HU198736B - Process for producing 16-dehydro-20-oxopregnane derivatives - Google Patents

Abstract

A new process for preparing 16-dehydro-20-oxopregnane derivatives characterized by reacting a steroid having 17(20)-dehydro-23,24-dinorcholan-22-oic acid structure or a salt thereof with hydrogen peroxide in neutral or alkaline medium in the presence of salts of oxo-acids of transition metals as catalysts. Compounds prepared include the novel compounds 9 alpha -hydroxy-4, 16-pregnadiene-3,20-dione; 1,4,9(11), 16-pregnatetraene-3,20-dione; 3-methoxyimino-4, 9(11), 16-pregnatrien-20-one and 5,9(11), 16-pregratriene-3, 20-dione 3-ethylene ketal.

Description

SUMMARY OF THE INVENTION The present invention relates to novel 16-dehydroxy-20-oxo-pregnane derivatives of formula (I) wherein R is oxo, C 1-4 alkoxyimino or ethylenedioxy, X is hydrogen. or a hydroxyl group and dotted lines may represent additional valence bonds.

Among the compounds of formula I, those derivatives are known in the literature where R is oxo. X is hydrogen and double bonds are present between the carbon atoms 9 (11) and / or 4 (5) and 16 (17).

16-Dehydro-20-oxopregnane derivatives are classical intermediates in the synthesis of corticosteroids since the 1950s / P.L. Julián et al., J.Am.Chem.Soc. 72, 5145 (1950). They are preferably prepared by oxidative chemical degradation from various sapogenins such as diosgenin, tigogenin, hecogenin, R.E. Marker et al., J.Am.Chem.Soc. 61, 3592 (1939); 62, 518 (1940); 69, 2167 (1947), "as well as aglucones of certain steroid bases, such as solasodine and tomatidine (Y. Satato et al., J. Org. Chem., 22, 1496 (1958)).

Methods are known in which 16-dehydro-progesterone is produced from sapogenin derivatives or from solasodine derivatives. Thus, No. 2,875,198. United States Patent No. 22,423, issued to U.S. Patent No. 132,437 to 22-iso-4-spirosten-3-one; and the German Democratic Republic patent discloses the preparation of the above compound from solasodenone and N-acetylsolasodenone. Since these starting steroid derivatives are made from naturally occurring sapogenins or steroid alkaloids, these processes have no economic advantage over methods that directly utilize natural starting materials.

No. 921,753. According to the German patent, 16-dehydro-progesterone is prepared starting from dehydro-epiandrosterone acetate by constructing a pregnane side chain. Denidroepiandrosterone acetate, however, is most often made from 3? -Acetoxy-5,16-pregnadiene-20-one of the same structural type as our target compounds, diosgenin and solazodine (Gazz.Chim. (1957), thus, the process disclosed in the cited German Patent Application for the preparation of croticosterol intermediates with Δ16-20-oxo-pregnane backbone is not industrially applicable.

Bernstein et al., J. Am. Chem. Soc., 81, 4956 (1959) - 4,9 III for the synthesis of triamcinolone and dexamethasone and other high-potency 16-substituted corticosteroid drugs, 16-prenatriene-3,20-dione. It is prepared from 17α-hydroxy-4-pregnene-3,11,20-trione. This starting material contains the 11-oxo and 1-hydroxyl group, characteristic of corticosteroids. In order to obtain the desired 4.9 (II), 16-pregnatriene-3,20-dione, these two valuable functional groups formed by a long synthetic process must be eliminated. Therefore, this process for the preparation of 4,9 (II), 16-pregnatrien-3,20-dione is uneconomical.

Starting in the mid-1960s, sterols, especially plant-based sitosterol, have become increasingly important as starting materials for drug synthesis, in addition to sapogenins and steroid alkaloids, due to their cheaper products and easier availability.

It is known that 3-oxo-23,24-dinor-4,17 (20) -choladiene-22-acid / 3,994,933 by partial microbiological degradation of animal and plant sterols. 9a-hydroxy-3-oxo-23,24-dinor-4,17, (20) colladeno-22-acid (British Patent No. 2,098,218).

From the sterol degradation products of 23,24-dinorkolane skeleton, attempts have been made to prepare pregnane skeleton corticosteroid synthesis intermediates.

