Herein are described improvements in a discovery synthesis to enable a rapid scale up of 1 to support early phase clinical trials and formulation development studies. Process modifications included route redesign, simplifying a Mitsunobu reaction product's isolation, improving yields and impurity profiles for isolated intermediates, and removal of a chromatographic purification. Particle engineering studies identified a recrystallization protocol to produce 1 with enhanced solid-state properties. This improved process was scaled up to generate multikilogram quantities of drug substance with >99.8% area purity.

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal of transition metal from the process, (2) a streamlined process with significantly improved overall yield, and (3) appropriate impurity control (including potential mutagenic impurities), which enabled delivery of quality material for toxicology studies and clinical trials.

The formation and fate of monomethyl sulfate (MMS) and dimethyl sulfate (DMS) were studied by proton NMR for a sulfuric acid catalyzed esterification reaction in methanol. The kinetic rate constants for DMS and MMS were determined at 65 degrees C by fitting time-dependent experimental data to a model using DynoChem. In refluxing methanol, sulfuric acid was converted to monomethyl sulfate (MMS) in nearly quantitative yield within 45 mm. Once formed, the MMS underwent a reversible esterification reaction to form DMS. Dimethylsulfate reacted with methanol to regenerate MMS and form dimethyl ether. A byproduct of the esterification reaction was water, which further consumed DMS through hydrolysis. On the basis of derived rate constants, in refluxing methanol, DMS would not be expected to exceed 4 ppm in the reaction mixture at equilibrium. In the presence of the carboxylic acid substrate, DMS was not detected in the reaction mixture. The reaction pathways of this system have been systematically investigated, and the results of this study will be presented.

Mild reaction conditions for Petasis reactions of substituted salicylaldehydes with various amines and arylboronic acids in the presence of molecular sieves were developed. Molecular sieves (MS) significantly accelerated the reaction rates and drove the reactions to high conversions. The conditions were applied to the synthesis of the core structure of BIIB042, a γ-secretase modulator, without stereochemical erosion of a stereogenic center in the salicylaldehyde intermediate.

We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

A practical synthesis Of L-valyl-pyrrolidine-(2R)-boronic acid (1) is detailed. A previously disclosed synthesis of 1 (Snow, R.; Kelly, T. R.; Adams, J.; Coutts, S.; Perry, C. (Boehringer Ingelheirn Pharmaceuticals, Inc.). WO 93/10127, 1993) was significantly improved by developing an efficient process for recycling the costly chiral auxiliary (+)- pinanediol.

A novel and highly efficient synthesis of [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[2-(3-methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]-heptane-3-carboxylic acid (A), a key intermediate in the synthesis of ifetroban sodium, BMS-180291, is described. Reaction of chiral imides such as [2(S),3a alpha,4 beta,7 beta,7a alpha]-hexahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (B) with the Grignard reagent derived from 2-(2-bromophenyl)-1,3-dioxolane and subsequent in situ transformations give [2S-(2 alpha,3a alpha,4 beta,7 beta,7a alpha)]-2-(octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde, converted in two steps to A. Efficient syntheses of B from furan and maleic anhydride are described.

In an effort to remove residual palladium from a drug candidate prepared by palladium-catalyzed indolization, many treatments were examined. The most effective treatment was to precipitate palladium from solution using 2,4,6-trimercapto-s-triazine (TMT), which reduced palladium levels from 600-650 ppm to 20-60 ppm in an isolated indole intermediate. Subsequent crystallizations routinely afforded active pharmaceutical ingredient with <1 ppm of palladium. TMT treatment should prove useful to reduce the concentration of residual palladium in other reactions.