HU189460B - Process for producing new 21,21-dihalogeno-17alpha-alkanoyloxy-steroide derivatives - Google Patents

Abstract

The present invention relates to a novel 21,21-dihalo-17α-alkanoyloxy steroid derivative of formula (I), which may be used as an intermediate for the treatment of 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 a diiodomethyl group or a dibromomethyl group. The novel compounds are prepared by reacting the corresponding 173-ethynyl-17a-alkanoyloxy steroid of formula (II) with a reagent capable of liberating a positive iodine or positive bromine ion, preferably an N-bromide, N-bromide. , N-iodo-imide, N-iodo-amide or iodine oxidizing reagent and elemental iodine. -1-

Description

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

Recently, a process has been known which allows the production of androst-4-ene-3,7-dione and androst-1,4-diene-3,17-dione at low cost and in large quantities, by . cholesterol, sitosterol, etc. react 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 used as active ingredients in most steroid-based drugs is still a step-by-step process; using pregnane derivatives that can only be prepared under much less favorable conditions, e.g. progesterone from stigmasterol, 16-dehydro-pregnenolone from diosgenin, or the active ingredient is synthesized from a bile acid in a multistep process.

We also sought to make corticosteroids using the aforementioned inexpensive 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 has already been suggested using other structured starting materials [e.g. J.C.S. Chem. Comm., 774, 1981; Tetrahedron Lett., 1971, No. 22. In such known processes, however, the 3-oxo group must be protected and thus not applicable to e.g. for conversion of androst-1,4-diene-3, 17-dione because the selective protection of the 3-oxo group is problematic here.

The present invention allows for the synthesis of corticosteroids without the need to protect the 3-oxo group of the starting material, including the androstal-1,4-diene-3,17-dione derivative. Increases the importance of the invention is that the synthesized end products, the therapeutically effective corticosteroids part also due ^1,4 -szerkezetű other hand, the including of the invention, the ⁴ -szerkezetű corticosteroids synthesis can be advantageously used can be prepared according to the invention The ⁴ -szerkezetű new intermediates of the ^{1 , 4-} structure corticosteroids, e.g. and in the synthesis of prednisolone, intermediates of structure A ^1,4 according to the invention; Thus, androstane derivatives, which are inexpensively obtainable or obtainable, can be used as starting materials in a minimal number of steps and with good coverage to provide important pharmaceutical agents. The flow chart B discussed below illustrates that, according to our discovery, 3,17-dione-androstane derivatives may also be used in a variety of corticosteroids synthesis.

The androstane derivative starting materials can thus be converted into the dihalo intermediates of formula (I) in the process of the invention and, in a further step, into the corresponding monohalogen intermediate, which intermediate can be further synthesized into the desired corticosteroid hormone.

The monohalo intermediates obtained from the dihalo intermediate of formula (I) obtained in the process of the present invention are also novel compounds, and their synthesis based on the foregoing discovery is described in more detail in Hungarian Patent Application Serial No. 2331/82. For the sake of greater clarity, the novel intermediates which may be prepared according to the invention, and the novel intermediates that may be directly derived therefrom, are expressly designated as such. Depending on the different meanings of Y, the intermediates obtained by the process of the present invention are referred to as the dihalone steroid derivatives of formula (Ia) and (Ic), respectively. s. According to the process of the Hungarian patent application, the monohalogen intermediate of formula (Ia) may be referred to as the compound of formula (Ib) and the monohalogen intermediate of formula (Ic) as compounds of formula (Id).

The present invention therefore relates to a process for the preparation of new 21,21-dihalo-17? -Alkanoyloxy steroid derivatives of the formula (I) which include, inter alia, 21,21-iodo-17-hydroxy-pregna-1,4-diene-3 , 20-dione-17-acetate, a

21,21-dibromo-17α-hydroxypregn-4-ene-3,20-dione 17-acetate, etc.

The process according to the invention may be carried out in different ways, in which Y is a diiodomethyl or dibromomethyl group in the general formula (I).

