Process Chemistry News
A recent OPRD paper from Sanofi describes the synthesis of a GCS inhibitor where one of the key steps was to convert acid (3) in to the final product carbamate (1) via trapping of isocyanate (5) (see Scheme 1).
Sulfonate salts have had a very bad press in recent years, because they are often prepared in alcoholic solvents which potentially creates problems with the formation of alkyl sulphonates which are potentially genotoxic impurities.
Dr Trevor Laird (Scientific Update) talked about appearing and disappearing polymorphs and other solid forms in process development, during the '2nd Winter Process Chemistry' Conference in December. This involved a number of case studies including axitinib, Pfizer's anti-cancer drug, has 5 anhydrous forms and over 70 different solvates known to date and requires a complex crystallisation wash procedure to obtain the correct form. In another example from Merck-Schering Plough batches from one reactor train started to fail because of a yellow colouration. Product from an older reactor train did not have this problem. Temperature and humidity, particularly during drying were found to be critical. During drying a new anhydrate was being formed which then formed a new hydrate when exposed to moist air. The new hydrate is unstable forming the yellow impurity. The problem was solved by a modified wash and drying sequence.