NO136727B - - Google Patents

Description

Process for the preparation of 16a-methylsteroid compounds.

This invention relates to the preparation of steroid compounds, and more particularly the preparation of 16α-methylsteroid compounds which have anti-inflammatory and/or adrenocorticoid effects.

Various steroids which have a methyl group in the α- or β-configuration in the 16-position are indicated in the literature to have important pharmacological properties and are generally assumed to have more prominent anti-inflammatory properties and fewer unwanted side effects than the corresponding steroids that do not have the 16-methyl group. It has therefore become important to be able to produce such compounds.

The production of 16-methylsteroids from 11-ketosteroids of the 5|3-pregnan series has previously been described. However, certain compounds that are readily available and have hitherto been used as starting materials for the production of adrenocorticoid hormones belong to the 5a series. Hecogenin is an important example of such a compound.

It is therefore generally an object of the present invention to provide an advantageous method for the production of steroids of the 5a series which are characterized by a 17a-hydroxy-16a-methyl-20-keto structure, from corresponding steroids of the 5ct series which have 16Tmethyl-16-ene-20-keto structure.

Steroid compounds of the 5a-pregnan series which have a 16-methyl-16-en-20-keto structure can be prepared from starting substances such as hecogenin in various known ways depending on the nature of the other parts of the molecule. Thus, e.g. he-cogenin acetate be transferred in a series of steps to 3(3-acyloxy-5a-pregna-9(11) :16-dien-20-yne compounds (cf. Djerassi et al, J. Org. Chem. 1951, 16 , 1278 and Callow and James J.C.S., 1956, 4739) which can be converted to 3(3-acyloxy-16-methyl-5a-pregna-9(11) :16-dien-20-one compounds).

These latter intermediates are analogous compounds with intermediates that have hitherto been used in the syntheses of anti-inflammatory compounds. Other similar intermediates in the 5α-pregnan series which have 16-methyl-20-keto structure are the corresponding 9:11-dichloro compounds and the corresponding compounds containing a saturated ring C and an oxygen function in the 11-position.

The 17α-hydroxy-16α-methyl-20-keto compounds produced according to the present invention can be converted to compounds containing a saturated ring C and an oxygen function in the 11-position.

The 17a-hydroxy-16a-methyl-20-keto compounds produced according to the present invention can be transferred to compounds that have anti-inflammatory and/or adrenocorticoid effects according to various methods known for such transfers. Thus, one can e.g. from the products produced according to the present invention, prepare 16a-me-

thyl analog compounds of cortisone, hydrocortisone, prednisone, prednisolone, the 9-halogen derivatives of such compounds, 9 : 11-dichloro-11-deoxyprednisolone, etc. As will be seen, the preparation of such compounds from the products prepared according to the invention requires the formation of the 3-keto group, the introduction of unsaturation in ring A, the introduction of the desired substituent(s) in ring C and the introduction of a hydroxy (or acyloxy) group in the 21-position, all of these steps in principle can be carried out by methods that have been used up to now in the production of anti-inflammatory and/or adreno-corticoid hormones. For example can the compound 16α-methyl-9α-fluoro-prednisolone-acetate

which is of particular interest be prepared from 3|3-acyloxy-17a-hydroxy-16a-methyl-5a-pregn-9(yl)-en-20-one by hydrolysis of the 3-acyloxy group, bromination followed by acetoxylation by the 21-position, the formation of the 3-keto group, dibromination and dehydrobromination in ring A to A1'<4->structure, epoxidation of the 9(11)-double bond and then reaction of the 9,11-epoxy group with hydrogen fluoride to 16a -methyl-9a-fluoro-prednisolone acetate. In part or all of the reactions in this order up to and including the acetoxylation in the 21 position, the double bond in the 9(ll) position can be protected by dichlorination, as the chlorine atoms are later removed, e.g. by hydration.

Australian patent 238,088 discloses a process for the rearrangement of 16:17-epoxy-16|3-methylsteroids of the 5(3) series using perchloric acid and aqueous dioxane, and the resulting product contains a 16-methylene steroid and a 16-methyl A<]5->steroid in the ratio 1:1.

