US3035050A - 1-dehydrogenation of 11beta-hydroxy steroids by 2, 3-dibromo-5, 6-dicyanoquinone - Google Patents

Description

United States Patent Ollice 3,035,959 Patented May 15, 1962 3,035,050 l-DEHYDROGENATION OF llp-HYDROXY STER- OEDS BY 2,3-DIBROM-5,6-DICYANOQUINONE Allan Eugene Hydorn, Highland Park, N.J., assignor to Olin Mathieson Chemical Corporation, New York,

N.Y., a corporation of Virginia N0 Drawing. Filed Aug. 19, 1960, Ser. No. 50,596 6 Claims. (Cl. 269-23955) This invention relates to a process for preparing steroids and more particularly to an improved process for the chemical l-dehydrogenation of steroids.

With the discovery that the introduction of a double bond into the l,2-position of hydrocortisone increased its glucocorticoid activity, attention was directed to processes for the l-dehydrogenation of steroids of the llfi-hydroxy- 3,20-diketo-A -pregnene series. Subsequently other l-dehydrogenated steroids were found to have commercial utility as glucocorticoid and anti-inflammatory drugs. It was also found that the desired l-dehydrogenation could be accomplished either chemically or microbiologically. The chemical method most commonly used hereinbefore was one involving selenium dioxide. This process, however, suffered the disadvantage of yielding in addition to the desired l-dehydro steroid, selenium containing byproducts which were diflicult to separate.

It is an object of this invention, therefore, to provide an improved process for the l-dehydrogenation of a steroid of the l1fi-hydroxy-3,ZO-diketo-M-pregnene series. It is another object of this invention to provide a process for the l-dehydrogenation of a steroid of the llfl-hydroxy- 3,2O-diketo-A -pregnene series, wherein the concomitant formation of undesired, dirhcultly-removable by-products is obviated.

These objects are achieved by the process of this invention which essentially comprises treating a steroid of the ll,B-hydroxy-3,ZO-diketo-M-pregnene series with 2,3-dibromo-5,6-dicyanoquinone and recovering the A -pregnadiene thus formed.

Among the steroids of the 1lfi-hydroxy-3,20-dil eto-A pregnene series which may be converted into useful l-dehydro derivatives by the practice of this invention may be mentioned monohydroxyprogesterones (e.g., llfi-hydroxyprogesterone, 6-methyl-lLB-hydroxyprogesterone, 6-halo- 1lB-hydroxyprogesterones, the 90cand IZa-halo-llB-hy droxyprogesterones, the 6,9-dihalo-llfi-hydroxyprogesten ones, and Zl-fluoro-l lB-hydroxyprogesterone); the dihyciroxyprogesterones (e.g., corticosterone, the 9aand 12ahalocorticosterones, 1 1,6, l 7a-dihydroxyprogesterone, 2 lfiuoro-l1,6,l7a-dihydroxyprogesterone, 90:,2l-dlfill01011fi, l7a-dihydroxyprogesterone, the 6,9aand 6,12a-dihalocoriicosterones, and G-methylcorticosterone); the trihydroxyprogesterones (e.g., hydrocortisone, the 9aand 12ahmchydroccrtisones, the l6-methyl-9tx-halo-hydrocortisones, the 6,9aand 6,l2a-dilialohydrocortisones, 6-methylhydrocortisone, and the 6-halohydrocortisones); and the tetrahydroprogesterones (e.g., 9a-fiuoro-l6u-hydroxyhydrocortisone, 6-methyl-9a-fluoro-l6cz-hydroxyhydrocortisone and the 6,9aand 6,l2a-dihalo-l6a-hydroxyhydrocortisones) in order to appreciably increase the yield of desired product, if a polyhydroxyprogesterone is used as the reactant, all hydroxyl groups other than the one in the 11,8- position should be protected. This may be done in the usual manner by forming esters, ethers, acetals or ketals thereof. The preferred esters are those which are formed with hydrocarbon carboxylic acids having less than ten carbon atoms, as exemplified by the lower fatty acids (e.g., acetic and propionic acids), the monocyclic aryl carboxylic acids (e.g., benzoic and cz-toluic acids), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and [3- phenylpropionic acids), the cycloalkanecarboxylic acids and the cycloalkenecarboxylic acids. The preferred ethers are those of hydrocarbon radicals having less than ten carbon atoms, as exemplified by lower alkyl (e.g., methyl and ethyl) and monocyclic aryl lower alkyl (e.g., benzyl and phenethyl). The preferred acetals and ketals are those formed with hydrocarbon ketones and aldehydes having less than twelve carbon atoms, as exemplified by the lower alkanals (e.g., acetaldehyde and propionaldehyde), the lower alkanones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone and B-pentanone), the monocyclic aralkanals (e.g., phenylacetaldehyde), and the monocyclic aralkanones (e.g., acetophenone and phenylpentanone-3 Particularly preferred as steroid reactants are those of the general formula wherein X is a hydrogen or fluoro, Y is hydrogen, methyl or fluoro, Z is hydrogen or the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, P is hydrogen or lower alkyl, and Q is lower alkyl or monocyclic aryl (especially phenyl).

