HU191467B - Process for preparing new 21-halo-17alpha-alcanoyl-derivatives of steroids - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a process for the preparation of novel 21-halo-17α-alkanoyloxy steroid compounds of formula (I), which can be used under favorable conditions as corticosteroid hormones, e.g. hydrocortisone or prednisolone. In the formula, the dotted line represents an optional double bond, A is a C 1-4 alkanoyloxy group and Y is an iodomethyl group or a bromomethyl group. The mono-di-alkanoyl-steroid derivative is otherwise similar in structure but is prepared from the diode-substituted starting material at position 21 by contacting with a hydrogen-containing organic solvent or using a dithionite compound. The monobromo-alkanoyl-steroid derivative is otherwise of the same structure but is prepared from the dibromo-coupled starting material at position 21 by reaction with a phosphite compound. (l) -1-

Description

The present invention relates to novel 21-halo-17α-alkanoyloxy steroid derivatives, wherein the dotted line in formula (I) represents an optional double bond, A is C 1 -C 4 alkanoyloxy and Y is iodomethyl or bromomethyl. The novel compounds of formula I are useful as intermediates in corticosteroid hormones, e.g. hydrocortisone, prednisolone, etc. preparation.

A process has recently become known which allows the production of androst-4-ene-3,17-dione and androst-1,4-diene-3,7,7-dione at low cost and in large amounts by sterol, e.g. cholesterol, sitosterol, etc. with a microorganism belonging to the genus Mycobacterium. The compound thus obtained can be used as an intermediate in the preparation of various steroid-based drugs, e.g. estrone, testosterone, spironolactone.

However, the synthesis of corticosteroids, which are used as active ingredients in most steroid-based drugs, is still multi-step; pregnane derivatives are used which can only be prepared under much less favorable conditions, e.g. stigmasterol or diosgenin; or the active ingredient is synthesized from a bile acid in a multistep process.

We have also sought to make corticosteroids using the above-mentioned cheap starting materials more economically and have found that said 17-oxo-androstane derivatives provide novel intermediates useful in the synthesis of corticosteroids. Derivation of the corticoid side chain from 17-oxo groups has already been suggested, partly before the priority of our application [e.g. J. C. S. Chem. Comm., 1981, 774; Tetraliedron Lett., 1971, No. 22. 2005]. However, in these processes, the 3-oxo group must be protected and thus not applicable, e.g. for conversion of androsta-1,4-diene-3,17-dione, since the selective protection of the 3-oxo port is problematic here.

The present invention provides for the synthesis of corticosteroids without the need to protect the 3-oxo group of the starting material, including the androst-1,4-diene-3,17-dione derivative. The significance of the present invention is enhanced by the fact that some of the final products to be synthesized, the pharmacologically active corticosteroids, are also? ^14- editing agents. Due to application of the present invention may be used in the Δ ⁴ -szerkezetű corticosteroids synthesis preferably obtainable according to the invention, Δ ⁴ -szerkezetű new intermediates, the Δ ¹⁴ -szerkezetű corticosteroids, e. Prednisone may be prepared by the synthesis of Δ ¹⁴ -szerkezetű intermediates according to the invention; Thus, the inexpensive androstane derivative can be used as a starting material in a minimal number of steps and in good yield to provide important pharmaceutical agents. The Flow Chart to be discussed below illustrates that, according to our discovery, 3,17-dione androstane derivatives may also be used in a variety of corticosteroids synthesis.

17-Oxo-androstane derivatives can be used under favorable conditions in the synthesis of corticosteroids by first being treated with a suitable 21-dihalo2

Converted to a -17α-alkanoyloxy steroid and then to the corresponding monohaloalkanoyloxy steroid in the process of the present invention. The preparation of the corresponding dihaloalkanoyloxy steroid derivatives is described in more detail in Hungarian Patent Application No. 1743/85 (No. 189,460), and the resulting dihaloalkanoyloxy steroid derivatives are used as starting materials in the process of the present invention. Thus, in the preparation of corticosteroids, the process disclosed in Hungarian Patent Application No. 1743/85 and the present invention can be used in the sequential steps of a synthesis which results in the stepwise conversion of the desired 17-oxo-androstane derivatives to the desired end product. The sequence of steps starting from the dihaloalkanoyloxy steroid derivatives is illustrated in the Flow Chart, which shows that 17-oxo-containing androstane derivatives can be synthesized in a variety of corticosteroid end products.