According to the present invention, it has been found that the rearrangement of 16:17-epoxy-16|3-methylsteroids of the 5a series can be carried out with the aid of an acidic catalyst in an ionizing medium so that a relatively high proportion of 16-methyl is obtained The -A15-steroid and this product can, after D-homo-ring formation to remove 16-methylenesteroid, be catalytically hydrogenated in the presence of palladium to obtain a relatively high yield of 16a-methylsteroid.

In accordance with the foregoing, the method according to the invention involves the production of 17ct-hydroxy-16a-methyl-20-ketosteroids of the 5a series by rearrangement of a 16,17-epoxy-16(3-methyl-20-ketosteroid of the 5a series with the following general formula:

where R is hydrogen or an acyl group, X is a keto, acyloxy, hydroxy or halogen group, Y is hydrogen or halogen or X and Y together represent a carbon-carbon bond, in an ionizing solvent medium in the presence of an acidic catalyst so that a mixture of a 16-methyl-A<1>5-steroid and a 16-methylene steroid is formed, said steroid(s), which preferably has a double bond in the 9(11) position, is then hydrogenated in the presence of a palladium hydrogenation catalyst, and the characteristic feature of the method is that said mixture of the 16-methyl-A,<5->steroid and the 16-methylene steroid is treated with boron trifluoride for D-homo-ring formation of the latter compound, after which the 16-methyl-A15-steroid the resulting mixture is separated and subjected to said hydration.

A hydroxylic solvent is advantageously used as an ionizing solvent, e.g. a lower alcohol such as methanol, ethanol or an aqueous medium such as aqueous dioxane, aqueous tetrahydrofuran or aqueous acetic acid.

The method according to the invention can be illustrated with formulas as follows, with only ring D in the molecule being drawn:

The method according to the invention will be clarified in the following with a number of examples.

Rearrangement of the 16:17 epoxy compound.

This rearrangement involves treating the 16:17-epoxide in an ionizing solvent with an acid catalyst, which is preferably a strong or medium-strong acid. Suitable acids are e.g. hydrogen bromide, hydrogen chloride, sulfuric acid, perchloric acid or formic acid. Mineral acids are generally preferred.

It was found that when the rearrangement is carried out in the presence of a solvent with a relatively strong ionizing ability, e.g. when the acid used can be freely ionized, the rearrangement product is generally substantially the A15 compound. Such solvents or media include hydroxy-containing solvents, e.g. methanol or ethanol. The latter solvents can be mixed with other solvents which do not significantly reduce the ionization ability of the medium, but serve to improve the solubility of the steroid therein, e.g. methylene chloride, chloroform, dioxane, tetrahydrofuran, etc. Media with high ionization power also include aqueous mixtures of water-miscible solvents for the steroid, e.g. dioxane, tetrahydrofuran and acetic acid, the conversion in such cases being advantageously carried out by dissolving the steroid epoxide in the water-miscible solvent and adding aqueous acid to get the reaction going.

The rearrangement product, which is a mixture of the A15 and 16-methylene compound, can be separated, e.g. by fractional crystallization. However, the A15 compound is easily freed from the 16-methylene compound due to the fact that the latter compound is more easily D-homo-annulated than the A15 compound. The A15 compound is thus easily separated from the mixture formed. Thus, treatment of the mixture of the 16-methylene compound and A15 compound with boron trifluoride in a solvent, e.g. dioxane, tetrahydrofuran etc. under mild conditions surprisingly essentially only D-homo-annulation of the 16-methylene compound.

The 16-methylene compounds can advantageously be distinguished from the A<13-> compounds by comparing infrared spectra. The 16-methylene compounds in particular have a marked band at approximately 910 cm-<1>.

Hydrogenation of the product formed to a 16-methylene compound.

The hydrogenation is carried out using a palladium catalyst.

When the hydrogenation is carried out with compounds which also have a double bond in the 9 (11) position, it is usually best to carry out the reaction under neutral or basic conditions, preferably in the presence of an organic base, e.g. pyridine, N-methyl-morpholine and collidine, as relatively strong bases, such as e.g. triethylamine or triethanolamine is preferred. Supported palladium catalysts, e.g. charcoal, calcium carbonate or diatomaceous earth are advantageous. Metallic palladium may optionally be used. Acidic conditions can also be used, but these give an increasing tendency to the formation of unwanted by-products.

