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The Rapid Two Step Microwave Assisted Synthesis of Acetaminophen

January 26, 2016


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Introduction

Performing complex chemical reactions can often lead to challenging product isolation. The formation of multiple products and leftover starting materials can make for challenging separations. The application of gas phase reagentsflow_cell_with_text.jpg in complex chemical reactions can help to simplify the isolation process, as the starting material simply evolves from the reaction. In many cases, the primary obstacle preventing the use of gaseous reagents is the equipment required for its safe handling. The complicated and costly setup required to perform many of these reactions has made them inaccessible to many. The CEM Gas Addition Kit for the Discover® Microwave is designed for the safe and simple use of gaseous reagents at pressures up to 250 psi and temperatures up to 250 °C.

The Gas Addition Kit was used in the two step synthesis of the pain medication acetaminophen. Starting from 4-nitrophenol, the Pd/C catalyzed, microwave assisted hydrogenation1 of the nitro group yielded 4-aminophenol which was then acylated in 5 minutes with acetic anhydride under microwave irradiation.

Acetaminophen.gif

Procedure

To a 10 mL microwave vial equipped with a magnetic stirring bar was added 4 nitrophenol (0.139 g, 1 mmol), 10% Pd/C (0.010 g, 0.01 mmol) and 2 mL EtOAc. The vial was then inserted and sealed in the Discover Microwave cavity equipped with the Gas Addition accessory. The reaction vessel was purged 3 times with 5 bar of H2, the vial was then pressurized to 5 bar and heated to 80 °C using 150 W of power and a dynamic control method. After ten minutes, the reaction vessel was recharged with hydrogen and heated to 80 °C for another ten minutes. After cooling, the solution was decanted into a fresh microwave vial and the Pd/C washed with 1 mL EtOAc. Acetic anhydride (0.19 mL, 2 mmol) was then added and the reaction placed in the Discover and heated to 60 °C for 5 minutes using a dynamic control method and 100 W of power. After cooling, the reaction mixture was loaded directly on a silica gel column and eluted with a mixture of EtOAc/hexanes (2:1). Removal of solvent under reduced pressure provided acetaminophen a white solid (0.095 g, 0.063 mmol) in 63% yield.

(1) Vanier, G. Synlett 2007, 0131.

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