Concise and Scalable Synthesis of Thalidomide

Key words

thalidomide - crystallization - gram scale

Significance

Thalidomide is a widely used drug in clinics for its immunomodulating and anti-­inflammatory properties. Previously, thalidomide was synthesized with three steps, but the last step is a high-temperature melt reaction to afford crude thalidomide that needs to be purified with multiple recrystallizations. The authors aim to develop a more efficient and convenient synthesis to aid further research into thalidomide’s biological activities and mode of action.

Comment

The synthesis starts with readily available L-glutamine. Treatment of L-glutamine with Na₂CO₃ in water, followed by the addition of N-carbethoxyphthalimide yields a white solid that does not need purification. Thalidomide crystallizes out of the cyclization-reaction mixture during the reflux. Then thalidomide is filtered out as a white solid, generally of greater than 99% purity.

Publication History

Article published online:
13 February 2023