(a) Procedure

The diiodo steroid derivatives of formula Ia of formula I can be prepared as shown in Scheme A, wherein the dashed line and A are as defined in the various formulas.

According to the present invention, the target product of formula (Ia) is prepared by reacting a 17? -Ethynyl-17? -Alkanoyloxy steroid derivative of formula (II) with an iodine reagent capable of releasing a positive iodine ion.

The starting material of formula (II) may be e.g. 17 β-ethynyl-17α-hydroxy-androst-1,4-diene-3-one-17-acetate, 17 β-ethynyl-17α-hydroxy-andros-4-ene-3-one17-acetate, etc., which are starting materials e.g. respectively, 21,21 -dodd-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, 21,21-diiodo-17α-hydroxypregn-4-ene-3,20-dione- 17-acetate etc. obtained by reacting the starting material with a positive source of iodine, which may be a

189,460 iodinating reagents for liberating iodine ions, e.g. N-iodosuccinimide, N-iodoacetamide, etc., or the positive iodine ion already present in the reaction medium, formed by oxidation of iodine in the reaction medium with persaw, e.g. peracetic acid or metal ions with oxidation potential, e.g. with metal ions of copper acetate.

Thus, the iodinating reagent for releasing positive iodine ions may be, for example, an N-iodoimide or an N-iodoamide, e.g. the already. said N-iodosuccinimide, N-iodoacetamide or the like.

The iodine ion required for the desired reaction can also be liberated in the reaction system itself by reacting elemental iodine with one of a variety of oxidizing agents. In the latter case, the oxidizing agent may be, for example, a peracid, e.g. peracetic acid, perbenzoic acid, etc .; a hydroperoxide, e.g. hydrogen peroxide, t-butyl hydrogen peroxide, etc .; salts of metal ions with oxidation potential, e.g. silver nitrate, copper nitrate, copper acetate, etc. It is most preferred to use peracid as an oxidizing reagent because it is cheap, readily available on an industrial scale and has good reactivity. The amount of iodinating reagent should be at least twice, preferably 2.05 to 2.5 times, the equivalent of the acetylene compound used.

The reaction mixture may be used in any solvent conventionally used in the industry, but methyl ketones, e.g. acetone, methyl ethyl ketone, etc. which may also react with iodinating reagents. A preferred solvent is an aliphatic acid, e.g. acetic acid, propionic acid and the like.

In the reaction process, water is generally allowed to be present along with the solvent (s). If no water is present, water is added to the reaction mixture after completion of the reaction to hydrolyze the reaction product to give the desired diiodetone. The water is generally employed in an amount equimolar to the acetylene compound, and is preferably 5-20% of the amount of solvent used.

The alkanoyloxy steroid derivatives of formula (II) used as starting materials in the process of the present invention can be prepared by reacting the corresponding 17β-ethynyl-17α-hydroxy steroid derivative of formula (III) - the dashed line with a carboxylic acid anhydride if desired.

There are several variants of this production.

In one embodiment, it is of formula (III)

1.7 a β-ethynyl-17α-hydroxy steroid derivative with a carboxylic anhydride, e.g. acetic anhydride, by reacting an aromatic amine, e.g. pyridine is used. In this case, the acid anhydride is used in an amount at least equimolar to the steroid derivative, preferably in an amount greater than 5 times the equimolar amount. The reaction temperature is 80 to 150 ° C, preferably 100 to 135 ° C.

Alternatively, the steroid derivative of formula (III) is reacted with the carboxylic anhydride using acetic acid or the like as a solvent. In this case, the catalyst is preferably an acidic compound or a Lewis acid, e.g. p-toluenesulfonic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, zinc chloride, ferric chloride and the like. apply. The reaction temperature is usually 0 to 50 ° C.

Process b) 'θ The diiodo steroid derivatives represented by the general formula (I), the dotted line and A being as defined above, include e.g. 21,21-dibromo-17α-hydroxypregn-4-ene-3,20-dione 17-acetate, 21,21-dibromo-17α-hydro ¹⁵ xi-pregn-4-ene-3,20-dione- 17-propionate, 21,21-dibromo-17a-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, and the like.

