Acceleration of Petasis reactions of salicylaldehyde derivatives with molecular sieves

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. © 2011 American Chemical Society

Process Development of an N‑Benzylated Chloropurine at the Kilogram Scale

A two-step pharmaceutical manufacturing process was developed for the large-scale preparation of 6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)­methyl)-9<i>H</i>-purin-2-amine methanesulfonic acid salt (<b>4</b>) from commercially available starting materials. In the first step, the benzylpurine free base (<b>3</b>) was prepared by benzylation of 6-chloro-9<i>H</i>-purin-2-amine (<b>1</b>) with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (<b>2</b>). The benzylpurine free base was then directly converted into the methanesulfonic acid salt. It was necessary to charge the pyridine hydrochloride <b>2</b> in portions into the mixture of K₂CO₃ (−325 mesh) and the chloropurine compound <b>1</b> in dimethylacetamide (DMA). The major regioisomeric impurity (<b>6</b>), formed by <i>N</i>⁷ benzylation, and inorganic salts were removed by filtration. Treatment of the DMA filtrate with MsOH afforded the target salt with negligible degradation. In the second step, recrystallization of the crude salt from DMSO–EtOAc with seeding gave crystalline API in high yield and purity despite the hydrolytic instability of the product in solution

Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium

Designation and justification of active pharmaceutical ingredient starting material (API SM) is a standard part of the drug development and commercialization process. However, knowledge of current practices used within the industry varies, depending on the individual company interpretation of regulatory guidelines. In 2011, the API and Analytical Leadership Groups within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ), established a Working Group on API SMs to determine current practices within the pharmaceutical industry on this topic. A survey composed of four key areas, representing (1) drug substance (DS) attributes, (2) API SM attributes, (3) control strategy, and (4) regulatory practices and strategy, was developed and distributed to IQ member companies. Data representing a total of 50 API SMs (used to prepare 24 late stage clinical or marketed DSs) were obtained. This data was used to gain a better understanding of approaches utilized by pharmaceutical companies to define API SMs. The data gathered was anonymous, and the key information obtained is summarized in this manuscript. While no single approach to justifying API SMs emerged from the survey data, key trends were evident that will provide valuable insight for the reader on this important topic