HU193129B - Process for producing ergoline compounds free of isomeres - Google Patents

Abstract

The present invention relates to a process for the preparation of an inoline-free isomer-free (left-turn) -ergoline-skeletal compound by catalytic hydrogenation of ergolene-skeletal compounds with hydrogen gas in a solvent, such that the starting material is a 10-fold double-bonded ergolene. with a compound (s) of skeleton (s) containing up to 60% (right-handed) -inin derivative is treated with a monovalent acid having a pK of less than 3.5 and / or a pK of less than 3.5, and then treated with a monocarboxylic acid having a pK value of less than 3.5. the hydrogenation is carried out in a pH of 4 system, the resulting inin-free (left-handed) -ergoline compound is isolated. The known ergoline-skeletal compounds obtained by this process are active pharmaceutical ingredients. -1-

Description

BACKGROUND OF THE INVENTION The present invention relates to a novel process for the preparation of ergoline backbone compounds free of inin-type isomers by catalytic hydrogenation of ergoline backbone compounds with hydrogen gas in a solvent.

Ergolene backbone compounds have been used in medicine for a long time. However, in recent years, undesirable side effects (mainly central nervous system effects) have been discovered in lysergic acid derivatives. However, hydrogenation of the double bond in the D-ring has been shown to significantly reduce side effects. Thus, it is an important task to hydrogenate the 9,10-unsaturation of the ergoline backbone, in particular to prepare dihydrolysergic acids as starting compounds for the synthesis of pharmaceutically valuable ergoline backbones, and to produce high purity ergot alkaloids in pharmaceutical formulations.

However, it is also known that the crude alkaloid mixture obtained by fermentation or from the mother-of-a-rye drug contains significant amounts of biologically inactive _C8 epimers which are not easy to remove or transform.

There are few methods known in the literature for the direct hydrogenation of lysergic acid to 9,10-dihydro-lysergic acid; Also known from U.S. Patent No. 161,090. Hungarian Patent No. 5,198, which directly hydrogenates lysergic acid: in liquid ammonia, at a temperature of about -50 ° C, 9,10-dihydro-lysergic acid is obtained in 90% yield with the aid of an alkali metal and a proton donor. Czechoslovak authors (Fharmazie 26, 740 (1971)), hydrogenation of dihydro-lysergic acids and esters with Raney nickel catalyst in water-ammonia solution at 60-65 ° C and 60-65 atm for 2 hours, they also gain 90%.

The disadvantages of the processes are the technical difficulties caused by the low temperature and the technological disadvantages and high costs of the high pressure equipment.

There are several known methods for hydrogenation of natural nutmeg alkaloids, which are acid amides with tripeptides of lysergic acid. No. 129,061. According to the patent, the reduction is carried out with hydrogen gas in the presence of palladium on carbon at a pressure of 20-30 atmospheres. The disadvantage of the process is that only high purity alkaloids can be used as starting material and the reduction must be carried out under pressure. The reaction still takes a very long time (24-80 hours). A further disadvantage of the process is that yields are volatile and low (60-80%).

No. 192,546. According to the process disclosed in Austrian patent application, the above-mentioned disadvantages are solved by using palladium catalyst on a barium sulfate support. Here again, however, the process can only be carried out in an appropriate yield from a starting material of excellent purity (pharmacopoeial quality). It is well known in the art that such purification of natural rye alkaloids results in very high losses (35-50%). A further disadvantage of the process is that the alkaloids are epimerized in the solvent mixture used during the 6 hour hydrogenation reaction, so that the product obtained by the process is inconsistent and only suitable for pharmaceutical preparation after further purification. Of the hydrogenated mother-rye alkaloid salts, only the preparation of dihydrogen ergotamine tartrate is disclosed.

No. 205,676. According to the Austrian patent, hydrogenation of the ergotamine base is carried out in a solution of dioxane and glacial acetic acid in the presence of a supported palladium catalyst. Following the lengthy isolation procedure described in the example, the dihydro-ergotamine base is obtained in only 72-75% yield.

No. 167,606. According to the Hungarian patent, in contrast to the above catalytic hydrogenation processes, the reduction of mother-rye alkaloids with sodium and protondonor in liquid ammonia is also carried out in the presence of contaminants. However, the process has the disadvantage that during the reduction, a coloring agent is formed which necessitates the isolation and purification of the hydrogenated mother rosa alkaloid base. Thus, a pharmaceutical grade product can be produced in only two steps, i.e. at a loss.

