Industrial process for the synthesis of 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process

1. 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.

2. The process according to claim 1 , characterized by using a chloroform solution of phenylsulfenyl chloride in step ii).

3. The process according to claim 1 , characterized by carrying out the reaction with phenylsulfenyl chloride at 0-5° C. in step ii).

4. The process according to claim 1 , characterized by carrying out the reaction with phenylsulfenyl chloride in the presence of 1.2 equivalent of acetic acid in step ii).

5. The process according to claim 1 , characterized by carrying out the reaction with sodium methoxide and trimethyl phosphite at 62-64° C. in step iii).