Patent ID: 8110691

Claim:
Industrial process for the synthesis of solvate-free 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione of formula (I) via ketal formation from 3-(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene-20-one of formula (VI) epoxide formation in position 5,10 of the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene of formula (V) reaction of the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-5,10-epoxy-19-norpregna-9(11)-ene of formula (IV) with the Grignard reagent obtained from bromo-N,N-dimethyl-aniline, deprotection of the so formed 3,3,20,20-bis(ethylene-dioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregna-9(11)-ene of formula (III) acetylation of the obtained 11β-[4-(N,N-dimethylamino)-phenyl]-17α-hydroxy-19-norpregna-4,9-diene-3,20-dione of formula (II) and finally liberation of the solvate-free form of the desired product, characterized by i) reacting 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) with potassium acetilyde formed in situ in dry tetrahydrofuran, ii) reacting the obtained 3-(ethylene-dioxy)-17α-ethynyl-17β-hydroxy-estra-5(10),9(11)-diene of formula (IX) with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid, iii) reacting the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) first with sodium methoxide in methanol, then with trimethyl phosphite, iv) reacting the obtained 3-(ethylene-dioxy)-17α-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) with hydrogen chloride in methanol, then v) reacting the obtained 3-(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene-20-one of formula (VI) with ethylene glycol in dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid, vi) reacting the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene of formula (V) with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone, vii) reacting the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5α,10α- and 5β,10β-epoxides, with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran in the presence of copper(I) chloride catalyst without separation of the isomers, viii) reacting the obtained 3,3,20,20-bis(ethylene-dioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregn-9(11)-ene of formula (III) with potassium hydrogensulfate in water, ix) acetylation of the obtained 11β-[4-(N,N-dimethylamino)-phenyl]-17α-hydroxy-19-norpregn-4,9-diene-3,20-dione of formula (II) with acetic anhydride in the presence of perchloric acid, finally x) liberation of the solvate-free compound of formula (I) from the obtained solvate containing compound of formula (I) in a 1:1 mixture of ethanol and water at 70° C.