Method for preparing 4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde (E)-oxime (asoprisnil)

1. 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.

2. The method according to claim 1 , where hydroxyestradienone is converted into nordienedione ketal by ketalization with Lewis acids and by chromic acid oxidation or Oppenauer oxidation.

3. The method according to claim 2 , where either the hydroxyestradienone is first oxidized and then ketalized.

4. The method according to claim 2 , carrying out the ketalization first and an Oppenauer oxidation subsequently.

5. The method according to claim 3 , where the chromic acid oxidation is carried out as two-phase reaction between two liquid phases.

6. The method according to claim 5 , where water is added to a solution of hydroxyestradienone in acetone in such a way that a defined systemic water concentration is set up, with the steroid concentration not exceeding 8 g/ 1 of acetone.

7. The method according to claim 4 , where the ketalization is carried out first.

8. The method according to claim 5 , where water, 2-10% by weight based on acetone, is added to a solution of hydroxyestradienone in acetone in such a way that a defined systemic water concentration of 10-15% by weight, is set up, with the steroid concentration not exceeding 8 g/1 of acetone.

9. The method according to claim 4 , where the ketalization is carried out first on an acidic ion exchanger.

10. The method according to claim 7 , where the ketalization takes place in a bypass method.

11. The method according to claim 3 , where the Oppenauer oxidation takes place with catalysis by aluminium diisopropoxide trifluoroacetate (DIPAT).

12. The method according to claim 1 , where nordienedione ketal is converted completely to trimethoxydiene via nordienespirane and nordiene ether in three steps, comprising

a) producing nordienespirane in DMF in an initial phase with addition of the reactants in a temperature range from 0 to 25° C., and in an after-reaction phase between 20 to 40° C.;

b) the reaction product obtained in step a) not being isolated but being employed as solution of nordienespirane in solvents;

c) conversion of the nordienespirane from step b) into the nordiene ether changing the solvent, optionally during the reaction with sodium methanolate, or by azeotropic distillation, and thus reaching the required reaction temperatures of 70° C. or more;

d) crystallizing trimethoxydiene from methanol by cooling the steroid solution, to 20-35° C., for about 1 to 2 hours, and then cooling further to −5° C. to −15° C.

13. The method according to claim 1 , where the drying in g) takes place in such a way that contamination of the dried asoprisnil microparticles with seed centers in the drying device is greatly reduced.

14. The method according to claim 13 , where the drying takes place by spray drying, a narrow particle size range is achieved through geometrical and aerodynamic conditions in the atomizing device, and wetting events by spray drops on surfaces of the apparatus with which the product makes contact are avoided.

15. The method according to claim 14 , in which the narrow size range is generated by a high atomizing efficiency of the spraying unit by maintaining a mass ratio of spraying gas employed to sprayed solution of from 1.5 to 10, and a mass ratio of drying gas employed to sprayed solution employed of at least 10, and with a drying temperature of from 40° C. to 90° C.

16. The method according to claim 15 , where the high atomizing efficiency of the spraying unit is produced by a high speed of rotation of a rotating disc or by a high atomizing gas throughput through a twin-fluid nozzle.

17. The method according to claim 13 such that the wherein spray-dried asoprisnil microparticles are subjected to an after-drying procedure which takes place in vacuo and/or with flushing of the asoprisnil microparticles with a solvent-free drying gas below 90° C., for at least 12 h.

18. The method according to claim 13 , where the deposition of the asoprisnil microparticles after the spray drying takes place on a product filter, optionally using fresh unused filter surfaces.