Compounds of formula (Ic) may be prepared by reacting a compound of formula (II) - the ² θ dashed line and Aa - with the previously described 17 β-ethynyl-17α-alkanoyloxy steroid compound capable of releasing positive bromine ions. .

In doing so, the halogenating reagent can be applied to the ²⁵ N-bromo and N-bromo imides, amides, eg. N-bromosuccinimide, N-dibromo-dimethylhydantoin, N-dibromobenzenesulfonamide, N-bromoacetamide and the like. The molar amount of the halogenating reagent should be at least twice that of the 17? -Ethynyl-17? -Acyloxy steroid derivative, preferably 2.1 to 3 times. sa. The solvent used in the reaction medium is usually a mixture of solvents which is water and aliphatic carboxylic acid (s), e.g. acetic acid, propionic acid, butyric acid, etc. form (s). The reaction temperature is -5 to 60 ° C, preferably 0 to 30 ° C. To neutralize the resulting hydrobromic acid, the reaction medium has an alkali metal salt of a carboxylic acid, e.g. sodium acetate, potassium propionate, etc. It can be given.

The dihaloalkanoyloxysteroid derivatives of formula (I) obtained by Method a) or Process b) above can then be converted into pharmaceutically active corticosteroids, e.g. prednisolone, hydrocortisone. The next 45 steps of the conversion are the reduction of the corresponding compounds of formula (I) at the 21-position to give the corresponding 21-monohalo-17α-alkanoyloxy steroid. This procedure, which is the next step in the multi-step synthesis, is described in detail in the aforementioned Hungarian Patent Application No. 50 2331/82. No. 2331/82. s. In process (a) of the Hungarian patent application, the corresponding diiodoalkanoyloxy steroid derivative of formula (Ia) is contacted with a hydrogen-containing organic solvent or reduced with a dithionite compound; in process b), the corresponding dibromoalkanoyloxy steroid derivative of formula Ic is reacted with a phosphite compound, the dashed line and gQ A being as defined above.

It has already been mentioned that the preparation of the intermediates thus obtained is not within the scope of the present invention, but for the sake of better traceability of the synthesis, it is also stated in their nom

And derivatives derived from further conversions of compounds of Formula -3, 18.9,460. The intermediates of formula (Ib) or (Id) are the starting materials for the additional syntheses described below:

Claims 1. A steroid derivative of formula (IV) represents the optional double bond, while A and A 'represent an alkanoyloxy group, respectively, and may be prepared from an alkanoyloxy steroid derivative of formula (Ib) or (Id).

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, e.g. tetramethylammonium acetate, tetramethylammonium propionate, tetraethylammonium acetate trimethylbenzylammonium 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 the formulas Ib or Id, preferably 1.05 to 1.6 times the equimolar amount. Generally, the alkanoyloxy steroid of formula (Ib) and (Id) is reacted in a solvent with the quaternary ammonium salt. An aprotic solvent is preferably used, e.g. DMF, N-methylpyrrolidone, dimethylacetamide and the like.

The reaction temperature is -10 to 80 ° C, preferably 0 to 40 ° 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.

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 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 and the like. 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 a by-product is formed of a steroid derivative which also has a double bond at the 16-position but does not have an acyloxy substituent at position 17, e.g. 21-acetoxy-pregna-4,16-diene-3,20-dione, 21-acetoxy-pregna-1,4,16-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-21-acyloxy steroid derivatives of the general formula (IV) being converted into the by-products mentioned above. Generally, the reaction is stopped when the conversion of the starting material has reached 80 to 97%, preferably 85 to 95%. The use of N-methylpyrrolidone or dimethylacetamide as a solvent has been found to be particularly advantageous because of the outstanding yield and reduction of by-product formation.

