Incorporation of a carboxyl acid to an aryl group by the addition of carbon dioxide to a Grignard or lithium anion is a well-known transformation that is widely used in chemical and pharmaceutical industries. While several major safety concerns have been reported on large scale for the formation of Grignard reagents or other organometallic species, it is still a common practice to form an organometallic species in a batch mode and subsequent quench with carbon dioxide. In general, most of these reactions are carried out at low temperatures and temperature extrusions during carbon dioxide quench due to inefficient mixing often leads to several by-products.
Compound 1, shown in scheme 1, is an intermediate used in the preparation of an active pharmaceutical ingredient (API). Several kilogram quantities of this intermediate are required to support the production of the API for early phase work. Compound 1 can prepared by adding carbon dioxide to lithium anion 3 which is generated from compound 2 at −78° C. in 75% yield. This reaction is sensitive to temperature and isolated yields are low from large scale runs with significant amounts of dark tar-like material isolated during the work up. In addition, several impurities are formed at higher temperature (>−65° C.) due to the instability of the anion. Such uncontrolled reactions on large scale can lead to the formation of reactive benzyne type intermediates which polymerize violently.
Accordingly, there is a great need in the art for new effective methods for synthesizing carboxylic acid intermediates in high yield and under conditions suitable for kilogram scale. This invention addresses these and other needs.