The reactiono fe nol esters with SelectFluor is facile andl eads to the corresponding a-fluoroketones under mild conditions and, as ar esult, this route is commonly employed for the synthesis of medicinally importantc ompoundss uch as fluorinated steroids. However,d espite the use of this methodology in synthesis, the mechanism of this reactiona nd the influence of structureo nr eactivity are unclear.Arigorous mechanistic study of the fluorination of these substrates is presented,i nformed primarily by detailed and robust kinetic experiments. The resultso ft his study implicateapolar two-electron process via an oxygen-stabilised carbenium species, rather than as ingle-electron process involvingr adical intermediates. The structure-reactivity relationships revealed here will assist synthetic chemists in deploying this type of methodology in the syntheses of a-fluoroketones.Scheme1.The fluorination of steroid structures via enol ester intermediates.[a] S.Scheme2.Literature studies that implicate two-electron or single-electron reaction mechanisms.Scheme14. Values of 1 for the three different Hammett studies conductedd uring thiswork.Scheme15. Proposed mechanisms for the hydrolysisof( a) 3 and (b) 8c after fluorination.

The process development to the manufacturing route to (2S)-7-([4,4′-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hydrochloride (SB-214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2RS)-2,3,4,5-tetrahydro-4methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2S)-2,3,4,5tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid. The unreacted (R)-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladiumcatalysed aminocarbonylation of the aryl iodide with 4,4′pyridylpiperidine to give (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2S)-7-([4,4′-bipiperidin]-1-ylcarbonyl)-2,3,4,5tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.

Palladium-catalysed aminocarbonylation of a 7-bromo- or 7-iodo-1,4-benzodiazepine with N-Cbz-4,4‘-bipiperidine hydrochloride efficiently introduced the 7-(4,4‘-bipiperidinylcarbonyl) moiety of (2S)-7-(4,4‘-bipiperidinylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid.

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Amidation of indole 2-carboxylate 1 with ammonia gas via the imidazolide 2 gave GSK2248761A API 3, which was in development for the treatment of HIV. Three significant impurities, namely the phosphinic acid 4, the N-acyl urea 8, and the indoloyl carboxamide 6, were formed during the reaction, and the original process was unable to produce API within clinical specification when run at scale. Investigation into the origin, fate, and control of these impurities led to a new process which was able to produce API within clinical specification.