The hydrogenation is advantageously carried out in an inert solvent. Suitable leavening agents are e.g. tetrahydrofuran, dioxane, ethanol, ethyl acetate, tert. butanol, methanol and the like or mixtures of one or more of these solvents. The reaction is further advantageously carried out at atmospheric temperature and pressure.

The hydration reaction can naturally cause some changes in other parts of the molecule. Thus, e.g. hydrogenation of the 9 : 11-dichloro compounds with palladium catalyst usually removing the chlorine atoms while forming a double bond. However, a 9:11 bond is quite resistant to hydration and under the preferred hydration conditions set forth herein it usually remains unchanged.

When the hydrogenation product contains a little of the 16(3-methyl compound), separation can be carried out if desired, e.g. by recrystallization. Small changes in the molecule can sometimes facilitate this separation.

Thus, e.g. 3|3,17a-dihydroxy-16a-methyl-5ct-pregn-9(11)-en-20-one when contaminated with the 16|3-epimeric compound be purified by (a) crystallization of 3|3, the 17a-diol (which is preferred over the 3-acetate) or (b) controlled treatment of the mixed 3-acetates with boron trifluoroetherate in dioxane which affects the 16(3-isomer more rapidly than the 16a-isomer).

The 16ct compound can be distinguished from 16|3 compounds in various ways, e.g. by difference in specific rotation, infrared spectra and paper chromatography. Thus, usually the specific rotation for a 16|3-methyl compound is more positive than for the corresponding 16α-epimeric compound. In paper chromatography, a 16a compound usually moves faster than the corresponding 16(3-epimeric compound).

The following examples are given to illustrate the invention and facilitate its understanding.

Example 1.

Rearrangement of 3fi- acetoxy- 16fi- methyl-16a:17a- epoxy- 5a- pregn- 9( 11) - en- 20- one.

3(3-acetoxy-16-methyl-16a:17a-epoxy-5a-pregn-9(11)-en-20-one (5 g) in acetic acid (110 ml) was treated with stirring at room temperature with 3.1 weight percent hydrogen bromide in acetic acid (3.55 mL). The mixture was stirred for 10 minutes until the mixture turned yellow and then anhydrous potassium acetate (0.15 g) was added to remove the color and stop the reaction. The separated solid was filtered off, washed with water and dried in vacuo at 100° C. Weight = 1.8 g (36 percent), mp 180-182° C, (a)D = — 69° (eli CHCl 3 ). The filtrate was concentrated under reduced pressure until solid began to separate.The mixture was set aside at room temperature for 2 hours, isolated by filtration, washed with dilute acetic acid, water and then dried at 100°C in vacuo.

Weight = 1.9 g (38 per cent), m.p. 178-181°C (a)D = 68.5 (c, 1 in CHCl 3 ).

The filtrate was diluted with water (200 ml), extracted with methylene chloride (4 x 25 ml) and the organic layers combined, washed with water (1 x 50 ml), saturated sodium bicarbonate solution (1 x 50 ml) and water (1 x 50 ml). The solvent was evaporated under reduced pressure and the residue recrystallized from petroleum ether (bp. 100-120° C).

Weight = 0.36 g, m.p. (166) 175-180° C, (a)n = _ 60° (c, 1 in CHCl 3 ). The product consisted of approximately 40 percent 16-methylene compound and 60 percent 16-methyl-A<15> compound.

Example 2.

3|3-acetoxy-16β-methyl-16α:17α-epoxy-5α-pregn-9(11)-en-20-one (1.0 g) was treated as in Example 1, but with 56% aqueous hydroiodic acid (0.04 ml) in place of hydrobromic acid. The same product (0.56 g) was obtained, m.p. 180-182° C, (a)n = 68° (c, 1 in CHCl 3 ).

Example 3.

