S-Thalidomide

A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, whereas the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. PK modeling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6 h would have little influence on the maximal blood concentration of formed R-thaKdomide. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in vim... 

More recent studies have indicated a probable mechanism, which relies on the interaction of thalidomide with DNA. The phthalimide double-ring structure of S-thalidomide can intercalate with DNA and binds to the polyG sites in the promoter regions coding for growth factors and integrins. 

In 1964, in order to compare the pharmacological behavior of both antipodes of thalidomide (1), Casini and Ferappi in Italy examined the preparation of (S)-thalidomide (1) from N-phthaloyl-L-glutamine (12) for the first time [85]. Namely, treatment of N-phthaloyl-L-glutamine (12) with one equivalent of thionyl chloride, pyridine, and then triethylamine in dichloromethane at - 30 °C gave (S)-thalidomide (1), [a]p° - 62° (Scheme 17). Although the reported method was straightforward, it was devoid of many synthetic details. 

Scheme 17 Synthesis of (S)-thalidomide (1) from N-phthaloyl-L-glutamine (12) [85]...

D-ornithine (43) with 99% ee in good yield. The advantage of the present method is that all the steps to thalidomide (1) can be performed without purification by silica-gel column chromatography therefore, it is particularly useful for the practical synthesis of (R)- and (S)-thalidomides (1). 

We have recently patented the preparation of optically active thalidomide (1) by the imidation reaction of aminopiperidinedione with phthalic anhydride (4) in the presence of hexamethyldisilazane and ZnCh without racem-ization (Scheme 23) [100]. The process gives the thalidomide (1) in a reduced number of steps in a simple procedure and thereby is advantageous for industrial production of optically active thalidomide (1). Thus, a solution of 100 mg (S)-2-aminoglutarimide hydrobromide (46) in 5 mL benzene was treated with 92.0 mg phthalic anhydride (4), stirred for 1 h, treated with 98.0 mg ZnCl2 and 0.304 mL hexamethyldisilazane (HMDS), refluxed at 80 °C for 6 h, and cooled to room temperature. After the usual workup, (S)-thalidomide (1) was obtained in 58% yield with > 99% ee. (ft)-Thalidomide (1) can be prepared in the same way from (it)-47 with 99% ee in good yield. 

Figure 3.25 Chemical structures and optimized geometries of (/ )- and (S)-thalidomide.

A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide, briefiy empioyed as a sedative and antinausea drug in Europe and Great Britain during the period 1959-1962. The desired properties are those of (/ )-thaiidomide. (S)-Thalidomide, however, has a very different spectrum of biological activity and was shown to be responsible for over 2000 cases of serious birth defects in children born to women who took it whiie pregnant. 

In humans given racemate or individual enantiomers of thalidomide by the oral route, stereoselective differences were noted in the plasma concentrations of the enantiomers [45]. In cases where the enantiomers were given alone, presence of antipode was detected in each group. After R(+) thalidomide or S(—) thalidomide alone, the R S AUC ratios were 3.0 and 0.74, respectively. After racemate, the R S ratio was 1.6. It was concluded that in addition to the interconversion of enantiomers, which was equal in both directions, the S enantiomer is preferentially metabolized in vivo [45]. 

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