A Novel Green Synthesis of Thalidomide and Analogs

Abstract

Thalidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer properties. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures. Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its analogs in a one-pot multicomponent synthesis system. The multicomponent synthesis system developed involves an array of cyclic anhydrides, glutamic acid, and ammonium chloride in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP) to produce thalidomide and structurally related compounds within minutes in good isolated yields.

Greener synthesis of chemical compounds and materials

“…Other recently developed greener techniques deal with compounds such as poly(tanninhexamethylendiamine), which can be used as an effective adsorbent for Cr(VI) [73], a lipophilic cantharidine-like model compound for pharmacological probe [74], thalidomide and some of its derivatives [75], 3,4-dihydropyrimidin-2(1H)-ones [76], biologically important spiro-2-oxindole derivatives [77], methyl nitroacetate [78]. Milder conditions, higher yields and other advantages are characteristic features for these processes.…”

“…Also, important recent small molecules, prepared via greener processes, and comparative advantages of applications of greener methods for obtaining N- and O-containing compounds are as follows: a series of five, six, seven and eight-membered pyrrolo[1,2-a]benzimidazoles , prepared [67] using hydrogen peroxide in ethyl acetate from commercial o -(pyrrolidin-1-yl)anilines as precursors without further steps such as chromatography or organic-aqueous extraction;tetra-substituted pyrrole derivatives , synthesized with good yields (88–93%) in one step under ultrasound-assisted standard Knoevenagel condensation in water as a solvent and without catalyst followed by the reaction of Michael type [68];for 1,3,5-triazine, the use of silica supported Lewis acids (TiCl 4 , ZnCl 2 and AlEt 2 Cl supported on silica gel) under microwave conditions leads to tris-pyrazolyl-1,3,5-triazines , where triazine and pyrazole rings are connected with C–C bonds [69];synthesis of adipic acid from cyclohexene as precursor by oxidation with H 2 O 2 in a microemulsion system in the presence of stearyldimethylbenzylammonium chloride without N 2 O emissions (as in a conventional method), extreme reaction time, pressure, mixing and temperature, applying non-dangerous ultrafiltration instead evaporation;synthesis of soluble polyphenol via a simple formaldehyde-free route by direct oxidation of phenol by potassium ferricyanide in alkaline water; compared with classic routes, the use of dimethyl carbonate as an alternative reagent under solid/liquid phase conditions at 90°C for 5 h led to final products, methyl eugenol and veratraldehyde, in 95–96% yield, avoiding toxic compounds [70];higher-yield synthesis of propylene carbonate (PC) in solvent-free conditions by exothermic cycloaddition reaction of CO 2 and propylene oxide in a Parr high-pressure reactor using some heterogeneous catalysts (Ce–La–Zr–O) [71]; andsynthesis of hydroquinone by several steps (benzene-cumene-phenolhydroquinone) from petroleum-derived benzene as a precursor, using the Rh on Al 2 O 3 catalyst with 59% yield [72]. Other recently developed greener techniques deal with compounds such as poly(tannin-hexamethylendiamine), which can be used as an effective adsorbent for Cr(VI) [73], a lipophilic cantharidine-like model compound for pharmacological probe [74], thalidomide and some of its derivatives [75], 3,4-dihydropyrimidin-2(1H)-ones [76], biologically important spiro-2-oxindole derivatives [77], methyl nitroacetate [78]. Milder conditions, higher yields and other advantages are characteristic features for these processes.…”

Crystal structure of the thalidomide analog (3aR*,7aS*)-2-(2,6-dioxopiperidin-3-yl)hexahydro-1H-isoindole-1,3(2H)-dione

“…Some details of the synthesis have been previously reported (Benjamin & Hijji, 2017). cis-1,2-Cyclohexane dicarboxylic acid anhydride (0.10 g, 0.65 mmol), glutamic acid (0.095 g, 0.65 mmol), DMAP (0.02 g, 0.16 mmol), and ammonium chloride (NH 4 Cl) (0.040 g, 0.75 mmol) were mixed thoroughly in a CEM-sealed vial with a magnetic stirrer.…”

Microwave-promoted synthesis of cyclic imides

“…Recently Benjamin and Hijji 115 have reported the synthesis of thalidomide and thalidomide analogs (Scheme 19) under MW irradiation conditions through a one-pot reaction of glutamic acid with the corresponding anhydride and ammonium chloride, using DMAP as a basic catalyst (150 o C, 10 min). Considerable quantities of the N-unsubstituted cyclic imide are also produced during the reaction.…”