For the sake of greater clarity, the dihaloalkanoyloxy steroid derivatives which are not the products of the present invention but are the products of the preceding step (Ia) and (Ic), respectively, whereas the target compounds of the formula I obtained by their conversion denoted as compounds of formula (Ib) or (Id) of formula (I).

Accordingly, the present invention relates to a process for the preparation of new 21-monohalo-17α-alkanoyloxy-steroid derivatives of formula I, the dashed line, A and Y being as defined above, which includes, inter alia, 2I-iodine. 17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, 21-bromo-17α-hydroxypregn-4-ene-3,20-dione-7-acetate, etc. ., which may be used under favorable conditions for corticosteroids, e.g. hydrocortisone or prednisolone.

The process according to the invention may be carried out in different ways, in which Y is an iodine atom or a bromine atom in the target product to be produced.

(a) Procedure

By this method, monoiodoalkanoyloxy steroid derivatives of formula (Ib) which are included in the general formula (I) can be prepared. 2I-iodo-17α-hydroxypregn-4-ene-3,20-dione-17-acetate, 21-iodo-17α-hydroxypregn -4-ene-3,20-dione-17-propionate , 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, and the like.

For the preparation of the monoiodoalkanoyloxy steroid derivatives of formula (Ib), it is sufficient to contact the corresponding diiodoalkanoyloxy steroid derivative of general formula (Ia) with an organic solvent containing a hydrogen atom.

It has already been mentioned that the starting materials of the formula (Ia) are also novel compounds, the preparation of which is described in detail in Hungarian Patent Application No. 1743/85, including 21,2-diiodo-17? -Hydroxypregn-4-ene. 3, 20-dione-17-acetate, 21. 21-diiodo-17α-hydroxypregn-4-ene-3, 20-dione-17-propionate; 21,21-diiodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, etc.

The process may include hydrogen containing organic

191,467 solvents are substances which can be liberated from hydrogen ion (proton) or hydrogen radicals, and include almost all solvents commonly used in the industry, e.g. acetic acid, triethylamine, dimethylformamide (DMF), acetonitrile, ethyl acetate, acetone, tetrahydrofuran (THF), methanol, chloroform, benzene, etc. Preferred amines, e.g. triethylamine, diethylamine, etc., and methyl ketones, e.g. acetone, methyl ethyl ketone, etc., of which methyl ketones are particularly useful. Such solvents are used in the amounts customarily employed.

When a methyl ketone is used in the preparation of the monoiodo ketones of formula (Ib) according to the invention, the reactivity and thus the yield are greatly improved if at least one alkaline compound, e.g. an alkali metal hydroxide, is present in the reaction mixture. sodium hydroxide, potassium hydroxide, etc .; an aliphatic amine, e.g. triethylamine, diethylamine, etc .; an aromatic amine, e.g. dimethylaminoaniline, pyridine; or a carbonate or carboxylate of an alkaline compound, e.g. potassium carbonate, potassium acetate, triethylamine acetate, and the like.

The alkaline compounds or their carbonates or carboxylates are generally used in an amount equimolar to or greater than the intermediate of formula (Ia). The reaction temperature is usually -10 to 100 ° C.

The monoiodoalkanoyloxy steroid derivatives of formula (Ib) may also be prepared by reacting the intermediate of formula (Ia) with a dithionite compound. so e.g. sodium dithionite (vulg. bidrosulfite), potassium dithionite, calcium dithionite, zinc dithionite, lithium dithionite, magnesium dithionite, etc., the most preferred of which are sodium dithionite. Generally 1.0 to 1.3 times, preferably 1.0 to 1.2 times the amount of the dithionite compound is equivalent to α, α-diiodo ketone. If more is used, further reduction of the mono-iodine ketone may occur to the ketone thereby reducing the yield.

