METHOD OF PRODUCING N-(2-CHLOROETHYL)-N'-CYCLOHEXYL-N-NITROSOUREA Russian patent published in 2023 - IPC C07C275/68 C07C273/18 

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to a method of producing 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (lomustine). The method consisting in the fact that to cooled to a temperature (-2–0)°C a solution of monoethanolamine in acetonitrile, cyclohexyl isocyanate is added dropwise and the resulting composition is stirred for 4 hours at a temperature of 0–5°C, the separated precipitate is filtered off, washed with acetonitrile, and after drying in vacuum at 20°C and a minimum pressure of 12 mbar, dissolved in a chlorinated hydrocarbon with a boiling point of 50–70°C followed by cooling, adding a soft organic base and thionyl chloride, keeping the reaction mixture on heating for no more than 50–60°C to give the chloroethyl derivative. Then the chloroethyl derivative is dissolved in 85% formic acid while cooling to (-5±2)°C, sodium nitrite is added, the resulting reaction mixture at a temperature up to (-5+2)°C is kept for 2 hours and treated with concentrated hydrochloric acid for 1 hour, followed by precipitation of the final product from water, filtration and recrystallization from acetonitrile and final drying in vacuum at 28°C and a minimum pressure of 12 mbar, or the chloroethyl derivative is dissolved in 98–99% formic acid while cooling to 0±5°C, sodium nitrite is added, the resulting reaction mixture is stirred for 30 min, then cold water is added and stirred for another 30 min, and the precipitate is filtered off and dried in vacuum at 28°C and a minimum pressure of 12 mbar.

EFFECT: simplifying the method of obtaining lomustine to increase the safety of the synthesis and also to increase the yield of the final product.

1 cl, 1 tbl, 3 ex