SU1711675A3 - Method of 22(r,s)-11@@@,21-dihydroxy-16@@@,17-butylidene-bis- oxypregna-1,4-d- iene-3,20-dione synthesis - Google Patents

Abstract

The invention relates to steroids, in particular the preparation of 22 (R, S) -11 /, 21-dihydroxy-16a, 17-butylidene-bisoxy-preg-1,4-diene-3,20 dione, which has a pharmacological effect on a living organism. The goal is to create a method to obtain the specified product with the desired ratio of isomers. Synthesis is carried out by the reaction of 11 /, 16 (2, 17-trihydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione-16,17-methyl cycloortemcuric acid methyl ester with n-butyraldehyde at mol 1: 2 ratio in tetrahydrofuran medium in the presence of acetic anhydride at room temperature, followed by saponification of the obtained product in the presence of perchloric acid. In this case, the target product is obtained with a ratio of 22R: S isomers of 1: 1, purity up to 96% and Ј

Description

The invention relates to steroids, in particular the preparation of 11 /, 21-dihydroxy-16 2, 17-butylidenebisooxy-pregna-1,4-diene-3, 20-dione with 22R / S budesonide in a 1: 1 ratio of isomers.

16a-hydroxycorticoids are known, having similar or improved anti-phlogistic effect as EC; The natural hormones of the cortical layer of the adrenal gland, such as hydrocortisone, while their negligible negative sodium inhibitory effect, which affects the salt content in the body, is practically not taken into account.

The known corticoid-16,17-cycloaldehyde acetals, obtained from 16a -hydroxy corticoid, have an anti-logistic effect. Among these derivatives are such active substances that are used in therapy as (22 R.SJ-ID 21-dihydroxy-16a, 17-butylidene-bisoxy-pregna-1,4-diene-3.20-dione (hereinafter referred to as budesonide). The active substance used in therapy is a mixture of isomers containing approximately 50-50% of the 22R and 225 isomers. Such a mixture of isomers is necessary in the pharmaceutical industry.

ON VJ SL

 WITH

The aim of the invention is to develop such a synthesis, by which it is possible to obtain an end product with the desired ratio of isomers.

It is known that budesonide with an epimeric ratio of 1: 1 can be obtained by the following synthesis, which gives a good yield and is advantageous for industrial conditions.

In the first stage, acetylation is carried out in the usual manner. 16a-hydroxyhydrocortisone in the 21-position, Derivative of acetoxy is converted into. 16,17-cycloortoformate in which the cyclic orthoformate forms a 1,2-double bond; the resulting prednisolone derivative is combined with butyraldehyde and the budesonide-21-acetate formed is hydrolyzed.

The invention is based on the fact that the ketal obtained by the exchange reaction of 16,17-cycloortoformate with butyraldehyde contains 22R- and 225-epimers in a 1: 1 ratio. The good epimeric ratio is not affected by the latter acetylation. The most important stage of the proposed method is the exchange reaction of a cyclic orthoester with butyraldehyde. Synthesis containing the above exchange, you can get budesonide with epimeric ratio of 1: 1. and 52% yield. In accordance with the invention, 11/3 16a, 17-trihydroxy-21-acetoxy pregna-1,4-diene-3.20-dione-16,17-methyl ester of cyclortoformic acid exchanges with butyraldehyde in the presence of an acidic catalyst and, if necessary, in the presence of a solid, water-containing agent in a polar aprotic solvent and the resulting 21-acetoxy derivative is washed in the usual way in the presence of an acid.

When cyclic orthopic acid ester is exchanged to the cyclic aldehyde diet, the acetyl group of the 21-hydroxy group and the D-ring remain intact, and the R and S isomers form in a 22: 1 ratio of 1: 1.

As an acid catalyst, it is possible to use tslotho, perchloroacid, toluenesulphonic acid, methanesulphonic acid, ethanesulphonic acid, pyridinosylate, lutidine tosylate, colindintosylate or sulfuric acid, preferably perchloroacid, methanesulphonic acid or pyridintosylate. Consume 0.1 to 2 mol of the catalyst per mole of 11 /, 16 a, 17-trihydroxy-21-acetoxypregna-1,4-diene-3,20-diene-16,17-cyclo-orthomethyl formate. Substances are usually consumed in equimolar amounts. In order to eliminate undesirable side reactions, one uses an aqueous acid as an acid catalyst in the presence of a water-binding agent. Acetic anhydride or phosphorus pentoxide is used as a water binding agent.

The exchange process can be controlled

using thin layer chromatography. To isolate the final product, the reaction mixture is poured into 100–200-fold amount of water, calculated on the starting material of orthoformic acid used, - and the water may contain a base in an insignificant excess equivalent to the catalyst. Sodium carbonate or carbonic acid may be mentioned as a base.

potassium.