The reduction may be carried out using a solvent customary in the industry, e.g. benzene, THF, acetone, acetic acid, etc. The reaction temperature is 0 to 50 ° C, preferably 5 to 30 ° C.

In this process, the monoiodo alkanoyloxy steroid derivative can also be obtained by directly adding the dithionite compound (s) to the reaction medium to produce the corresponding diiodo alkanoyloxy steroid derivative without further isolating the intermediate from the diiodo alkanoyloxyester. In this case, the complete sequence of steps may consist of reacting an ethinylated steroid derivative of formula (II), wherein A is as defined above, with positive iodine ions to give a solution of the corresponding compound of formula (Ia). containing the diiodoalkanoyloxy steroid slag product, the corresponding dithionite compound is added directly to this solution to give the corresponding ntonoiodo alkanoyloxy steroid derivative of formula (Ib).

(b) procedure

By this method, a new monobromoalkanoyloxy steroid derivative of formula (Id) represented by formula (I) can be prepared, wherein the dashed line and A are as defined above.

According to the invention, the corresponding dibromoalkanoyloxy steroid derivatives of formula (Ic), in which the dashed line and A are as defined above, are used for this purpose and the starting material is a phosphate, e.g. reaction with trialkyl phosphite or triaryl phosphite. Outstanding yields can be achieved if the compound of formula Ic is, e.g. with trimethyl phosphite, triethyl phosphorite and triphenyl phosphite.

The phosphite compound should be at least equimolar to the amount of the dibromoalkanoyloxy steroid derivative, preferably 1.2 to 10 times the equimolar amount.

Generally, the reactants are reacted in a solvent, which may be any of the agents used in the industry for similar purposes. Preferably, the solvent is a nitro compound, e.g. nitromethane, nitrobenzene, etc .; a short-chain alcove, e.g. methanol, ethanol, etc .; a lower carboxylic acid, e.g. acetic acid, propionic acid, etc. Water soluble lower alcohols or carboxylic acids are particularly preferred as solvents! use, because in this case enough water is added to precipitate the reaction product and thus the monobromo steroid target product can be obtained by a simple operation, e.g. can be isolated by filtration. The reaction temperature is 0 to 50 ° C, preferably 5 to 30 ° C.

The target product of formula (Id) can be obtained by the process according to the invention e.g. 21-bromo-17α-hydroxy-pegti-4-ene-3, 20-dione-17-acetate, 21-bromo-17α-hydroxy-pregn-4-ene, 20-dione-17-propionate, 21 bromo-17? -hydroxy-pregna-1,4-diene-3,20-dione-17-acetate;

The flow chart illustrates how the alkanoyloxy steroid derivatives of formula Ib or Id produced according to the invention can be converted to hydrocortisorine and prednisolone, respectively.

The following are processes for the use of the novel alkanoyloxy steroid derivatives of formula (I) according to the invention as starting materials for the preparation of various steroid derivatives: 1. Process for steroid derivatives of formula (IV): wherein the dashed line is optionally double bonded. means, while A and A 'are for the preparation of an alkanoyloxy group from alkanoyloxy steroid derivatives of formula (Ib) or (Id) as starting materials:

a) The alkanoyloxy steroid derivative of formula (Ib) or (Id) is reacted with a quaternary ammonium salt of a lower aliphatic acid.

Quaternary ammonium salts of aliphatic acids having up to 10 carbon atoms can be used for this purpose, e.g. tetramethylammonium acetate, tetramethylammonium propionate, tetraethylammonium acetate, trimethylbenzylammonium acetate, and the like. The quaternary ammonium salt is used in an amount of at least equimolar relative to the amount of the steroid derivative of formula (Ib) and (Id), preferably in an amount of 1.05 to 1.6 times the equimolar amount. Generally, the alkanoyloxy steroid of formula (Ib) or (Id) is reacted in a solvent with the quaternary ammonium salt. It is preferred to use an aprotic solvent, e.g. DMF, N-methylpyrrolidone, dimethylacetamide, etc.

The reaction temperature is -10 to 80 ° C, preferably 0 to 4 ° C. Higher temperatures are disadvantageous because larger amounts of olefinic by-products are formed which no longer have the acyloxy group at the 17-position.