Surprisingly, 3-oxo-23,24-dinor-4,17 (20) -choladiene-22-acid was found to yield 4,16-pregnadiene-3,20-dione in good yield. the 9t "-hydroxy-3-oxo-23 _l 24-dinor-4.17 (20) 22--koíadién acid and in the literature yet undescribed 9a-hydroxy-4, 16-pregnadiene-3,20 is converted to a dione by hydrogen peroxy in the presence of salts of transition metal (tungsten, mohodene, vanadium, titanium) oxides in a neutral or alkaline aqueous medium. ;

This type of conversion has not yet been reported in the literature. It has now been discovered that 16-achtdor 20-oxo-pregnane derivatives, which are useful intermediates in natural corticosteroid synthesis, can be prepared from natural sterols in good yields.

In the course of this work, 3-oxo-23,24-dinor-4,9 was first cleaved from 9? -Hydroxy-3-oxo-23,24-dinor-4,17 (20) -choladiene-22-acid by cleavage of the 9? -Hydroxy group. (111,17 (20) -cholecrolene-22- acid was prepared [Hungarian Patent Application Publication No. T-46366]. The 9 (II) double bond present in this compound provides the opportunity for the 1? -Hydroxy and U-oxo groups, and the incorporation of C 9 -halogen substituents which enhance the anti-inflammatory action of corticosteroids.

3-0X0-23,24-dinor-4,9 (11). (17) (20) -cholecrene-22-acid has also been introduced by microbiological aehiurogenation at the 1-position double bond commonly found in corticosteroid drugs. Hungarian Patent Application Publication No. 366.

With our new method for the decomposition of 23,24-dinorkolanoic acid derivatives which are unsaturated at position 17 (20) to pregnane backbone compounds, 3-oxo-23,24-dinor-4,9 (11), 17 (20) -cholalrenene-22 acid to the previously prepared 4.9 (11), 16-pregnatriene-3,20-dione (S. Bernstein, J. Ara. Chem. Soc., 81, 4956 (1959)), 3-0X0-23.24 and -dinor-1,4,9 (11), 17 (20) -choletretrane-22-acid gave 1,4,9 (11) -16-pregnatetraene-3,20-diol, a novel corticosteroid synthesis intermediate.

HU 198736 Β

In converting 16-dehydro-20-oxopregnane derivatives of 3-oxo-23,24-dinor-4,17 (20) -choladiene-22-acid and steroid-substituted derivatives to corticosteroids, it is preferred that oxo group is present in protected form. In this case, the 16-double bond can be selectively epoxidized and the resulting 16α, 17β-oxido derivative can be easily converted to the 17α-hydroxyl group characteristic of corticosteroids, Julian et al., J.Am.Chem.Soc. 72, 5145 (1950). Therefore, the 3-oxo groups of the steroid derivatives of 3-oxo-23,24-dinor-4,17 (2?) -Choladiene-22-acid have been protected (oximes, ketals, enol ethers) and the resulting protected derivatives was converted to the corresponding 16-dehydro-20-oxo-pregnanes.

Accordingly, the present invention provides a process for the preparation of 16-debidro-20-oxopregnane derivatives of formula (I) wherein R is oxo, C 1-4 alkoxyimino or ethyleneoxy, X is hydrogen or hydroxy and dotted lines may represent additional valence bonds, for the known compounds, R is oxo. X is hydrogen and double bonds are present, X is hydrogen and double bonds are present between carbon atoms 9 (11) and / or 4 (5) and 16 (17) with the proviso that if there is double bonding between carbon atoms 4 (5) then there must be no double bond between the 5 (6) carbon atoms or, if there is a double bond between the 9 (II) carbon atoms, then X can only be a hydrogen atom which is present. that a steroid having the structure 17 (20) -aehiaro-23,24-dinorkolan-22-acid of formula II, wherein R, X and the dotted lines have the meanings given above, or a salt thereof, is in the presence of salts of oxo acids as a catalyst, with hydrogen peroxide.

The process of the present invention can be started from any steroid having 23,24-dinorkolan-22-acid having a double bond at the 17 (20) position.

In order to obtain the most advantageous 16-dehydro-20-oxo-pregnane intermediates of natural corticosteroid hormones and drugs, it is desirable to make structural modifications to the backbone of 17 (20) -denidro-23,24-aino-cholanoic acid to be converted in the process of the present invention. which promote the formation of hydroxyl groups at position 17a and 21, which are characteristic of corticosteroids. From an economic point of view, it may be advantageous to develop a synthesis strategy in which the stereochemically inexpensive dichloroacetic acids which are microbiologically inexpensive form the specific structural elements of the corticosteroid to be produced.

