HU204067B - New process for producing steroid succinic acid esters - Google Patents

Abstract

Corticosteroid-21-hemisuccinate esters and alkali metal salts of formula (I) (where R1 = H or F; R2 = H or Me; R3 = H or alkali metal and dotted line represents an opt. double bond) are prepd. from cpds. of formula (II), and succinic anhydride in the presence of catalytic concns. of tert.-amine base. Opt. the steroid is converted to its salt. At least three molar equivs. of succinic anhydride are used. Reaction temp. is 50-100 deg.C. No solvents are present

Description

The present invention relates to a novel process for the preparation of formula (I) wherein

R 1 is hydrogen or fluorine,

R ₂ is hydrogen or methyl,

R3 is hydrogen or an alkali metal, the dotted line between the carbon atoms of 1 (2) being an additional valence bond to form corticosteroid-21-hemisuccinates and their alkali metal salts.

The compounds of formula (Π), wherein R _b R ₂ and the dotted line are as defined above, are of outstanding medical importance, particularly in the treatment of inflammatory diseases. However, their use is limited by their insolubility or low solubility in water. There has been an old quest to make them water-soluble derivatives that can be used intravenously without loss of effect.

The alkali metal salts of the corticosteroid-21-hemisuccinates of formula (I) are water-soluble, stable, and more preferably used in the field of action of the corticosteroids than the parent compounds of formula (Π). Their use as anti-inflammatory agents is important in the treatment of allergic symptoms, endocrine, respiratory and hematopoietic disorders, overweight and edema. The lipo, 17a, 21-trihydroxy-1 _, 4-pregnadiene-3,20-dione-21-hemisuccinate sodium salt (prednisolone 2 H-hemisuccinate sodium salt), known as Di-Adreson-F, is outstanding in this type of compound. It was introduced in medicine as Aquosum.

Several processes are known in the patent for the preparation of corticosteroid-21-hemisuccinates of the formula I, in particular prednisolone hemisuccinate.

In fact, these processes differ only in the reaction conditions employed and essentially involve the reaction of the appropriate corticosteroid with succinic anhydride in a basic solvent.

No. 3,193,759. United States and U.S. Patent No. 1,059,907. U.S. Patent Nos. 4,663,630 and 630,119, according to the invention, react prednisolone with succinic anhydride, dissolved in pyridine, at room temperature for 24 hours. the German patent specification does not disclose yield data. The same reaction is described in U.S. Pat. According to Japanese Patent Specification, it is carried out at 100 ° C for 6 hours. No. 1,045,400. Quinoline is used as a solvent in the process described in the German patent. í Production data are not included in the latter descriptions either. The methods described in these patents were reproduced starting from hydrocortisone and prednisolone. According to our experimental results, significant amounts (10-15%) of impurities were formed in each reaction as a contamination of the desired product. This by-product was found to be the corresponding corticosteroid-17,21-bis-hemisuccinate. From the resulting mixture, only about 65-15% of the product was obtained in pharmacopoeial quality. A further disadvantage of the known processes is that the large amounts of pyridine and quinoline used as solvents in the preparation of the products form a dilute aqueous solution, from which it is hardly possible to recover the amine (environmental pollution).

Surprisingly, we have found that corticosteroids (Π) with succinic anhydride greater than 3 molar equivalents in the presence of 0.5-2.0 molar equivalents of pyridine or pyridine derivative at a relatively low temperature (60-80'C) esterification is complete within a few hours without any side reaction. It has been found that the reaction components already form a perfectly homogeneous melt at such low temperatures, and thus the reaction was not expected to be complete, for example the hydrocortisone melting point is 220 ° C, the prednisolone melting point is 240 'C and the succinic anhydride is 120 ° C. and the product also has a melting point above 170 ° C.

According to the above method of the invention of general formula (I) - wherein R is hydrogen or fluoro, _R2 is hydrogen or methyl, R3 is hydrogen or an alkali metal atom, the dotted line between carbon atoms 1 (2) and an additional bond - corticosteroid-21 -hemiszukcinátok and alkali metal salts for preparing a compound of formula (H) - dotted line, wherein between Ri, _R2 and the carbon atoms in 1 (2) are 50 and succinic anhydride in the above reaction with a tertiary amine base and if desired the resulting corticosteroid-21-hemisuccinate to the salt, which comprises using at least 3 molar equivalents of succinic anhydride in the reaction, without the addition of a solvent, in the presence of a catalytic amount of tertiary amine base at a temperature between 50 and 100 ° C.

The starting compounds of formula (Π) according to the invention are known and are readily available commercially. Succinic anhydride should be used in an amount of at least 3 molar equivalents, and preferably not greater than 5 molar equivalents, to achieve a homogeneous melt and low reaction temperature. At lower rates no melt is formed. Use of more than 5 molar equivalents of succinic anhydride causes unnecessary loss of material.

The tertiary amine bases, preferably pyridine and pyridine derivatives (e.g. picoline, lutidine), are used as catalysts in the reaction. Even 0.1 molar equivalents of the above bases catalyze the reaction, but the reaction can only be completed in a long time. Therefore, it is advisable to use between 0.5 and 2.0 molar equivalents of these inexpensive, large-scale products to achieve a perfect reaction within 3-5 hours. It is advisable to complete the reaction at the temperature of the pure melt formed, because at higher temperatures the reaction mixture is colored which indicates the formation of decomposition products.

