A general synthetic route to a series of novel N-aryl and N-benzyl diaminocyclobutenedione derivatives and pertinent SAR data have been reported elsewhere. KCO-616 can be conveniently synthesized in two steps as shown in Scheme 26121401a. An ethanolic solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (I) is allowed to react with tert-amylamine (II) at room temperature for a period of 24 h to give intermediate 3-(1,1-dimethylpropylamino)-4-ethoxy-3-cyclobutene-1,2-dione (III) in 90% isolated, purified yield. The condensation of this compound with 2,4-dichloro-6-methylbenzylamine (IV, recrystallized from boiling diethyl ether) in ethanol at room temperature for 24 h affords analytically pure 3-(2,4-dichloro-6-methylbenzylamino)-4-(1,1-dimethylpropylamino)-3-cyclobutene-1,2-dione (KCO-616) in 92% yield.
The condensation of 4-amino-3-ethylbenzonitrile (I) with 3,4-diethoxy-3-cyclobutene-1,2-dione (II) in refluxng acetonitrile gives 4-(2-ethoxy-3,4-dioxo-1-cyclobutenylamino)-3-ethylbenzonitrile (III), which is finally condensed with (R)-1,2,2-trimethylpropylamine (IV) in ethanol.