In a preferred embodiment of the process of the invention, the inorganic or organic base of the salt of 17 (20) -dehydro-23,24-dinorcholate used as the starting material, optionally formed in situ, is first used as a catalyst. ammonium or alkali metal salt of metal oxo acid is added in an amount of 20 to 50 mol%, followed by addition of 5 to 50 times molar excess of 30% hydrogen peroxide.

As the catalyst, it is preferable to use ammonium paramolybdate or sodium tungstate.

The 16-dehydro-20-oxopregnane products, unlike the dinorkolanoic acid salts used as starting materials, are practically insoluble in water and precipitate out of the reaction mixture.

Preferably, the products can be purified by recrystallization. The products entering the recrystallization mother liquor can be purified by column and preparative layer chromatography.

The structures of the compounds of this invention were confirmed by ultraviolet, infrared, @ 1 H-NMR and mass spectroscopy.

The following examples illustrate the process of the invention:

Example 1

9a-hidrpiü-4,16-pre ^ Adien 3.20-DIPN mixture of _{9-alpha-hydroxy-3-oxo-23-one} 24 dinor4.U (20) -kolaagnSEsayEgr

1076 mg (3mM) of 9a-hydroxy-3-oxo-23,24-dinor-4,17 (2u) -choladiene-22-acid are dissolved in a mixture of 30 ml of water and 3 ml of 1N sodium hydroxide. To the solution was added 531 mg of a solution of ammonium paramolybdenate tetrahydrate in 6 ml of water, previously adjusted to pH 8.0 with concentrated ammonium hydroxide. To the resulting reaction mixture at pH 8.5, 20 ml of 25% hydrogen peroxide solution was added dropwise at room temperature over 2.5 hours. Upon dripping, the permolybdenate formed appears fMoO » ² ') red and product precipitation begins. The vigorous foaming of the reaction mixture was reduced by adding a few drops of dichloromethane. After completion of the reaction, the precipitated reaction mixture was kept at 45 ° C for 30 minutes to remove dichloromethane and then cooled to room temperature. The precipitated product is filtered off and dried. There was thus obtained 650 mg of 9-hydroxy-4,16-pregnadiene-3,20-diol acunk, which was recrystallized from acetone and then benzene.

M.p .: 186-192'C

Ultraviolet spectrum (ethanol): A _max 242 nm ( "

- 25400)

Infrared (KBr): vOH 3528, vC O 1666.1651, i / C = C 1610.1583 cm -1.

1 H NMR (CDCl 3, δ): 6.77 m (H 16), 5.9 s (H-4), 2.25 s (3 H-2 H), 1.32 s (3 H-9), δ , 94 s (3H-18) ppm.

Elemental Analysis: Calculated: Found:

C: 76.79% 76.67%

H: 8.59% 8.54% ² 'pre-feTl6 «acrinathrin 3-3,20-dione;

II) l7 (201 kolatridn-12:

from -oxoic acid, ~ T753 m -4.9 (11), 17 (5 mM) 3-0X0-23,24-dinorolcatriene-22-acid

GB 198736 Β ml of water and 5 ml of IN sodium hydroxide, To the solution was added 885 mg of a solution of ammonium paramolybdenate in tetrahydrate in 15 ml of water, previously adjusted to pH 7.5 with concentrated ammonium hydroxide. To the resulting reaction mixture at pH 8.0, 15 ml of 25% hydrogen peroxide solution (110 mM) was added dropwise over 2 hours at room temperature. Dripping begins to precipitate the product. The product was filtered off and dried. 975 mg of crude product 4,9 (11), 16-pregnatriene-3,20-dione are obtained, which is recrystallized from acetone and then from methanol.

