Real-Time Monitoring of Solid-Liquid Slurries: Optimized Synthesis of Tetrabenazine.

Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.

Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation.

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).

Mechanistic studies of a palladium-catalyzed intramolecular hydroamination of unactivated alkenes: protonolysis of a stable palladium alkyl complex is the turnover-limiting step.

Mechanistic studies of the intramolecular hydroamination of unactivated aminoalkenes catalyzed by a dicationic [bis(diphenylphosphinomethyl)pyridine]palladium complex highlight the important role that protonolysis plays in this reaction. Coordination of the aminoalkene substrate to this complex activates the alkene toward intramolecular nucleophilic attack to form a dicationic palladium alkyl complex (6). A stable monocationic palladium alkyl complex (7) was isolated by in situ deprotonation of 6 with mild base, and its structure was confirmed by X-ray crystallography. Complex 7 reacted rapidly with a variety of strong acids to undergo protonolysis, resulting in formation of hydroamination product 3 and regenerating the active catalyst. Evidence that formation of the palladium alkyl complex is reversible under the catalytic conditions was obtained from observation of the protonolysis at low temperature. During the course of all catalytic reactions, the resting state of the catalyst was palladium alkyl complex 7, indicating that protonolysis of the Pd-C bond was the turnover-limiting step. Kinetic studies reveal an unusual inverse dependence of the reaction rate on the concentration of the aminoalkene substrate. This effect can be accurately explained by a model in which the carbamate protecting group of the aminoalkene acts as a Brønsted base to remove free protons from the catalytic cycle and thereby inhibits the turnover-limiting protonolysis step. Formation of a 2:1 complex (12) between the carbamate and the proton is most consistent with the kinetic data.

Synthesis of 2,6-disubstituted piperazines by a diastereoselective palladium-catalyzed hydroamination reaction.

A highly diastereoselective intramolecular hydroamination is the key step in a modular synthesis of 2,6-disubstituted piperazines. The requisite hydroamination substrates were prepared in excellent yields by nucleophilic displacement of cyclic sulfamidates derived from amino acids. A variety of alkyl and aryl substituents at the 2-position were tolerated. The stereochemistry of the piperazines was determined to be trans by X-ray crystallography, which also showed the preferred conformation of the 2,6-disubstituted piperazine to be a twist-boat due to A(1,3) strain.

Palladium-catalyzed intramolecular chloroamination of alkenes.

A mild and facile Pd-catalyzed intramolecular chloroamination of unactivated alkenes has been described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. Generally high exo-selectivities are observed in the formation of a variety of 5- and 6-membered rings. This system is unique in its ability to tolerate multidentate ligands on palladium, which opens up the possibility of controlling the absolute sense of induction using a chiral ligand.

Stereoselective synthesis of 2,5-disubstituted morpholines using a palladium-catalyzed hydroamination reaction.

A palladium-catalyzed hydroamination reaction is the key step in a stereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubsituted morpholines from carbamate-protected aziridines. Aziridines are selectively attacked at the more substituted position by unsaturated alcohol nucleophiles using Lewis acid catalysts. Palladium-catalyzed hydroamination of the resulting aminoalkenes gives morpholines as a single diastereomer in excellent yield.

Metal-free oxidative cyclization of urea-tethered alkenes with hypervalent iodine.

A metal-free oxidative cyclization of ureas onto unactivated alkenes using iodosylbenzene and an acid promoter is described. The products isolated are predominantly bicyclic isoureas resulting from an intramolecular oxyamination reaction. The acid type and urea substitution have a strong effect on the product formed. A variety of substrates form the isourea with high diastereoselectivity via syn addition including di- and trisubstituted alkenes. Hydrolysis of the isourea gives access to new diastereomerically pure prolinol derivatives.

Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase inhibitors.

We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.

Room temperature palladium-catalyzed intramolecular hydroamination of unactivated alkenes.

A mild and facile Pd-catalyzed intramolecular hydroamination of unactivated alkenes is described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. The formation of hydroamination products rather than oxidative amination products is due to the use of a tridentate ligand on Pd which effectively inhibits beta-hydride elimination.

Discovery of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase CFTR mediated chloride transport.

A series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase chloride transport in cells expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein has been identified from our compound library. Analoging efforts and the resulting structure-activity relationships uncovered are detailed. Compound potency was improved over 30-fold from the original lead, yielding several analogs with EC(50) values below 10nM in our cellular chloride transport assay.