Last week I was in Madrid running our chemical development and scale up course. I met a great group of people, one of whom worked at Dynamit Nobel. During a coffee break we struck up a conversation about (of all things) azides, in particular sodium azide. Fairly quickly we both discovered that we had no idea how it’s made industrially. Very carefully would be my somewhat cynical suggestion. Curiosity sufficiently piqued, I thought I would look into it. This post is a short summary of my findings. A quick google search revealed references to the use of sodium azide as a precursor to organic azi ..read more

For the past decade I have been intrigued by the emergence of micelle technology and its ability to enable many organic reactions in water, but perplexed about why the reactions work as effectively as they do, and have been waiting for more universal reaction conditions. Two recent papers address these issues. The title of the first paper, “Entropy reduction from strong localization – an explanation for enhanced reaction rates of organic synthesis in aqueous micelles”, summarizes a new hypothesis for why the micelle methodology is surprisingly effective and has helped me think about these reac ..read more

New Discount Available for Andrew Teasdale’s Book, ‘Mutagenic impurities’ click on the image below for more details. Andrew Teasdale is a senior principle scientist within AstraZeneca, with 25 years experience in the industry. Andrew is also the inventor of the purge factor concept applied to the risk assessment of mutagenic impurities. Over the last 10 years he has been an author of over 30 papers relating to mutagenic impurities. Andrew is current an advisor to China FDA for ICH M7. Prior to entering the pharmaceutical industry Andrew obtained a degree BSc (Hons) in analytical chemistry from ..read more

Several weeks ago I did my annual analysis of the synthetic routes used to prepare small molecule drugs approved by the FDA in the preceding year, obviously in this case 2022.1 I  hope those of you who have seen the presentation found it as interesting to watch as I found to put it together. One of the questions I was asked by an attendee related to an unusual CBz deprotection method used in the synthesis of the KRAS -G12C inhibitor Adagrasib , developed and marketed by Mirati Therapeutics (Figure 1).2 The method is a little unusual. It involves nucleophile attack at the CBz- benzylic car ..read more

Love it or hate it, triphenylphosphine oxide (TPPO, Figure 1) is something we all encounter at some point during our chemistry careers. Most of the time it’s just a by-product from well-established and widely used process such as the Mitsunobou, Wittig, Staudinger, Appel and Corey-Fuchs reactions.1 I remember having a vial full of the white, crystalline material on the shelf during my PhD. I’d isolated it from a Wittig reaction, having assumed at the time that it must be my product, not a stochiometric by-product. I then had to go on a tedious hunt for my olefin in various aqueous and organic ..read more

Nirmatrelvir, the active ingredient of the Pfizer drug Paxlovid (Figure 1), is an inhibitor of the SARS-CoV-2 main protease enzyme.1 Figure 1: Nirmatrelvir (Paxlovid) A key transformation- the final synthetic step in the synthesis of Nirmatrelvir- is dehydration of a primary amide (Figure 2).The amide starting material is prepared by reaction of the corresponding ester with ammonia.2 Figure 2: Nitrile formation via primary amide dehydration Various methods for the dehydration process have been disclosed by Pfizer including use of the Burgess reagent, T3P, trifluoroacetic anhydride or POCl3 imi ..read more

Many organic impurities, such as nitrosamines, are known to be harmful to human health. Therefore, regulatory bodies and government set strict limits to protect us all. Even in small quantities, pharmaceutical impurities can have serious negative health impacts and influence the behaviour and efficacy of a drug. Organic impurities fall into a number of categories. They can be degradants of the drug API or starting materials, unintended by-products of the manufacturing process or untransformed production intermediates. An API failing to separate from other materials involved in its synthesis ..read more

We spoke to chemists at different stages of their careers about their experiences of attending our ‘Chemical Development and Scale Up in the Fine Chemical and Pharmaceutical Industries’ training course. Ben Littler  Ben told us that he had taken the ‘Chem Dev’ course twice as an early career process chemist!  Both courses were held as in-house training events. It was fascinating to hear about Ben’s experiences going back to the start of his career journey! The first time Ben took the course was at AMRI in his first year after finishing his academic career and it was led by Trevor (T ..read more

What an experience to treasure! Claire and Hannah from Scientific Update Ltd were invited to travel on the beautiful British Pullman last week, for a specially hosted event ‘Golden Age of Travel with The Netherlands’. Passengers were encouraged to dress up in 1920’s costume and it certainly was a rather glamorous and special occasion. Everyone enjoyed fine dining and champagne in a rather glorious setting. The Phoenix Carriage (pictured below) was restored after a fire, hence the name! Apparently, it was one of the Queen’s favorite carriages to travel in and Claire and Hannah were bo ..read more

One of the most challenging reactions we carry out as synthetic chemists is bromination of a benzylic carbon- the so called Wohl-Ziegler reaction.1 It’s a seemingly simple transformation – not particularly difficult to perform- and potentially very useful. In fact it’s a little too easy. Just add NBS and a radical initiator to an aryl methyl (tolyl) substrate and the over-zealous bromide radicals jump into a feeding frenzy- giving a mixture of mono– and bis– halogenated products (amongst other things). The problem then is two-fold. How to control the process to get better selectivity (mono- v ..read more