US4524134A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Process for preparing 1,2-dehydro steroids
Assignee: Pharmacia and Upjohn Co
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Filing: 1982-10-25
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Granted: 1985-06-18
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Expires: 2002-10-25
Abstract
Abstract Disclosed and claimed is an improved microbial bioconversion to produce 1,2-dehydro steroids from their corresponding 1,2-saturated derivatives.
Inventors
- 👤 Leo A. Kominek
- 👤 Holly J. Wolf
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 05:56
CPC Classifications
C; C12; C12P; C12P33/00; C12P33/02
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
280 words
A process for preparing a 1,2-dehydro-Δ 4 -3-keto steroid selected from the group consisting of ##STR5## R 6 is a hydrogen or fluorine atom or methyl group. R 6 ' is a hydrogen atom or methyl group. R 9 is nothing, a hydrogen, fluorine or oxygen atom which makes the C ring (a) Δ 9 (11) when R 9 is nothing and (b) 9β,11β-epoxide when R 9 is an oxygen atom; R 11 is a hydrogen or oxygen atom, two hydrogen atoms, or α- or β-hydroxyl group which makes the C-ring (a) Δ 9 (11) when R 11 is a hydrogen atom, (b) 9β,11β-epoxide when R 11 is an oxygen atom and between C 11 and R 11 is a single bond, and (c) a ketone when R 11 is an oxygen atom and between C 11 and R 11 is a double bond; indicates that the attached group can be in either the α or 62 configuration; is a single or double bond; R 1l 40 is a β-hydroxyl group, an oxygen atom (11-ketone), or hydrogen atom (Δ 9 (11)); R 16 is a hydrogen atom or methyl group; R 16 ' is a hydrogen atom, methyl or hydroxyl group, when R 16 ' is an α-hydroxyl group the 16α and 17α-hydroxyl groups can be in the form of an acetonide; R 21 is a hydrogen atom or --OC--OR 21 40; R 21 ' is methyl, ethyl, or phenyl which comprises exposing the corresponding 1,2-saturated-Δ 4 -3 keto steroid to air-dried or heat-dried cells of Arthrobacter simplex having a moisture content of about 1 to about 10% where the cells are dried in the absence of an organic solvent.
Claim 2
Dependent Claim
280 words
A process for preparing a 1,2-dehydro-Δ 4 -3-keto steroid selected from the group consisting of ##STR5## R 6 is a hydrogen or fluorine atom or methyl group. R 6 ' is a hydrogen atom or methyl group. R 9 is nothing, a hydrogen, fluorine or oxygen atom which makes the C ring (a) Δ 9 (11) when R 9 is nothing and (b) 9β,11β-epoxide when R 9 is an oxygen atom; R 11 is a hydrogen or oxygen atom, two hydrogen atoms, or α- or β-hydroxyl group which makes the C-ring (a) Δ 9 (11) when R 11 is a hydrogen atom, (b) 9β,11β-epoxide when R 11 is an oxygen atom and between C 11 and R 11 is a single bond, and (c) a ketone when R 11 is an oxygen atom and between C 11 and R 11 is a double bond; indicates that the attached group can be in either the α or 62 configuration; is a single or double bond; R 1l 40 is a β-hydroxyl group, an oxygen atom (11-ketone), or hydrogen atom (Δ 9 (11)); R 16 is a hydrogen atom or methyl group; R 16 ' is a hydrogen atom, methyl or hydroxyl group, when R 16 ' is an α-hydroxyl group the 16α and 17α-hydroxyl groups can be in the form of an acetonide; R 21 is a hydrogen atom or --OC--OR 21 40; R 21 ' is methyl, ethyl, or phenyl which comprises exposing the corresponding 1,2-saturated-Δ 4 -3 keto steroid to air-dried or heat-dried cells of Arthrobacter simplex having a moisture content of about 1 to about 10% where the cells are dried in the absence of an organic solvent.
