DD270917A5 - METHOD OF GENERATING 11BETA, 21-DIHYDROXY-16ALPHA, 17-BUTILYDE-BISOXY-PREGNA-1,4-DIENE-3,20-DION WITH A 1: 1 22R / S ISOMER RATIO - Google Patents

Abstract

The invention relates to a process for the preparation of 11b, 21-dihydroxy-16a, 17-butilydenebisoxy-1,4-diene-3,20-dione having a 22R / S isomer ratio of almost 1: 1, characterized in that 11b , 16a, 17-trihydroxy-21-acetoxy-pregna-4-diene-3,20-dione-16,17-cycloorthoameisensuremethylester with butiraldehyde in the presence of an acid catalyst and optionally in the presence of water binders in a polar aprotic solvent and the 21 obtained Acetoxy derivative saponified in the usual way.

Description

Field of application of the invention

The invention relates to a novel process for preparing 11β-dihydroxy-α-butyl-bisoxy-pregna-M-diene-S, O-dione having a 22 R / S isomer ratio of nearly 1: 1.

Characteristic of the known state of the art

Biological studies in the mid-fifties demonstrated (J. Am. Chem. Soc, 78, 1909 [1956]) that 1 βα-hydroxycorticoids have a similar or improved antiflogistic action as the native adrenocortical hormones, for example hydrocortisone, wherein their low adverse sodium-retaining effect, which affects the salt balance of the organism, can be practically neglected (J. Am. Chem. Soc., 81, 1689 [1959]). The corticoid-16,17-cycloaldehyde acetals producible from 16a-hydroxycorticoids have an antiflogistic effect exceeding that of the basic motif (US Pat. No. 3,197,468, J. Am. Chem. Soc., 80, 2338 [1958]). Among these derivatives are those drugs useful in therapy, such as (22RS) -11β-21-dihydroxy-16a, 17-butylidertbisoxy-pregna-1,4-diene-3,20-dione (hereinafter called budezonide). The drug used in therapy is an isomer mixture containing about 50% each of 22R and 50% 22S isomer (Arzneim. Forsch. 29 (11), 1687-1690 [1979]). In the pharmaceutical industry, this mixture of isomers is produced because the tests required for approval have been carried out with it. The subsequent change of a certain isomer ratio is associated with significant material losses, which is why there is a need to work out a synthesis process with which the end product can be prepared with a desired isomer ratio.

Steroid-ie.n-cycloaldehyde or ketone acetals (ketals) can be prepared by reacting corresponding 16,17-dihydroxycorticoid derivatives with aldehydes or ketones in the presence of acid catalysts (DE-PS 1131213, DE-OS 1118779, GB PS 916996 and 933867, USP 3197469 and 3798216 and HU-PS 166680). According to the literature, budezonide can be prepared from readily available 1α-hydroxy-hydrocortisone as follows:

1) First, according to US Pat. No. 3,037,914, a 1,2-double bond is formed by microbial oxidation. The yield of the reaction is 10%. From the formed 16a-hydroxyprednisolone is obtained after the o.e. Process from medic. Forsch, with Butiraldehvd by acid catalysis the Budezonid. From this one obtains the crude Budezonid with a very good yield (94.4%). From this, the pure 1: 1 isomer mixture is finally obtained by column chromatography (yield: 83.8%). The overall yield of the synthesis method is 0.10χ0.944χ0.838 = 0.079, i. almost 8%. It follows that this synthesis method is economically unreasonable because of the low overall yield.

2) In a first step, the hydroxyl group in the 21-position is protected by acetylation. The obtained 21-acetoxy derivative can be mixed with butiraldehyde e.g. according to Example 4 into a 16a, 17-Butilydenbisoxy derivative. In this one can by dehydration z. Example, according to Example 5 form a 1 ^ double bond and cleave by hydrolysis, the 21-acetoxy. In the first stage, the acetylation can be carried out with a yield of about .00%. In Ketalbildung (Example 4) gives the Ketalzwischeriprodukt with an epimer of 70:30 and a yield of 57,59%, and from this according to Example 5 acetylated Budezonid with an epimer of 84:16 and a yield of 60.26% , The latter is converted by saponification according to Example 2 in Budezonide with an unchanged epimer ratio and a yield of 90.25%. The total yield of the synthesis process is 31.32%, the epimer ratio üc final product 84:16. It can be seen that this synthetic method is unsuitable for commercial use, since for the production of a product with an epimer ratio of 1: 1, a subsequent Epimentrennung must be carried out.

