page_title: Immunomodulatory imide drug
section_title: Thalidomide
hierarchical_section_title: Immunomodulatory imide drug / Synthesis / Thalidomide
caption_attribution_description: English: A newer easier way to synthesize Thalidomide
context_page_description: Immunomodulatory imide drugs are a class of immunomodulatory drugs containing an imide group. The IMiD class includes thalidomide and its analogues. These drugs may also be referred to as 'Cereblon modulators'. Cereblon is the protein targeted by this class of drugs.
  The name "IMiD" alludes to both "IMD" for "immunomodulatory drug" and the forms imide, imido-, imid-, and imid.
  The development of analogs of thalidomide was precipitated by the discovery of the anti-angiogenic and anti-inflammatory properties of the drug yielding a new way of fighting cancer as well as some inflammatory diseases after it had been banned in 1961. The problems with thalidomide included; teratogenic side effects, high incidence of other adverse reactions, poor solubility in water and poor absorption from the intestines.
  In 1998 thalidomide was approved by the U.S. Food and Drug Administration for use in newly diagnosed multiple myeloma under strict regulations. This has led to the development of a number of analogs with fewer side effects and increased potency which include lenalidomide, pomalidomide and apremilast, all of which are currently marketed and manufactured by Celgene.
context_section_description: Synthesis of thalidomide has usually been performed as seen in scheme 1. This synthesis is a reasonably simplistic three step process. The downside of this process however is that the last step requires a high-temperature melt reaction which demands multiple recrystallizations and is not compliant with standard equipment.
  Scheme 2 is the newer synthesis route which was designed to make the reaction more direct and to produce better yields. This route uses L-glutamine rather than L-glutamic acid as a starting material and by letting it react with N-carbethoxyphthalimide gives N-phthaloyl-L-glutamine (4), with 50–70% yield. The substance 4 is then stirred in a mixture with carbonyldiimidazole (CDI) with enough 4-dimethylaminopyridine (DMAP) in tetrahydrofuran (THF) to catalyze the reaction and heated to reflux for 15–18 hours. During the reflux thalidomide crystallizes out of the mixture. The final step gives 85–93% yield of thalidomide, bringing the total yield to 43–63%.
caption: Scheme 2: Newer thalidomide synthesis, two step reaction
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