The reaction is preferably carried out in an inert organic solvent for the steroid, such as dioxane, at an elevated temperature, such as the reflux temperature of the solvent. Other utilizable solvents include tetrahydrofuran; lower alkyl alkanoates, such as ethyl acetate and amyl acetate; and hydrocarbon solvents, such as benzene. The desired steroid product can be recovered by conventional means, such as filtration or centrifugation and recovering the steroid from the filtrate. The precipitated 2,3-dibromo-S,G-dicyanohydroquinone can then be separately recovered and oxidized and reused.

The following examples are illustrative of the invention (all temperatures being in centigrade). The first example, disclosing the method by which the 2,3-dibromo- 5,6-dicyanoquinone is prepared, also illustrates another advantage of this invention, namely, the ease by which the reactant can be prepared in two steps from 2,3-dicyano hydroquinone (which in turn is prepared in one step from quinone). By way of contrast six steps are needed to prepare 2,3-dichloro-5,6-dicyanoquinone from quinone.

EXAMPLE 1 6oc-Flu0r0-1oa-Hydroxyprednisolone 16,17-Acet0nide ZI-Acetate (a) Preparation of 2,3-dibr0m0-5,6-dicyan0hydr0quinone-To a solution of 16.0 g. of 2,3-dicyanohydroquinone in g. of g acial acetic acid containing 19.6 g. of potassium acetate is added 35 g. of bromine. The solution is refluxed for two hours, cooled and diluted with 300 ml. of Water. The precipitated solid is filtered, washed with water and dried. Weight about 30 g. of the hydroquinone, MP. about 255 (dec.);

(1')) Preparation of 2,3-dibr0m0-5,6-dicyanoquinone.- To a suspension of 30 g. of 2,3-dibromo-5,6-dicyanohydroquinone in 450 ml. of carbon tetrachloride at 5 is added with stirring 9 g. of nitrogen dioxide in small portions. After the addition, the reaction mixture is stirred vigorously for two hours. The suspended solid is filtered and recrystallized from chloroform to give about 25 g. of 2,3-dibromo-5,6-dicyanoquinone as red needles, M.P. about 233235 (dec.).

Preparation of 6a-flu0r0-16a-hydroxyprednisolone 16,17-ace20nide 2Z-acetate.To a solution of 2.4 g. of 6u-fiuoro-l6ahydroxyhydrocortisone 16,17-acetonide 21- acetate in 50 ml. of dioxane is added 1.7 g. of 2,3-dibromo-5,6-dicyanoquinone. The solution is refluxed for six hours, cooled to and the precipitated 2,3-dibromo- 5,6-dicyanohydroquinone is filtered and washed with benzene. The filtrate and washing are combined and diluted with an equal volume of benzene. The resulting solution is passed through a column of 120 g. of acid washed alumina. Elution with two liters of chloroform-benzene (1:1, v.:v.) and evaporation of the solvent gives about 1.7 g. of 6a-fiuoro-l6a-hydroxyprednisolone 16,17-acetonide 21-acetate, M.P. about 263-265". The infrared spectrum is identical to that of an authentic sample.

