The racemization process can occur in vivo. The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine. As shown in the image below, N-carbethoxyphthalimide (1) can react with L-glutamine to yield N-phthaloyl-L-glutamine (2). Cyclization of N-phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3). Celgene Corporations original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure. History
In 1952, thalidomide was synthesised by Chemical Industry Basel (CIBA), but was found "to have no effect on animals and was discarded" on that basis. In 1957, it was acquired by Chemie Grünenthal in Germany. The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics. Heinrich Mückter was appointed to head the discovery program based on his experience working with the German armys antiviral research. While preparing reagents for the work, Mueckters assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative. The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide.
However, thalidomide is a teratogenic substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE. Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be a challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs. Brand names
Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many others. Research
Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide. Thalidomide analogs
The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative.