The development of reactions in a continuous fashion in plug flow tube reactors (PFR) offers unique advantages to the drug development and scale-up process and can also enable chemistry that would be difficult to perform via batch processing. Herein, we report the development of two different continuous flow approaches to a key 1H-4-substituted imidazole intermediate ( 5). In a first generation approach, rapid optimization and scale-up of a challenging cyclization reaction was demonstrated in a PFR under GMP conditions to afford 29 kg of protected product 2. This material was further processed in batch equipment to deliver di-HCl salt 4. This first generation approach highlights the rapid development of chemistry in research-scale PFRs and speed to material delivery through linear scale up to a pilot-scale PFR under GMP conditions. In a second generation effort, a more efficient synthetic route was developed, and PFRs with automated sampling, dilution, and analytical analysis allowed for rapid and data-rich reaction optimization of both a key cyclization reaction and thermal removal of a Boc protecting group. This work culminated in 1 kg demonstration runs in a 0.22 L PFR for both continuous steps and shows the potential of commercialization from a lab hood footprint (1−2 MT/year).

A practical method for palladium-catalyzed cyanation of aryl halides using Pd/C is described. The new method can be applied to a variety of aryl bromide and active aryl chloride substrates to effect efficient conversions. The process features many advantages over existing cyanation conditions and the practical utility of the process has been demonstrated on scale.

A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.

[reaction: see text] A palladium-catalyzed cascade carbometalation-cross coupling of alkyne route was developed for the preparation of tetrasubstituted exocyclic alkenes with high stereo- and regiocontrol. The effectiveness of this novel methodology was demonstrated by the synthesis of a number of dibenzoxapines in sufficient quantities to support their further development.

A practical and scaleable synthesis of (Z)-3-(1-(8-bromodibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)aniline hydrochloride (1 • HCl), a key intermediate in the synthesis of a selective nuclear hormone receptor modulator, is described. The target compound is prepared in five steps from commercially available (5-bromo-2-iodophenyl)methanol (5) with a 47% overall yield. The key step involves a palladium-catalyzed intramolecular carbometalation of an alkyne, which affords the dibenzoxapine containing tetrasubstituted exocyclic alkene framework stereoselectively in a single step from readily available building blocks 4-bromo-2-(2-iodo-phenoxymethyl)-1-prop-1-ynyl-benzene (3) and 3-nitrophenylboronic acid (4). The development of each step is described. The main focus of the paper is the description and optimization of the intramolecular carbometalation of an alkyne. Eventually, the target compound 1 • HCl was prepared in multikilogram quantities with >97% purity.

A new synthetic route to LY2497282 (1), a potent and selective DPP IV inhibitor for the potential treatment of diabetes, suitable for the preparation of multikilogram quantities is described. The key step involved a stereoselective addition of the dianion of nicotinamide 8 to N-dibenzyl-protected α-amino aldehyde 12, which was derived from N-acetyl-protected amino ester 14 without epimerization. The desired Felkin-Anh nonchelation controlled anti-amino alcohol 11 was isolated with >99% HPLC area and >99% ee by crystallization. After removing the dibenzyl protecting group under transfer hydrogenation conditions, LY2497282 (1) was finally obtained in 39% overall yield with a six-step longest linear sequence starting from N-acetyl-protected amino ester 14.

A practical pilot plant convergent synthesis of MR antagonist LY2623091 was established. For synthesis convergence, a vinyl bromide geometric isomer and chiral alaninol derivative were required building blocks. Key to the synthesis route development is a stereoselective synthesis of the E-vinyl bromide via a sequential double Heck reaction, Suzuki–Miyaura cross-coupling of the vinyl bromide, a selective nitro reduction, and a highly sensitive cyanamide hydrolysis to the urea. Improvements in yield and processing were accomplished by two sets of telescoping methods which decreased the manufacturing time and provided purity enhancements.

The selective androgen receptor modulator, (S)-(7-cyano-4-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)carbamic acid isopropyl ester, LY2452473, is a promising treatment of side effects of prostate cancer therapies. An acid-catalyzed Fischer indolization is a central step in its synthesis. The reaction leads to only one of the two possible indole regioisomers, along with minor decomposition products. Computations show that the formation of the observed indole is most favored energetically, while the potential pathway to the minor isomer leads instead to decomposition products. The disfavored [3,3]-sigmatropic rearrangement, which would produce the unobserved indole product, is destabilized by the electron-withdrawing phthalimide substituent. The most favored [3,3]-sigmatropic rearrangement transition state is bimodal, leading to two reaction intermediates from one transition state, which is confirmed by molecular dynamics simulations. Both intermediates can lead to the observed indole product, albeit through different mechanisms.