CS271482B2 - Method of 11-beta, 21-dihydroxy-16-alpha, 17-butylidenbis oxypregna-1,4-diene-3,20-dione production - Google Patents

Abstract

The solution concerns the method of production of 11 beta, 21-dihydroxy-16 alpha, 17-butyliden bis (oxy)-1.4-diene-3.20-dione with a ratio of isomers 22R/S equal to 1:1 that is characteristic by the fact that the methyl ester of acid of 11 beta,16 alpha, 17-trihydroxy-21-acetoxypregn-4-ene-3.20-dione-16,17 cyclo-orthoformic is let to react with butyraldehyde in the presence of an acid catalyst or in the presence of an agent binding water in a polar aprotic dissolvent and the acquired 21-acetoxyderivate is saponified in the usual manner.

Description

This invention relates to a novel process for the preparation of 11 (b, 21-dihydroxy-16, 17-butylldenbieuxypregna-1,4-diene-3,20-dione 8 with a ratio of 22R / S isomers of 1: 1.

Biological investigations have shown in the mid-1950s (□ · Am. Chem. Soc., 78, 1909 (1956)) that 16ώ-hydroxycorticoids have a similar or better anti-inflammatory effect to natural adrenal cortex hormones, such as hydrocortisone, with little the harmful effect promoted by sodium, which affects the management of the organism with salts, may remain virtually out of focus (3, Am. Chem. Soc., 81, 1689 (1959)).

Corticosteroid-16,17-cycloaldehyde acetals made from 164-hydroxycorticoids have an anti-inflammatory effect that outperforms the parent molecule (U.S. Pat. No. 3,197,468, 3rd Am. Chem. Soc., 80, 2338 (1958)). Among these derivatives are those useful in therapy, such as [22RS] -11 [beta], 21-dihydroxy-16 <, 17-butylidenebisoxypregna-1,4-dlene-3,20-dione (hereinafter referred to as budesonide) . The active ingredient useful in therapy is a mixture of isomers that contains the 22R- and 22S-isomers in approximately 50 and 50% (Arzneim. Forsch., 29 (11), 1687-1690 (1979)). A mixture of isomers is being prepared in the pharmaceutical industry, while the necessary assays have been performed on these isomers.

The subsequent change in a given ratio of isomers is associated with a significant loss of substance, therefore, it is necessary to develop a synthesis that provides the end product with the desired ratio of isomers.

The steroid 16,17-cykloaldehyd- _r or ketone acetal (ketal) can be prepared by reacting the corresponding 16,17-derivatives dihydroxykortikoidů with an aldehyde or ketone in the presence of acidic catalysts (DE Pat. No. 1,131,213, 0E Offenlegungsschrift no. 1118 779, GB Patent Specification Nos. 916,996 and 933,867, US Patent Nos. 3,197,469 and 3,798,216 and HU Patent Specification 166,680).

According to scientific literature, budesonide can be prepared from readily available 16? -Hydroxyhydrocortisone as follows:

1. As a first step, a double bond is formed at the 1,2 position according to U.S. Pat. No. 3,037,914 by microbial oxidation. The yield of the reaction is 10 vol. Budenozide is obtained from the resulting 16,6-hydroxyprednisolone according to the above-mentioned method from Arzneim. Forsch. by reaction with butyraldehyde under acid catalysis. From the last stage he gets raw. budesonide in very good yield (94.4%). From this product a pure 1: 1 isomer mixture is obtained by column chromatography (yield 83.8 4). The total yield of the synthesis is 0.1 x 0.944 x 0.838 = 0.079, i.e. almost 84. It may be obvious that the synthesis is not economically feasible due to the low overall yield.

2. As the first step, the hydroxy group at position 21 is protected by acetylation. The 21-acetoxy derivative obtained is converted by reaction with butyraldehyde, for example according to Example 4, to the 16α, 17-butylidenebisoxy derivative. A bond in the position can be formed in this derivative

1,2 by dehydrogenation according to, for example, Example 5 and hydrolysis, the 21-acetoxy group can be cleaved off. In the first step, acetylation can be carried out with a yield of nearly 100%. The crystal formation (Example 4) yields a ketal intermediate with an epimer ratio of 70:30 and yield

57.59%, and acetylated budesonide having an epimer ratio of 04; 16 and a yield of 60.25 This compound was saponified according to Example 2 to budesonide with an epimer ratio that remained unchanged and a yield of 90.25%. The overall yield of the synthesis is

It may be appreciated that this synthesis is also not suitable for industrial use, since the following epimer separation is to be carried out to produce a product with an epimer ratio of 1: 1.

