NO145255B - DEVICE SENSITIVE TO ELECTROMAGNETIC RADIATION - Google Patents

Description

Process for the production of 17α-hydroxy-20-keto-16β-methylsteroids.

The invention relates to a method

for the preparation of 17α-hydroxy-20-keto-16|3-methylsteroids with the partial formula:

where X is a hydrogen atom or an acyloxy group, by catalytic hydrogenation of corresponding 17α-hydroxy-20-keto-16-methylene steroids with the formula:

where X has the above meaning.

It has been proposed (Belgian patent

no. 593 215) a method for the reduction of 17α-hydroxy-20-keto^methylene steroids by treatment with hydrogen in the vicinity of

be of a platinum hydrogenation catalyst or a Raney nickel catalyst, it having been found that by using such a catalyst a mixture of 16a and 16(3-methylsteroids is obtained, in which, however, 16(3-methylsteroids predominate. Although The 16(3-methylsteroid dominates in the mixture, it is still generally necessary to apply a purification step, in order to exclude the unwanted 16a-methylsteroid. In practice, it has been established that such a step is difficult to carry out and that it leads to further losses in yield of the desired compound. The 16(3-methylsteroids must be used for the production of therapeutically active substances which must meet certain standards in terms of purity, and these standards will not be achieved if: dencépimére''16a-iriethylsteroid is also present; 1

It has been found that if the hydrogenation of 17a-hydroxy-20-keto-16-methylene steroids, particularly 21-acyloxy-17a-hydroxy-20-keto-16-methylene steroids, is carried out in the presence of a iridium catalyst, the reaction is more stereospecific so that the formation of the desired 16(3-methylsteroid is favored, which is evident from e.g. measurements of optical rotation and thin-layer chromatography in comparison with the use of platinum or Raney nickel catalysts. In some cases, such a high yield of the 16(3->methylsteroid can actually be obtained that it becomes unnecessary to carry out a purification. This increases the stereospecificity of the process and the possibility of avoiding the need to separate any 16a-methylsteroid from makes it possible to obtain an increased yield of the desired 16|3-methylsteroid.

, The invention therefore relates to a process for the production of 17a-hydroxy-20-keto-16(3-methylsteroids with the above-mentioned partial formula I by catalytic hydrogenation of corresponding 17a-hydroxy-20-'keto-16-methylene steroids with the above* indicated partial formula II, and the method is characterized in that the catalyst is an iridium catalyst.

The improved results which can be obtained by the use of iridium have not generally been found to have any noticeable advantages as a hydrogenation catalyst.

The conditions under which the hydrogenation can be carried out vary from one solvent to another and also from one support material to another. The optimum conditions should therefore be determined in a given; case in previous attempts. In general, hydrogenation in ethanol or ethyl acetate has given better results than hydrogenation in other solvents, but such other solvents can be used, e.g. isopropanol. The use of ethyl acetate in particular makes it possible to achieve high concentrations. The iridium catalyst can consist of iridium metal (without support material) or iridium metal deposited on a suitable support. Boron sulfate was found to be a suitable carrier for the iridium catalyst, but other carriers such as diatomaceous earth and calcium carbonate can be used if desired. It is convenient to use a carrier which can later be dissolved, whereby the iridium, which is expensive after all, can be recovered. For this reason, calcium carbonate is particularly suitable. Charcoal was not found to be a particularly suitable carrier material in the hydrogenation of 21-deoxy compounds, the process, when carried out in the presence of this carrier material, results in the D-homoring formation of the steroid.

The iridium catalyst can be produced in the form of the dioxide, optionally deposited on a carrier. The iridium dioxide can then be subjected to a preliminary reduction or it can be reduced in situ.

The hydrogenation is conveniently carried out at atmospheric pressure and normal temperature. However, higher pressures and/or temperatures can be used if desired.

When the hydrogenation product contains some 16α-methylsteroid, the purification can be carried out as desired, e.g. by repeated crystallization.

As starting material, it can e.g. 21-acetoxy-17a-hydroxy-20-keto-16-methylene steroids are used. These can be prepared by bromination of the corresponding 21-desoxy compound followed by acetolysis of the resulting 21-toramide.

By using a 21-acetoxy compound as starting material, it has proved possible to obtain very high yields of the desired 16p-methyl compound by hydrogenation. In certain cases, it may even be possible to achieve a yield corresponding to the theoretical.

The method in question must be considered to be generally applicable in connection with pregnane precursors of the type described. Such steroids may contain various other substituents including 3-acyloxy-, 3-hydroxy- or 3-keto groups;

11-acyloxy, 11-hydroxy or 11-keto groups; 9,11-dichloro groups; 9(11)-double bond, and the hydrogen atom in the 5-position can, if present, have a- or p-configuration. It will be understood that some of these groups, such as the 3-keto group, will also be reduced during the hydrogenation.