EXAMPLE 2 Triamcinolone 16,17-Acetonide 21 Acetate To a solution of 3.0 g. of 9u-fluoro-lfia-hydroxyhydrocortisone 16,17-acetonide 21-acetate in 50 ml. of dioxane is added 2.2 g. of 2,3-dibromo-5,6-dicyanoquinone. The solution is refluxed for 6.5 hours, cooled and filtered to remove the precipitated 2,3-dibromo-5,6-dicyanodroquinone. After Washing the precipitate with benzene, the filtrate and washing are diluted with an equal volume of benzene and chromatographed over 150 g. of alumina using a 1:1 mixture of benzene-chloroform as eluant. Evaporation of the solvent gives about 2.1 g. of triamcinolone 16,17-acetonide 2l-acetate, M.P. 268-270". The infrared spectrum is identical to that of an authentic sample.

EXAMPLE 3 6 a-F luorotriamcinolone 16,17-Acet0nide 21-Acetate Following the procedure of Example 2 but substituting 3.1 g. of 6u,9a-difluoro-16a-hydroxyhydrocortisone 16, 17-acetonide 2l-acetate for the 9a-fluoro-16a-hydroxyhydrocortisone 16,17-acetonide 21-acetate, fia-fiuorotriamcinolone 16,17-acetonide 2l-acetate is obtained.

EXAMPLE 4 16,17-Acet0phen0ne Derivative of 16a-Hydr0xyphednisolone 21-Acetate Following the procedure of Example 1, step 0, but substituting 2.5 g. of the 16,17-acetophenone derivative of 16a-hydroxyhydrocortisone 21-acetate for the Got-fluorol6ix-hydroxyhydrocortisone 16,17-acetonide 2l-acetate, 16,17-acetophenone derivative of 16a-hydroxyprednisolone 21-acetate is obtained.

4 EXAMPLE 5 Prednisolone 21-A cetate Following the procedure of Example 1, step c, but substituting 2.0 g. of hydrocortisone 21-acetate for the fluoro-l6a-hydroxyhydrocortisone 16,17-acetonide 21-acetate, prednisolone 21-acetate is obtained.

The 2,3-dibromo-5,6-dicyanohydroquinone obtained in Examples 1 and 2 can be reoxidized to 2,3-dibromo-5,6- dicyanoquinone by the procedure of Example 1, step b, and then reused to 1,2-dehydrogenate fresh steroid reactant.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

l. A process for l-dehydrogenating steroids which comprises treating a steroid of the 11fi-hydroxy-3,20- diketo-A -pregnen series, unsubstituted in the 1 and 2 positions, with 2,3-dibromo-5,6:dicyanoquinone.

2. The process of claim 1 wherein the steroid reactant is of the general formula wherein X is selected from the group consisting of hydrogen and fluoro, Y is selected from the group consisting of hydrogen, methyl and fluoro, Z is selected from the group consisting of hydrogen and the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, P is selected from the group consisting of hydrogen and lower alkyl, and Q is selected from the group consisting of lower alkyl and monocyclic aryl.

3. The process of claim 1 wherein the steroid reactant is 16a-fiuoro-l6a-hydroxyhydrocortisone 16,17-acetonide 2l-acetate.

4. The process of claim 1 wherein the steroid reactant is 9aruoro-l6u-hydroxyhydrocortisone 16,17-acetonide 2l-acetate.

5. The process of claim 1 wherein the steroid reactant is 6a,9a-difluoro-16a-hydroxyhydrocortisone 16,17-acetonide ZI-acetate.

6. The process of claim 1 wherein the steroid reactant is the 16,17-acetophenone derivative of 16a-hydroxyhydrocortisone 2l-acetate.

References Cited in the file of this patent Brande et al.: Iour. Chem. Soc., 3548-3563 (1954). Brande et al.: Iour. Chem. Soc., 3569-3574 (1954).

Claims (1)

1. A PROCESS FOR 1-DEHYDROGENATING STEROIDS WHICH COMPRISES TREATING A STEROID OF THE 11B-HYDROXY-3,20DIKETO-*4-PREGNEN SERIES, UNSUBSTITUTED IN THE 1 AND 2 POSITIONS, WITH 2,3-DIBROMO-5,6-DICYANOQUINONE.