3. Another possibility is to directly convert 16 &apos; -hydroxyhydrocortisone according to, for example, Arzneim. Forsch. to a 16 * 6,17-butylidene bis-oxy derivative which dehydrogenates to form a double bond at the 1,2-position. According to the literature, however, ketal formation is effected by conversion of approximately 70%. By changing the reaction conditions of Example 6, the epimer ratio can be changed to 71: 29. The yield here is 78.7%. A second double bond may be formed in this product according to Example 7, but the budesonide obtained has a very poor ratio

CS 271482 ep2 epimers 87: 14, besides yield 58.97 The total yield is 46.4%. To produce the final product with a 1: 1 epimer ratio, epimer separation is to be performed.

The present inventors have discovered that budesonide with a 1: 1 epimer ratio is obtainable in good yield by a synthesis described below suitable for industrial use:

The first step is acetylated in the usual manner by the 16o-hydroxyhydrocortisone at the 21-position. The acetoxy derivative is converted by treatment with trimethyl orthoformate to the 16,17-cyclo-orthoformate in which the cyclic orthoformate forms a double bond at the 1,2-position. The prednisolone derivative obtained is reacted with butyraldehyde and the budesonide-2-acetate obtained is hydrolyzed.

The invention is based on the discovery that the ketal obtained by reaction of 16,17-cycloorthoformate with butyraldehyde contains the 22R- and 22S-epimers in a ratio of 1: 1, which is needed in the pharmaceutical industry. A good epimer ratio is not affected by subsequent acetylation. The most important step of the reaction according to the invention is the reaction of the cyclic orthoester with butyraldehyde. Budesonide with an epimer ratio of 1: 1 and a yield of 52% can be prepared by the synthesis of the above reaction according to the invention.

The process according to the invention is carried out by reacting 11β, 16 ¢ 6,17-trihydroxy-21-аso-oxypregna-1,4-diene-3,20-dione-16,17-cyclohexyl methyl ester with butycaldehyde in the presence of acidic acids. catalysts and optionally in the presence of a water-binding agent in a polar aprotic solvent and the 21-acetoxy derivative obtained is saponified in a conventional manner.

In the reaction of the cyclic orthoformic ester in the cyclic aldehyde acetals of this invention, the acetyl group of the 21-hydroxy group remains and does not damage the D-ring, wherein the R- and S-isomers are formed at the 22-position in a 1: 1 ratio.

As the acid catalyst, acids such as perchloric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, pyridintosilate, lutidintosilate, collidine tosilate or sulfuric acid, preferably perchloric acid, methanesulfonic acid or pyridintosylate, can be used. Preferably, 0.1 to 2 parts by mole are used per part by mole of 11, 6, 17, 6,17-trihydroxy-21-acetoxypregna-1,4-diene-3,20-dione-16,17-cycloortomethylformate. They are preferably used in equimolar amounts.

In order to avoid undesired side reactions, an aqueous acid is used as an acid catalyst in the presence of a water-binding agent. Acetic anhydride or phosphorus pentoxide is preferably used as such a water-binding agent.

Tetrahydrofuran, dioxane or dimethylformamide may be used as the polar aprotic solvent. However, a corresponding excess of butyraldehyde may also serve as the solvent.

When butyraldehyde is used as solvent, 1.5 to 10 parts by weight of butyraldehyde per part by weight of the mercuric acid ester are used. It is particularly preferred to use a 3 to 5-fold excess of aldehyde.

The process according to the invention is carried out at a temperature of from 0 to 100 ° C, preferably at 20 to 40 ° C, in particular at 30 ° C.

The progress of the reaction can be controlled by thin layer chromatography. To isolate the final product, the reaction mixture is poured on a 100 to 200-fold amount of water, calculated on the orthoformic acid ester used as starting material, and the water may contain a slight excess of base relative to the equivalent amount of catalyst.

Bases which may be mentioned are sodium hydrogen carbonate and potassium hydrogen carbonate.

The final product is filtered off, extracted with a water-miscible solvent such as methylene chloride, chloroform or ethyl acetate and purified in the usual manner.

CS 271482 82

The 21-acetoxy derivative obtained is saponified in the next step after its isolation or without carrying out the isolation. The ratio of isomers in the final product does not affect the subsequent saponification.

The invention is illustrated in more detail by the following examples, without the scope of protection being limited to these examples.

