Claims
- 1. A process for the preparation of an 11.beta.-hydroxy steroid of formula (IIA) ##STR4## where is a single or double bond; where R.sub.6 is .alpha.-R.sub.6-1 :.beta.-R.sub.6-2, where one of R.sub.6-1 and R.sub.6-2 is --H and the other is --H, --F or --CH.sub.3 ;
- where (D-I) R.sub.16 is .alpha.-R.sub.16-1 :.beta.-R.sub.16-2 where one of R.sub.16-1 and R.sub.16-2 is --H and the other is --H, --OH or --CH.sub.3 and R.sub.17 is
- .dbd.O,
- .alpha.--H:.beta.--CO--CH.sub.3,
- .alpha.--OR.sub.17-5 :.beta.--CO--CH.sub.3 where R.sub.17-5 is --H or --CO--R.sub.17-51 where R.sub.17-51 is C.sub.2 --C.sub.4 alkyl or --.phi. optionally substituted with 1 or 2 --OCH.sub.3,
- .alpha.--OR.sub.17-1 :.beta.--CO--CH.sub.2 --OR.sub.21-1 where R.sub.17-1 is --H or --CO--R.sub.17-2 where R.sub.17-2 is C.sub.1 --C.sub.3 alkyl or --.phi. and where R.sub.21-1 is --H or --CO--R.sub.21-2 where R.sub.21-2 is C.sub.1 --C.sub.3 alkyl or --.phi. optionally substituted with --Cl or --NO.sub.2,
- .alpha.--OR.sub.17-3 :.beta.--CN where R.sub.17-3 is
- --H,
- THP,
- --CH.sub.2 --OCH.sub.3,
- --CHR.sub.17-31 --O--R.sub.17-32 where R.sub.17-31 is C.sub.1 --C.sub.3 alkyl and R.sub.17-32 is C.sub.1 --C.sub.4 alkyl or --.phi. and
- --SiR.sub.17-33 R.sub.17-34 R.sub.17-35 where R.sub.17-33, R.sub.17-34 and R.sub.17-35 are the same or different and are selected from the group consisting of C.sub.1 --C.sub.4 alkyl, C.sub.1 --C.sub.4 alkoxy, C.sub.1 --C.sub.4 monohaloalkyl where halo is --Br or --Cl, --.phi. optionally substituted with 1 or 2 --OCH.sub.3 or --NH.sub.2 ;
- where (D-II) the 16,17-acetonide of a compound where R.sub.16-1 is --OH, and where R.sub.17 is .alpha.-OR.sub.17-1 :.beta.--CO--CH.sub.2 --OR.sub.21-1 where R.sub.17-1 is --H where R.sub.21-1 is as defined above which comprises
- (1) contacting a 9.alpha.-halo steroid of formula (IA) ##STR5## where R.sub.9 is --Cl or --Br with <1 equivalent of chromium ion (II) or (III), a hydrogen radical source and a means for reducing the chromium (III) to chromium (II) where all the reactants are in solution in the solvent, co-solvent or mixture of solvents used, where R.sub.6, R.sub.16, R.sub.17 and are as defined above.
- 2. A process according to claim 1 where is a double bond.
- 3. A process according to claim 1 where R.sub.17 is .alpha.-OR.sub.17-1 :.beta.--CO--CH.sub.2 --OR.sub.21-1.
- 4. A process according to claim 1 where is a single bond and R.sub.17 is .dbd.O, .alpha.-OR.sub.171 :.beta.--CO--CH.sub.2 --OR.sub.21-1, .alpha.-H:.beta.--CO--CH.sub.3 or .alpha.-OR.sub.17-5 :.beta.--CO--CH.sub.3 and .alpha.-OR.sub.17-3 :.beta.--CN.
- 5. A process according to claim 1 where the 9.alpha.-halo steroid (I) is added to the chromium ion.
- 6. A process according to claim 1 where there is sufficient water as co-solvent present to solubilize the chromium ion if not solubilized by the solvent or solvent mixture.
- 7. A process according to claim 1 where 9.alpha.-halo steroid (I) is slowly added to the chromium ion.
