US4076708A
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Process for the preparation of 7α-halogeno-3-oxo-4-dehydro steroids and novel 7α-halogeno derivatives produced thereby
Assignee: Merck Sharp & Dohme LLC
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Filing: 1976-12-22
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Granted: 1978-02-28
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Expires: 1996-12-22
Abstract
Abstract 3-Oxo-6-unsubstituted-7α-halogeno-4-dehydro steroids, wherein said halogen is chlorine, bromine or iodine, are prepared by reaction of a 3-oxo-6,7-di-unsubstituted-4,6-bis-dehydro steroid with at least an equimolar quantity of the corresponding hydrogen halide in a non-reactive organic solvent at temperatures no higher than about 30° C, and then are isolated by removal of said solvent and any excess acid at temperatures no higher than about 25° C without subjecting said 3-oxo-6-unsubstituted-7α-halogeno-4-dehydro steroid to a basic medium. A preferred species of this process is that wherein the starting steroid is a 3,20-dioxo-9-unsubstituted-11-oxygenated-1,4,6-pregnatriene-17,21-diol or ester thereof, preferably a 17,21-di-lower alkanoate or a 17-benzoate 21-lower alkanoate ester thereof, whereby is prepared in good yields a 3,20-dioxo-7α-halogeno-1,4-pregnadiene-17α,21-diol or ester thereof, useful as topical anti-inflammatory agents. Also described are novel 3,20-dioxo-7α-halogeno-4-pregnene-17α,21-diols and esters thereof having anti-inflammatory activity as well as 3-oxo-7α-halogeno-17α-4-pregnene-21,17β-carbolactone aldosterone antagonists.
Inventors
- 👤 Michael J. Green
- 👤 Ho-Jane Shue
- 👤 Elliot L. Shapiro
- 👤 Margaret A. Gentles
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 00:39
CPC Classifications
C; C07; C07J; C07J21/00; C07J21/001; C07J21/003; C07J5/00; C07J5/0046; C07J5/0061; C07J5/0069; C07J5/0076; C07J5/0084
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
132 words
The process for the preparation and isolation of a 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid of the pregnane and androstane-17-spirolactone series wherein said halogen has an atomic weight greater than 20, and wherein said 17-spirolactone is defined by one of following formula I and II: ##STR5## V being oxygen or hydrogen; which comprises the reaction of a 3-oxo-6,7,9-triunsubstituted-4,6-bis-dehydro steroid of the pregnane and androstane-17-spirolactone series with at least an equimolar quantity of the corresponding hydrogen halide in a non-reactive, organic solvent at temperatures no higher than about 30° C and thence isolation of the 3-oxo-6-unsubstituted-7α-halogeno-4-dehydro steroid thereby formed at temperatures no higher than about 25° C by removing any excess acid and said solvent without subjecting said 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid to a basic medium, so as to obtain said 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid substantially free of acid or base.
Claim 2
Dependent Claim
132 words
The process for the preparation and isolation of a 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid of the pregnane and androstane-17-spirolactone series wherein said halogen has an atomic weight greater than 20, and wherein said 17-spirolactone is defined by one of following formula I and II: ##STR5## V being oxygen or hydrogen; which comprises the reaction of a 3-oxo-6,7,9-triunsubstituted-4,6-bis-dehydro steroid of the pregnane and androstane-17-spirolactone series with at least an equimolar quantity of the corresponding hydrogen halide in a non-reactive, organic solvent at temperatures no higher than about 30° C and thence isolation of the 3-oxo-6-unsubstituted-7α-halogeno-4-dehydro steroid thereby formed at temperatures no higher than about 25° C by removing any excess acid and said solvent without subjecting said 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid to a basic medium, so as to obtain said 3-oxo-6,9-di-unsubstituted-7α-halogeno-4-dehydro steroid substantially free of acid or base.
Claim 3
Dependent Claim
38 words
The process of claim 1 wherein there is at least a 5 molar excess of hydrogen halide per mole of steroid and wherein the reaction temperature is in the range of from about 0° to about 20° C.
Claim 4
Dependent Claim
51 words
The process of claim 1 wherein the reaction temperature is in the range of from about 0° to about 20° C, wherein said non-reactive, organic solvent is dioxane or tetrahydrofuran, and wherein said hydrogen halide is hydrogen chloride in at least a 10 to 50 molar excess per mole of steroid.
Claim 5
Dependent Claim
49 words
The process of claim 1 wherein the reaction temperature is in the range of from about 0° to about 20° C, wherein said non-reactive, organic solvent is a lower alkanoic acid and wherein said hydrogen halide is hydrogen bromide in at least 10-50 molar excess per mole of steroid.
Claim 6
Dependent Claim
13 words
The process of claim 4 wherein said lower alkanoic acid is acetic acid.
Claim 7
Dependent Claim
39 words
The process of claim 3 wherein said 3-oxo-6,7,9-tri-unsubstituted-4,6-bis-dehydro steroid is a 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene of the corticoid series, wherein said non-reactive, organic solvent is tetrahydrofuran and wherein the molar quantity of said hydrogen chloride is about 40 per mole of steroid.
Claim 8
Dependent Claim
84 words
The process of claim 6 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is a compound of the following formula I: ##STR6## wherein Y is oxo or (H,βOH); W is (H,H); (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; and wherein the reaction temperature is at about 0° C; whereby is isolated a 3-oxo-7α-chloro-1,4-pregnadiene of formula II: ##STR7## wherein Y, W, V and V 1 are as hereinbefore defined.
