Kevin M. Maloney

A Practical, One-Pot Synthesis of Sulfonylated Pyridines

A concise and efficient one-pot synthesis of functionalized sulfonylated pyridines via an S(N)Ar reaction of readily available pyridines and sodium sulfinate salts in the presence of tetrabutylammonium chloride is presented.

A General Procedure for the Preparation of β-Ketophosphonates

A mild, high-yielding procedure for the preparation of beta-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0 degrees C. The reaction procedure is operationally simple and amenable to large-scale preparations.

One-Pot Iodination of Hydroxypyridines

A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purification. In addition, the iodination works on both 2- and 4-hydroxypyridines and -hydroxyquinolines.

Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis.

Brutons tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model.

Direct Conversion of Haloarenes to Phenols under Mild, Transition-Metal-Free Conditions

A high-yielding and practical method for the synthesis of phenols from electron-deficient haloarenes and heteroarenes has been developed. The products are formed from acetohydroxamic acid as the hydroxide source via a novel SNAr reaction/Lossen rearrangement sequence. Notably, these reactions employ inexpensive and air-stable reagents, require no special handling, occur under mildly basic conditions, and form products in high yields in the presence of electrophilic and protic functionality. The utility of this methodology is demonstrated by the high-yielding hydroxylation of two base-sensitive complex substrates.

Potassium isopropyl xanthate (PIX): an ultra-efficient palladium scavenger

The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceutical ingredients (APIs) has created a pressing need for ultra-efficient palladium removal of the resulting metal contaminants. This communication discusses the identification and development of Potassium Isopropyl Xanthate (PIX) as a simple, readily available and ultra-efficient palladium scavenger capable of removing residual palladium from the API to levels less than 1 ppm. In addition, the discovery of a synergistic effect of iodine, in combination with PIX and other palladium scavengers, to enhance palladium removal has further increased the efficiency of the palladium removal process. The PIX and I2 system has been successfully applied to the ceftolozane sulfate 2nd generation manufacturing chemistry to reduce palladium in the API resulting from a late stage palladium-catalyzed coupling reaction to only 0.1 ppm.

Synthesis of Complex Phenols Enabled by a Rationally Designed Hydroxide Surrogate

The conversion of aryl halides to phenols under mild reaction conditions is a longstanding and formidable challenge in organic chemistry. Herein, we report the rational design of a broadly applicable Pd-catalyzed method to prepare phenols with benzaldehyde oxime as a hydroxide surrogate. These reactions occur under mildly basic conditions and enable the late-stage hydroxylation of several functionally-dense drug-like aryl halides.

The design and synthesis of novel spirocyclic heterocyclic sulfone ROMK inhibitors as diuretics

A spirocyclic class of ROMK inhibitors was developed containing a structurally diverse heterocyclic sulfone moiety and spirocyclic core starting from lead 1. These compounds not only displayed exquisite ROMK potency but significantly improved selectivity over hERG. The lead compounds were found to have favorable pharmacokinetic properties and displayed robust diuretic, natriuretic and blood pressure lowering effects in spontaneously hypertensive rats.

A high-yielding method for the preparation of isoxazolopyridin-3-amine derivatives

A highly efficient and green method has been developed for the rapid preparation of highly functionalized isoxazolopyridin-3-amine derivatives in excellent yields. This process has a broad substrate scope, is operationally simple, and generally requires no chromatographic purification. In addition, the process is scalable and significantly greener than current alternatives with a PMI of 18 and water as the reaction solvent.

Discovery of novel BTK inhibitors with carboxylic acids

We report the design and synthesis of a series of novel Brutons Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.