The final product is filtered, extracted with water with an immiscible solvent, for example, methylene chloride, chloroform or ethyl acetate, or purified in the usual way.

Example 1. 22 (P, 5) -21-acetoxy-11 / -hydroxy-16a, 17-butylidene-bisoxy-pregna -1,4-diene-3,20-dione.

100 ml of stabilized free

from tetrahydrofuran peroxide is mixed with 2.0 ml (0.021 mol) of a 70% aqueous perchloric acid solution and 5.7 ml (0.06 mol) of acetic anhydride is added dropwise with cooling and stirring. Solution

Shake for 15 minutes at room temperature and add 1.8 ml (0.02 mol) of distilled butyraldehyde under nitrogen. 4.63 g (0.01 mol) of 11/7, 16a, 17-trihydroxy-21-acetoxypreg-1, 4-diene-3,20-dione-16, 17-cyclohortomethyl formate is added to the solution in small portions . The reaction mixture is stirred for 9 hours and the excess solvent is separated under reduced pressure. Oily

the precipitate is dissolved in ethyl acetate, extracted with 5% aqueous sodium hydrogencarbonate solution and concentrated. T. pl. 168-171 ° C. Purity (thin film chromatography under elevated pressure) 97.1%.

The epimeric ratio is 53:47.

Example 2. 22 (R, S) -11jS, 16a, 17,21-tetrahydroxy-16a, 17-butylidene-bis-sypreg-1,4-dibn-3,20-dione.

4.4 g of 22 (P, 5) -21-acetoxy-11 D-hydroxy1ba, 17-butylidene bis-pregna-1,4-diene-3.20-dione, prepared according to example 1 under nitrogen atmosphere, was dissolved in 66 ml methanol, 4.40 ml of a 70% aqueous perchloric acid solution are added and left for 8

. The reaction mixture was poured into 880 ml of water, stirred for 1 hour and filtered. The resulting crude compound (3.98 g) was dissolved in methylene chloride and dripped dropwise with n-hexane while stirring. The fallen purified product is recrystallized from anhydrous ethanol to give 3.62 g (90.25%) of pure title compound, mp. 239-242 ° C. "About 25 99.8 ° C 1%, methylene chloride). Epimeric CQOT-10 wearing 51.55: 47,45. Purity 98.2%.

Example 3. 22 (R, S) -11Ј, 16a, 17,21-etrahydroxy-16a, 17-booylidene-bisoxyp-regna-1,4-diene-3,20-dione.

It is carried out analogously to example 1, one to 15 to the final product containing a precipitate, instead of recrystallization and a nitrogen atmosphere at room temperature in 66 ml of methanol, dissolve 4.4 ml of 70% aqueous perchloric acid solution, mix and equip to 20 h. The reaction mixture was poured into 880 ml of water, stirred for an hour and filtered. The resulting compound is dissolved in methylene chloride and 25 drops, while stirring, 25 are poured into n-hexane. The precipitated purified product is recrystallized from anhydrous ethanol to obtain 3.68 g (91.74%) of pure title compound, mp. 239-242 ° C. oo25 99.8 ° (C 1%, methy 30 chloride chloride). The epimeric ratio is 51.55: 48.46. Purity 98.2%.

Example 4. 22 (R, S) -11Ј, 16a, 17,21-etrahydroxy-16a, 17-butylidene 5-oxy-regna-4-ene-3,20-dione-21-acetate. 92 ml of acetonitrile, 2.0 ml of 70% aqueous perchloric acid solution and 1.21 ml of disilated butyraldehyde are mixed in nitrogen atmosphere at room temperature. After 20 stirring missions, 40 4.0 g of 16 a-hydroxy-hydrocortisone-21, -acetate are added in small portions over 30 minutes. The exchange takes place within 30 minutes. The reaction mixture is mixed with 50 ml of a 5% aqueous solution of potassium hydrogencarbonate in a nitrogen atmosphere, extracted with ethyl acetate, the extract is washed with water to neutrality, dried on sodium sulfate and the solvent is distilled off under reduced pressure. After recrystallization of the learned oil (epimeric ratio of 65:35), first from ethanol and then from ether, 2.6 g (57.59%) of pure title compound are obtained with an epimeric ratio of 70: 30.55

Example 5. 22 (R, S) -11Ј, 16a. 17.21. tetrahydroxy-16a, 17-butylidenebisoxyp-regna-1,4-diene 3,20-dione-21-acetate.

