David A. Conlon

Asymmetric synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor.

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

Practical Synthesis of Chiral N,N′-Bis(2′-pyridinecarboxamide)-1,2-cyclohexane Ligands

A simple and scalable procedure for the preparation of chiral ligands 1and 2from trans-1,2-diaminocyclohexane and 2-picolinic acid is described.

Synthesis of the 6-Azaindole Containing HIV-1 Attachment Inhibitor Pro-Drug, BMS-663068

The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.

Molybdenum‐Catalyzed Asymmetric Allylic Alkylation Reactions Using Mo(CO)6 as Precatalyst

Molybdenum-catalyzed asymmetric allylic alkylation reactions were carried out using the inexpensive, air-stable, and readily available Mo(CO)6 as precatalyst. In situ IR was used to determine the required activation time and temperature required to achieve the maximum concentration of the ‘‘active’’ catalyst from the molybdenum-precatalyst and chiral ligand. Results from comparison studies are consistent with the notion that the same active catalyst is generated regardless of molybdenum-precatalyst.

Selective Removal of a Pharmaceutical Process Impurity Using a Reactive Resin

Abstract A low‐level (0.5%), but troublesome, aldehyde impurity in a pharmaceutical product was conveniently removed from an existing process stream by employing a reactive, polystyrene‐based sulfonylhydrazine resin. Selection of this resin resulted from screening a number of adsorbents and reactive resins using a high throughput LC–MS approach. The sulfonylhydrazine resin was able to quickly remove an impurity from an existing, highly concentrated, product stream in DMF at a level of 20 mg resin for each gram of product. The material obtained from such treatment showed a greatly improved impurity profile, with an 85% reduction in the level of the aldehyde impurity and without introduction of additional impurities.

A simple and scalable method to prepare 1-aza-5-chloro-5-stannabicyclo[3.3.3]undecane

Abstract A simple and scalable method for the preparation of a potentially versatile organostannane, 1-aza-5-chloro-5-stannabicyclo[3.3.3]undecane ( 1 ), is described. Stannane 1 was prepared by the disproportionation of N(CH 2 CH 2 CH 2 SnBu 3 ) 3 and SnCl 4 at 70–100°C. This reaction requires the addition of water or an alcohol to proceed efficiently. Under typical conditions, 1 was isolated in 50–55% yield after a simple acid/base extraction sequence.

Inhibitors of HIV-1 Attachment: The Discovery and Development of Temsavir and its Prodrug Fostemsavir

Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials.

A Preferred Synthesis of 1,2,4‐Oxadiazoles

Abstract An efficient and high‐yielding one‐pot synthesis of 1,2,4‐oxadiazoles from carboxylic acids and amidoximes is described. Activation of the carboxylic acid using hydroxybenzotriazole (HOBt) and EDC/HCl followed by reaction with an amidoxime generates an oxime ester. Without isolation, the oxime ester is dehydrated to give the oxadiazole ring.

Preparation of Cyclic Sulfites by Transesterification of Diols and Diisopropyl Sulfite

Abstract Cyclic Sulfites of 1,2-, 1,3- and 1,4-diols can be prepared in high yield by acid or base catalyzed transesterification with diisopropyl sulfite.