A Convenient Synthesis of a Lymphocyte Function-Associated Antigen-1 (LFA-1) Antagonist of ‘Compound 4’

The lymphocyte function-associated antigen-1 (LFA-1) antagonist of ‘Compound 4’ was synthesised by a convenient route using cheap, commercially available starting materials and catalysts under mild reaction conditions and by easily handled reactions. The total yield in the preparation of ‘Compound 4’ was more than 38% via Sonogashira coupling of an iodide and an alkyne, reduction of the alkyne catalysed by Raney nickel and later steps involving hydrolysis of an ester, condensation of an acid and an amine and a final hydrolysis of an ester.

Mechanism of α-acetyl-γ-butyrolactone synthesis

The mechanism of α-acetyl-γ-butyrolactone (ABL) synthesis from γ-butyrolactone (GBL) and ethyl acetate (EtOAc) was explored by detecting the material changes involved and the enthalpies of formation of the synthons, products, and possible intermediates were calculated using the density functional theory. GBL forms a carbanion of γ-butyrolactone by losing an α-H under strongly alkaline conditions. ABL is then obtained via two reaction mechanisms. One of the reaction mechanisms involves direct reaction of the carbanion of GBL with EtOAc to produce ABL. The other involves the formation of a carbanion of α-(2-hydroxy-tetrahydrofuran-2-yl)-γ-butyrolactone through the reaction of two molecules of GBL, and the subsequent combination of this anion with EtOAc to produce ABL. ABL is thus formed through the above two kinds of competitive ester condensation reactions. It is unnecessary to take into account synthons’ local thickness, and their self-condensation under these conditions. Both reactions of the carbanion of GBL with EtOAc and GBL are exothermic, so the control of their reaction rate is the key to their security. Considering the reasons above, this work applied synthon as the solvent, and avoided environmental pollution by alkylbenzene; also, accidents such as red material and fire were avoided by specific surface area of sodium metal control. Effective isolation of the organic and aqueous phases was performed using the salting out method. Thus, an environmentally friendly, safe, simple, and efficient new method for the synthesis of ABL with the yield higher than 90 % has been established.