M.p. 202-105'C [α] D + 237 ° (C = 1, chloroform)

Example 3 sSnw Preparation 3-0X0-23, Preparation of Snatetraene-3,20-Dione from Reno-22 Acid to 1,4,9 F, 17 (20) -cholate

6.28

TUT3 mg (3 mN) of 3-oxo-23,24-dinor-1,4,9 (11), 17 (20) colatetraeno-22-acid is dissolved in a mixture of 30 ml of water and 3 ml of 1N sodium hydroxide. To the solution was added a solution of 160 mg (0.5 mM) of sodium tungstate dihydrate in 1 ml of water. To the resulting mixture was added dropwise 60 'Con of 3.2 mL of 25% hydrogen peroxide solution with stirring over 1.5 hours. Subsequently, the reaction mixture was cooled to room temperature and the precipitate was filtered off and dried. This gives 534 mg of crude product 4,4 (11), 16-pregnatetraene-3,20-dione, which is prepared by preparative layer germography (adsorbent: Kiselegel G / Reanal, Budapest / and Kieselgel 60 H F754 + ^ / Reanal, Budapest). 2: 1 mixture, developing mixture: benzene-acetone (4: 1)], then recrystallized twice from benzene.

Mp 204-208 'C

Ultraviolet spectrum (ethanol): λ _max 240 nm (λ - 24300)

Infrared (KBr): t C = O 1670, 1659, * zC = C 1630, 1608.1591 cm ⁴ .

1 H NMR (CDCl 3, δ): 7.22 (H-1

....... '05 (H-4), AMXm (J, ₂ - 12 Hz tj 4 ~ O Hz), 6.72 t (H-16), 5.60 (III, 2.28 s) (3 H-21), 1.46 (3 H-19), 0.93 (3 18 ppm).

Tome

Mass Spectrum (m / z): On Molecule: Typical Ions (m / z): 308, 293, 265, 121.91, 43.

Elemental Analysis: Calculated: Found:

C: 81.78% 81.70%

H: 7.84% 7.74%

308

172, 257,

Example 4

Preparation of 3-methoxyimino-4,9 (III-6-pregnatrien-22-one) from 110-mg of 3-methoxyimino-23,24-dinor-4,9 (11), 17 (20) -Ethetrene-22-acid. 3mM) 3-methoxyimino-23,24-dinor-4,9 (1L), 17 (20) -cholenene-22-acid is dissolved in 25 ml of water and 3 ml of 1N sodium hydroxide and 3 ml of dichloromethane are added. First, a solution of sodium tungstate dihydrate (500 mg, 1.5 mM) in water (3 ml) was added to the solution.

J5 bez at 55 'C with stirring for 2 hours

5.5 ml of 25% hydrogen peroxide solution were added dropwise. During dripping, foaming begins to precipitate the product. The precipitate was filtered off and dried. 967 mg of 3-methoxyimino-4,9 (11), 16-pregnatrien-20-one are obtained as a mixture of E and Z methoxime isomers.

IR:? / CO 1659, + CC 1620 cm ⁴ .

Elemental Analysis: Calculated: Found:

C. 77.84% 77.61%

H: 8.61% 8.59%

N: 4.13% 4.53%

Preparation of 3-mcloximino * no-23,24-dinor-4,9 (II), 17 (20) -cholecollen-22-acid as starting material *

2.04 g (6 mM) of 3-oxo-23.24, _1- dinor-4, M (11). 17 (20) -Colollriene-22 acid in 15 ml of pyridine was stirred at room temperature in 0.55 g (6.3 mM) of methoxyamine hydrochloride for 20 hours. The reaction mixture was poured into water (60 mL) and extracted with dichloromethane (3 x 20 mL). The combined extracts were evaporated in vacuo. Trace residual pyridine is removed by azeotropic distillation with toluene followed by methanol. Thus 2.13 g

3-Methoxyimino-23,24-4,9 (11), 7,7 (20) -cholecrene-22-acid is obtained.

Example 5

Preparation of 4,16-pregnadiene-3,20-dione 3-oxo-23 H, 4 R, 7 (2-toluene-2-dichloro-28,28 mg (3mM) 3-oxo-23,24-dinor-4,17 (20) -choladiene. Dissolve 22 in 30 ml of water and sodium hydroxide and add a solution of 160 mg (0.5mM) sodium tungstate dihydrate in 1 ml of water to 4.0 ml of 30% with stirring at 60 ° C. Hydrophenic peroxide solution was added dropwise over 1 hour.

Vigorous foaming may be reduced by a few drops of methyl ethyl ketone). The reaction mixture was then cooled to 5 'C and maintained at this temperature overnight. The precipitate formed is filtered off and dried. 623 mg of 4,6-pregnadiene-3,20-dione are obtained, which is recrystallized from acetone.