Example 1

Method for the preparation of [22RS] -21-acetoxy-11/2) -hydroxy-16α, 17-butylidenebisoxypregna-1,4-diene-3,20-dione

100 ml of stabilized peroxide-free tetrahydrofuran were mixed with 2.0 ml (0.021 mol) of a 70% aqueous solution of perchloric acid, and 5.7 ml (0.06 mol) of acetic anhydride was added dropwise with stirring and cooling. The solution was stirred at room temperature for 15 minutes and then 1.8 ml (0.02 mol) of distilled butyraldshyde was added under nitrogen. 4.63 g (0.01 mol) of 11β, 16β, 17-trihydroxy-21-acetoxypregna-1,4-diene-3,20-dione-16,17-cycloortomethyl ethyl formate are added in small portions, The reaction mixture was stirred for 9 hours and excess solvent was distilled off under reduced pressure. The oily residue was dissolved in ethyl acetate, extracted with 5% aqueous sodium bicarbonate solution and evaporated. Recrystallization from ether / diisopropyl ether gave the title compound (4.40 g, 93.11%). Its melting point is 168-171 ° C.

Purity (TLC): 97.1%. Spimer ratio: 53: 47.

Example 2

Method for producing [22RS] -11β, 16 fa, 17,21-tetrahydroxy-16o6, 17-butylidenebisoxypregna-1,4-diene-3,20-dione

4.4 g of [22RS] -21-0CStoxy-11H-hydroxy-16,10,17-butylidenbleoxypregno-1,4-diene-3,20-dione, prepared according to Example 1, are dissolved in 66 g of nitrogen under nitrogen. ml of methanol, 4.40 ml of a 70% aqueous solution of perchloric acid is added and the mixture is left to stand for 6 hours. The reaction mixture is poured onto 880 mL of water, stirred for one hour and filtered. 3.98 g of the crude title compound obtained are dissolved in methylene chloride and the solution is added dropwise to n-hexane with stirring. The precipitated purified product was recrystallized from anhydrous ethanol. Thus, 3.62 g (90.25%) of the pure title compound are obtained, m.p. 239-242 ° C.

[Α] D ^{= = 8} ° (c = 1%, methylene chloride).

Epimer ratio: 51.55: 48.45.

Purity: 98.2%.

Example 3

Production method [22RS] -11/5, 16, 17,21-tetrahydroxy-16,17-butylidenebisoxypregna-1,4-diene-3,20-dione

The procedure was analogous to Example 1 except that instead of being recrystallized, the residue containing the final product was dissolved in 66 ml of methanol under nitrogen at room temperature, mixed with 4.40 ml of a 70% aqueous solution of perchloric acid and left to stand for 8 hours. The reaction mixture was poured onto 880 mL of water, stirred for one hour, and filtered. The crude title compound obtained was dissolved in methylene chloride and added dropwise to n-hexane with stirring. The precipitated purified product was recrystallized from anhydrous ethanol. Thus, 3.68 g (91.74%) of the pure title compound are obtained, m.p. 239-242 ° C.

= 99.8 ⁰ (c = 1%, methylene chloride).

Epimer ratio; 51.55: 48.45,

Purity: 98.2%.

Example 4

Production method [22RS] -11/3, 16, 17,21-tetrahydroxy-16,17-octylidenebisoxypregn-4en-3,20-dione-21-acetate ml acetonitrile, 2.0 ml 70% aqueous perchloric acid and 1 21 ml of distilled butyraldehyde are stirred under a nitrogen atmosphere at room temperature. After stirring for 20 minutes, 4.0 g of 16O-hydroxyhydrocortisone-21-acetate is added in small portions over 30 minutes. The reaction was complete in 30 minutes. The reaction mixture was mixed with 50 ml of 5% aqueous potassium bicarbonate solution under nitrogen, extracted with ethyl acetate, washed with water until neutral, dried over sodium sulfate and the solvent was distilled off under reduced pressure. After recrystallization of the oil obtained (epimer ratio: 65:35) first from methanol and then from ether, 2.6 g (57.59%) of the pure title compound obtained in the title β were obtained with an epimer ratio of 70 and 30, respectively.

Example 5

Production method [22RS] -11/3, 16 ¢ 6,17,21-tetrahydroxy-16o6,17-butylidenebisoxypregna-1,4-diene-3,20-dione-21-acetate ml of benzene is mixed with 1.0 g (0.0021 mol) [22 R] -11 / 3.16 »6,17,21-tetrahydroxy-16,17-butylidene-blsoxypregn-4-ene-3,20-dione-21-azoate, 0.64 g benzoic acid and 0.72 g

2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature. The reaction mixture was refluxed for 24 hours, after cooling, washed with water and 5% aqueous sodium hydroxide solution and made neutral with water. After evaporation, the oily residue was recrystallized from methylene chloride / n-hexane (1: 5) to give 0.60 g (60.26%) of the title compound which contained epimers of 84-116.

Purity: 96%.

Example 6

Production method of [22RS] -11/3, 16ώ, 17,21-tetrahydroxy-16 ', 17-butylidenebisoxypregn-4-ene3,20-dione.

