Method for preparing 4-[17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11-beta-yl]benzaldehyde (e)-oxime (asoprisnil)

1) Method for preparing asoprisnil on the pilot or manufacturing scale via the stages

• comprising the following steps:
• a) synthesis of nordienedione ketal from hydroxyestradienone either
• by oxidation of 17β-hydroxyestra-4,9-dien-3-one (hydroxyestradienone) to estra-4,9-diene-3,17-dione (nordienedione) and subsequent selective ketalization to 3,3 dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione ketal) or
• by ketalization of hydroxyestradienone to 17β-hydroxy-3,3-dimethoxyestra-5(10),9(11)-diene (hydroxy ketal) and subsequent oxidation to nordienedione ketal.
• b) synthesis of trimethoxydiene from nordienedione ketal in three steps via the stages 3,3-dimethoxyestra-5(10),9 (11)-diene-17β-spiro-1′,2′-oxirane (nordienespirane) and 3,3-dimethoxy-17α-methoxymethylestra-5(10),9 (11)-dien-17β-ol (nordiene ether), not isolating nordienespirane and nordiene ether,
• c) synthesis of 3,3,17β-trimethoxy-11β-[4-(dimethoxymethyl)phenyl]-17α-methoxymethylestr-9-en-5α-ol (dimethoxy acetal) from trimethoxydiene via 17α-(methoxymethyl)-3,3,17β-trimethoxy-5α,10α-epoxyestr-9(11)-ene (enepoxide) in a Cu(I)— catalyzed Grignard reaction with bromobenzaldehyde dimethyl acetal
• d) synthesis of the dienone aldehyde by reaction with acids
• e) synthesis of asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride solution,
• f) purification by chromatography,
• g) drying.