Thalidomide synthesis

Reepmeyer JC, Cox DC (1987) FDA monograph guidelines to thalidomide synthesis. US Food Drug Administration, Washington, DC... 

More recently this procedure has been used for a new synthesis of thalidomide, now a rehabilitated drug [94] (Scheme 8.68). 

The thalidomide analogs CPS49 (30) and CPS11 (31) have been reported to inhibit PI3/AKT signaling in multiple myeloma cells via an anti-angiogenic effect. These compounds are devoid of the teratogenic properties seen with thalidomide and are currently in preclinical development [66]. Compound 30, and to a lesser extent 31, induced a dose-dependent inhibition of proliferation in several multiple myeloma cell lines and reduced phospho-AKT levels [66]. These compounds also inhibited DNA synthesis in cell lines resistant to conventionally used anti-multiple myeloma drugs (e.g. dexamethasone, anthracyclines and melphalan) in a dose-dependent manner. 

We must inteiject an interesting historical sidelight at this point. Despite its reputation, thalidomide made a bit of a comeback in the 1990s (Blakeslee, 1994). Among other properties, thalidomide has been shown to have good anti-inflammatory properties, because it apparently decreases the synthesis and/or release of tissue necrosis factor. 

Tetrydamine, 352 Thalidomide, 296 Thebaine, 318 Theniurn closylate, 99 Theobromine, 456 Theophylline, 464 Thiabendazole, 352, 353 1,2,5-Thiadiazole synthesis,... 

In a placebo-controlled study in six patients with type 2 diabetes mellitus thalidomide 150 mg/day for 3 weeks reduced insulin-stimulated glucose uptake by 31% and glycogen synthesis by 48% (1115). However, it had no effect on rates of glycolysis, carbohydrate oxidation, non-oxidative glycolysis, lipolysis, free fatty acid oxidation, or re-esterification. The authors concluded that thalidomide increases insulin resistance in obese patients with type 2 diabetes. 

Iqbal N, Zayed M, Boden G. Thalidomide impairs insulin action on glucose uptake and glycogen synthesis in patients with type 2 diabetes. Diabetes Care 2000 23(8) 1172-6. 

Keywords Asymmetric synthesis Drug synthesis Teratogenicity Thalidomide... 

The increasing interest in thalidomide (1) during the last decade is clearly represented by the number of hits in the scientific literature dealing with the word thalidomide under SciFinder search. It is worth mentioning that most of the documents were published in the last 10 years (Fig. 2). Most of them concerned the biological, physiological, and clinical aspects of thalidomide (1) and they are now systematically well summarized [1-14]. However, review of the synthetic side of thalidomide (1) is still rare. In this review, we focus on the synthesis of racemic thalidomide (1), which is now commercially... 

Scheme 1 First synthesis of thalidomide (1) in Chemie Grunenthal GMBH [18]...

Hijji and Benjamin also accomplished a microwave synthesis of thalidomide in acceptable yield in 2004 (Scheme 5) [36-39]. Ammonium chloride was found to be an effective source for nitrogen. Namely, phthalic anhydride (4), glutamic acid (8), and ammonium chloride were mixed in 1 1 1 ratio with a catalytic amount of DMAP and heated in a conventional microwave oven for 6.5 min. The mixture melted to a brown liquid. The heating continued for an additional 1 min to give thalidomide (1) in 52% yield in this two-step, one-pot reaction after solubilization, precipitation, and recrystal-lization. 

In 2003, a Chinese group reported a one-pot synthesis of thalidomide (1) in 24.1% yield by allowing phthalic anhydride (4) to be reacted with glu-... 

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