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Details for Patent: 4,076,708

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Details for Patent: 4,076,708

Title: Process for the preparation of 7.alpha.-halogeno-3-oxo-4-dehydro steroids and novel 7.alpha.-halogeno derivatives produced thereby
Abstract:3-Oxo-6-unsubstituted-7.alpha.-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.degree. C, and then are isolated by removal of said solvent and any excess acid at temperatures no higher than about 25.degree. C without subjecting said 3-oxo-6-unsubstituted-7.alpha.-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-7.alpha.-halogeno-1,4-pregnadiene-17.alpha.,21-diol or ester thereof, useful as topical anti-inflammatory agents. Also described are novel 3,20-dioxo-7.alpha.-halogeno-4-pregnene-17.alpha.,21-diols and esters thereof having anti-inflammatory activity as well as 3-oxo-7.alpha.-halogeno-17.alpha.-4-pregnene-21,17.beta.-carbolactone aldosterone antagonists.
Inventor(s): Green; Michael J. (Kendall Park, NJ), Shue; Ho-Jane (Belleville, NJ), Shapiro; Elliot L. (Cedar Grove, NJ), Gentles; Margaret A. (Bloomfield, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Dec 22, 1976
Application Number:05/753,257
Claims:1. The process for the preparation and isolation of a 3-oxo-6,9-di-unsubstituted-7.alpha.-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.degree. C and thence isolation of the 3-oxo-6-unsubstituted-7.alpha.-halogeno-4-dehydro steroid thereby formed at temperatures no higher than about 25.degree. C by removing any excess acid and said solvent without subjecting said 3-oxo-6,9-di-unsubstituted-7.alpha.-halogeno-4-dehydro steroid to a basic medium, so as to obtain said 3-oxo-6,9-di-unsubstituted-7.alpha.-halogeno-4-dehydro steroid substantially free of acid or base.

2. 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.degree. to about 20.degree. C.

3. The process of claim 1 wherein the reaction temperature is in the range of from about 0.degree. to about 20.degree. 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.

4. The process of claim 1 wherein the reaction temperature is in the range of from about 0.degree. to about 20.degree. 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.

5. The process of claim 4 wherein said lower alkanoic acid is acetic acid.

6. 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.

7. 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,.beta.OH);

W is (H,H); (H,CH.sub.3) or .dbd.CH.sub.2 ;

V and V.sub.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.degree. C;

whereby is isolated a 3-oxo-7.alpha.-chloro-1,4-pregnadiene of formula II: ##STR7## wherein Y, W, V and V.sub.1 are as hereinbefore defined.

8. The process of claim 7 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is 16.alpha.-methyl-1,4,6-pregnatriene-11.beta.,17.alpha.,21-triol-3,20-dione 17,21-dipropionate whereby is isolated 7.alpha.-chloro-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.,21-tri ol-3,20-dione 17,21-dipropionate.

9. 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.

10. 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,.beta.OH);

W is (H,H); (H,CH.sub.3) or .dbd.CH.sub.2 ;

V and V.sub.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.degree. C;

whereby is isolated a 3-oxo-6,9-di-unsubstituted-7.alpha.-bromo-1,4-pregnadiene of formula II: ##STR9## wherein Y, W, V and V.sub.1 are as hereinabove defined.

11. The process of claim 10 wherein said 3-oxo-6,7,9-tri-unsubstituted-1,4,6-pregnatriene is 16.alpha.-methyl-1,4,6-pregnatriene-11.beta.,17.alpha.,21-triol-3,20-dione 17-benzoate 21-acetate whereby is obtained 7.alpha.-bromo-16.alpha.-methyl-1,4-pregnadiene-11.beta.,17.alpha.,21L -triol-3,20-dione 17-benzoate 21-acetate.

12. 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,.beta.OH);

W is (H,H) (H,CH.sub.3) or .dbd.CH.sub.2 ;

V and V.sub.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-7.alpha.-chloro-1,2-dihydro-4-dehydro steroid of formula II: ##STR11## wherein Y, W, V and V.sub.1 are as hereinabove defined.

13. 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,.beta.OH);

W is (H,H); (H,CH.sub.3) or .dbd.CH.sub.2 ;

V and V.sub.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-7.alpha.-bromo-1,2-dihydro-4-dehydro steroid of formula II: ##STR13## wherein Y, W, V and V.sub.1 are as hereinbefore defined.

14. A 7.alpha.-halogeno-4-pregnene-3,20-dione of following formula: ##STR14## wherein Y is oxo or (H,.beta.OH);

W is (H,H); (H,CH.sub.3) or .dbd.CH.sub.2 ;

V and V.sub.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.

15. A compound of claim 14 wherein Z is chlorine or bromine.

16. A compound of claim 14 which is 7.alpha.-chloro-4-pregnene-11.beta.,17.alpha.,21-triol-3,20-dione 17,21-dipropionate.

17. 3-Oxo-7.alpha.-halogeno-17.alpha.-4-pregnene-21,17.beta.-carbolactone wherein said halogeno is chlorine or bromine.

18. 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-17.alpha.-4,6-pregnadiene-21,17.beta.-carbolactone, 3-oxo-17.alpha.-1,4,6-pregnatriene-21,17.beta.-carbolactone, (17R)-spiro-[1,4,6-androstatriene-17,1'- cyclobutane]-3,2'L -dione and 2',3'.alpha.-tetrahydrofuran-2'-spiro-17(1,4,6-androstatriene-3-one);

whereby is isolated a 3-oxo-6-unsubstituted-7.alpha.-halogeno-4-dehydro steroid of the spirolactone series selected from the group consisting of 3-oxo-7.alpha.-halogeno-17.alpha.-4-pregnene-21,17.beta.-carbolactone, 3-oxo-7.alpha.-halogeno-17.alpha.-1,4-pregnadiene-21,17.beta.-carbolactone , (17R)-spiro-[7.alpha.L -bromo-1,4-androstadiene-17,1'-cyclobutane]-3,2'-dione and 2',3'.alpha.-tetrahydrofuran-2'-spiro-17(7.alpha.-bromo-1,4-androstadiene- 3-one), respectively.
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