PROCESS FOR THE SYNTHESIS OF HIGH PURITY D-(17ALPHA)-13- ETHYL- 17HYDROXY-18,19-DINOR-PREGN-4-ENE 20- YNE-3-ONE-OXIME

The invention relates to a process for the synthesis of high purity d-(17α)-13-ethyl-17 -hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one- oxime (further on norelgestromine) via acetylation of d-norgestrel at position 17, oximation of the oxo group at position 3 of the obtained 17-acetoxy derivative, and finally hydrolyzing the acetoxy group at position 17 of the obtained 3-oxime derivative. The process according to our invention is as follows: the starting material, d-(17α-17-hydroxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3 -one (d- norgestrel) - purity 93-94 % - is acetylated with acetic anhydride in acetic acid, in the presence of zinc chloride and hydrogen chloride, or 70 % perchloric acid in an inert gas atmosphere, and after completion of the reaction the excess of acetic anhydride and the "enol acetate" by-product are decomposed with aqueous hydrochioric acid, then the formed d-(17α)-17-acetoxy-13-ethyl-18,19-dinorpregn- 4-ene-20-yne-3-one is isolated from the reaction mixture by addition of ice-water, the precipitated product is filtered off, washed with water, dried, dissolved in dichloromethane or acetone and clarified with silica gel or aluminum oxide and charcoal, after filtration of the clarifier the resulted solution is concentrated and the residue is recrystallized, the obtained d-(17α)-17-acetoxy-13-ethyl-18,19- dinorpregn-4-ene-20-yne-3-one is reacted either with hydroxylammonium acetate or with hydroxylammonium chloride in the presence of sodium acetate, in acetic acid in nitrogen atmosphere under vigorous stirring for about 1 hour, after completion of the reaction water is added, the precipitated product is filtered off, washed with water, dried and recrystallized, the obtained d-(17α-17-acetoxy-13-ethyl- 18,19-dinorpregn-4-ene-20-yne-3-one-oxime is hydrolyzed with an equivalent amount of an alkali metal hydroxide in a C1-C4 alkanol solution, in nitrogen atmosphere between a temperature of about 5-38°C, under vigorous stirring, after completion of the reaction the Pronalazak se odnosi na postupak za sintezu d-(17α)-13-etil-17-hidroksi-18,19-dinorpregn-4-en-20-in-3-on-oksima visoke isto e (dalje norelgestromin) putem acetilacije d-norgestrela na polo aju 17, oksimacije okso grupe na polo aju 3 dobijenog 17-acetoksi derivata i kona no, hidrolizom acetoksi grupe na polo aju 17 dobijenog 3-oksim derivata. Postupak prema našem pronalasku je slede i: po etni materijal, d-(17α)-17-hidroksi-13-etil-18,19-dinorpregn-4-en-20-in-3-on (d-norgestrel) - is