3β-acetoxy-16|3-methyl-16α,17α-epoxy-5α-pregn-9(11)-en-20-one was treated with 0.02% by weight hydrochloric acid in acetic acid as above in Example 1 and this gave the same product (0.61 g), m.p. 178-180° C, (a)D = 68° (c, 1 in CHCl 3 ).

Example 4.

3|3-acetoxy-16|3-methyl-16<x,17cc-epoxy-5a-pregn-9(11)-en-20-one (0.94 g) in methylene chloride (10 ml) was treated with 50 wt. aqueous hydrobromic acid (10 ml)

at room temperature for 1 hour and gave a product (0.55) m.p. 178-182°C, (a)D = -70°

(c, 1 in CHCl.,) which was assumed to contain about 40 percent of the 16-methylene compound and about 60 percent of the 16-methyl-A15 compound.

Example 5.

3β-acetoxy-16-methyl-16a, 17a-epoxy-5a-pregn-9(11)-en-20-one (0.5 g) in acetic acid (11 ml) was treated with N-sulfuric acid (1 ml) and set aside at room temperature for iy2 hours. The product (0.3) was isolated by working up, m.p. 178-181° C, (a)D = 67° (c, 1 in CHCl3) and contained about 70 per cent of the 16-methyl-A<15-> compound.

Example 6.

3β-acetoxy-16(3-methyl-16α,17α-epoxy-5α-pregn-9(11)-en-20-one (0.5 g) was dissolved in acetic acid (20 ml) containing 2 drops of perchloric acid The reaction was followed polarometrically:

The reaction was stopped by the addition of anhydrous potassium acetate and worked up in the same way, whereby a product (0.15 g) with m.p. 180-182° C, (;a)D = -71° (C, 1 in CHCl 3 ).

Example 7.

Preparation of 3β-acetoxy-17α-hydroxy-16α-methyl-5α-pregn-9 (11)-en-20-one.

A catalyst that consisted of 10 percent

Pd/C (0.25 g) was reduced in tetrahydrofuran (2 ml) (9.7 ml of hydrogen absorbed after 30 minutes) and the conversion product from Example 1 (1.0 g) was then added in tetrahydrofuran (7 ml) and triethylamine (0.15 ml). An additional 1 mL of tetrahydrofuran was used for washing and hydration began. The theoretical amount of hydrogen (62.8 ml at 22°C) was absorbed after about 4 hours and the catalyst was then filtered off, washed with tetrahydrofuran (4 x 5 ml) and the filtrate evaporated under reduced pressure to near dryness and water (50 ml ) added. The solid was filtered off, washed with water and dried at 100° C. in vacuum.

Weight = 0.95 g, m.p. 158-163°C.

The steroid (0.95 g) was dissolved in methanol, filtered while hot, evaporated to about 10 ml and subjected to crystallization. This product (m.p. 162-166° C) was recrystallized from petroleum ether (b.p. 100-120° C) (15 ml), set aside overnight at room temperature, filtered off, washed with a little petroleum ether (b.p. 100-120 ° C) and dried at 100° in vacuum.

Weight = 0.58 g, m.p. 165—170° C (a.D.)

= -17.4° (c, 1 in CHCl 3 ).

Example 8.

Example 7 was repeated without the use of triethylamine, using steroid (0.5 g), tetrahydrofuran (6.0 ml) and previously reduced 10% Pd/C catalyst (0.25 g). The hydration was complete after about 1 hour. The product was isolated by complete separation from water.

Weight = 0.47 g, m.p. 169-174°C, (a)D = -17.0° (c, 1 in CHCl.3). The product (0.4 g) was recrystallized from cyclohexane (25 mL) and dried in vacuo at 100°C.

Weight = 0.25 g, m.p. 174-177° C, (a)n = -18.6° (c, 1 in CHCl 3 ).

Example 9.

The rearrangement product of Example 1 (0.5 g) in acetic acid (8 ml) and methylene chloride (2 ml) was added to a catalyst consisting of 10% Pd/C (0.25 g) which had been previously reduced in acetic acid (2 ml). The hydrogen absorption was finished after iy2 hours and the product was worked up as in example 7.

Weight = -0.47 g, m.p. 167—172° C, (a)D = -15° (c. 1 in CHClg).