Also suitable as the solvent for the process is a polyethylene glycol having a molecular weight of 200 to 1500, preferably 300 to 600, e.g. polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol dimethyl 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 and the like. Although the steroid derivatives are insoluble in these polyethylene glycols, they can be used if mixed with a suitable solvent for 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, alkali metal salts of up to 10 carbon atoms, e.g. sodium formate, potassium formate, sodium acetate, 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 in (b).

Crown ethers may be macrocyclic compounds, e.g. 18-crown-6, dibenzo-18-crown-6, dicyclohexyl-18-crown-6, cyclohexyl-12-crown-4, dibenzo-14-crown-4, tetrabenzo-24-crown-8, and so on. The appropriate crown ether is selected depending on the alkali metal salt used: 18-crown6, e.g. it is preferred 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 amount of 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 and the like.

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

2. The widely used gestagenic hormone, 17? -Hydroxy progesterone, can be prepared from a starting material of an alkanoyloxy steroid of formula (Ia) or (1b).

When a iodo-17α-alkanoyloxy steroid derivative of the formula (Ia) or (Ib) is contacted with a methyl ketone, a progesterone-type compound of the formula (V), wherein dashed lines and A are as defined above, can be obtained.

Useful methyl ketones for this purpose include acetone, methyl ethyl ketone, acetophenone, etc .; the most preferred of these being acetone. Such methyl ketones are usually used in amounts sufficient for use as a solvent, and are preferably used as a solvent.

To carry out this procedure, the iodoalkanoyloxy steroid of formula (Ia) or (Ib), 41,189,460, e.g. dissolved in a suitably selected methyl ketone, e.g. acetone and shake for a fixed period. If the starting material is a diiodoalkanoyloxy steroid derivative of formula (Ia), e.g. 21,21-diiodo-17α-hydroxypregn-4-ene-3,20-dione 17-acetate, first of which is the corresponding monoiodoalkanoyloxy steroid derivative, e.g. 21-iodo-17? -Hydroxy-pregn-4-ene-3,20-dione-17-acetate is formed, followed by further shaking to form 17? -Hydroxy-pregn-4-ene-3,20-dione-17-acetate.

In this process, the concomitant presence of acidic compounds can accelerate the reaction while increasing progesterone production.

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 a salt thereof is used in an equimolar amount with the iodine steroid derivative. 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. Examples 1 and 2 illustrate the preparation of the target compound of formula (I), Examples 3, 10, 11 and 12, while the other examples illustrate the further conversion of the target product to the corresponding pharmaceutically active corticosteroid hormones. for synthesis.

Example 1

Preparation of 17β-βΙϊηϊ1-17α-hydroxyandrost-1,4-dien-3-one (A) Preparation of the starting material, 17α-ethynyl-17β-nitrooxyandrost-1,4-diene-3-one

To 8.0 g of 17a-ethynyl-17? -Hydroxyandrostta-1,4-dien-3-one is added 64 ml of acetic anhydride, then the mixture is cooled to -20 ° C, then 6.4 ml of fuming nitric acid is added dropwise and the resulting mixture was shaken at -20 ° C for 1 hour. The reaction product is poured into 500 g of ice water and shaken. The resulting crystals were filtered off and dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried and liquefied to give 8.97 g

17a-Ethynyl-17'-nitrooxy-androsta-1,4-dien-3-one is obtained. This product can be used without further purification as starting material for the next hydrolysis step.

(B) Hydrolysis. To 25.0 g of 17α-ethynyl-17β-nitrooxyandrosta-1,4-dien-3-one is added 170 ml of THF, 30 ml of water and 2.0 g of copper (I) chloride, and the mixture is stirred under nitrogen, Shake at 65 ° C for 1.5 hours.

After completion of the reaction, benzene (200 mL) and saturated brine (200 mL) were added to the reaction mixture and the reaction product was extracted. The organic layer was separated, washed twice with brine and dried over anhydrous sodium sulfate.