3) Another possibility is the direct conversion of lea-hydroxy-hydrocortisone (for example, according to the cited reference from Arzneim. Research into a 16a, 17-butylyl bisoxy derivative, which is dehydrogenated to form the 1,2-double bond However, according to the literature, ketal formation can be achieved with a conversion of about 70%.

carry out. By modifying the reaction conditions of Example 6, however, the Eplmer ratio is shifted to 71:29. The yield here is 78.7%. In this product can be formed according to Example 7, a second double bond, but the obtained Budezonid shows a very poor epimer ratio of 87:14 next to a yield of 58.97%. The total yield is 46.4%. For the preparation of a final product with an epimer ratio of 1: 1 one must perform Epirrmrtrennung.

Object of the invention

With the invention, an economical process for the preparation of the aforementioned compound with the desired isomer ratio is to be provided.

Explanation of the essence of the invention Budezonide having an epimer ratio of nearly 1: 1 was found to be commercially useful in the following synthetic method

can be produced advantageously and in good yield:

As a first step, 16a-hydroxy-hydrocortisone is acetylated in the 21-position as usual. The acetoxy derivative is carried along Trimethyl orthoformate in le. ^ - Cycloorthoformiat about. In the cyclic orthoformate, a 1,2-double bond is formed. The resulting prednisolone derivative is mixed with butyraldehyde and hydrolyzed the resulting Budezonid-21-auitat. The invention is based on the finding that by reacting 16,17-cycloorthoformate with butyraldehyde, the ketol, ii? S r * id

22 R and 22 S epimers in a ratio of almost 1: 1, and which is required in the pharmaceutical industry, can be obtained. The good epimer ratio is not affected by the last acetylation. The most important step of the process according to the invention is thus the reaction of the cyclic orthoester with butiraldehyde. By syntheses containing the above reaction according to the invention, one can Budezonid with an epimer ratio of almost 1: 1 and with a

Yield of 52%. In accordance with the invention, the procedure is such that one obtains 11 β-α-trihydroxy-1-acetoxy-pregna-1-diene-β-dione, ie

cyclo ortho ants. methyl ester with butyraldehyde in the presence of column catalysts and optionally in

Reacting the presence of water binders in a polar aprotic solvent and the resulting 21-acetoxy derivative

in the usual way vorseift.

In the inventive reaction of cyclic orthoformate to cyclic aldehyde acetals remains the Acetyl group of the 21-hydroxy group and the D-ring undamaged and the R and S isomers are formed in the 22-position in

a ratio of almost 1: 1.

As the acid catalyst, an acid, e.g. Perchloric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, Pyridintosilat, Lutidintosilat, Coldidintosilat or sulfuric acid, preferably perchloric acid, methanesulfonic acid or Use pyridine-silicate. 0.1 to 2 moles of catalyst per mole of 11β, 16α, 17-trihydroxy-21-acetoxy-pregna-1,4-diene are used.

3.?0-dion-26,17-cycloorthomethyl-formiat. These substances are preferably used in equimolar amounts.

In order to avoid unwanted side reactions, it works when using aqueous acid as the acid catalyst in Presence of a water binder. As a water binder is preferably used acetic anhydride or Phosphorus pentoxide. As polar aprotic solvent can be used tetrahydrofuran, dioxane or dimethylformamide. When However, solvent can also serve a corresponding excess of butiraldehyde. If the excess of butiraldehyde is not used as the solvent, 1.5 to 10 mol of butyraldehyde are used per Mole of orthoformic acid ester. It is particularly advantageous to use the aldehyde in 3 to 5 times excess. According to the invention is carried out at a temperature of 0 to 100 ° C, preferably from 20 to 40 ° C, in particular 3O ⁰ C. The course of the reaction can be monitored by thin layer chromatography. For isolation of the final product

is poured into the reaction mixture in a 100 to 200 times the amount of water (calculated on the starting material used

Orthoameisensäureester), wherein the water may contain a base in slight excess equivalent to the catalyst. As the base, sodium bicarbonate or potassium hydrogencarbonate can be used. The final product is filtered by means of a water-immiscible solvent, such as methylene chloride, chloroform or Ethyl acetate, extracted or purified in a conventional manner. The resulting 21-acetoxy derivative is saponified as a last stage after or without isolation. In the latter methods can

an isolation level is eliminated. The epimer ratio of the final product is not affected by the subsequent saponification.

