Process for the synthesis of high purity norgestrel 3-one-oxime

• Main Authors: TERDY, LASZLO, TUBA, ZOLTAN, MAGYARI, ENDRENE, MAHO, SANDOR, KISS, JANOS
• Format: Patent
• Language: English
• Published: 29.02.2008
• Edition: 7

Process for the synthesis of high purity d-(17alpha)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yne-3-one-oxime 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, comprising the steps of carrying out the acetylation of the starting material, d-(17alpha)-17-hydroxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one (d-norgestrel) - purity at least 93-94% -, 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 decomposing the excess of acetic anhydride and the "enol acetate" by-product with aqueous hydrochloric acid, then isolating the formed d-(17alpha)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one from the reaction mixture by addition of ice-water, filtering off the precipitated product, washing with water, drying, dissolving in dichloromethane or acetone and clarifying with silica gel or aluminium oxide and charcoal, concentrating the resulted solution after filtration of the clarifier and recrystallizing the residue, reacting the obtained d-(17alpha)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one 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, addition of water after completion of the reaction, filtering off the precipitated product, washing with water, drying and recrystallizing, hydrolyzing the obtained d-(17alpha)-17-acetoxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime 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 deg C, under vigorous stirring, diluting the reaction mixture with water after completion of the reaction and adjusting the pH of the resulted suspension to 7.5-9 with acetic acid, filtering off the precipitated product, washing with water, drying, dissolving the crude product in ethanol, clarifying with charcoal, and addition of water after filtration of the clarifier to the obtained solution, filtering off the precipitated high purity d-(17alpha)-17-hydroxy-13-ethyl-18,19-dinorpregn-4-ene-20-yne-3-one-oxime, washing with water and in given case recrystallizing from ethanol.