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b) The alkanoyloxy steroid derivative of formula Ib or Id is reacted with an alkali metal salt of an aliphatic acid in the presence of a polar aprotic acid (s) and / or polyethylene glycol (s).

In this process, one of the solvents is a polar, aprotic solvent, e.g. dimethylsulfoxide (DMSO),

DMF, dimethylacetamide, N-methylpyrrolidone, etc. When such a solvent is used, the halogen is replaced by an acyloxy group. The reaction temperature is up to 100 ° C, preferably 40 to 80 ° C. Higher temperatures are disadvantageous because by-products of steroid derivatives are formed

16-positionbc also has double bonds but no

An acyloxy substituent at the 17-position, e.g. 21-acetoxy-pregna-4,16-diene-3,20-dione, 21-acetoxy-pregna-1,4,16-15-triene-3,20-dione, and the like. Too long a reaction time is not favorable as this may also lead to the desired 17-acyloxy steroid derivatives of the general formula (IV) being converted into the by-product mentioned above. In general, the reaction is stopped when the conversion of the starting material has reached 80%, preferably 85% to 95%. Particularly advantageous as N-methylpyrrolidone or dimethylacetamide as solvent! because of the outstanding yields and reduced by-product formation. 25

Also suitable as a solvent in the process is a polyethylene glycol derivative having a molecular weight of 200 to 1500, preferably 300 to 600, e.g. polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol dinethyl ether, and the like. When such a solid polyethylene glycol is used, it is mixed with a suitable solvent, e.g. N-methylpyrrolidone, dimethylacetamide, DMF, etc. Although the steroid derivatives are insoluble in these polyethylene glycols, they may still be used when mixed with a suitable solvent for the steroid derivatives. The reaction temperature is generally 10 to 80 ° C, preferably 20 to 50 ° C.

As the alkali metal salt of an aliphatic acid, the process may use alkali metal salts of acids having up to 10 carbon atoms. sodium formate, potassium formate, sodium stearate, potassium acetate, potassium propionate, etc., with potassium acetate being most preferred.

c) The alkanoyloxy steroid derivative of the formula (Ib) or (Id) is reacted with an alkali metal salt of a lower aliphatic acid in the presence of a crown ether, where the alkali metal salts may be as defined under (b).

The crown ethers can be macrophage compounds, e.g. 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-53-crown-6, cyclohexyl-12-crown4, dibenzo-14-crown4, tetrabenzo-24-crown-8, and so on. The appropriate crown ether is selected depending on the alkali metal salt used: 18-crown-6, e.g. it is advantageous to use potassium salts, e.g. potassium acetate, potassium propionate, etc. in the case; and cyclohexyl-15-crown-5 or dibenzo-18-crown-6 compounds are sodium salts, e.g. sodium acetate, sodium propionate, etc. when used. The most preferred combination is potassium acetate and 18-crown-6. The go amount of the crown ethers should be at least equimolar to the amount of steroid derivative used, but preferably more than 1.2-2.0 times more.

Generally, a solvent is used for the reaction. A variety of aprotic solvents may be used, preferably highly polar aprotic solvents, e.g. DMF, N-methylpyrrolidone, dimethylacetamide, etc.

The reaction temperature is generally 0 to 80 ° C, preferably 10 to 40 ° C. If the temperature is higher, olefmic by-products are formed which do not have an acyloxy substituent at the 17-position.

2. A process for the preparation of the widely used gestagenic hormone, 17α-hydroxy progesterone, from an alkanoyloxy steroid derivative of formula (Ia) or (Ib) as a starting material.

By contacting an iodoalkanoyl steroid derivative of formula (Ia) or (lb) with a methylcyano, a progesterone type compound of formula (V) wherein dashed lines and A is as defined above can be obtained.

Methyl ketones useful for this purpose include acetone, methyl ethyl ketone, acetophenone, etc., with acetone being the most preferred. Such methyl ketones are the solvent! is usually used in an amount sufficient for the application and preferably also used as a solvent.