- 8. A process according to claim 1 where the hydrogen radical source is selected from the group consisting of hypophosphofous acid, 1,4-dihydrobenzene, 1-benzyl-1,4-dihydronicotinamide, cyclopentadiene, catechol, thiols, H--Si(R).sub.3 where the R's are the same or different and are selected from the group consisting of C.sub.1 --C.sub.4 alkyl and --.phi. optionally substituted with 1 or 2 --OCH.sub.3, and H--Sn(R).sub.3 where R is as defined above.
- 9. A process according to claim 1 where >1 equivalent of hydrogen radical source is used.
- 10. A process according to claim 1 where the means for reducing chromium (III) to chromium (II) is selected from the group consisting of zinc, magnesium, zinc amalgam and magnesium amalgam.
- 11. A process according to claim 1 where the 11.beta.-hydroxy steroid (II) is
- 1.beta. . 17.alpha.,21-trihydroxypregn-4-ene-3,20-dione 21-acetate,
- 11.beta.-hydroxyandrost-4-ene-3,17-dione,
- 11.beta.,17.alpha.,21-trihydroxypregna- 1,4-diene-3,20-dione 21-acetate,
- 11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregn-1,4-diene-3,20-dione 21-acetate,
- 11.beta.-16.alpha.,17.alpha.,21-tetrahydroxypregn-1,4-diene-3,20-dione 21-acetate
- 11.beta.,17.alpha., 21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-trihydroxypregn-4-ene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregn-4-ene-3,20-dione 21-acetate 16,17-acetonide,
- 11.beta.,17.alpha.,21-trihydroxypregn-4-ene-3,20-dione,
- 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregn-4-ene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-acetate 16,17-acetonide or
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20dione 21-acetate.
- 12. A process for the preparation of an 11.beta.-hydroxy steroid of formula (IIA) ##STR6## where R.sub.6 is .alpha.-R.sub.6-1 :.beta.-R.sub.6-2, where one of R.sub.6-1 and $.sub.6-2 is --H and the other is --H, --F or --CH.sub.3 ;
- where is a single or double bond;
- where R.sub.6 is .alpha.-R.sub.6-1 :.beta.-R.sub.6-2, where one of R.sub.6-1 and R.sub.6-2 is --H and the other is --H, --F or --CH.sub.3 ;
- where (D-I) R.sub.16 is .alpha.-R.sub.16-1 :.beta.-R.sub.16-2 where one of R.sub.16-1 and R.sub.16-2 is --H and the other is --H, --OH or --CH.sub.3 and R.sub.17 is
- .dbd.O,
- .alpha.-H:.beta.--CO--CH.sub.3,
- .alpha.-OR.sub.17-5 :.beta.--CO--CH.sub.3 where R.sub.17-5 is --H, --CO--R.sub.17-51 where R.sub.17-51 is C.sub.2 --C.sub.4 alkyl or --.phi. optionally substituted with 1 or 2 --OCH.sub.3,
- .alpha.-OR.sub.17-1 :.beta.--CO--CH.sub.2 --OR.sub.21-1 where R.sub.17-1 is --H or --CO--R.sub.17-2 where R.sub.17-2 is C.sub.1 --C.sub.3 alkyl or --.phi. and where R.sub.21-1 is --H or --CO--R.sub.21-2, where R.sub.21-2 is C.sub.1 --C.sub.3 alkyl or --.phi. optional substituted with --Cl or --NO.sub.2,
- .alpha.-OR.sub.17-3 :.beta.--CN where R.sub.17-3 is
- --H,
- THP,
- --CH.sub.2 --OCH.sub.3,
- --CHR.sub.17-31 --O--R.sub.17-32 where R.sub.17-31 is C.sub.1 --C.sub.3 alkyl and R.sub.17-32 is C.sub.1 --C.sub.4 alkyl or --.phi. and
- --SiR.sub.17-33 R.sub.17-34 R.sub.17-35 where R.sub.17-33, R.sub.17-34 and R.sub.17-35 are the same or different and are selected from the group consisting of C.sub.1 --C.sub.4 alkyl, C.sub.1 --C.sub.4 alkoxy, C.sub.1 --C.sub.4 monohaloalkyl where halo is --Br or --Cl, --.phi. optionally substituted with 1 or 2 --OCH.sub.3 or --NH.sub.2 ;
- where (D-II) the 16,17-acetonide of a compound where R.sub.16-1 is --OH, and where R.sub.17 is .alpha.-OR.sub.17-1 :.beta.--CO--CH.sub.2 --OR.sub.21-1 where R.sub.17-1 is --H where R.sub.21-1 is as defined above which comprises
- (1) adding a 9.alpha.-halo steroid of formula (IA) ##STR7## where R.sub.9 is --Cl or --Br to a mixture of<1 equivalent of chromium ion (II) or (III), a hydrogen radical source and a means for reducing chromium (III) to chromium (II) where all the reactants are in solution in the solvent, co-solvent or mixture of solvents used, where R.sub.6, R.sub.16, R.sub.17 and are as defined above.