M.p. 186-189'C [q | d - + 175 '(c »0.9, chloroform)

Example 6

5/9 (Preparation of lithium 6-pregnatriene-3,2-dione-3-ethylene ketal ~

1.920 mg (5 mM) of 3-oxo-23,24-dinorola-5.9 (11 L), 17 (20) -triene-22-acid-3-ethylene ketal in 8.6 mL of methanol, 4.3 of methylethylketone (5.2 mL), 10 M sodium hydroxide (5.2 mL) and water (86 mL). To the solution was added 0.21 g of a solution of sodium tungstate dihydrate in 4.3 ml of water. The resulting mixture was stirred at 60 ° C

12.9 ml of 30% hydrogen peroxide solution are added dropwise over 1 hour. The reaction mixture is then heated to 85 ° C to remove organic solvents. The residue was slowly cooled and allowed to stand at 5 ° C overnight. The precipitate was collected and dried. 1.01 g (5.9 (111,10-pregnatrien-3,20-diol-3-ethylene ketal) are obtained.

HU 198736 Β which is recrystallized from methanol.

Mp 210-214 ° C

Ultraviolet spectrum (ethanol): A _max 329 n (<9600)

Infrared (KBr) vC = O 1657, C-C

1589 cm -1 ¹ H-NMR (CDCl 3, tMS): 5.45 m (1H-6, 11 -11), 6.70t (1H-16), 1.15s (3H-21), L20s ( 3H-19), 0.80 (3H-18) ppm

Elemental analysis: calculated (%) found (%)

C: 77.92 77.66

H:. 8.59 8.29

Preparation of 3-oxo-23,24-dinor-5,9 (II), 17 (zO) -cholecrene-22-acid 3-ethylene ketal as starting material:

1.022 mg (3mM) of 3-oxo-23,24-dionor-4.9 (II),

17fz0) -cholenylene-2z acid in 10 ml of dichloromethane was added to the oil, followed by 20 mg of p-toluenesulfonic acid, 1 ml of ethylene glycol and 0.5 ml of trimethyl orthoformate. The reaction mixture was stirred at room temperature for 4 hours, heated to 40 ° C and concentrated to half the volume of the solution. After adding a drop of triethylamine, the solution was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution, then with water, then dried and concentrated in vacuo. The product, which is almost theoretical, is recrystallized from methanol.

Mp 240-243 ° C

Infrared (KBr): λ ⁼ 1701 cm -1 ¹ H NMR (CDCl 3, δ, TMS): 11.05 (1 H, -COOH), 5.45 m (1H-6, H-11), 3, 95s (4H-dioxolane), 1.95ds (3H-21), 1.20s (3H-19),

0.90S (3H-18) ppm;

Elemental analysis: calculated (%) found (%)

C, 74.97 75.02

H 8.39 8.45

Claims (7)

Claims A process for the preparation of 16-dehydro-20-oxopregnane compounds of formula I wherein R is oxo, C 1-4 alkoxy-imino or ethylenedioxy, X is hydrogen or hydroxy and dotted lines 5 additional valence bonds - to be prepared with the proviso that if there is a double bond between the 4 (5) carbon atoms, then there cannot be a double bond between the 5 (6) carbon atoms Or if there is a double bond between the 9 (II) carbon atoms, then X may be hydrogen only, characterized in that one of the 17 (20) -dehydro-23,24-dinorkolan-22-acids of the formula II a steroid, wherein R, X and the dotted lines are as defined above, or a salt thereof in a neutral or alkaline medium, in the presence of salts of transition metal oxoacids as a catalyst, with hydrogen peroxide. 2. A process according to claim 1 wherein the starting material is 3-oxo-23,24-dinor-4,17 (20) -choladiene-22-acid. 3. A process according to claim 1 wherein the starting material is 9alpha-hydroxy-3-oxo-23,24-dinor-4,17 (20) -choladiene-22 acid. The process according to claim 1, wherein the starting material is 3-oxo-23,24-dinor30 -4.9 (II), 17 (20) -cholenylene-22-acid. The process according to claim 1, wherein the starting material is 3-oxo-23, z 4-dinor-1,4.9 (11), 17 (20) -cholethetraeno-22-acid. 35 Process according to claim 1, characterized in that the starting material is> methoxyimine 23, z 4 -dinor-4.9 (II), 17 (zO) -cholecroleic-22-acid. A process according to claim 1, wherein the catalyst is sodium tungstate dihydrate.