To carry out this process, the iodoalkanoyl steroid derivative of formula (Ia) or (lb) may be prepared, e.g. dissolved in a suitably selected methyl ketone, e.g. acetone and shake for a fixed period. If the starting material is a diiodoalkanoyl steroid derivative of formula (Ia), e.g. 21,21-diiodo-17? -Hydroxypregn4-ene-3,20-dione-17-acetate, first of which is the corresponding monoiodoalkanoyl steroid derivative, e.g. 21-iodo-17? -Hydroxy-pregn4-ene-3,20-dione-17-acetate is formed, followed by further shaking to form 17? -Hydroxy-pregn4-ene-3,20-dione-17-acetate.

In this process, the concomitant presence of acidic compounds may accelerate the reaction while increasing the yield of the progesterone derivative.

Such acidic compounds include inorganic acids, e.g. hydrogen chloride, hydrobromic acid, perchloric acid, etc .; organic acids, e.g. methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like. These acidic compounds are weakly basic compounds, e.g. or in the form of their pyridine salts. The acidic compound or its salt is used in an equimolar amount with the iodine steroid derivative as starting material. In general, the reaction temperature is from 0 to 100 ° C, preferably from 10 to 40 ° C.

The invention will be described in more detail by way of examples. 1-13. Examples 14 to 19 illustrate the preparation of starting materials of formula (Ia) and (Ic), followed by the preparation of target products of general formula (I) according to the invention. and examples further converting the target product to synthesize a pharmaceutically effective corticosteroid.

Example 1

To a mixture of 162 ml of acetic acid and 18 ml of water was added 4.08 g of elemental iodine and 5.71 g of 17β-ethyl-17α-hydroxy-androsta-1,4-diene-3-one-17-acetate and shake at room temperature. A mixture of 2.6 ml of 40% peracetic acid solution, 45 ml of acetic acid and 5 ml of water is added dropwise with shaking and the mixture is shaken for a further 2.5 hours. Addition of 1500 ml of water gives a crystalline precipitate, which is filtered, washed with water and dried to give 9.61 g of

191,467

21.21-Diiodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is obtained.

Nuclear Magnetic Resonance Spectrum (CDC £ ₃ ) δ ppm:

0.89 (s, 3H); 1.24 (s, 3H); 2.09 (s, 3H); 5.52 (s, 1H);

6.11 (s, 1H); 6.31 (q, 1H); 7.10 (d, 1H).

Example 2

To 1.04 g of 21,21-diiodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione 17-acetate is added 25 ml of acetone, 4.1 ml of triethylamine and 2.6 ml of acetic acid, and the resulting mixture was shaken for 2 hours at room temperature (25 ° C).

The reaction product is extracted with methylene chloride and the organic phase is washed with water. The methylene chloride was distilled off to give 0.818 g of amorphous crystalline material.

Liquid chromatographic analysis showed that the crystalline product had a purity of 95.3% of 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate (% yield).

The amorphous crystals were recrystallized from acetone-heptane to give pure 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDC £ ₃₎ δ ppm:

0.79 Cs, 3H); 1.26 (s, 3H); 2.14 (s, 3H); 3.93 (d, 2H);

6.12 (s, 1H); 6.25 (q, 1H); 7.09 (d, IFI).

Example 3

To 0.1 g of 21,21-diiodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is added 1.5 ml of acetone and the mixture is shaken at 28 ° C for 4 hours. The resulting reaction product was extracted with methylene chloride and analyzed by liquid chromatography. It can be stated that

Yield: 83.5% of 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, and 11.4% of 17a-hydroxy-pregna-1. , 4-diene-3,20-dione-17-acetate, a by-product.

Example 4

Example 3 was repeated except that 4.0 mL of triethylamine was used as solvent instead of steel; the target product obtained was 21-iodo-17? -hydroxy-pregna-1,4-diene-3,20-dihydro-17-acetate, yield 40.7%.

Example 5

Example 3 except that 4.0 mL of T11F was used as solvent instead of acetone. The target product obtained was 21.5-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate (35.5% yield).

