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Synthesizing Aromatic Nitriles via Cyanation

Cyanation of aromatic/heteroaromatic halides/pseudohalides is still not always a straightforward transformation, especially if the reaction needs to be scaled up. 2 Ar-X  +  Zn(CN)2  ®  2 ArCN  +  ZnX2 Workers at BMS have recently published a paper where they describe an improved protocol for this transformation1. They found that Pd2(dba)3 with XantPhos, Zn(CN)2 and i-Pr2NEt

Oxazole Synthesis from Acetylenes and Nitriles

Oxazoles are relatively common heterocyclic rings, but are not always the easiest rings to prepare by de novo synthesis.  Two recent papers describe new methods for the preparation of these compounds1,2. In the first paper1, a heterogeneous gold catalyst (MCM-41-Ph3PAuNTf2) is used prepare oxazoles from an acetylene, a nitrile with the oxygen atom coming from

Biocatalysis

Francis Arnold and her group have published a series of papers using modified Cytochrome P450 enzymes to cyclopropanate olefins with diazo esters1.  More recently they have used a related system to create chiral carbon-silicon bonds2. P.S. Coelho, E.M. Brustad, A. Kannan, and F.H. Arnold et al, Science, 2013, 339, 307-310; Z.J. Wang, H. Ranata, N.E.

Regulatory Starting Materials (RSMs)

There have been a number of papers on the subject of how to specify regulatory starting materials, with a bench marking exercise carried out by the IQ Consortium1.  Now a sub-group has published a risk assessment tool to evaluate potential regulatory starting materials2, particularly in early development. For any proposed RSM a score is built

Reaction Calorimetry in Microreactor Environments

Flow chemistry is big news at the moment, but one of the issues from a scale up perspective has been carrying out some of the process hazard analysis, and in particular reaction calorimetry.  If reactants are unstable either thermally or chemically is it possible to get meaningful results from a conventional reaction calorimeter?  A recent

Photochemistry

Photochemistry has to me always seemed to be an area whose potential for industrial manufacture has never been realized. I may be biased (I did my PhD on photochemistry from 1967-1970) but I feel the tremendous synthetic potential of photoreactions has not been exploited enough.  One of the reasons is that scale up of batch

Sustainability and Analysis

Considering the environmental footprint of a typical pharmaceutical / agrochemical process, 60-80% arises from the use of solvents.  Good solvent selection and use – can be the biggest positive hit on improving the sustainability of a process. The timely identification of an optimum chemical route can save you time and money.  An efficient route, selected

Predicting Greenness Scores

This excellent paper from BMS describes a method for predicting the process mass intensity (PMI) for a given chemical step or for a whole synthesis, and thus provides a new way to compare synthetic routes even at the design stage. At the heart of this approach is an internal database of PMI scores for 15

Impurities Guidelines

Permissible limits for impurities during clinical development has always been a grey area. Existing guidelines, specifically ICH Q3A only formally apply to marketed products. How factors such as duration of clinical trials have never been effectively addressed.

Risk Analysis for Quality by Design (QbD) (part 1)

Whereas process parameter risk quantification is conducted using mathematical calculations (Monte Carlo simulations) based on a process model, risk analysis is a semi-subjective methodology, of value for both early, as well as for late process development work. Herein we will focus on early process development, when little experimental information is available. In spite of its

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