Claim 3
Dependent Claim
72 words
A process according to claim 1 where the 1,2-dehydro-Δ 4 -3-keto steroid or 21-monoester thereof is selected from the group consisting of 1. 6α-methylprednisolone 2. Androsta-1,4,9(11)-triene-3,17-dione 3. androsta-1,4-diene-3,17-dione 4. 6α-fluoroandrosta-1,4,9(11)-triene-3,17-dione 5. 6α-methylandrosta-1,4,9(11)-triene-3,17-dione 6. 16β-methylandrosta-1,4,9(11)-triene-3,17-dione 7. 17α-hydroxypregna-1,4-diene-20-yn-3-one 8. 17α-hydroxypregna-1,4,9(11)-triene-20-yn-3-one 9. 17α-hydroxy-16β-methylpregna-1,4,9(11)-triene-20-yn-3-one 10. 11β,21-dihydroxypregna-1,4,17(20-trien-3-one 11. 21-acetoxy-11β-hydroxypregna-1,4,17(20)-trien-3-one 12. 6α-methyl-11β,21-dihydroxypregna-1,4,17(20)-trien3-one 13. 20-chloropregna-1,4,9(11),17(20)-tetraen-21-al-3-one 14. prednisolone 15. 21-acetoxy-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dion 16. 11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17. 21-acetoxy-9α-fluoro-11β,17dihydroxy-16β-methylpregna-1,4-diene-3,20-dione 18. 9α-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 19. 21-acetoxy-9β, 11β-epoxy-17-hydroxy-16β-methylpregna-1,4-diene-3,20-dione 20. 9β,11β-epoxy-17,21-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione 21 . 21-acetoxy-17-hydroxypregna-1,4,9(11)-triene-3,20-dione 22. 17,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione 23. 21-acetoxy-16α,17-dihydroxypregna-1,4,9(11)-triene-3,20-dione 24. 16α,17,21-trihydroxypregna-1,4,9(11)-triene-3,20-dione
Claim 4
Dependent Claim
55 words
21-acetoxy-17-hydroxy-16α-methylprega-1,4,9(11)-triene-3,20-dione 26. 17,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene3,20-dione 27. 21-benzoyloxy-17-hydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 28. 21-acetoxy-17-hydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 29. 17,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 30. 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione 31. 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 32. 21-acetoxy-6α-fluoropregna-1,4,9(11),16-tetraene-3,20-dione 33. 6α-fluoro-21-hydroxypregna-1,4,9(11), 16-tetraene-3,20-dione 34. 21-acetoxy-9α-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione 35. 9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 36. 21-acetoxy-6α,9α-difluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione-16,17-acetonide 37. 6α,9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide 38. 21-acetoxy-6α-fluoro-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione 39. 6α-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 40. 21-acetoxy-6α-fluoro-11α,17-hydroxypregna-1,4-diene-3,20-dione 41. 6α-fluoro-11β,17,21-trihydroxy-1,4-diene-3,20-dione 42. 21-acetoxy-6α,9α-difluoro-11β, 17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 43. 6α,9α-difluoro-11β,17,21-trihydroxy-1,4-diene-3,20-dione 44. 21-acetoxy-9α-fluoro-11α,16α,17-trihydroxypregna-1,4-diene-3,20-dione 16,17-acetonide 45. 21-acetoxy-9β, 11β-epoxy-6α-fluoro-16α, 17-dihydroxypregna-1,4-diene,3,20-dione-16,17-acetonide 46. 21-acetoxy-9β,11β-expoxy-16-hydroxypregna-1,4-diene-3,20-dione 47. 9β,11β-epoxy-16β, 21-dihydroxypregna-1,4-diene-3,20-dione; 48. 21-acetoxy-9β,11β-epoxy-16α,17-dihydroxypregna-1,4-diene-3,20-dione 16,17acetonide
Claim 5
Dependent Claim
55 words
21-acetoxy-17-hydroxy-16α-methylprega-1,4,9(11)-triene-3,20-dione 26. 17,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene3,20-dione 27. 21-benzoyloxy-17-hydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 28. 21-acetoxy-17-hydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 29. 17,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 30. 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione 31. 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 32. 21-acetoxy-6α-fluoropregna-1,4,9(11),16-tetraene-3,20-dione 33. 6α-fluoro-21-hydroxypregna-1,4,9(11), 16-tetraene-3,20-dione 34. 21-acetoxy-9α-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione 35. 9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 36. 21-acetoxy-6α,9α-difluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione-16,17-acetonide 37. 6α,9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide 38. 21-acetoxy-6α-fluoro-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione 39. 6α-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 40. 21-acetoxy-6α-fluoro-11α,17-hydroxypregna-1,4-diene-3,20-dione 41. 6α-fluoro-11β,17,21-trihydroxy-1,4-diene-3,20-dione 42. 21-acetoxy-6α,9α-difluoro-11β, 17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 43. 6α,9α-difluoro-11β,17,21-trihydroxy-1,4-diene-3,20-dione 44. 21-acetoxy-9α-fluoro-11α,16α,17-trihydroxypregna-1,4-diene-3,20-dione 16,17-acetonide 45. 21-acetoxy-9β, 11β-epoxy-6α-fluoro-16α, 17-dihydroxypregna-1,4-diene,3,20-dione-16,17-acetonide 46. 21-acetoxy-9β,11β-expoxy-16-hydroxypregna-1,4-diene-3,20-dione 47. 9β,11β-epoxy-16β, 21-dihydroxypregna-1,4-diene-3,20-dione; 48. 21-acetoxy-9β,11β-epoxy-16α,17-dihydroxypregna-1,4-diene-3,20-dione 16,17acetonide
Claim 6
Dependent Claim
15 words
11β, -hydroxyandrosta-1,4-diene-3,17-dione 50. 11β,-hydroxy-16β, -methylandrostra-1,4-diene-3,17dione 51. 11β-hydroxy-16α-methylandrostra-1,4-diene-3,17-dione 52. 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione 53. 6α-methyl-11β-hydroxyandrosta-1,4-diene-3,17-dione 54. 11α-hdyroxyandrosta-1,4-diene-3,17-dione 55. androsta-1,4-diene-3,11,17-trione.