One can e.g. apply steroids of the general formula:

where R is a hydrogen atom or an acyloxy group. Compounds of the general formula III, where R is a hydrogen atom, can be obtained from hecogene acetate by preparing 3(3-acyloxy-17a-hydroxy-16-methylene-5a-9(11)-pregnen-20-one and converting this in a solvent medium of low ionization power in the presence of a practically anhydrous acidic catalyst The hitherto unknown compounds of the general formula III, wherein R is an acyloxy group, can be obtained from compounds wherein R is a hydrogen atom, by bromination and er-replacement of the bromine atom with an acyloxy group.

Compounds with the general formula stated above can be hydrogenated in accordance with the invention without reduction of the 9(ll) dotable bond generally occurring to form compounds of the general formula:

where R has the meaning given above. These compounds can be used as an intermediate in the production of anti-inflammatory steroids, such as 9a-fluoro-16p-methylprednisolone acetate.

To facilitate the understanding of the invention, the method is described in more detail in the following examples.

Example 1.

Hydrogenation of 21-acetoxy-3fi,17a-dihydroxy-16-m§thylen-5a-pregn-9-en-20-one using 5% iridium on basic sulfate as catalyst and ethanol as solvent.

4.0 g of the catalyst was shaken for 25 minutes in 100 ml of absolute ethanol under hydrogen at atmospheric pressure and room temperature. 5.0 g of the steroid and 400 ml of absolute ethanol were then added, and the suspension was shaken under hydrogen. The rate at which hydrogen was taken up was negligible after 310 minutes (total uptake 273 ml), and the hydrogenation was then stopped. The catalyst was filtered off and washed with ethanol, and the combined filtrates were evaporated to dryness in vacuo. The crystalline residue was freed from solvent at 100°C and 0.1 mm Hg, whereby 4.965 g (99%) of 21-acetoxy-3β,17α-dihydroxy-16β-methyl-5α-pregn-9- 2n-20-on, m.p. 189.5 — 194°C, [a]r, : + 57.5° (c, 1.79 in CHCl).

The optical rotation of the product agreed with the 16p-methyl compound's [a]D : + 57.5° (CHC13), while the 16a-methyl-j isomer shows [a]D : +23° (CHC13). Likewise, its infrared spectrum was now the same as that of the 16p-methyl compound, and thin-layer chromatography on aluminum oxide showed that it contained less than 2 percent of the 16a-methyl isomer.

When 1.80 g of the steroid in 200 ml of ethanol was hydrogenated in a similar manner using 100 mg of barium sulfate containing 5% platinum as catalyst, 1.81 g of a product with [a]D : +|

55.3° (c, 1.52 in CHCl;1), showing that it contained 94 per cent of the 16p-methyl compound. Crystallization of a portion of the product (1.70 g) from 10 ml of ethyl acetate gave 1.384 g (81.5%) of the 16β-methyl compound, m.p. 194-198°C, [a]D : + 56.7° (c, 1.80 in CHClj), which according to optical rotation and thin-layer chromatography contained approx. 2 percent of the 16a isomer.

The starting material in this example

can be produced as follows:

5.0 g of 3β-17α-dihydroxy-16-methylene-5α-pregn-9-en-20-one suspended in 100 ml of chloroform was treated with 9.5 N hydrogen chloride in 11 ml of ethanol, whereby a clear yellow solution. 1.02 mol of bromine in 23.5 ml of chloroform was added dropwise over 25 minutes with stirring, whereby

obtained a pale brown solution; within another 10 minutes the solution began to darken rapidly. A saturated aqueous solution of sodium hydrogen carbonate (about 150 ml) was added until the aqueous phase became alkaline, the chloroform layer was washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo, leaving the crude bromine compound as a brown foam, which weighed 7.51 g.

7.46 g of this foam and 22.0 g of potassium acetate in 200 ml of acetone were refluxed and stirred for 2 hours. After cooling, the mixture was treated with sufficient water to give a clear solution, and most of the acetone was distilled off under reduced pressure. About. 450 ml of water remained

added, and the yellow solid, which weighed

5.48 g, was filtered off, washed with water and

dried. The crude acetoxylated product with

weight 3.9 g was recrystallized twice from

acetone, giving an acetone solvent which after desolvation at 110°C and 0.1 mg Hg gave 1.902 g of 21-acetoxy-3β,17α-dihydroxy-16-methylene-5α-pregn-9-ene-20- on, sm.p. 193 — 196°C. Further crystallization from ethyl acetate gave the analytically pure material in the form of prisms, weight 1.20

g, sm.p. 195.5 - 197.5°C, [a]n - 21.3° (c, 1.03 in CHCl 3 ). (Found: C, 71.3; H, 8.6);

C 24 H 3 , 0, corresponds to C, 71.6; H, 8.5 per cent).

