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ABT-450 (8), a potent hepatitis C (HCV) NS3/4A protease inhibitor, was approved as part of AbbVie's first generation HCV treatment for the United States in December 2014. A series of process optimizations were developed over six years to support the program starting with recycling of a previous protease inhibitor candidate through route development and final process. This discussion will focus on optimization of the final six steps starting from dipeptide 12 and amino acid 13 and highlights the use of a large scale ring closing metathesis (RCM), reactive crystallizations for isolation of intermediates, and detailed process understanding of the final sulfonamide coupling. The process provides ABT-450 (8) in 72% overall yield for the final 6 steps.

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.

During the process safety analysis of a fluoride displacement reaction, a highly exothermic event was observed when the reaction mixture was heated, which appears to be due to the decomposition of DMSO catalyzed by the HF byproduct from the displacement reaction. Although the TD24 for the decomposition is 42 °C above the reaction temperature and the synthesis reaction is mild, the consequences of the decomposition reaction are severe and could exceed the emergency venting capability of the reactor in the case of uncontrolled heating or an external fire, even at pilot plant scale. The use of several bases, cosolvents, and alternative solvents was investigated. Administrative safeguards, including temperature control system limits and removal of flammable solvents from the area, were identified to establish a basis of safety for a scale up to pilot scale. However, these safeguards would be impractical in a manufacturing facility. Eventually, an N-methyl-2-pyrrolidone (NMP)/tert-butyl methyl ether (MTBE) sol...

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.

An efficient and convergent process for the preparation of a potent and selective H 3 receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-( R )-methylpyrrolidine ( 9 ) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile ( 3 ). Additionally, the key amine component 2-( R )-methylpyrrolidine ( 7 ) was effectively synthesized from the readily available Boc- l -prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A .

A practical and highly efficient process for the preparation of β-arylethylamines 7 was developed. Benzylic organozinc compounds 10 were reacted with the iminium salts 9 generated in situ from the amine salt 8 and paraformaldehyde in one pot and in a polar and aprotic solvent, such as NMP. A variety of the β-arylethylamines were prepared in 43–91% yields.

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).

A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized high-yielding and high-throughput Negishi protocol. The quinoline core 8 was constructed by using a modified Skraup reaction. The final product was obtained by a direct allylation reaction of lactol 10 with allyltrimethylsilane. The process was accomplished efficiently to produce 1A in 25% overall yield and >99% purity with simple and practical isolation and purification procedures.

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]

N-Arylation of pridazinone derivatives 1 with an aryl or heteroaryl bromide or iodide 2 has been achieved in 70–94% isolated yield using catalytic amounts of the stable and structurally well defined copper catalyst 4b under standard Ullmann–Goldberg reaction conditions. The structure of copper catalyst 4b was characterized by ESI-MS, DSC and the single crystal X-ray.