Example 10.

(a) To a solution of 3(3-acetoxy-16|3-methyl-16a,17a-oxido-5a-pregn-9(11)-en-20-one (20 g) in tetrahydrofuran (400 ml) was added added 9 N sulfuric acid (100 ml). The resulting homogeneous solution was set aside at room temperature for 72 hours during which the α reading of a sample followed polarometrically decreased from + 4.61° to 3.1°. Chloroform (600 ml ) and water (400 ml) were added, the organic phase separated, washed with sodium bicarbonate solution, water and evaporated. The residue was acetylated at 95° C. for 15 minutes with acetic anhydride (40 ml) and pyridine (40 ml). Excess acetic anhydride was cleaved by addition of a little water and the steroid separated by further addition of water totaling 480 ml. The product was collected, washed with water and dried (19.5 g), (a)D = -51.2°

(CHC13). Infrared examination suggested that it contained about 80 percent of the 16-methyl-15-ene and 20 percent of the 16-methylene-ene compound. The product was recrystallized twice from methanol and gave pure 3(3-acetoxy-17a-hydroxy-16-methyl-5a-pregna-9(11) :dien-20-one, m.p. 184—188° C, (a) D = -60° (CHCl 3 ).

The previous experiment was repeated with different solvent/acid combinations and the results were as follows:

(b) A solution of the same 16a, 17a-oxide as in (a) (30 g) in tetrahydrofuran (120 mL) and acetic acid (6 mL) was stirred at 19 °C and treated with concentrated (11N) hydrochloric acid (12 ml). After iy2 hours, the reaction mixture was poured into an excess of water containing some sodium acetate, and the product was collected, washed with water, dried and recrystallized twice from methanol to give the 16-methyl-15-ene compound (14.44 g , 48.1 percent) m.p. 184— 189° C, (a)D = -60.2° (c, 1.0 in CHCl 3 ), -46.4°

(c, 1.0 in dioxane).

(c) 10% palladium on charcoal (1.25 g) in tertiary butanol (20 ml) was reduced 1 hydrogen and a solution of the 16-methyl-15-ene compound from (b) (2.5 g) in tertiary butanol (100 mL) and methylene chloride (25 mL) were added. The mixture was hydrated for 2 hours, the catalyst removed by filtration and the filtrate evaporated to dryness to give a crystalline residue (2.43 g)„ (a).D = +7.7° (dioxane). Recrystallization from methanol gave plates consisting essentially of the 16α-methyl compound, m.p. 173—176° C, (a)D = +6.8° (c, 1.0 in dioxane),

-22° (c, 10 in CHCl 3 ).

Example 11.

(a) Preparation of 3β-acetoxy-17α-hydroxy-16-methyl-5α-pregna-9(11), 15-dien-20-one. (i) 3|3-acetoxy-16a,17a-epoxy-16|3-methyl-5a-pregn-9(11)-en-20-one (1.0 g) in methanol (20 ml) and methylene- chloride (11 mL) was treated with hydrogen bromide in acetic acid (3.2N, 1.0 mL). The rotation dropped from a» = +2.0 to aD = -1.25° in 22 hours and remained stable for another 2 hours. The solution was then shaken with water (200 mL) and methylene chloride (50 mL), and the aqueous layer was extracted with more methylene chloride (3 x 10 mL). The combined methylene chloride extracts were washed with aqueous sodium bicarbonate and water and dried over magnesium sulfate. Removal of the solvent from the dried extract in vacuo left a residue (922 mg), (cOjj = -59.5° (c, 0.86 in CHCl 3 ) which, judging from its infrared spectrum, contained ca.

40 percent of the 3|3-acetate.

The solid was heated at 100°C for 30 minutes in dry pyridine (10 mL) and acetic anhydride (10 mL) and the mixture was poured into ice water (200 mL). The separated product (952 mg), m.p. 158-166°C, (a)D = -55° (c, 0.99 in CHCl 3 ) was collected by filtration. Crystallization of a portion (800 mg) from ethyl acetate gave needles (516 mg) of 3|3-acetoxy-17α-hydroxy-16-methyl-5α-pregna-9(11), 15-dien-20-one, m.p. 179— 182° C, (a)D = -63.5° (c, 0.93 in CHClS) which contained some of the 16-methylene isomeric compound.