In a preferred embodiment of the process of the present invention, the starting cortosteroid and succinic anhydride are present in an amount of about 10%. 1-1

The mixture is homogenized in solid state at a weight ratio of 204067 Β, added to the liquid organic base and heated to 60-80 ° C in a hot water bath. A light yellow melt is formed, the composition of which is examined every hour by thin layer chromatography. Adsorbent: Silica gel-G, eluent mixture: chloroform-acetic acid-methanol = 30: 0.5: 3, developed under UV light. After complete consumption of the starting compound, the hot melt was dissolved in ethyl alcohol, cooled and poured into ice water containing inorganic acid. The crystalline product is filtered off and washed with water to neutralize, if desired, recrystallize.

Corticosteroid hemisuccinates are not used directly in medicine but as their sodium salt. The sodium salt is prepared from the hemisuccinate with equivalent aqueous sodium hydroxide, usually using suitable buffers. The corticosteroid hemisuccinate sodium salt solution is lyophilized at the desired dose (so-called lyophilisate) and prepared into a parenteral preparation.

The main advantages of the process according to the invention are:

1. Generally applicable to the preparation of succinic acid semi-esters of 21-hydroxycorticosteroids.

2. The process can be carried out in a high yield without formation of a by-product and results in a product of pharmaceutical purity without purification.

3. Does not use solvent, so there is no problem in recovering or destroying it. The process is extremely environmentally friendly.

4. In industrial size, simple equipment can be easily implemented.

The following examples illustrate the process of the present invention, but are not limited to these examples:

Example 1 Preparation of β, 17α, 21-Trihydroxy-1,4-pregnadiene-3,20-dione-21-hemisuccinate and its sodium salt (piednisolone hemisuccinate sodium salt) g (0.0139 mole) IIp, 17a, 21 trihydroxy-l, 4-pregna. diene-3,20-dione (prednisolone) and 5 g (0.05 mol) of succinic anhydride were added and the mixture was heated to 80 ° C. Pyridine (0.79 g, 0.01 mol) was added. The reaction components are ca. They form a melt at an internal temperature of 70 'C which is heated to 80' C and maintained at that temperature for 3 hours. Meanwhile, the esterification is complete. The end point of the reaction was determined by thin layer chromatography.

To the melt was poured 50 ml of ethyl alcohol, the resulting solution was cooled to room temperature and then added with stirring to a cooled solution of 250 ml of distilled water and 30 ml of concentrated hydrochloric acid below 10 ° C. After stirring for 1 hour, it is filtered, washed neutral with distilled water and dried. 5.9 g (96.0%) of the title product are obtained. M.p. 202-209 'C, [α] 2 M03,6' (c-0.67, dioxane).

Recrystallization from 100 ml of acetone and 140 ml of hexane gave the op. Rising to 205-209C; Yield: 5.1 g (83.0%). The prednisolone hemisuccinate (5.1 g) obtained above was micronized to 20-30 microns, resuspended in 200 ml of distilled water and treated with 0.1 M aqueous sodium hydroxide with vigorous stirring. In the case of sodium salt formation, the pH of the suspension may never rise above pH-8. The solution is sterile filtered and filled into lyophilized vials and lyophilized.

Example 2 Preparation of 17,17a, 21-Trihydroxy-4-pregnene-3,20-dione-21-hemisuccinate (hydrocortisone hemisuccinate)

36.2 g (0.1 mol) of 1 ip, 17x, 21-trihydroxy-4-pregnene-3,20-dione (hydrocortisone) are combined with 33.3 g (0.3 mol) of succinic anhydride and 9.3 g (0.1 mol) pyridine was esterified as in Example 1. This gives 43.9 g (98.8%) of hydrocortisone hemisuccinate. M.p .: 170-174 'C, [α] 20 D = + 244 (c = 1, ethanol).

Example 3

Preparation of 9a-Fluoro-1-, 17a, 21-trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione-21-hemisuccinate (dexamethasone hemisuccinate)

9.92 g (0.01 mol) of 9α-fluorophenyl, starting from 17α, 21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione and 3.3 g (0.03 mol) of succinic anhydride Using 1 g (0.01 mol) of triethylamine catalyst and following the procedure of Example 1, 3.8 g (96.9%) of dexamethasone hemisuccinate were obtained. M.p. 218-221 'C, [α] D 20 +80' (c-1, acetone).

Claims (4)

A process for the preparation of a compound of formula (I) wherein R 1 is hydrogen or fluorine, R 2 is hydrogen or methyl, R 3 is hydrogen or an alkali metal, and the dotted line between carbon atoms (1) may represent an additional valence bond by reacting a compound of formula (Π), wherein the dotted line between R 1, R 2 and C 1 (2) is as defined above, with succinic anhydride in the presence of a tertiary amine base and optionally converting the resulting corticosteroid-21-hemisuccinate into a salt. characterized in that the reaction utilizes at least 3 molar equivalents of succinic anhydride and is carried out in the presence of a catalytic amount of tertiary amine base in the presence of a catalytic amount of from 50 to 100 ° C. 2. The process of claim 1 wherein the tertiary amine base is pyridine or a pyridine derivative. The process according to claim 1 or 2, wherein the tertiary amine base catalyst is used in an amount of 0.5 to 2.0 molar equivalents. 4. The process according to claims 1 to 3, wherein the succinic anhydride is used in an amount of at least 3 molar and at most 5 molar equivalents.