Example 6

To 1.00 g of 21,21-diiodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione 17-acetate is added 15 ml of acetone and 70 mg of sodium hydroxide, and the mixture is heated to 28 ° C. shake at room temperature for 10 minutes. After further treatment according to Example 2, analysis according to Example 2 shows that the target product, 2L-iodo-17α-hydroxy-pregna-1,4-diene-3, is obtained in 87.8% yield. 20-dione-17-acetate and 12.2% of the by-product, 17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Example 7

Example 6 except that 4.2 ml of triethylamine was used in place of sodium hydroxide and the mixture was shaken for 30 minutes; 21-iodo-17α-hydroxy-prgna-1,4-diene-3,20-dione-17-acetate is obtained in 98.5% yield.

Example 8

2.016 g of a mixture of 17β-ethynyl-17β-hydroxyandrosta-1,4-diene-3-one-17-acetate, 1.49 g of elemental iodine, 27 ml of acetic acid, 3 ml of water and 5 ml of benzene, 93 ml of a 40% peracetic acid solution, 19.5 ml of acetic acid and 2.2 ml of water were added and the resulting mixture was stirred at room temperature.

Shake for 2.5 hours.

Part of the resulting 21,21-diiodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is precipitated as crystals. Then 6.1 ml of an aqueous solution containing 4.25% by weight of sodium hydrosulphite are added dropwise with shaking. Shake for 3 hours after the addition is complete.

The reaction mixture was poured into water and was made oral with dichloromethane. The dichloromethane phase is washed first with dilute aqueous sodium bicarbonate solution, then with water, and then dried.

The dichloromethane solution was analyzed by liquid chromatography and found that 91.5 mol% of 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate and

2.7 mol% of 17a-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is obtained.

The chloroform solution was evaporated and evaporated to dryness under reduced pressure to give an oily medium which gradually solidified. Recrystallization from a mixture of acetone and heptane gave 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDCd ₃ ) δ ppm:

079 (s, 3H); 1.26 (s, 3H); 2.14 (s, 3H); 3.93 (d, 2H); 6.2 (s, 1H); 6.25 (q, 1H); 7.9 (d, 1H).

Example 9

7.86 g of 176-ethynyl-17? -Hydroxyandrosta-1,4-diene-3-one-17-ace (via 130 ml of acetic acid, 13 ml of water and 7.35 g of sodium acetate at 0 ° C After cooling, 6.43 g of N-bromoacetamide are added in small portions, and the mixture is shaken for 1 hour. dibromo-17a: -hydroxypregn; -1,4-diene-3,20-dione-17-acetate NMR (CDCS ₃ ) δ ppm:

0.98 (s, 3H); 1.25 (s, 3H); 2.08 (s, 3H); 6.01 (s, 1H);

6.04 fs, 1H); 6.20 (q, 1H); 7.02 (d, 1H).

Mass spectrum m / e: 528

-5191 467

Example 10

A mixture of acetic acid (100 ml), water (10 ml) and sodium acetate (2 g) was cooled to 0 ° C, followed by addition of 2.0 g of 17 N -ethynyl-17α-hydroxyandrost4-en-3-one-17-acetate.

1.7 g of N-bromoacetamide are added and the mixture is shaken for a further 2 hours. The reaction mixture was then poured into 500 ml of ice water and the resulting crystals were filtered off and dried, yielding 2.9 g of 21,21-dibromo-17α-hydroxy-pregti-4-ene-3,20-diothi-17-acetate. , whose NMR spectrum (CDCC ₃₎ δ ppm: 0.88 (s, 311); 1.26 (s, 3H); 2.10 (s, 3H); 5.68 (s, 1H).

For 0.22 g of 21,21-dibromo-17α-hydroxypregn-4-ene-3,20-dione 17-acetate, 5.0 ml of acetic acid, 0.5 ml of water, 0.1 g of sodium acetate and 1 g of zinc powder is added and the mixture is shaken at 80 ° C for 15 minutes. The zinc powder was filtered off and the filtrate was poured into water to give 0.114 g of crystalline material. Recrystallization from ethanol afforded 0.063 g of a white crystal having the same IR and NMR spectra as the control 17α-hydroxy-progesterone-17-acetate.