The solvent was distilled off and 250 ml of dichloromethane and 250 ml of n-hexane were added to the resulting crystals; recrystallization yields 12.69 g of 17β-εΙϊηϊ117α-hydroxyandrosta-1,4-dien-3-one.

The crystals thus obtained were recrystallized first from a mixture of benzene and THF and then from ethyl acetate to give pure 17? -Ethynyl-17? -Hydroxyandrostal-1,4-dien-3-one, m.p. 228-219 ° C.

Specific rotation [α] 20 D = + 90.9 ° 1.02, THF).

MS; 310 (M ⁺⁾ Nuclear Magnetic Resonance Spectrum [(CD _3/2 SO]:

H in the 18-methyl group H in the 19-methyl group H in the ethynyl group (C:

δθ, 91 ppm (3H, s) δ 1.21 ppm (3H, s) δ2.43 ppm (1H, s).

Example 2 Preparation of β-ethynyl-17α-hydroxyandrost-1,4-diene-3-one17-acetate

To 12.0 g of 17? -Ethynyl-17? -Hydroxyandrostta-1,4-dien-3-one was added 50 ml of addine and 50 ml of acetic anhydride, and the reaction mixture was heated at reflux for ⁵ hours. The reaction product is poured into ice water, and the tar product is extracted with dichloromethane. The organic layer was washed first with 5% aqueous hydrochloric acid and then with 5% aqueous sodium bicarbonate. The organic ³⁰ phase was dried over anhydrous sodium sulfate and evaporated. The distillate is chromatographed on a column containing 250 g of alumina using 500 ml of solution as eluent containing 9 benzene and ethyl acetate: 1 mixture to give 12.3 g of crystals ³⁵ would wedge is obtained which is recrystallized first octane THF, 20: 1 mixture, then heptane: ethanol (5: 1) and finally octane: THF (30: 7). 8.1 g of pure ß-β-β-hydroxyandrost-1,4-diene-3-one-17-acetate ^{40 are} obtained, m.p. 171.8-172.6 ° C (increase in temperature: 1 ° C / min). .

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm:

1.00 (s, 3H); 1.26 (s, 3H); 2.02 (s, 3H); 2.56 (s, 1H); 6.04 (s, 1H); 6.15 (q, 1H); 6.98 (d, 1H).

Example 3

To a mixture of acetic acid (5 x 162 ml) and water (18 ml) was added 4.08 g of elemental iodine and 5.71 g of N-ethynyl-17α-hydroxyandrosta-1,4-diene-3-one-17-acetate and the mixture was shaken at room temperature. A mixture of 2.6 ml of 40% peracetic acid solution in water (55 ml), acetic acid (45 ml) and water (5 ml) was added dropwise with shaking and the shaking was continued for a further 2.5 hours.

Addition of 1500 ml of water gives a crystalline precipitate, which is filtered, washed with water θθ and dried to give 9.61 g of 21,21-diiodo-17ahydroxy-pregna-1,4-diene-3,20-dione-17 (1). -acetate.

Nuclear Magnetic Resonance Spectrum (CDCl 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).

189,460

Example 4

To 1.04 g of 21,21-diiodo-17α-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 reaction mixture is added. shake at room temperature (25 ° C) for 2 hours.

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 product.

Analysis by liquid chromatography showed the crystalline product to be 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate (95%) in 95.3% purity.

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 (CDCl ₃ ) δ ppm:

0.79 (s, 3H); 1.26 (s, 3H); 2.14 (s, 3H); 3.93 (d, 2H); 6.12 (s, 1H); 6.25 (q, 1H); 7.09 (d, 1H).

Example 5

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 for 4 hours at 28 ° C. The resulting reaction product was extracted with methylene chloride and analyzed by liquid chromatography. It is found that 83.5% yield of 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate, and 11.4% of 17? -Hydroxy-pregna, 4-diene. -3,20-dione-17-acetate is a by-product.

Example 6

Example 5 was repeated except that 4.0 mL of triethylamine was used as solvent instead of acetone; 21-iodo-17-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate (yield: 40.7%).

