Acefluranol

Originator

Acefluranol ,ZYF Pharm Chemic

Manufacturing Process

4.5 g erythro-3,3'-difluoro-4,4'-dihydroxy-α-ethyl-α'-methylbibenzyl in 30 ml pyridine and 10 ml acetic anhydride were left to stand for 24 h at room temperature, thereafter the reaction mixture was worked up to give a crude product, recrystallisation of which from chloroform-diethyl ether (1:4 v/v) gave 5.5 g erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl, melting point 118°-120°C.
5.0 g of the erythro-3,3'-difluoro-4,4'-diacetoxy-α-ethyl-α'-methylbibenzyl were ground with 10.0 g aluminum chloride and the mixture was heated at 150°C for 30 min. After cooling, the mass was added portion-wise to ice, stirred and extracted with chloroform. The chloroform solution was washed with water, dried with anhydrous sodium sulfate and concentrated to half its volume. An equal volume of diethyl ether was added thereto and the solution was treated with charcoal and filtered. The filtrate was evaporated and the residue obtained was crystallized from chloroform-diethyl ether (1:1 v/v) to give 2.6 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'- methylbibenzyl, melting point 194°-196°C.
0.9 g erythro-3,3'-diacetyl-4,4'-dihydroxy-5,5'-difluoro-α-ethyl-α'- methylbibenzyl were suspended in a mixture of 10 ml dioxan and 6 ml 1 N aqueous sodium hydroxide solution. The solution was cooled to 10°C and 0.8 ml 30% hydrogen peroxide added dropwise thereto. The reaction mixture was stirred at 20°C for 1.5 h and then poured into a mixture of dilute hydrochloric acid and ice. The product was extracted with peroxide-free diethyl ether, the extract was evaporated and the residue was crystallized from benzene to give a yellow solid. This was treated in 5 ml ethanol with 2.0 mg sodium borohydride, followed by acidification with hydrochloric acid, rapid extraction with diethyl ether, evaporation of the extract and immediate crystallization from benzene to give 350.0 mg of pure erythro-4,4',5,5'-tetrahydroxy-3,3'- difluoro-α-ethyl-α'-methyldibenzyl, melting point 143°-145°C.
1.0 g erythro-3,3'-difluoro-4,4',5,5'-tetrahydroxy-α-ethyl-α'-methyldibenzyl in a mixture of 10 ml pyridine and 5 ml acetic anhydride was left to stand at 20°C for 20 h and at 60°-80°C for 1 h. The reaction mixture was then poured into a mixture of dilute hydrochloric acid and ice, stirred for several h and filtered. The filtrate was evaporated and the residue was taken up in chloroform and the chloroform solution was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the solvent removed. The gummy residue was taken up with benzene and the benzene solution filtered through a neutral alumina. The benzene was removed from the filtrate to give 1.0 g pure erythro-3,3'-difluoro-4,4',5,5'-tetraacetoxy-α-ethyl-α'- methyldibenzyl; melting point 160°-162°C (crystallised from diethyl ether).

Therapeutic Function

Antiestrogen