- 13. A process according to claim 12 where the 9.alpha.-halo steroid (I) is added slowly.
- 14. A process according to claim 12 where there is sufficient water (co-solvent) present to solubilize the chromium ion if not solubilized by the solvent or solvent mixture.
- 15. A process according to claim 12 where <1 equivalent of chromium ion is present.
- 16. A process according to claim 12 where the hydrogen radical source is selected from the group consisting of hypophosphorous acid, 1,4-dihydrobenzene, 1-benzyl-1,4-dihydronicotinamide, cyclopentadiene, catechol, thiols, H--Si--(R).sub.3 where the R's are the same or different and are selected from the group consisting of C.sub.1 --C.sub.4 alkyl and --.phi. optionally substituted with 1 or 2 --OCH.sub.3, and H--Sn--(R).sub.3 where R is as defined above.
- 17. A process according to claim 12 where >1 equivalent of hydrogen radical source is used.
- 18. A process according to claim 12 where the means for reducing chromium (III) to chromium (II) is selected from the group consisting of zinc, magnesium, zinc amalgam and magnesium amalgam.
- 19. A process according to claim 12 where the 11.beta.-hydroxy steroid (II) is
- 11.beta.,17.alpha.,21-trihydroxypregn-4-ene-3,20-dione 21 -acetate,
- 11.beta.-hydroxyandrost-4-ene-3,17-dione,
- 11.beta.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate,
- 11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate,
- 11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-acetate,
- 1.beta. . 17.alpha.,21-trihydroxy-6.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregn-4-ene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregn-4-ene-3,20-dione 21-acetate 16,17-acetonide,
- 11.beta.,17.alpha.,21-trihydroxypregn-4-ene-3,20-dione,
- 11.beta.,17.alpha.,21-trihydroxy-6.alpha.-methylpregn-4-ene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,21-dihydroxy-16.alpha.-methylpregna-1,4-diene-3,20-dione 21-acetate,
- 6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-acetate 16, 17-acetonide or
- 6.alpha.-fluoro-11.beta.,17.alpha.,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate.
CROSS-REFERENCE TO RELATED APPLICATIONS
The present patent application is a continuation-in-part (national phase) application of PCT patent application PCT/US88/02430 filed Jul. 22, 1988 which is a continuation-in-part application of U.S. patent application Ser. No. 07/095,803, filed Sep. 11, 1987 (now abandoned) which is a continuation-in-part application of U.S. patent application Ser. No. 07/085,907, filed Aug. 14, 1987 (now abandoned).
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Number |
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Date |
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3480622 |
Barton |
Nov 1969 |
|
4304727 |
Heather et al. |
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|
4325881 |
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|
Non-Patent Literature Citations (7)
Entry |
Castro, et al JACS vol. 85, 1963 pp. 2768 to 2773. |
Graber, et al Chemical Abstracts vol. 109, 1988 Abstract 38061c. |
Barton et al. JACS 88(13) 1966 pp. 3016-3021. |
Robinson et al. J. Org. Chem. 31, 1966 pp. 2749-2756. |
Djerassi, Steroid Reactions, Holden Day Inc. San Francisco, 1963 pp. 249-251. |
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Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
95803 |
Sep 1987 |
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Parent |
85907 |
Aug 1987 |
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