Example 7

Example 5 was repeated except that 4.0 mL of THF was used as solvent instead of acetone. The product was 21.5-iodo-17α-hydroxypregna-1,4-diene-3,20-dione-17-acetate (33.5%).

Example 8

To 1.00 g of 21,21-diiodo-17α-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 at 28 ° C for 10 minutes. shake. After further treatment according to Example 4, analysis according to Example 4 shows 87.8% yield of 21-iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-. acetate and 12.2% of the by-product, 17? -hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Example 9

Example 8 except that 4.2 ml of triethylamine was used instead of sodium hydroxide and the mixture was shaken for 30 minutes; 21 iodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate was obtained in 98.5% yield.

Example 10

To a mixture of 2.016 g of 17β-ethynyl-17α-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 are 0.93 ml of 40% A solution of peracetic acid, 19.5 ml of acetic acid and 2.2 ml of water was added and the reaction mixture was shaken at room temperature for 2.5 hours.

Part of the resulting 21,21-diiodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate precipitates as crystals. Then drop by drop while shaking

6.1 ml of an aqueous solution containing 4.25% by weight of sodium hydrogen sulphite. Shake for 3 hours after the addition is complete.

The reaction mixture was poured into water and extracted 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 to be 91.5 mol% of 21-iodo-17-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate and

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

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

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm:

0.79 (s, 3H); 1.26 (s, 3H); 2.14 (s, 3H); 3.93 (d, 2H); 6.12 (s, 1H); 6.25 (q, 1H); 7.09 (d, 1H):

Example 11

A mixture of 7.86 g of 17? -Ethynyl-17? -Hydroxyandrosta-1,4-dien-3-one-17-acetate, 130 ml of acetic acid, 13 ml of water and 7.35 g of sodium acetate is cooled to 0 ° C. 6.43 g of N-bromoacetamide are added in small portions and the system is shaken for 1 hour. The reaction product was poured into 3 L of ice water, and the resulting crystals were filtered off and dried, yielding 11.58 g of 21,21-dibromo-17a-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm:

0.98 (s, 3H); 1.25 (s, 3H); 2.08 (s, 3H); 6.01 (s, 1H); 6.04 (s, 1H); 6.20 (q, 1H); 7.02 (d, 1H).

Mass spectrum m / e: 528

Example 12

A mixture of 100 ml of acetic acid, 10 ml of water and 2 g of sodium acetate is cooled to 0 ° C and then 2.0 g is added.

17.beta.-ethynyl-17-hydroxy-androst-4-ene-3-one 17acetátot.

189,460

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-hydroxypregn-4-3,20-dione-17-acetate, NMR. spectra (CDCl ₃ ) δ ppm;

0.88 (s, 3H); 1.26 (s, 3H); 2.10 (s, 3H); 5.68 (s, 1H).

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

Example 13

To 1.34 g of 21,21-dibromo-17? -Hydroxy-pregna-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 for 50 minutes. shake. The reaction solution was diluted with ether and washed with water until the aqueous phase was neutralized.

The ether layer was dried and evaporated and the solvent was distilled off under reduced pressure to give 1.117 g of crystalline product. Recrystallization from a mixture of octane and THF gives 0.827 g of 21-bromo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm:

0.8 (s, 3H); 1.28 (s, 3H); 2.10 (s, 3H); 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 Found: C, H (%): 61.47 6.50

O Br 14.25 17.18 14.03 17.18

61.59 6.61 Found (%):

Example 14

To 2.03 g of 21,21-dibromo-17? -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 shaken for 80 minutes at room temperature.

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 75

To 2.0 g of 21,21-dibromo-17? -Hydroxypregn-4-ene, 3,20-dione 17-acetate is added 20 ml of acetic acid and 2.2 ml of trimethyl phosphite and the mixture is shaken at room temperature for 70 minutes.