(ii) 16a, 17a-epoxy-3|3-hydroxy-16[3-methyl-5a-pregn-9(11)-en-20-one (5.0 g) was treated as in the previous experiment (i ) and after acetylation gave an impure product (5.824 g) (a)D = -33° (CHClg). Crystallization from ethyl acetate gave impure 16-methyl-A15-steroid in two portions, the first portion (3.30 g) having m.p. 179—182° C, (<x)D= -64.3° (C 1.5 in CHC13), (a)D<=> -<4>2.5°

(c, 2.0 in dioxane) and the second portion (573 mg), m.p. 178-182°C, (a)D = -64.1°

(c, 1.92 in CHCl3). The product from the mother liquor was separated into hexane-insoluble (460 mg) and hexane-insoluble (1.2 g) fractions. The insoluble fraction crystallized from methanol to give pure 16-methyl-A<15> compound (200 mg), (a)D = -60.6°C (c, 1.56 in CHClg).

The impure 16-methyl-A15-steroid (3.0

g) from the first portion which contained some of the 16-methyleneisomer compound

was in solution in pure dioxane (150 ml) treated with boron trifluoride ether (3.0 ml) at room temperature. Within 75 minutes

the solution rotation changed smoothly from (<x)D = -42.5° to (a) = -28° and continued to rise. D-homo-annulation of the 16-methylene compound is complete under these conditions. The solution was then poured into ice water (1200) ml and after 2 hours the precipitated product (2.91 g), (a)D = -42°

(CHClg) collected by filtration, washed with water and dried. A crystallization from hexane (1000 mL concentrated to 400 mL) gave the 16-methyl-A15 compound as needles (1.98

g), m.p. 182-184° C, (a)D = -63° (0.124 in CHClg). Further crystallizations from

hexane, then from methanol gave an analytical sample (1.10 g), m.p. 183.5-185°C (a)D = -61.4° (c, 1.22 in CHCl 3 ). (Found: C, 75.0;

H 9.0; <C>24H3404 requires 74.6% C. 8.9% H). (b) Hydrogenation of 3$- acetoxy- 17a- hydroxy- 16- methyl- 5a- pregna- 9 ( 11), 15- diene- 20- one.

3|3-acetoxy-17α-hydroxy-16-methyl-5α-pregna-9(11), 15-dien-one (152 mg) in ethyl acetate (15 mL) was reduced over a 5% palladium-on-charcoal -catalyst (56

mg). The hydrogenation ceased after the absorption of only 0.8 mol of hydrogen in the course of 3 hours. After it had been worked up in the usual way, the product had (a)D = +10° (c, 1.12 in dioxane). Three crystallizations from petroleum ether gave a mixture (46 mg) of 16a- and 16p-methylisomeric compounds, m.p. 171-174° C (a)D = +7.5° (c, 2.36 in dioxane) and which contained 80-90 per cent of the first-mentioned compound.

The crude acetate (260 mg) from a similar experiment was refluxed for 3 h with potassium bicarbonate (3 mL). The 3,17-diol (168 mg), (a)D = +8.5°

(c, 1.1 in dioxane) which separated and was filtered from the hot solution, washed with hot aqueous methanol and dried at 100°C/0.5 mm. Four crystallizations from aqueous methanol gave a pure sample of 3|3, 17α-dihydroxy-16α-methyl-5α-pregn-9(11)-en-20-one (68 mg), m.p. 233—237° C (a)D = +2.8° (c, 0.6 in dioxane).

The recrystallized diol (60 mg) was acetylated with acetic anhydride and pyridine at 100° C. for 15 min. and the crude product was crystallized from petroleum ether (b.p. 60-80° C.) to give 3|3-acetoxy-17a-hydroxy-16a-methyl-5a-pregn-9(11)-en-20-one (46 mg ) m.p. 175—177° C (a)D = + 3° (c, 2.0 in dioxane).

Example 12.