Example 11

To 1.34 g of 21,21-dibromo-17α-ludroxypregna-1,4-diene-3,20-dione 17-acetate is added 25 ml of nitromethane and 2.0 ml of trimethyl phosphite and the mixture is stirred at room temperature. Shake for 50 minutes. The reaction solution was diluted with ether and washed with water until the aqueous phase was neutral.

The ethereal phase was dried and the solvent was distilled off under reduced pressure to give 1.117 g of crystalline material. Recrystallization from a mixture of octane and THF gives 0.827 g of 21-bromo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDCC ₃ ) δ ppm:

0.8 (s, 311); 1.28 (s, 3H); 2.10 (s, 311); 3.87 (s, 1H); 3.89 (s, 1H); 6.07 (s, 1H); 6.22 (d, 1H); 7.05 (d, 1H). Mass spectrum m / e: 448.45

Analysis result: C H SHE Br calculated (Z): 61.47 6.50 14.25 17.78 found (%): 61.59 6.61 14.03 17.78

Example 12

To 2.03 g of 21,21-dibromo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is added 20 ml of methanol and 2.2 ml of trimethyl phosphite and the mixture is stirred at room temperature for 80 minutes. shake.

Water (200 mL) was added to the reaction solution and the resulting crystals were filtered and dried to give 1.69 g of 21-bromo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Example 13

To 2.07 g of 21,21-dibromo-17? -Hydroxypregn-4-ene-3,20-dione-17-acetate are added 20 ml of acetic acid and 2.2 ml of trimethyl phosphite and the mixture is shaken at room temperature for 70 minutes. .

Water (200 mL) was added to the reaction solution, and the resulting crystals were filtered and dried to give 1.63 g of 21-bromo-17a6

-hydroxy pregn-4-ene-3,20-dione acetate having an NMR (CDCS ₃ ) δ ppm;

0.78 (s, 3H); 1.24 (s, 3H); 2.08 (s, 3H); 3.98 (d, 2H); 5.69 (s, 1H).

Example 14

To a mixture of 2.006 g of 17α-hydroxy-21-iodo-pregna-1,4-diene-3,20-dione 17-acetate and 0.801 g of tetramethylammonium acetate was added 6.0 ml of N-methylpyrrolidone and Shake at 8 ° C for 8 hours. Then 60 ml of water are slowly added dropwise with shaking. The resulting crystals were filtered off, washed with water and dried to give 1.64 g of crystals which were recrystallized from 16 ml of ethanol to give 1.21 g of 17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21 -diacetate.

Nuclear Magnetic Resonance Spectrum (CDC2 ₃₎ 5 ppm:

0.80 (s, 3H); 1.06 (s, 3H); 2.12 (s, 3H); 2.22 (s, 3H); 4.82 (q, 2H); 6.12 (s, 1H); 6.08 (d, 1H); 7.13 (d, 1H).

Example 15

A mixture of 1.93 g of 17α-hydroxy-21-bromo-pregna-1,4-diene-3,20-dione 17-acetate, 2.51 g of potassium acetate and 20 ml of DMF is shaken at 60 ° C for 14 hours. . Water (200 mL) was added and crystals precipitated. After filtration and drying, 1.519 g of crystals are obtained. Recrystallization twice from a mixture of octane and THF gives 0.835 g of 17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate.

Example 16

4.08 g of 17α-hydroxy-21-iodo-pregna-1,4-diene-3,20-dione 17-acetate, 4.55 g of potassium acetate, 28 ml of polyethylene glycol monomethyl ether (molar weight: 400) and 12 ml of N-methylpyrrolidone was stirred at 40 ° C for 13 hours. The reaction solution was added dropwise to 400 ml of water. The resulting crystals were filtered and dried to give crude 17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione-7,21-diacetate (3.29 g). Liquid chromatography showed a purity of 70.13%.

Example 17

1.86 g of 17α-hydroxy-21-iodo-pregna-1,4-diene-3,20-dione 17-acetate, 2.00 g of potassium acetate, 1.952 g of 18-crown and 20 ml of N- the methylpyrrolidone mixture was shaken at 20 ° C for 4 hours. The reaction solution was poured into water (200 mL) and the resulting crystals were filtered and dried to give 1.33 g of 17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione-7,21-diacetate. Liquid chromatography showed that the product was 90% pure (yield:

⁷ 4.5 mol%).