With 200 ml of water was added to the reaction solution, the resulting crystals were filtered off and dried, yielding 1.63 g 21bróm-17-hydroxy-pregn-4-ene-3,20-dione acetate, whose NMR spectrum (CDC1 ₃₎ δ ppm :

_c 0.78 (s, 3H); 1.24 (s, 3H); 2.08 (s, 3H); 3.98 (d, ⁵ 2H); 5.60 (s, 1H).

Example 16

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 is added 6.0 ml of N-methylpyrrolidone and the mixture is shaken at 21 ° C. 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 was recrystallized from 16 ml of ethanol to give 1.21 g of 17x, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate. we get.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 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 17

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 was 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 ³⁵ 1,4-diene-3,20-dione-17,21-diacetate.

Example 18 ⁴⁰ 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 were 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-17,21-diacetate (3.29 g). Liquid chromatography showed a purity of 70.13%.

Example 79

1.86 g of 17α-hydroxy-21-iodo-pregna-1,4-diene-3,2055 dione 17-acetate, 2.00 g of potassium acetate, 1.952 g of 18-crown-6 and 20 ml of N-methyl The pyrrolidone mixture was shaken at 20 ° C for 4 hours. The reaction solution was poured into water (200 mL) and the resulting crystals were filtered off and dried, yielding 1.33 g of crude 17a, 21-dihydroxy60 pregna-1,4-diene-3,20-dione-17,21-diacetate. Liquid chromatography showed a purity of 90% (yield: 74.5 mol%). Recrystallization from ethanol gives pure 17a, 21-dihydroxypregna-1,4-diene-3,20-dione-17,21-diacetate.

189,460

Example 20

To 1.0 g of 21,21-diiodo-17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is added 15 ml of acetone and the mixture is shaken at 28 ° C for 4 hours. 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 crystalline mixture was 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate and 11.4% 17? -Hydroxy-pregna-1,4-. diene-3,20-dione-17-acetate.

If the reaction is continued for 21 hours, 46.0% of the resulting mixture is 21-iodo-17a-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate and 48.3% of 17a-hydroxy-pregna-1. , 4-diene-3,20-dione 17-acetate. Reaction over 50 hours gives 17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate in 80% yield.

Example 21

To 1.0 g of 21-iodo-17? -Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate is added 20 ml of acetone and 0.80 g of pyridine p-toluenesulfonate, followed by 2.5 reflux for one hour. 17a-Hydroxy-pregna-1,4-diene-3,20-dione-17-acetate was obtained in 98% yield. The post-treatment was carried out as in Example 20 to give white crystals. Recrystallization from a mixture of heptane and steel gives 17α-hydroxy-pregna-1,4-diene-3,20-dione-17-acetate.

Nuclear Magnetic Resonance Spectrum (CDCl 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 (4)

Claims 1. A method (I) 21,21-dihalo-17-alkanoyloxy-steroid derivatives Preparation of Formula ⁰ sachet, wherein the dotted line represents an optional double bond wherein Y represents a diiodomethyl group or a dibromomethyl group and A is 1- A C4 alkanoyloxy group characterized in that ⁵ a) for the preparation of a target product wherein the dashed line and A are as defined above and Y is diiodomethyl, a 17β-εΐίηί1-17α of formula II reacting the alkanoyloxy steroid derivative, dashed ²⁰ and A, as defined herein, with a iodine reagent capable of releasing a positive iodine ion; obsession b) for the preparation of a target product wherein the dashed line and A are as defined in the preamble and Y is dibromomethyl, a 17β-ethynyl-17a-alkanoyloxy steroid derivative of the formula (II) - the dashed line and A meaning given in the scope - to release a positive bromine ion 3 ° C halogenating reagent. Process (a) according to claim 1, characterized in that the iodinating reagent is an N-iodoimide or an N-iodoamide. Process (a) according to claim 1, characterized in that the oxidizing agent and elemental iodine are used as iodinating agents. Process b) according to claim 1, characterized in that the halogenating agent is selected from the group consisting of N-bromimide and N-bromamide. 3 page drawing