70 ml of benzene are mixed with 1.0 g (0.0021 mol) 22 (R, SH1), 16a, 17,21-tetrahydroxy-16a, 17-butylidenebis bis-pregn-4-ene-3,20-dione-21- acetate, 0.64 g of benzoic acid and 0.72 g of 2,3-dichloro-5.6-dicyzno-1,4-benzoquinone at room temperature. The reaction mixture is boiled for 24 hours at reflux, after cooling, washed with water and 5 After concentration, the oily precipitate from methylene chloride / n-hexane 1: 5 gives 0.6 g (60.26%) of the title Compound in an epimeric ratio of 84:16, purity 96%.

Example 6. 22 (R, S) -11/3, 16a, 17,21-tetrahydroxy-16a, 17-butylidenebisoxy-regn-4-ene-3,20-dione.

46 ml of acetonitrile, 1.21 ml (2.4 mol eq) of 70% aqueous perchloric acid solution and 0.69 ml (1.4 mol eq) of distilled butyraldehyde are mixed under nitrogen at room temperature. After 20 minutes of stirring, 2.0 g (0.0053 mol) was added. 16a -hydroxy-hydrocortisone in small portions over 30 minutes. The reaction proceeds for 1.5 hours. The reaction mixture is mixed with 28 ml of a 5% aqueous solution of potassium hydrogen carbonate under nitrogen, extracted with ethyl acetate, washed with water until neutral, dried on sodium sulfate and the solvent is evaporated under reduced pressure. The resulting oil crystallizes (2.2 g, epimeric 75:25 ratio) from ether. Thus, 1.8 g (78.7%) of the pure title compound was obtained with a mp of 191-198 ° C.

Example 7: 22 (R, S), 17,21-tetrahydroxy-16 a, 17-butylidene bisoxyp-regna-1,4-diene-3,20-dione.

80 ml of benzene are mixed with 0.92 g (0.0021 mol) of 22.5) -11 /, 16a, 17.21-tetra-hydroxy-16 ", 17-butylidenebisoxypregn-4-ene-3.20-di 1na (Compound according to Example 6 with an epimeric 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 is boiled for 27 hours under reflux, washed with water while cooling, then with a 5% aqueous solution of sodium hydroxide and again with water. After concentration, the oily residue is recrystallized from methylene chloride / n-hexane 1: 5. Thus, 0.54 g (58.97%) of the title compound with an epimeric ratio of 86.5: 13.5, purity of 94.2%, m.p. 240-243 ° C (decomposition).

Example eleven/,. 1 demon, - 17-trihydroxy-21-acetoxypregn-4-ene-3,20-dione-16,17-cycloormethyl formate. .

5 g (0.0119 mol) of 16a-hydroxy-hydrocortisone-21-acetate and 1.3 g (0.00582 mol) of pyridinosylate are dissolved in 75 ml of dimethylformamide (0.05% Karl Fischer water content) with stirring in a nitrogen atmosphere at room temperature. 5.3 ml of trimethyl orthoformate are added and the solution is stirred for 1.5 hours. The reaction mixture is poured into 2 liters of a 5% aqueous solution of sodium hydrogencarbonate and stirred for one hour. After filtration, it is recrystallized from anhydrous alcohol with ether 2: 5. 5.95 g (90%) of the title compound are obtained, mp. 110-114 ° C, purity 95.03%.

Example 9. 22 (P, 5) -21-acetoxy-11/3, 16 a., 17-trihydroxypreg-1,4-diene-3,20-dione-16a, 17-cyclo-methyltetramyl formate.

300 ml of benzene are mixed with 4.63 g (0.01 mol) of 22 (P.5) -21-acetoxy-11 /, 16a-trihydroxypregna-4-ene-3,20-dione-1ba, 17-cycr - orthomethyl formate, 3.02 g (0.0248 mol) of benzoic acid and 3.13 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature. The reaction mixture is boiled for 14 hours under reflux and is treated as in Example 5. Thus,

3.18 g (69%) of a diene derivative as a title compound.

Thus, the proposed method allows to obtain budesonide with the required ratio of isomers and high yield.

Claims (1)

Claims for the preparation of 22 (R, S) -11/3, 21-dihydroxy-16a, 17-butylidene-bisoxy-pregna-1,4-diene-3,20-dione with a ratio of 22 R / S isomers 1: 1 by treatment of the derivative 1-hydroxycortisone n-butyraldehyde in an aprotic polar solvent in the presence of perchloric acid, characterized in that. in order to increase the yield of the target product 11/3, 1ba, 17-three hydro xi-21-a, cethoxy-ppna-1,4-d-ene-3,20-dione-16, 17-methyl ester acids as a 1ba-hydroxycortisone derivative are reacted with n-butyraldehyde at a molar ratio of 1: 2 in tetrahydrofuran medium as an aprotic polar solvent in the presence of acetic anhydride at room temperature and the resulting 22 (R, S) -21-acetoxy - 11/3 -hydroxy-16a, 17-butylidenebisoxy-pregna-1,4-diene-3,20-dione is washed in the presence of acid.