No. 174,577. The Hungarian patent attempts to provide a general method for the hydrogenation of ergolene backbone compounds of natural origin. The process involves catalytic hydrogenation in a lower alkanolic solution at a pressure of 1-2 atmospheres for 0.5 to 3 hours and immediately forming an acid addition salt in the solution. The process has the disadvantage that the unfavorable epimer, which is almost always present as the starting material, also appears in the product as dihydroinin. Thus, although the overall yield of the alkaloid is favorable, the dihydroinine derivative must be freed by separate manipulation and purification steps.

As a general disadvantage of the known hydrogenation processes so far, it can be stated that even with the present hydrogenation operation, taking into account all the steps of the process, there is only a considerable loss in the preparation of drug-quality compounds.

Thus, according to the state of the art, a naturally occurring ergolene backbone compound can only be hydrogenated catalytically in purified state. After hydrogenation of the contaminated starting compound-2193129, it is possible to obtain a hydrogenated base suitable for salt formation only by repeated purification.

From the literature, it can be concluded that although an ergoline skeleton is an important endeavor, a generally applicable good procedure is not yet known.

It is an object of the present invention to provide a process for the simple, rapid and selective hydrogenation of crude alkali mixtures having a significant C _g epimer content.

The invention is based on the recognition that the starting compounds must be treated in a system having a pH of at least 4; in this case _C8 -as center favorable epimerisation also takes place simultaneously with the reduction. In this way, the biologically active left-rotating saturated derivatives can be easily obtained in one step.

The discovery is surprising because the formation of epimer pairs has been reported in the literature in the case of reductions in protic media, and a new technological step has yet to be introduced to separate the resulting dihydro-epimer pair.

The present invention relates to a process for the preparation of ergoline backbone compounds free from inin-type isomers by catalytic hydrogenation of ergoline backbone compounds with hydrogen gas in a solvent, wherein Mixture of compound (s) containing up to 60% by weight of a (deodorant) -inin derivative with a monovalent acid having a pH of less than 3,5 and / or pK | ^: Treated monovalent polyvalent acid, and the pH value was 4, the hydrogenation system is performed, the resulting free-inin (levorotatory) - ergoline compound is isolated.

In a preferred embodiment of the process according to the invention, the monovalent acid used is monochloroacetic acid, and the multivalent acid is, for example, sulfuric acid, phosphoric acid, maleic acid, tartaric acid.

Preferably, the process of the invention. in the solvent and / or water mixture with an acid having a pK value of less than 3.5 in the mixture of epimer used as starting material, in which the amount of the right-turning modifier can be up to 60% by weight, but generally in the range of 10-45%. and the reaction mixture is hydrogenated for 2 to 4 hours in the presence of a catalyst prepared in a known manner, for example a charcoal palladium catalyst, and the reaction is run at room temperature. After filtration of the catalyst, the desired dihydro compound (or, alternatively, the desired ergoline compound) is obtained directly in basic form by alkaline treatment with the appropriate pH adjustment.

Thus, for example, 9,10-dihydrolysergic acid can be prepared from 9,10-double-bonded ergolene derivatives, 9,10-dihydro-ergotamine from ergotamine, and 9,10-dihydro-ergocristine from ergocristine, for example.

For hydrogenation, it is best to use palladium metal on a support, activated alumina or activated carbon having a content of 5 to 10% palladium metal.

Starting compounds of natural ergolene skeleton are known. They are distinguished by the fact that they can be obtained from natural materials such as plants, mother-rye or from fermentation saprophytic cultures. Lysergic acid can be produced by hydrolysis of mother-rose alkaloids or other lysergic acid amides.

A great advantage of the process according to the invention is that the starting compounds need not be prepared in the high purity generally required for catalytic reduction. The process according to the invention may use 10-15% crystalline solvents (e.g. benzene, acetone), 10-25% but not more than 60% by weight of unfavorable epimer, and 1-5% by weight of co-alkaloids, isolates of organic acid and inorganic acids and salts. containing starting materials.

The main advantages of the process according to the invention can be summarized as follows:

1. Suitable for hydrogenation of a natural compound of ergolene skeleton or mixtures thereof.

2. Hydrogenation from the starting material containing epimer pairs and co-alkaloids proceeds very rapidly under atmospheric conditions.

3. A very high proportion of the starting material containing the unfavorable epimer produces a high quality compound containing only the desired epimer.

4. The process, when magnified, is suitable for industrial implementation in all production sizes.

In order to carry out the process of the invention, the following embodiments are provided:

t. example

9,10-dihydro-ergotamine

10.0 g of ergotamine base (HPLC content: 7.2 g, ergotamine content: 0.85 g) in 125 ml glacial acetic acid, 50 ml acetone and 25 ml water. To the reaction mixture was added 1 g of maleic acid and 5 g of palladium on charcoal, and the mixture was stirred under a hydrogen atmosphere at room temperature and pressure for 3 hours. The catalyst was filtered off and the mixture was added dropwise to a mixture of 250 ml of 20% ammonium hydroxide and 100 g of ice. The precipitated 9,10-dihydro-ergotamine base is filtered off, washed three times with 50 ml of water and dried.

