A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schöllkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schöllkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.

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The potential for N -nitrosamine impurities in pharmaceutical products presents a challenge for the quality management of medicinal products. N -Nitrosamines are considered cohort-of-concern compounds due to the potent carcinogenicity of many of the structurally simple chemicals within this structural class. In the past 2 years, a number of drug products containing certain active pharmaceutical ingredients have been withdrawn or recalled from the market due to the presence of carcinogenic low-molecular-weight N , N -dialkylnitrosamine impurities. Regulatory authorities have issued guidance to market authorization holders to review all commercial drug substances/products for the potential risk of N -nitrosamine impurities, and in cases where a significant risk of N -nitrosamine impurity is identified, analytical confirmatory testing is required. A key factor to consider prior to analytical testing is the estimation of the daily acceptable intake (AI) of the N -nitrosamine impurity. A significant proportion of N -nitrosamine drug product impurities are unique/complex structures for which the development of low-level analytical methods is challenging. Moreover, these unique/complex impurities may be less potent carcinogens compared to simple nitrosamines. In the present work, our objective was to derive AIs for a large number of complex N -nitrosamines without carcinogenicity data that were identified as potential low-level impurities. The impurities were first cataloged and grouped according to common structural features, with a total of 13 groups defined with distinct structural features. Subsequently, carcinogenicity data were reviewed for structurally related N -nitrosamines relevant to each of the 13 structural groups and group AIs were derived conservatively based on the most potent N -nitrosamine within each group. The 13 structural group AIs were used as the basis for assigning AIs to each of the structurally related complex N -nitrosamine impurities. The AIs of several N -nitrosamine groups were found to be considerably higher than those for the simple N , N -dialkylnitrosamines, which translates to commensurately higher analytical method detection limits.

The amination of 2-fluoronitrobenzene was Pd(0) catalyzed at 65 degrees C in DMF, and the effectiveness of the catalysis was ligand-dependent. Among the five catalyst systems investigated, Pd(PPh3)4 was the most effective catalyst. The control experiments revealed that Pd(OAc)2 or PPh3 was not responsible for the catalysis. 4-Fluoro-3-nitro-benzonitrile and 4-fluoro-3-nitro-benzaldehyde also underwent Stille coupling and Suzuki coupling in the presence of Pd(PPh3)4, and the reactions afforded the coupling products in 28-86% yields. The control experiments showed no sign of reaction in the absence of palladium. These results were in agreement with the oxidative addition/reductive elimination pathway, where the oxidative addition could conceivably proceed via the SNAr mechanism.

AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has been a persistent issue. The development of a much improved process for palladium removal and a useful screening technique developed to rapidly identify the most efficient reagents for this purpose are outlined. The performance of the new endgame process in pilot-plant scale-up is also discussed.

N-Arylation of electron-deficient pyrroles has been achieved by cross-coupling with arylboronic acids at room temperature in the presence of stoichiometric amounts of copper(II) acetate. The generality of this reaction has been established with variously substituted pyrroles as well as boronic acids. A key intermediate in the synthesis of a matrix metalloprotease inhibitor has been achieved using this methodology.

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

A chemoenzymatic route for the production of an intermediate to a gamma secretase inhibitor is described. The route is robust and was run at multikilogram scale. The process employs both a transaminase catalyzed reductive amination of a substituted tetralone and an alcohol dehydrogenase catalyzed reduction of an α-ketoester to generate the two chiral centers in the molecule, with nearly perfect stereoselectivity. The process also features simple isolation schemes, including a direct drop isolation of the aminotetralin phosphate salt.