It is clear that discovery chemists feel relatively comfortable using hazardous reagents in the confines and safety of their laboratories. However, traditional fine chemical manufacturing techniques are ill-suited to these types of processes and chemists often waste a great deal of time searching for a safer synthesis route.
Phoenix has a great deal of experience in handling the following chemistries:
Azides
Azides, usually in the form of sodium azide, are widely used in the chemical and pharmaceutical industry in the preparation of organic azides, triazoles, tetrazoles, isocyanates and chiral amines.
However, issues of toxicity, thermal or shock sensitivity and the potential for formation of the highly explosive hydrazoic acid render the generation, and use, of many azides a hazardous operation. Azide chemistry must therefore be carried out with due care and, at commercial scale, such processing requires specialised handling techniques.
Through the use of continuous processing systems, able to maintain reaction conditions constantly within the safe operating envelope, Phoenix Chemicals is able to handle a variety of azides, including hydrazoic acid, at all scales from laboratory through to commercial production.
Diazomethane
Diazomethane is an extremely useful reagent with applicability in a wide range of reactions. With carboxylic acids it generates methyl esters in essentially quantitative yield, and with acidic hydroxyl groups such as those in phenols, methyl ethers are produced. It can be used in cycloaddition reactions with olefins to generate cyclopropanes and nitrogen heterocycles, and with ketones it readily generates epoxides. One of its most important uses is in carbon to carbon bond formation by reaction with acid chlorides or anhydrides; the so-formed diazoketones are themselves useful intermediates.
Because diazomethane reacts under neutral conditions and only produces nitrogen as by-product, it has found wide application in the synthesis and reactions of chirally sensitive molecules. Furthermore, its high selectivity lends itself to reactions where the minimization of impurity formation is paramount.
Although used extensively in the discovery lab, its toxicity and explosive nature have, until quite recently, precluded the scaling up of such work. However, through the use of continuous processing technology, Phoenix Chemicals regularly handles diazomethane in complete safety at laboratory, pilot and full commercial scale.
Diazoketones
Diazoketones, readily prepared by the reaction of diazomethane with an acid derivative such as an acid chloride or anhydride, are easily converted to a variety of downstream products, with a wide range of applications. With olefins, for instance, they react to generate cyclopropanes, and upon reduction, ketones are produced. In the Wolff rearrangement, they readily react with water in the presence of light to give β-amino acids in high purity and yield: these products are themselves increasingly used as building blocks for new drug candidates.
Some of the most important applications for diazoketones are accessed through their reaction with anhydrous HCl or HBr: the chloro- and bromo- methylketones which are produced may be reacted on with substrates such as aryl ethers or acids, or else the ketone asymmetrically reduced to a chiral alcohol. Cyclisation under basic conditions leads to a chiral epoxide. Such derivatives have been used in the preparation of a wide variety of pharmaceutical products, with perhaps the most important being the HIV protease inhibitors.
Chloramine/hydrazines
Chloramine, formed by the reaction of chlorine with ammonia, is a useful reagent for the preparation of unsymmetrical hydrazines. Such hydrazines are themselves valuable building blocks used in a wide variety of pharmaceutical and agrochemical products, with many applications.
Phoenix Chemicals uses continuous processing methods to generate gaseous chloramine for use in the production of high purity functionalized hydrazines for pharmaceutical applications. The process is highly efficient, very high yielding, and provides only ammonium chloride as by-product.