Preparation of pure 3fi-acetoxy-17a-hydroxy-16a-methyl-5a-pregn-9(11)-en-20-one by partial D-homo-annulation of the mixture of 16a- and 16fi-methyl-3$-acetoxy -17α-hydroxy-5α-pregn-9(11)-en-20-one.

A mixture of 16a- and 16(3-methyl-3(3-acetoxy-17a-hydroxy-5a-pregn-9(11)-en-20-one (265 mg) (ca. 1 : 1) in dioxane ( 10 ml) was treated with boron trifluoride etherate (0.2 ml) and stored at room temperature. After 15 minutes, when the rotation had become constant at +4.9° C, the mixture was diluted with water, extracted with ether, washed with dilute sodium bicarbonate- solution and water and evaporated in vacuo to dryness to give a mixture of crystals and oil (270 mg).Two crystallizations from petroleum ether gave 3[3-acetoxy-17a-hydroxy-16a-methyl-5a-pregn-9(ll)- en-20-one (50 mg) as needles, mp 177—180° C after previous wetting, (a)D = +4.1°

(c, 2.21 in dioxane).

Example 13.

3(3, 17a-dihydroxy-17a-methyl-5a-pregn-9(ll)-en-20-one.

3(3-acetoxy-17α-hydroxy-16-methylene-5α-pregn-9(11)-en-20-one (5.0 g) in ethyl acetate (50 mL) was added to a previously reduced suspension of 5 wt. palladium on charcoal (1.66 g) in ethyl acetate (200 ml). One mole of hydrogen was taken up in 9 minutes and the reaction was complete after the uptake of 1.13 moles after 30 minutes. The product which was isolated in the usual manner had (a)n = +16.5° (c, 157 in dioxane).The infrared spectrum and the optical rotation indicated the presence of about 60-70 percent of the 16a-isomeric compound.

The hydrogenation product (1.0 g) in methanol (30 mL) was heated under reflux for 3 h with a solution of potassium carbonate (600 mg) in water (12 mL). The reaction mixture was filtered hot to give white cubic crystals (583 mg, 65%), m.p. 215—230° C (<x)n = +1.3° (c, 1.58 in dioxane). Crystallization from ordinary methanol gave 33, 17α-dihydroxy-16α-methyl-5α-pregn-9(11)-en-20-one (351 mg, 40 wt), m.p. 225—235° C (a),, = +1° (c, 1.10 in dioxane).

The filtrate from the aforementioned hydrolysis was set aside to cool and gave needles (190 mg, mp 201-208° C (a)n = +29° C, (c, 1.3 in dioxane)) which essentially ( about 75 percent) consisted of 36. 17a-dihydroxy-16a-methyl-5a-pregn-9(11)-en-20-one.

A portion (202 mg) of the 3(3,17α-dihydroxy-16α-methyl-5α-pregn-9(11)-en-20-one prepared as above was acetylated with acetic anhydride in pyridine for 6 hours at room temperature. The reaction mixture was heated in the usual manner and crystallized from petroleum ether to give a slightly impure 3(3-acet-oxy-17a-hydroxy-16"-methyl-5a-pregn-9(11)-en-20-one (192 mg, 87 per cent), mp 160-165° C, («)„ = +1° (c, 2.2 in dioxane).

Claims (1)

Process for the production of 17a-hydroxy-16a-methyl-20-ketosteroids of the 5a series by rearrangement of a 16,17-epoxy-16|3-methyl-20-ketosteroid of the 5a series with the following general formula: where R is hydrogen or an acyl group, X is a keto, acyloxy, hydroxy or halogen group, Y is hydrogen or halogen or X and Y together represent a carbon-carbon bond, in an ionizing solvent medium in the presence of an acidic catalyst so that a mixture of a 16-methyl-A<15->steroid and a 16-methylene steroid is formed, which steroid product, preferably having a double bond in the 9 (11) position, is then hydrogenated in the presence of a palladium hydrogenation catalyst, characterized in that said mixture of the 16-methyl-A<15->steroid and the 16-methylene steroid is treated with boron trifluoride for D-homo-ring formation of the latter compound, after which the 16-methyl-A<t3->steroid is separated from the resulting mixture and exposed for said hydration.