Recrystallization from ethanol gave pure 17a, 21-dihydroxypregna-1,4-diene-3,20-dione-17,21-diacetate.

-6191467

Example 18

To 1.0 g of 21,21-diiodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is added 15 ml of acetone and the mixture is shaken at 28 ° C over 4 L. The reaction product is extracted with methylene chloride and the methylene chloride phase is washed with water and dried. The solvent was distilled off and evaporated to dryness to give amorphous crystals.

Analysis by liquid chromatography showed that 83.5% of the mixture constituting the crystals 1 was 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate and 11.4% of 17α-hydroxy. pregna-l, 4-diene-3,20-dione 17-acetate.

If the reaction is continued for 21 hours, 46.0% of the resulting mixture is 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-1-17-acetate and 48.3% 17a-hydroxy-pregna-l, 4-diene-3,20-dione 17-acetate. Reaction over 50 hours gives 17a-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate in% yield.

Example 19

To 1.0 g of 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione 17-acetate is added 20 ml of acetone and 0.80 g of pyridine-p-toluenesulfonate and the mixture is stirred for 2 hours. , Reflux for 5 hours while shaking. 17a-Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate was obtained in 90% yield. The post-treatment was carried out as in Example 18 to give white crystals. Recrystallization from a mixture of heptane and acetone gives 17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDC ? ₃ ) δ ppm:

0.71 (s, 3H); 1.25 (s, 3H); 2.02 (s, 3H); 2.06 (s, 3H);

6.03 (s, 1H); 6.32 (q, 1H), 7.01 (d, 2H).

Having thus fully described the invention, it will be apparent to those skilled in the art that it is possible to carry out the invention in a manner other than the examples given above in accordance with the inventive idea.

Claims (5)

Claims A process for the preparation of 21-halo-7α-alkanoyloxy steroid derivatives of formula (I) wherein the dashed line represents an optional double bond, Y is iodomethyl or bromomethyl cs A is C 1-4 alkanoyl; oxy, characterized in that a) for the preparation of a target product in which the dotted line and A are as defined in the present invention and Y is an iodomethyl group, a diiodo steroid derivative of the formula Ia, the dashed line and A being as defined in the present invention, contacting with a hydrogen-containing organic solvent or reducing it using a dithionite compound; obsession b) for the preparation of a target product wherein the dashed line and A are as defined in the preamble and Y is bromomethyl, a dibromo steroid derivative of the formula Ic, the dashed line and A being as defined in the preamble, reacting with a phosphite compound. (Priority: July 19, 1982) 2. A process for the preparation of new 21-halo-17α-alkanoyloxy steroid derivatives of formula I wherein the dashed line represents an optional double bond, Y is iodomethyl and A is C 1 -C 4 alkanoyloxy. characterized in that a diiodo steroid derivative of formula (Ia) is contacted with a hydrogen-containing organic solvent, the dotted line and A being as defined herein. (Priority: August 26, 1981) A process for the preparation of new 21-halo-17a-alkancyloxy steroid derivatives of formula (I) wherein the dashed line represents an optional double bond, Y is iodomethyl or bromomethyl, and A is C 14 alkanoyloxy, with characterized by a) for the preparation of a target product in which the dotted line and A are as defined in the present invention and Y is an iodomethyl group, a diiodo steroid derivative of the formula Ia, the dashed line and A being as defined in the present invention, reduction using a dithionite compound; obsession (b) for the preparation of a target product having a dotted line and A in the general formula (I) and a bromomethyl group in the general formula (I), a dibromo steroid derivative of the formula (Ic) - the dashed line and A - with a trialkyl or triaryl phosphite compound. (Priority: July 28, 1981) The process according to claim 2, wherein the hydrogen-containing organic solvent is methyl ketone and is preferably reacted in a medium in which at least one alkaline compound - or a carbonate or a carboxylate thereof - is also present. (Priority: August 26, 1981) 5. A process according to claim 2 wherein the hydrogen-containing organic solvent is an amine.