Process for the production of 3-oxo-pregn-4-ene-21, 17-carbolactones by the metal free oxidation of 17-(3-hydroxypropyl)-3, 17-dihydroxyandrostanes
View Patent ↗This invention relates to processes for the production of 3-oxo-pregnane-21,17-carbolactones of formula II as well as 3-oxo-pregn-4-ene-21,17-carbolactones of formula III by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes of formula I In addition, the invention relates to the dichloromethane hemisolvate of 6B,7B;15β,16β-diethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone (IV) as such.
1. A process for the production of a 3-oxo-pregnane-21,17-carbolactones of formula II
in which
R 5 is hydrogen, or hydroxy;
R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 -group;
R 6b is hydrogen, together with R 7b a —CH 2 -group or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 -group,
R 7b is hydrogen, or together with R 6b a —CH 2 -group;
R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group —O—;
R 10 is hydrogen, methyl, or ethyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
R 13 is hydrogen, methyl or ethyl;
R 15 is hydrogen, C 1 -C 4 -alkyl, together with R 16 a —CH 2 -group or a double bond,
R 16 is hydrogen, together with R 15 a —CH 2 -group or a double bond, comprising
reacting a compound of formula I
with at least 3 molar equivalents of an organic or inorganic hypoehiorite as oxidizing agent in the presence of a catalytic amounts of a 2,2,6,6-tetramethylpiperidine-N-oxide derivative at a pH of at least 8.0.
2. A process according to claim 1 for the production of a 3-oxo-17α-pregnane-21,17-carbolactones of formula IIa
in which
R 6a can be hydrogen or together with R 7a a —CH 2 -group;
R 6b can be hydrogen, together with R 7b a —CH 2 -group, or a double bond;
R 7a can be hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;
R 7b can be hydrogen, or together with R 6b a —CH 2 -group,
R 9 can be hydrogen, together with R 11 a double bond or together with R 11 an epoxy group —O—;
R 10 can be hydrogen, or methyl;
R 11 can be hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
R 15 can be hydrogen, together with R 16 a —CH 2 -group or a double bond;
R 16 can be hydrogen, together with R 15 a —CH 2 -group or a double bond, comprising reacting a compounds of formula Ia
3. A process according to claim 1 for the production of the compound of formula IIb,
comprising reacting the compound of formula Ib
4. A process for the production of a 3-oxo-pregn-4-ene-21,17-carbolactones of formula III
in which
R 6a is hydrogen, together with R 5 a double bond, or together with R 7a a —CH 2 group;
R 6b is hydrogen, together with R 7b a —CH 2 -group or a double bond;
R 7a is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl or together with R 6a a —CH 2 -group,
R 7b is hydrogen, or together with R 6b a —CH 2 -group;
R 9 is hydrogen, together with R 11 a double bond, or together with R 11 an epoxy group —O—;
R 10 is hydrogen, methyl, or ethyl;
R 11 is hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
R 13 is hydrogen, methyl or ethyl;
R 15 is hydrogen, C 1 -C 4 -alkyl, together with R 16 a —CH 2 -group or a double bond,
R 16 is hydrogen, together with R 15 a —CH 2 -group or a double bond, comprising reacting a compound of general formula I
in which
R 5 is hydroxy;
and R 6a ,R 6b , R 7a , R 7b , R 10 , R 11 , R 13 , R 15 , R 16 have the same meaning as in formula III, with at least 3 molar equivalents of an organic or inorganic hypochiorite as an oxidizing agent in the presence of a catalytic amounts of a 2,2,6,6-tetramethyl-piperidine-N-oxide derivative at a pH of at least 8.0
to form the corresponding compound of formula II
and subsequently eliminating water at pH<5, optionally in the presence of an acid.
5. A process according to claim 4 for the production of a 3-oxo-17α-pregn-4-ene-21,17-carbolactones of formula IIIa
in which
R 6a can be hydrogen or together with R 7a a —CH 2 -group;
R 6b can be hydrogen, together with R 7b a —CH 2 -group, or a double bond;
R 7a can be hydrogen, C 1 -C 4 -alkoxycarbonyl, or C 1 -C 4 -thioacyl;
R 7b can be hydrogen, or together with R 6b a —CH 2 -group,
R 9 can be hydrogen, together with R 11 a double bond or together with R 11 an epoxy group —O—;
R 10 can be hydrogen, or methyl;
R 11 can be hydrogen, together with R 9 a double bond or together with R 9 an epoxy group —O—;
R 15 can be hydrogen, together with R 16 a —CH 2 -group or a double bond;
R 16 can be hydrogen, together with R 15 a —CH 2 -group or a double bond, comprising reacting a compound of formula Ia
6. A process according to claim 4 for the production of a compound of formula IIIb
comprising reacting the compound of formula Ib
7. A process according to claim 4 , wherein the compound of formula II is isolated before step b).
8. A process of claim 5 wherein the compound of Formula II corresponding to the compound of formula Ia is isolated before step b).