Example 2.

Hydrogenation of 21-acetoxy-3fi,17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 5% iridium on barium sulfate as catalyst and ethyl acetate as solvent.

600 mg of the catalyst was shaken for 43 minutes in 10 ml of ethyl acetate under hydrogen at atmospheric pressure and room temperature.

900 mg of the steroid and 20 ml of ethyl acetate were then added, and the suspension was shaken under hydrogen. The rate at which hydrogen was taken up became negligible after 190 minutes (total uptake 58 ml), and isolation as described in example 1 then gave 867 mg of the 16(3-methyl-compound, m.p. 192-199.5°C , [a]n : + 56.7° (c, 1.71 in CHCl,), which according to optical rotation and thin-layer chromatography contained about 2 percent of the 16a-methyl isomer.

When 900 mg of the steroid in 30 ml of ethyl acetate was similarly hydrogenated using 100 mg of barium sulfate containing 5% platinum as a catalyst, 892 mg of a product with [a]D : + 53.6° (c, 1, 75 in CHC1,,), which indicates that it contained approx. 89 percent of 16(3-methyl isomer one.

Example 3.

Hydrogenation of 21-acetoxy-3fi, 17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 5% iridium on barium sulfate as catalyst and ethyl acetate as solvent at 40°C.

The hydrogenation of 900 mg of the steroid as described in Example 2, but at 40°C, was complete in 155 minutes and gave 869 mg of the 16|3-methyl compound, m.p. 189—194°C, [a]D : + 56.7° (c, 1.7 in CHCl.,), which according to optical rotation and thin-layer chromatography contained approx. 2 percent of the 16α-methyl isomer.

Example 4..

Hydrogenation of 21-acetoxy-3fi,17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 5% iridium on silica as catalyst and ethanol as solvent.

The hydrogenation of 900 mg of the steroid 1 in 100 ml of ethanol using iridium on silica (600 mg) as a catalyst was complete in 22.5 hours at room temperature to give 881 mg of the 16β-methyl compound, m.p. 184-188°C, [a]n : + 57.3° (c, 1.76 in CHCl,), which according to optical rotation contained less than 1 per cent of the 16a-methyl compound.

Example 5.

Hydrogenation of 3$-17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 5% iridium on barium sulfate as catalyst and ethanol as solvent.

1.0 g of the steroid and 400 mg of the previously reduced catalyst were shaken for 23.5 hours under hydrogen in 100 ml of ethanol, whereby 997 mg of a product with [a]D : f 35.3° (c , 1.57 in dioxane), which according to optical rotation contained approx.

90 percent of 3(3, 17a-dihydroxy-16(3-methyl-5a-pregn-9-en-20-one (pure compound, [a]D : + 39°) and about 10 percent of The 16a-methyl isomer (pure compound, [a]D : + 2°).

Example 6.

Hydrogenation of 3fi, 17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using iridium dioxide as catalyst.

1.0 g of the steroid and 40 mg of the previously reduced iridium dioxide were shaken under hydrogen in 100 ml of ethanol for 22 hours, whereby 963 mg of a product with [a]D : + 36.4° (c, 2.09 in dioxane), which according to optical rotation contained 93 per cent of the 16p-bethyl compound.

When 1.0 g of the steroid was reduced in a similar manner, but with 12 mg of Adams' platinum dioxide catalyst, the hydrogenation was complete in 160 minutes to give 1.00 g of a product with [a]D : + 33.8 °

(c, 2.28 in dioxane), which according to optical rotation contained approx. 86 percent of the 16(3-methyl-f orcompound.

Example 7.

Hydrogenation of 21-acetoxy-3fi,17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 7.5% iridium on calcium carbonate as catalyst and

ethyl acetate as solvent.

120.7 g (0.3 mol) of the steroid was suspended in 4.0 liters of ethyl acetate and stirred at 31 °C, whereby a solution was obtained. There

18.0 g of catalyst consisting of calcium carbonate with 7.5% iridium was added, which was rinsed with 20 ml of ethyl acetate, and the mixture was vigorously stirred at 31°C under

hydrogen. After 18 hours, the hydrogen uptake was over, as 7.5 liters had been added (theoretically 7.37 liters at atmospheric conditions). The hydrogen was removed, the suspension was filtered and the catalyst washed with 3 x 100 ml of ethyl acetate. The cloudy filtrate was clarified by filtering through a layer of silica glass followed by washing with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure at 85°C for 30 minutes. The product was slurried in 1.0 liters of acetone under reflux, which gave 123.0 g of acetone-solvated product. A sample was dried at 100°C in vacuo for 2.5 hours: [a]n 2 O : + 56.7° (c, 1.8 in CHCl 2 ), m.p. 194-197°C.