46 ml of acetonitrile, 1.21 ml (2.4 molar equivalents) of 70% perchloric acid aqueous solution and 0.69 ml (1.4 molar equivalent) of distilled butyraldehyde are mixed under nitrogen at room temperature. After stirring for 20 minutes, 2.0 g (0.0053 mol) of 16-hydroxyhydrocortisone was added in small portions over 30 minutes. The reaction proceeds within 1.5 hours. The reaction mixture was mixed with 20 ml of 5% aqueous potassium bicarbonate solution under nitrogen, extracted with ethyl acetate, washed with water until neutral, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The oil obtained (2.2 g) with an epimer ratio of 75:25 is recrystallized from ether. This gave 1.8 g (78.7%) of the pure title compound with an epimer ratio of 70.7: 29.3. Its melting point is 191-198 ° C.

Example 7

Method for the preparation of [22Rs] -111 / S, 16,17,21-tetrahydroxy-16,17-butylidenebisoxypregna-1,4-diene-3,20-dione ml benzene was mixed with 0.92 g (0.0021 mol). ) [22Rs] -11/3, 16> 6, 17,21-tetrahydroxy-16e6,17-butylidenebisoxypregn-4-ene-3,20-dione (compound of Example 6 with an epimer ratio of 70.7: 29.3) 0.64 g of benzoic acid and 0.72 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature. The reaction mixture was refluxed for 27 hours, after cooling, washed with water, 5% aqueous sodium hydroxide solution and again with water. After evaporation, the oily residue was recrystallized from a 1: 5 mixture of mythylene chloride and n-hexane to give 0.54 g (58.97%) of the title compound, with an epimer ratio of 86.5: 13.5. Mp .: 240-243 ° C (dec.).

Purity: 94.2%.

CS 271042 B2

Example 8

Process for the preparation of 11 / b, 16 b, 17-trihydroxy-21-acetoxypregn-4-ene-3,20-dione-16,17-cycloortomethylformmiate g (0.0119 mol) of 16β-hydroxyhydrocortisone-21-acetate and 1, 3 g (0.00582 mol) of pyridine tosylate are dissolved in 75 ml of dimethylformamide (0.05% water content, determined by Karl Fischer) with stirring under a nitrogen atmosphere at room temperature. To this is added

5.3 ml of trimethyl orthoformate and the solution was stirred for 1.5 hours. The reaction mixture was poured onto 2 L of 94 sodium bicarbonate solution and stirred for one hour. After filtration, the euro product was recrystallized from an anhydrous alcohol / ether (2: 5) mixture to give 5.95 g (90%) of the title compound, m.p. 110-114 ° C.

Purity: 95.03 V

Example 9

Method for producing [22RS] -21-acetoxy-11ft, 16 ώ, 17-trihydroxypregna-1,4-diene-3,20-dione-16,1,17-cycloortomethylformmiate

300 ml of benzene are mixed with 4.63 g (0.01 mol) of [22 Rs] -21-acetoxy-11β, 16 $ 0, 17-trihydroxypregn-4-ene-3,20-dlon-16,6,17-cycloortomethyl formate , 3.02 g (0.0248 mol) of benzoic acid and 3.13 g of 2,3-dihloro-5,6-dicyano-1,4-benzoquinone at room temperature. The reaction mixture is refluxed for 14 hours and then Work-up analogously to Example 5. This afforded 3.18 g (694) of the diene derivative as the title compound.

Claims (6)

SUBJECT OF THE INVENTION A process for the preparation of 11β, 21-dihydroxy-16β, 17-butylidenebisoxypregna-1,4-diene-3,20-dione with a ratio of 22R / S isomers equal to 1: 1, characterized in that the methyl ester of 11 / Φ is: The 16ώ, 17-trihydroxy-21-actoxyppegna-1,4-diene-3,2P-dione-16,17-cyclo-ortho-formate is reacted with butyraldehyde in the presence of an acid catalyst and optionally in the presence of a water-binding agent in a polar aprotic solvent. the acetoxy derivative is saponified in the usual manner. 2. The process of claim 1 wherein the acid catalyst is perchloric acid. 3. A process according to claim 1, wherein acetic anhydride is used as the water-binding agent. 4. The process according to claim 1, wherein tetrahydrofuran is used as the aprotic polar solvent. 5. A process according to any one of claims 1 to 4, wherein 1.5 to 10 parts by weight of butyraldehyde are used per 1 part by weight of the methyl 11,16,16-trihydroxy-21-acetoxypregn-1,4- diene-3,20-dione-16,17-cyclo-ortho-formate. 6. Process according to claims 1 to 5, characterized in that it is operated at a temperature of from 20 to 50 ° C.