Process for the synthesis of 1.alpha.,23(S),25-trihydroxycholecalciferol and 1.alpha.,23(R),25-trihydroxycholecalciferol

• US 4,594,432 A
• Filed: 12/27/1983
• Issued: 06/10/1986
• Est. Priority Date: 01/28/1983
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Uskokovic, Milan R., Wovkulich, Peter M., Baggiolini, Enrico G.
• Primary Examiner(s): Love, Ethel G.
• Application Number:
  US06/566,103
• Time in Patent Office: 896 Days
• Field of Search: 549/215, 549/374, 549/554, 549/214, 556/449, 568/819, 260/397.2
• US Class Current: 549/214
• CPC Class Codes: C07C 35/32 the condensed ring system being a (4.3.0) system, e.g. indenols
• CPC Class Codes: C07D 303/14 by free hydroxyl radicals
• CPC Class Codes: C07D 319/06 not condensed with other rings
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The invention is directed to a process and intermediates for the preparation of 1α,23(S),25-trihydroxycholecalciferol and 1α,23(R),25-trihydroxycholecalciferol. The end-products, 1α,23(S),25-trihydroxycholecalciferol and 1α,23(R),25-trihydroxycholecalciferol, are useful for the treatment of disease states which are characterized by insufficient amounts of 1,25 dihydroxycholecalciferol.

Claims

1. A compound of the formula ##STR24## wherein R₁ and R₂ each independently are lower alkyl.

2. A compound in accordance with claim 1, (1 alpha, 3 beta, SZ, 7E, 23S)-9,10-secocholesta-(4,7,10(9)-triene-1,3-bis[1,1-dimethylethyl)-dimethylsilyloxy]-23,25-diol-(1-methylethylidene)-cyclic acetal.

3. A compound in accordance with claim 1, (1 alpha, 3 beta, SZ, 7E, 23R)-9,10-secocholesta-4,7,10(9)-triene-1,3-bis[(1,1-dimethylethyl)-dimethylsilyloxy]-23,25-diol-(1-methylethylidene)-cyclic acetal.

4. A compound of the formula ##STR25##

5. A compound in accordance with claim 4 [1R-[alpha(R*,S*), 3a beta, 4 beta, 7a alpha]]-octahydro-1-(3-hydroxy-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-ol.

6. A compound in accordance with claim 4, [1R-[alpha(R*,R*), 3a beta, 4 beta, 7a alpha]]-octahydro-1-(3-hydroxy-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-ol.

7. A compound of the formula ##STR26## wherein R⁴ is tri-lower alkylsilyl, di-lower alkylarylsilyl, lower alkyldiarylsilyl, triarylsilyl.

8. A compound in accordance with claim 7 which is [1R-[1 alpha (R*,S*), 3a beta, 4 beta, 7a alpha]]-octahydro-1-(3-hydroxy-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-ol mono trimethylsilyl ether.

9. A compound in accordance with claim 7 which is [1R-[1 alpha (R*,R*), 3a beta, 4 beta, 7a alpha]]-octahydro-1-(3-hydroxy-1,5-dimethyl-5-hexenyl)-7a-methyl-1H-inden-4-ol mono trimethylsilyl ether.

10. A compound of the formula ##STR27##

11. A compound in accordance with claim 10 1R-[1alpha(R*,S*,R*),3a beta, 4 beta, 7a alpha]-octahydro-1-[3-hydroxy-1-methyl-4-(1-methyloxiranyl)butyl]-7a-methyl-1H-inden-4-ol or 1R-[1alpha(R*,S*,S*), 3a beta, 4 beta, 7a alpha-octahydro-1-[3-hydroxy-1-methyl-4-(1-methyloxiranyl)-butyl]-7a-methyl-1H-inden-4-ol.

12. A compound in accordance with claim 10, 1R-[1-alpha(R*,R*,R*),3a beta, 4 beta, 7a alpha]-octahydro-1-[3-hydroxy-1-methyl-4-(1-methyloxiranyl)butyl]-7a-methyl-1H-inden-4-ol or 1R-[1alpha(R*,R*,S*), 3a beta, 4 beta, 7a alpha-octahydro-1-[3-hydroxy-1-methyl-4-(1-methyloxiranyl)-butyl]-7a-methyl-1H-inden-4-ol.

13. A compound of the formula ##STR28##

14. A compound in accordance with claim 13 [1R-[1alpha(R*,S*),3a beta, 4 beta, 7a alpha]]-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl)-1,6-dimethyl-2,4-hexanediol.

15. A compound in accordance with claim 13, [1R-[1alpha(R*,R*),3a beta, 4 beta, 7a alpha]]-octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl)-1,6-dimethyl-2,4-hexanediol.

16. A compound of the formula ##STR29## wherein R¹ and R² each independently is hydrogen, lower alkyl or aryl, or taken together are lower alkylene of from 3 to 6 carbon atoms.

17. A compound in accordance with claim 16, 1R-[1alpha(R*,S*), 3a beta, 4 beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl-1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-ol.

18. A compound in accordance with claim 16, 1R-[1alpha(R*,R*), 3a beta, 4 beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl-1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-ol.

19. A compound of the formula ##STR30## wherein R¹ and R² each independently is hydrogen, lower alkyl or aryl or taken together are lower alkylene of from 3 to 6 carbon atoms.

20. A compound in accordance with claim 19, 1R-[1alpha(R*,S*), 3a beta, 4 beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl-1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-one.

21. A compound in accordance with claim 19, 1R-[1alpha(R*,R*), 3a beta, 4 beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl-1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-one.

22. A compound of the formula ##STR31##