The invention will be explained in more detail with reference to the following examples, without limiting the scope of protection to these. embodiments example 1

(22S) -21-Acetoxy-11β-hydroxy-16α, 17-butylylbisoxy-preg / iii-1,4-diene-3,10-dione 100 ml of stabilized peroxyd-free tetrahydrofuran are mixed with 2.0 ml (0.021 mol) 70% iger aqueous perchloric acid solution, and added dropwise with stirring and cooling 5.7 ml (0.06 mol) of acetic anhydride. The solution is then stirred for 15 minutes at room temperature and treated under nitrogen atmosphere with 1.8 ml (0.02 mol) of distilled butyraldehyde. Then, 4.63 g (0.01 mol) of 11β, lea.U-trihydroxy-1-i-acetoxy-pregna-M-diene-S, O-dione, ω, ω-cycloorthomethyl formate are added in small portions to the solution. The reaction mixture is stirred for 9 hours and the excess solvent is removed under reduced pressure. The oily residue is dissolved in ethyl acetate, extracted with 5% aqueous sodium bicarbonate solution and concentrated. Recrystallization from ether / diisopropyl ether gives 4.40 g (93.11%) of the title compound from the residue. Melting point: 168 to 171 ^° C. Purity (overprinted thin-layer chromatography): 97.1%

 Epimer ratio: 53/47.

Example 2

(22RS) -11 p-1 βQ, 17-21 -tetrahydroxy-1βa, 17-butyl-di-bis-pregna-1,4-diene-3,20-dione

Dissolve 4.4 g (22RS) -21-acetoxy-11β-hydroxy-iea.n-butllydecbisoxy-progna-M-diene-S, O-dione prepared according to Example 1,

under nitrogen atmosphere in 66 ml of methanol, 4.40 ml of 70% aqueous perchloric acid solution are added and the mixture is allowed to stand for 8 hours. Then the reaction mixture is poured into 080 ml of water, roasted for one hour and filtered. Dissolve the resulting crude title compound (3.98 g) in mathylene chloride and drip the solution into η-hexane with stirring. The precipitated gersinigte product is recrystallized from anhydrous ethanol. This gives 3.62 g (90.25%) of pure title compound.

Melting point: 239 to 242 ⁰ C.

(a) J ⁶ = 99.8 ^s (c = 1%, methylene chloride).

Epimer ratio: 51.65: 48.45.

Purity: 98.2%.

Example 3

(22RS) -11β, 16α, 17,21-tetrahydroxy-16α, 17-butylyblypsoxy-pregna-1,4-diene-3,20-dione

Mar. proceeds analogously to Example 1, but with the difference that the end product containing a residue instead of Recrystallization and the nitrogen atmosphere at room temperature in 66ml of methanol dissolves, with 4.40 ml of 70% aqueous Perchloric acid solution mixed and allowed to stand for 8 hours. Then the reaction mixture is poured into 880 ml of water, stirred

for one hour and filtered. The resulting crude titol compound is dissolved in methylene chloride and the solution is added dropwise to η-hexane with stirring. The precipitated purified product is recrystallized from anhydrous ethanol. 3.68 g (91.74%) of pure are obtained

Title compound. Melting point: 239 to 242 ⁰ C.

(a) S ⁶ = 99.8 ° (c = 1%, methylene chloride).

Epimer ratio: 51.55: 48.45.

Purity: 98.2%.

Example 4

(22RS) -11ß, 16a, 17 ^ 1-tetrahydroxy-16a, 17-butlylydenbisoxy-pregna-4-diene-3,20-dione-21-acetate. Mixed are 92 ml of acetonitrile, 2.0 ml of 70% aqueous perchloric acid solution and 1 , 21 ml of distilled butyraldehyde under nitrogen atmosphere at room temperature. After stirring for 20 minutes, 4.0 g of 16a-hydroxy-hydrocortisone 21-acetate are added in small portions within 30 minutes. The implementation will expire within 30 minutes. The reaction mixture is mixed with 50 ml of 5% strength aqueous potassium hydrogencarbonate solution under nitrogen atmosphere, extracted with ethyl acetate, the extract is washed neutral with water, dried on sodium sulfate and freed from the solvent under reduced pressure. After recrystallization of the obtained oil (epimer ratio 65:35) first from methanoi and then from ether, 2.6 g (57.59%) of pure title compound with an epimer ratio of 70:30.

