Editing Thalidomide (section)

== Chemistry ==
[[Image:Thalidomide-structures.png|thumb|right|300px|The two [[enantiomers]] of thalidomide:<br />Left: (''S'')-(−)-thalidomide<br />Right: (''R'')-(+)-thalidomide]]

Thalidomide is [[Racemic mixture|racemic]]; while ''S''-thalidomide is the bioactive form of the molecule, the individual enantiomers can [[Racemization|racemize]] to each other due to the acidic hydrogen at the [[chiral centre]], which is the carbon of the [[glutarimide]] ring bonded to the [[phthalimide]] [[substituent]]. The racemization process can occur ''[[in vivo]]''.<ref name = clinp/><ref name="stereospecific44">{{Cite journal |vauthors=Eriksson T, Björkman S, Roth B, Fyge A, Höglund P |year=1995 |title=Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide |journal=Chirality |volume=7 |issue=1 |pages=44–52 |doi=10.1002/chir.530070109 |pmid=7702998}}</ref><ref name="pmid14505639">{{Cite journal |vauthors=Man HW, Corral LG, Stirling DI, Muller GW |date=October 2003 |title=Alpha-fluoro-substituted thalidomide analogues |journal=Bioorganic & Medicinal Chemistry Letters |volume=13 |issue=20 |pages=3415–7 |doi=10.1016/S0960-894X(03)00778-9 |pmid=14505639}}</ref><ref name="Bartlett2004">{{Cite journal |vauthors=Bartlett JB, Dredge K, Dalgleish AG |date=April 2004 |title=The evolution of thalidomide and its IMiD derivatives as anticancer agents |journal=Nature Reviews. Cancer |volume=4 |issue=4 |pages=314–22 |doi=10.1038/nrc1323 |pmid=15057291 |s2cid=7293027}}</ref> The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.<ref>{{Cite journal |vauthors=Wsól V, Skálová L, Szotáková B |date=December 2004 |title=Chiral inversion of drugs: coincidence or principle? |journal=Current Drug Metabolism |volume=5 |issue=6 |pages=517–533 |doi=10.2174/1389200043335360 |pmid=15578945}}</ref>

[[Celgene Corporation]] originally synthesized thalidomide using a three-step sequence starting with [[Glutamate|<small>L</small>-glutamic acid]] treatment, but this has since been reformed by the use of [[Glutamine|<small>L</small>-glutamine]].<ref name="synth">{{Cite journal |vauthors=Muller GW, Konnecke WE, Smith AM, Khetani VD |date=19 March 1999 |title=A Concise Two-Step Synthesis of Thalidomide |journal=Organic Process Research & Development |volume=3 |issue=2 |pages=139–140 |doi=10.1021/op980201b}}</ref> As shown in the image below, ''N''-carbethoxyphthalimide (1) can react with <small>L</small>-glutamine to yield ''N''-phthaloyl-<small>L</small>-glutamine (2). Cyclization of ''N''-phthaloyl-<small>L</small>-glutamine occurs using [[carbonyldiimidazole]], which then yields thalidomide (3).<ref name="synth" /> Celgene Corporation's original method resulted in a 31% yield of ''S''-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure.{{cn|date=January 2025}}

In 2023, it is reported that [[phthalic anhydride]] and [[Glutamine|<small>L</small>-glutamine]] under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and <small>L</small>-glutamine are grounded and added into [[toluene]] solvent. The solution, along with [[triethylamine]] and [[acetic anhydride]], is refluxed at ~110°C for 9 hours; after that the solution goes through a simple [[vacuum filtration]] procedure to obtain the product.<ref>{{Cite journal |vauthors=Savini EB, Bandieri E |date=2023 |title=One step synthesis of thalidomide |url=https://cssp.chemspider.com/Article.aspx?id=964 |journal=[[ChemSpider]] |language=en}}</ref>

[[File:Thalidomide syntehsis.png|class=skin-invert-image|center|thumb|567x567px|Muller et al.'s two-step thalidomide synthesis]]