the propionic acid side chains. Thus, insertion of a methyl group at the pro-R site on the α-carbon of the propionic acid destabilizes the M-chirality intramolecularly hydrogen-bonded conformational enantiomer by introducing a severe nonbonded CH 3 |CH 3 steric interaction with a pyrrole methyl substituent