Example 5

(22RS) -11ß, 16a, 17 ^ 1-tetrahydroxy-16a, 17-butilydenblsoxy-pregna-4-dlen-3,20-dłoń

46 ml of acetonitrile, 1.21 ml (2.4 molar equivalent) of 70% aqueous perchloric acid solution and 0.69 ml are mixed

(1.4 mole equivalent) distilled butiraldehyde under nitrogen atmosphere at room temperature. After stirring for 20 minutes, 2.0 g (0.0053 mol · 16a-hydroxy-hydrocortisone are added in small portions over 30 minutes, the reaction proceeds in 1.5 hours, and the reaction mixture is mixed with 28 ml of 5% strength aqueous potassium bicarbonate solution

Nitrogen atmosphere, extracted with ethyl acetate, the extract washed neutral with water, dried on sodium sulfate and freed

under reduced pressure from the solvent. The resulting oil (2.2 g) (epimer ratio 75:25) is recrystallized from ether to give 1.8 g (78.7%) of pure title compound having an epimer ratio of 70.7: 29.3.

Melting point: 191 to 198 ^° C. Example 7

(22RS) -11β, 16α, 17,21-tetrahydroxy-16a, 17-butilydenbloxy-pregna-1,4-diene-3,20-dione

80 ml of benzene are mixed with 0.92 g (0.0021 mol) of (22SR) -I-iso-i-o-a-tri-tetrahydroxy-iea. -Butilydenebisoxy-pregna-diene.

3,20-dione (compound of Example 6 having an epimeric ratio of 70.7: 29.3), 0.46 g of benzoic acid and 0.72 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone room temperature. The reaction mixture is refluxed for 27 hours, washed first with water after cooling, then with 4% aqueous sodium hydroxide solution and then again with water. To

Concentration of the oily residue is crystallized from methylene chloride / n · hexane in the ratio of 1: 5 to. 0.54 g is obtained

(58.97%) title compound having an epimer ratio of 86.5-13.5.

Purity: 94.2%.

Melting point: 240 to 243 ° C (setting). Example 8 Hß.iea ^ -.. Trihydroxy ^ i-acetoxy-pregna ^ -dle'i-S ^ O dłoń-ie ^ - cycloorthomethylformiat Dissolve 5 g (0.0119 mol) of 1 ea hydroxy-hydrocortisone-21-acetate and 1.3 g (0.00582 mol) of pyridine in 75 ml of dimethylformamide

(Water content according to Karl Fischer: 0.05%) with stirring and nitrogen atmosphere at room temperature. Add 6.3 ml

Trimethylorthoformiat and the solution is stirred for 1.5 hours. Then the reaction mixture is poured into 115% aqueous Sodium bicarbonate solution and stirred for one hour. After filtration, the crude product crystallizes out

anhydrous alcohol and ethyl (2: 5) to yield 5.95g (90%) of the title compound.

Melting point: 110 to 114 ^° C.

Purity: 95.03%.

Example 9

300 ml of benzene are mixed with 4.63 g (0.01 mol) of (22RS) -21-acetoxy-11β, 16α, 17-trihydroxy-pregna-4-ene-3,20-dione-16,17-cycloorthomethylformate, 3 02g (0.0248 mol) of benzoic acid and 3.13g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone at room temperature. The reaction mixture is boiled for 14 hours under reflux and worked up analogously to Example 5 on. 3.18 g (69%) of Dienderiva are obtained; as title compound.

Claims (6)

A process for the preparation of bis-i-dihydroxy-IBa.U-butilydenebisoxy-pregna-IAdien-S ^ O-dione having a 22 R / S isomer ratio of almost 1: 1, characterized in that 11β, 16a , 17-Trihydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione 16,17-cycloorthoameisensäuremethylester reacted with butiraldehyde in the presence of water binders in a polar aprotic solvent and the obtained 21-acetoxy derivative in a conventional manner saponified. 2. The method according to claim 1, characterized in that one uses as the acid catalyst perchloric acid. 3. Process according to claims 1 and 2, characterized in da.j used as a water binder acetic anhydride. 4. The method according to claim 1 to 3, characterized in that one uses as aprotic polar solvent tetrahydrofuran. 5. The method according to claim 1 to 4, characterized in that 1.5 to 10 moles of butyraldehyde per mole of 11 ß, lea.U-trihydroxy ^ i-acetoxy-pregna-IAdien-S ^ O-dione-ie.U- cycloorthoformic acid methyloster used. 6. The method according to claim 1 to 5, characterized in that one works at a temperature of 20 to 50 ⁰ C.