The synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.

The synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.

The synthesis of RFCNU from 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide (III) has been described, as well as the preparation of 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-beta-D-ribosyl bromide from 2,3-O-isopropylidene-D-ribosyl-furanose (I). Briefly, the synthesis is as follows: A cold solution of 2,3-O-isopropylidene-D-ribofuranose (I) in dry pyridine is stirred and treated with p-nitrobenzoyl chloride (A). Workup gives 2,3-O-isopropylene-1,5-di-O-p-nitrobenzoyl-D-ribofuranose (II), which is crystallized from methylene chloride/ether. (II) is added in portions to a dry solution of methylene chloride saturated with HBr at 0 C and stirred for 0.5 h. It is warmed to room temperature, the precipitated p-nitrobenzoic acid removed by filtration (under argon) and the filtrate concentrated. Addition of petroleum ether/diethyl ether and partial concentration by vacuum gives crystals of 2,3-isopropylidene-5-O-p-nitrobenzoyl-beta-ribosyl bromide (III). (III), dissolved in toluene, is reacted with silver isocyanate and refluxed under nitrogen. Silver bromide is filtered off and the filtrate concentrated by evaporation, yielding an oil. Dissolution of the oil in acetonitrile and cooling to -40 C yields crystals of isocyanato-1-O-isopropylidene-2,3-O-p-nitrobenzoyl-5-D-ribofuranose (IV). (IV) is reacted with an aqueous solution of 2-chloroethylamine (B) and the solution extracted with benzene. The organic base is separated, dried and refrigerated. Warming gives a yellow oil, which is treated with ethanol to give crystalline (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-urea (V). (V) is dissolved in methylene chloride, cooled to -40 C and an excess of liquid nitrosyl chloride (NOCl) is added with stirring. Addition of a mixture of chloroform and petroleum ether gives crystals of (chloro-2-ethyl)-1-(ribofuranosylisopropylidene-2',3'-p-nitrobenzoate-5')-3-nitrosourea (RFCNU). The synthesis may be modified to yield either the alpha or beta anomer. Both anomeric forms have shown the same antitumor activity.