Example 8.

Hydrogenation of llfi, 21-diacetoxy-3fi-17a-dihydroxy-16-methylene-5a-pregnan-20-one using 7.5% iridium on calcium carbonate as catalyst and ethyl acetate as solvent.

To a solution of 5 g of the steroid in 175

ml of ethyl acetate, 0.75 g of catalyst consisting of 7.5 percent iridium on calcium carbonate was added there. The air above the reaction mixture was replaced with nitrogen and then with hydrogen and the mixture was stirred under hydrogen at 20°C until the hydrogen uptake had ended. The catalyst was filtered off, washed with a little ethyl acetate, and the filtrate and washing liquid were combined and evaporated to a slurry.

20 ml of light mineral oil was added

(boiling range 100-120°C), and the mixture was evaporated until all the ethyl acetate had been displaced. The remaining slurry was cooled to room temperature and the 11(3,21-diacetoxy-3|3,17a-dihydroxy-16(3-methyl-5a-pregnan-20-one) was collected by filtration, washed with a little light mineral oil and dried at 60° C. in vacuum. Yield: 4.95 g corresponding to 98.5%, mp 213-215° C., [a]D2« : + 97.7° (dioxane).

The starting material was prepared from 3(3,1l(3-diacetoxy-5a-pregn-16-en-20-one (cf. Callow and James, JCS, 1956, 4739)) by the following steps: Reaction with diazomethane, pyrolysis to a 16-methyl-16(17)-ene compound, epoxidation, conversion with the acid to a 17α-hydroxy-16-methylene compound, bromination to a 21-bromide and reaction with potassium acetate to the 21-acetate.

Example 9.

Hydrogenation of 21-acetoxy-3fi,17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 7.5% iridium on calcium carbonate as catalyst and ethyl acetate as solvent.

The hydrogenation of 900 mg of the steroid in 30 ml of ethyl acetate using 7.7% iridium on calcium carbonate (100

mg) as catalyst was completed within 24 hours at room temperature and gave 897 mg

of the 16[3-methyl compound, m.p. 195— 199°C, [α],, : + 57.3; measurement of optical rotation and thin layer chromatography indicated that the material contained less than

2 percent of the 16a-methyl compound.

When 900 mg of the steroid is hydrogenated in a similar manner using 7.5% platinum on barium sulfate (400 mg) as a catalyst, 902 mg of a product with [a]D : + 52.7° (in CHCl,,) is obtained. , which indicates that it contained approx. 86 percent of the 16|3-methyl isomer.

Example 10.

Hydrogenation of 21-acetoxy-3fi-17a-dihydroxy-16-methylene-5a-pregn-9-en-20-one using 5% iridium on barium sulfate as catalyst and ethyl acetate as solvent at elevated pressure.

The hydrogenation of 900 mg of the steroid in 30 ml of ethyl acetate using 600 mg of barium sulfate containing 5% iridium as a catalyst at room temperature and at 4.2 atmospheres of pressure (falling to 2.5 atmospheres within 22 hours) gave 881 mg of the 16(3-methyl compound, m.p. 190—197°C, [a]D : + 56.4°; thin-layer chromatography indicated that it contained less than 2 per cent of the 16a-methyl compound.

Example 11.

Hydrogenation of 3$-acetoxy-17a-hydroxy-16-methylene-5a-pregn-9-en-20-one using 7.5% iridium on calcium carbonate as catalyst and ethanol as solvent.

The hydrogenation of 1.0 g of the steroid

in 90 ml of ethanol using 600 mg

calcium carbonate containing 7.5% iridium as catalyst was completed in 270 minutes and gave 998 mg of a product with [α]D : + 30.9° (in dioxane); measurement of

optical rotation indicated that the product contained approx. 90 percent of the 16(3-methyl compound (pure compound: [a]D : + 34°) and approx.

10 percent of the 16a-methyl compound (pure

compound [a]D : +4°).

Claims (1)

Process for the production of 17a-hydroxy-20-keto-16(3-methyl-steroids with the formula: where X is a hydrogen atom or an acyloxy group, by catalytic hydrogenation of corresponding 17α-hydroxy-20-keto-16-methylene steroids with the formula: where X has the above meaning, characterized in that the catalyst is an iridium catalyst.