Manufacturing Process
63.6 g of potassium t-butylate in 300 ml of dry methanol were introduced into
a solution of 229 g of 2,4-dichlorobenzyltriphenylphosphonium chloride in 800
ml of dry methanol at 10°C, and 77.2 g of 4-chloroacetophenone were added
after half an hour. The reaction solution was refluxed for 3 hours, the
precipitated salt was filtered off at room temperature, the filtrate was
evaporated down under reduced pressure, the residue was digested with
petroleum ether at from 50°C to 70°C to free it from triphenylphosphine
oxide, and the solution was evaporated down under reduced pressure.
The residue was taken up in 1 liter of carbon tetrachloride, and the solution
was refluxed with 81.7 g of N-bromosuccinimide and 4 g of 2,2'-
azoisobutyrodinitrile. After the reaction was complete, the succinimide was
filtered off, the filtrate was evaporated down under reduced pressure and the
residue was recrystallized from methanol. 73.4 g (38.8%) of Z-1-(2,4-
dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene of melting point 128°C
was obtained.
58.9 g of Z-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)-3-bromoprop-1-ene
were refluxed with 52.3 g of 3-choroperoxybenzoic acid in 590 ml of
chloroform. After the reaction was complete, the chloroform phase was washed acid-free with aqueous sodium bicarbonate solution and water, dried
over sodium sulfate and evaporated down under reduced pressure, and the
residue was recrystallized from methanol to give two crystalline fractions:
41.3 g (70.2%) of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)
oxirane (isomer A) of melting point 98-99°C, and, 12 g (20.4%) of 2-
bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer B) of
melting point 93-95°C.
20.9 g of 1,2,4-triazole and 4.4 g of sodium hydride (50% strength dispersion
in mineral oil) were dispersed in 150 mL of N,N-dimethylformamide, and a
solution of 39.2 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-
dichlorophenyl)oxirane (isomer A) and 16.6 g of potassium iodide in 150 ml of
N,N-dimethylformamide was added at room temperature. After 8 hours, the
reaction solution was worked up, and the product was recrystallized from
diisopropyl ether. 31 g (81.9%) of 2-(1,2,4-triazol-1-ylmethyl)-2-(4-
chlorophenyl)-3-(2,4-dichlorophenyl)oxirane (isomer A) - alteconazole was
obtained. MP: 119°C.