Claim 7
Dependent Claim
15 words
11β, -hydroxyandrosta-1,4-diene-3,17-dione 50. 11β,-hydroxy-16β, -methylandrostra-1,4-diene-3,17dione 51. 11β-hydroxy-16α-methylandrostra-1,4-diene-3,17-dione 52. 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione 53. 6α-methyl-11β-hydroxyandrosta-1,4-diene-3,17-dione 54. 11α-hdyroxyandrosta-1,4-diene-3,17-dione 55. androsta-1,4-diene-3,11,17-trione.
Claim 8
Dependent Claim
36 words
A process according to claim 2 where the 1,2-dehydro-Δ 4 -3-keto steroid or 21-monoester thereof is selected from the group consisting of 6α-methylprednisolone, androsta-1,4,9(11)-triene-3,17-dione, androsta-1,4-diene-3,17-dione, 16β-methylandrosta-1,4,9-(11)-triene-3,17-dione, prednisolone, 17,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione, 21-acetoxy-16α,17-dihydroxypregna-1,4,9(11)-triene-3,20-dione, 16α,17,21-trihydroxypregna-1,4,9(11)-triene-3,20-dione, 21-acetoxypregna-1,4,9(11),16-tetraene-3,20-dione, 21-hydroxypregna-1,4,9(11),-16-tetraene-3,20-dione, 21-acetoxy-6α-fluoropregna-1,4,9(11),16-tetraene-3,20-dione, 6α-fluoro-11β,17,21-trihydroxyl-1,4-diene-3,20-dione, 11β-hydroxyandrosta-1,4-diene-3,17-dione, 11β-hydroxy-16β-methylandrosta-1,4-diene-3,17-dione.
Claim 9
Dependent Claim
46 words
A process according to claim 2 where the 1,2-dehydro-Δ 4 -3-keto steroid or 21-monoester thereof is selected from the group consisting of 21-acetoxy-90α-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione, 9α-fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione, 21-acetoxy-17-hydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione,17,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione, 21-acetoxy-9α-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 21-acetoxy-6α,9α-difluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione-16,17-acetonide, 6α,9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide, 21-acetoxy-6α-fluoro-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione, 6α-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione, 21-acetoxy-6α-fluoro-11β,17-hydroxypregna-1,4-diene-3,20-dione, 21-acetoxy-6α,9α -difluoro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione, 21-acetoxy-9α-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione 16,17-acetonide, 21-acetoxy9β,11β-epoxy-6α-fluoro-16α,17-dihydroxypregna-1,4-diene-3,20-dione 16,17-acetonide, 21-acetoxy-9β,11β-epoxy-16-hydroxypregna-1,4-diene-3,20-dione, 9β,11β-epoxy-16α,21-dihydroxypregna-1,4-diene-3,2-dione, 21-acetoxy-9β,11β-epoxy-16α,17-dihydroxypregna-1,4-diene-3,20-dione 16,17-acetonide, 11β-hydroxy-16α-methylandrosta-1,4-diene-3,17-dione, 11α-hydroxyandrosta-1,4-diene-3,17-dione, androsta-1,4-diene-3,11,17-trione.
Claim 10
Dependent Claim
17 words
A process according to claim 1 which is performed in the presence of an exogenous electron carrier.
Claim 11
Dependent Claim
32 words
A process according to claim 5, where the exogenous electron carrier is selected from the group consisting of menadione, phenazine methosulfate, dichlorophenolindophenol, 1,4-naphthoquinone, menadione bisulfite, ubiquinones (Coenzyme Q), or vitamin K-type compounds.
Claim 12
Dependent Claim
26 words
A process according to claim 6 where the exogenous electron carrier is selected from the group consisting of menadione, phenazine methosulfate, dichlorophenolidophenol, 1,4-napthoquinone or menadione bisulfite.
Claim 13
Dependent Claim
13 words
A process according to claim 7 where the exogenous electron carrier is menadione.
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1988-06-17 | 1988-12-17 | 1989-06-18 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1992-06-17 | 1992-12-17 | 1993-06-18 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1996-06-17 | 1996-12-17 | 1997-06-18 | $7700.00 | Window Closed / Lapsed |