Claim 9
Dependent Claim
16 words
The process of claim 7 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is 16α-methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17,21-dipropionate whereby is isolated 7α-chloro-16α-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione 17,21-dipropionate.
Claim 10
Dependent Claim
32 words
The process of claim 4 wherein said 3-oxo-6,7,9-tri-unsubstituted-4,6-bis-dehydro steroid is a 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene of the corticoid series and wherein the molar quantity of said hydrogen bromide is about 40 per mole of steroid.
Claim 11
Dependent Claim
92 words
The process of claim 9 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is a compound of the following formula I: ##STR8## wherein Y is oxo or (H,βOH); W is (H,H); (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; wherein said lower alkanoic acid is acetic acid; and wherein the reaction temperature is at about 0° C; whereby is isolated a 3-oxo-6,9-di-unsubstituted-7α-bromo-1,4-pregnadiene of formula II: ##STR9## wherein Y, W, V and V 1 are as hereinabove defined.
Claim 12
Dependent Claim
19 words
The process of claim 10 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is 16α-methyl-1,4,6-pregnatriene-11β,17α,21-triol-3,20-dione 17-benzoate 21-acetate whereby is obtained 7α-bromo-16α-methyl-1,4-pregnadiene-11β,17α,21L -triol-3,20-dione 17-benzoate 21-acetate.
Claim 13
Dependent Claim
80 words
The process of claim 3 wherein said 3oxo-6,7,9-tri-unsubstituted-1,2-dihydro-4,6-bis-dehydro steroid of the pregnane series is a compound of the following formula I: ##STR10## wherein Y is oxo or (H,βOH); W is (H,H) (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; whereby is isolated a 3-oxo-6,9-di-unsubstituted-7α-chloro-1,2-dihydro-4-dehydro steroid of formula II: ##STR11## wherein Y, W, V and V 1 are as hereinabove defined.
Claim 14
Dependent Claim
81 words
The process of claim 4 wherein said 3-oxo-6,7,9-tri-unsubstituted-4,6-bis-dehydro steroid is a 3-oxo-6,7,9-tri-unsubstituted-1,2-dihydro-4,6-bis-dehydro steroid of the pregnane series having the following formula I: ##STR12## wherein Y is oxo or (H,βOH); W is (H,H); (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms; whereby is isolated a 3-oxo-6,9-di-unsubstituted-7α-bromo-1,2-dihydro-4-dehydro steroid of formula II: ##STR13## wherein Y, W, V and V 1 are as hereinbefore defined.
Claim 15
Dependent Claim
55 words
A 7α-halogeno-4-pregnene-3,20-dione of following formula: ##STR14## wherein Y is oxo or (H,βOH); W is (H,H); (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms, and Z is a halogen having an atomic weight greater than 20.
Claim 16
Dependent Claim
55 words
A 7α-halogeno-4-pregnene-3,20-dione of following formula: ##STR14## wherein Y is oxo or (H,βOH); W is (H,H); (H,CH 3 ) or ═CH 2 ; V and V 1 are each hydrogen or an acyl radical of a hydrocarboncarboxylic acid having up to 12 carbon atoms, and Z is a halogen having an atomic weight greater than 20.
Claim 17
Dependent Claim
11 words
A compound of claim 14 wherein Z is chlorine or bromine.
Claim 18
Dependent Claim
9 words
A compound of claim 14 which is 7α-chloro-4-pregnene-11β,17α,21-triol-3,20-dione 17,21-dipropionate.
Claim 19
Dependent Claim
8 words
3-Oxo-7α-halogeno-17α-4-pregnene-21,17β-carbolactone wherein said halogeno is chlorine or bromine.
Claim 20
Dependent Claim
8 words
3-Oxo-7α-halogeno-17α-4-pregnene-21,17β-carbolactone wherein said halogeno is chlorine or bromine.
Claim 21
Dependent Claim
52 words
The process of claim 1 wherein said 3-oxo-6,7,9-tri-unsubstituted-4,6-bis-dehydro steroid of the spirolactone series is a member selected from the group consisting of 3-oxo-17α-4,6-pregnadiene-21,17β-carbolactone, 3-oxo-17α-1,4,6-pregnatriene-21,17β-carbolactone, (17R)-spiro-[1,4,6-androstatriene-17,1'- cyclobutane]-3,2'L -dione and 2',3'α-tetrahydrofuran-2'-spiro-17(1,4,6-androstatriene-3-one); whereby is isolated a 3-oxo-6-unsubstituted-7α-halogeno-4-dehydro steroid of the spirolactone series selected from the group consisting of 3-oxo-7α-halogeno-17α-4-pregnene-21,17β-carbolactone, 3-oxo-7α-halogeno-17α-1,4-pregnadiene-21,17β-carbolactone, (17R)-spiro-[7αL -bromo-1,4-androstadiene-17,1'-cyclobutane]-3,2'-dione and 2',3'α-tetrahydrofuran-2'-spiro-17(7α-bromo-1,4-androstadiene-3-one), respectively.
References Cited (Backward Citations)
US3148184A
Cited
US3574761A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1981-02-27 | 1981-08-29 | 1982-02-28 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1985-02-27 | 1985-08-29 | 1986-02-28 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1989-02-27 | 1989-08-29 | 1990-02-28 | $7700.00 | Window Closed / Lapsed |