Patent ID: 8324412

Claim:
A method for preparing asoprisnil on a pilot or manufacturing scale, by reacting as follows 17β-Hydroxyestra-4,9-dien-3-one (hydroxyestradienone) ↓ 3,3-Dimethoxyestra-5(10),9(11)-diene-17-one (nordienedione ketal) ↓ 3,3,17β-Trimethoxy-17α-methoxymethylestra-5(10),9(11)-diene (trimethoxydiene) ↓ 4-[17β-Methoxy-17α(methoxymethyl)-3-oxoestra-4,9-dien- 11β-yl]-benzaldehyde (dienone aldehyde) ↓ 11β- [4-(Hydroxyiminomethyl)-phenyl-17β-methoxy-17α-methoxymethyl-estra4,9-dien-3-one (asoprisnil) comprising: a) synthesizing 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) synthesizing 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) synthesizing 3,3,17β-trimethoxy-11β-[4-(dimethoxymethyl)phenyl]-17α-methoxymethylestr-9-en-5α-ol (dimethoxy acetal) from trimethoxydiene via 17α-(methoxymethy)-3,3,17β-trimethoxy-5α,10α-epoxyestr-9(11)-ene (enepoxide) in a Cu(I)- catalyzed Grignard reaction with bromobenzaldehyde dimethyl acetal d) synthesizing dienone aldehyde by reaction with acids e) synthesizing asoprisnil from dienone aldehyde with a hydroxyamine hydrochloride solution, f) purification by chromatography, g) drying.