9. A process of claim 5 wherein the compound of Formula II corresponding to the compound of formula Ib is isolated before step b).
10. A process according to claim 1 , wherein the reaction is performed in a two-phase solvent-water mixture.
11. A process according to claim 4 , wherein the reaction is performed in a two phase solvent-water mixture.
12. A process according to claim 10 , wherein the solvent is dichloromethane.
13. A process according to claim 11 , wherein the solvent is dichloromethane.
14. A process according to claim 12 for the production of dichloromethane hemisolvate IV:
15. A process according to claim 1 , wherein 1-5 mol % of the 2,2,6,6-tetramethylpiperidine-N-oxide derivative is used.
16. A process according to claim 4 , wherein 1-5 mol % of the 2,2,6,6-tetramethylpiperidine-N-oxide derivative is used.
17. A process according to claim 1 , wherein 1-1.5 mol % of 2,2,6,6-tetramethylpiperidine-N-oxide is used.
18. A process according to claim 4 , wherein 1-1.5 mol % of 2,2,6,6-tetramethylpiperidine-N-oxide is used.
19. A process according to claim 1 , wherein 3-6 molar equivalents of alkali hypochlorite are used.
20. A process according to claim 4 , wherein 3-6 molar equivalents of alkali hypochlorite are used.
21. A process according to claim 1 , wherein 3-4 molar equivalents of sodium hypochlorite are used.
22. A process according to claim 4 , wherein 3-4 molar equivalents of sodium hypochlorite are used.
23. A process according to claim 1 , wherein the pH of the reaction solution is between 8.5 and 10.0.
24. A process according to claim 4 , wherein the pH of the reaction solution is between 8.5 and 10.0.
25. A process according to claim 1 , wherein the pH of the reaction solution is set with potassium bicarbonate.
26. A process according to claim 1 , wherein the reaction temperature is 0 to 20° C.
27. A process according to claim 4 , wherein the reaction temperature is 0 to 20° C.
28. A process according to claim 1 , wherein after the oxidation reaction is completed, a reducing agent for annihilating excess hypochlorite reagent is added to the reaction mixture.
29. A process according to claim 4 , wherein after the oxidation reaction is completed, a reducing agent for annihilating excess hypochlorite reagent is added to the reaction mixture.
30. A process according to claim 28 , wherein the reducing agent is added with the addition of a base or a basic buffer at a pH of more than 5.
31. A process according to claim 29 , wherein the reducing agent is added with the addition of a base or a basic buffer at a pH of more than 5.
32. A process according to claim 28 , wherein an aqueous alkali hydrogen sulfite solution is used as a reducing agent.
33. A process according to claim 29 , wherein an aqueous alkali hydrogen sulfite solution is used as a reducing agent.
34. A process according to claim 28 , wherein as a reducing agent, sodium hydrogen sulfite or potassium hydrogen sulfite is used in the form of the aqueous solution of sodium disulfite or potassium disulfite.
35. A process according to claim 29 , wherein as a reducing agent, sodium hydrogen sulfite or potassium hydrogen sulfite is used in the form of the aqueous solution of sodium disulfite or potassium disulfite.
36. A process according to claim 30 , wherein sodium phosphate (Na 3 PO 4 ) is used as a base or a basic buffer.
37. A process according to claim 31 , wherein sodium phosphate (Na 3 PO 4 ) is used as a base or a basic buffer.
38. 6β, 7β, 15β, 16β-Dimethylene-3-oxo-17α-pregnan-5β-ol-21, 17-carbolactone-dichloromethane hemisolvate.
39. A process of claim 1 wherein said derivative is 2,2,6,6-tetramethylpiperidene-N-oxide, 4-methoxy-2,2,6,6-tetramethylpiperidene-N-oxide or 4-benzyloxy-2,2,6,6-tetramethylpiperidene-N-oxide.
40. A process for the production of drospirenone comprising reacting 6β, 7β; 15β, 16β-dimethylene-3-oxo-17α-pregnan-5β-ol-21,17-carbolactone-dichloromethane hemisolvate with an acid.
41. A process of claim 40 wherein the acid is sulfuric acid, hydrochloric acid or para-toluene sulfonic acid.