Product weight: 9.2 g.

-3193129

9,10-Dihydro-ergotamine tarphaloma (by HPLC): 7.84 g, (Ergotarrine utilization: 94.7%, HPLC not detectable content of 9,10-dihydro-ergotamine,).

Example 2

9.10- Dihydro-ergocristine

10.0 g of ergocristine base (ergocristine content by HPLC: 7.4 g, ergocristine content: 0.9 g) are dissolved in a mixture of 125 ml of glacial acetic acid, 50 ml of acetone and 25 ml of water. To the reaction mixture was added 1 ml cc. sulfuric acid and 5 g of palladium on charcoal are added and the mixture is stirred under a hydrogen atmosphere at room temperature and pressure for 4 hours. The catalyst was filtered off and the mixture was added dropwise to a mixture of 250 ml of 20% ammonium hydroxide and 100 g of ice. The precipitate was filtered off, washed three times with 50 ml of water and dried.

Product weight: 9.1 g.

Content of 9,10-dihydro-ergocristine by HPLC: 8.19 g, (Ergocristine utilization: 98.0%, 9,10-dihydro-ergocristine content cannot be detected by HPLC) -

Example 3

9.10- Dihydro-ergocriptine

10.0 g of α-ergocriptine base (ergocriptine content by HPLC: 7.6 g, α-ergocryptinin content: 0.7 g) are dissolved in 125 ml of glacial acetic acid, 50 ml of acetone and 25 ml of water. To the reaction mixture was added 1 ml cc. phosphoric acid and 5 g of palladium on charcoal are added and the mixture is stirred under a hydrogen atmosphere at room temperature and pressure. The catalyst was filtered off and the mixture was added dropwise to a mixture of 250 ml of 20% ammonium hydroxide and 100 g of ice. The precipitated product is filtered off, washed three times with 50 ml of water and dried.

Product weight: 9.4 g.

The content of 9,10-Dihydro-a-ergocriptine as measured by HPLC is 8.1 g, (Alkaloid utilization: 97.6%, HPLC cannot measure the content of 9,10-dihydro-ergocriptine).

9.10- Preparation of dihydro-lysergic acid g lysergic acid (content: lysergic acid content by HPLC: 6.4 g, isomeric acid: 0.6 g, other non-alkaloid impurity: 3.0 g) 125 ml glacial acetic acid, 50 ml acetone and 25 ml of water. 1 g of tartaric acid and 10 g of palladium on carbon are added and the mixture is stirred at room temperature under atmospheric pressure for 4 hours under a hydrogen atmosphere. After completion of the reaction, the catalyst is filtered and the pH of the solution is adjusted to the isoelectric point of 9,10-dihydro-lysergic acid with the ammonium hydroxide solution.

The precipitated dihydro-lysergic acid is filtered off, washed three times with 10 ml of water and dried.

The yield is 7.4 g, 9,10-dihydro-lysergic acid content by HPLC: 6.86 g (corresponding to 98% alkaloid utilization), 9,10-isomeric acid is not detectable by HPLC!

Example 5

9.10- Dihydro-ergocornine, 9,10-dihydro-a-eR gocriptine, 9,1O-dihydro-6-erocriptine

10.0 g of ergot toxin base (measured by HPLC: ergocornin content: 3.7 g, ergocorninine: 0.6 g, α-ergocriptine: 2.6 g, α-ergocriptinin: 0.5 g, β-ergocriptine: 1.2 g of β-ergocriptinine: 0.3 g) were hydrogenated according to Example 3 and the product isolated as described therein.

Product weight: 9.6 g, HPLC

9.10- Dihydro-ergocornine content: 4.2 g.

9.10- Dihydro-a-ergocriptine content: 2.9 g.

9.10- Dihydro-β-ergocriptine, content: 1.4 g. Alkaloid recovery: 95.5%.

9.10-dihydro-ergocorninine, respectively. -ergocriptinin derivatives not detectable.

Example 6

9.10- Dihydro-ergotamine

10.0 g of ergotamine base (measured by HPLC: 7.2 g of ergotamine, 0.85 g of ergotamine) are dissolved in a mixture of 125 ml of glacial acetic acid and 50 ml of water. To the reaction mixture was added 1.0 g of maleic acid and 5.0 g of bone palladium catalyst, and the mixture was stirred under hydrogen atmosphere at room temperature and atmospheric pressure for 2.5 hours. The catalyst was filtered off and the mixture was added dropwise to a mixture of 250 ml of 20% ammonium hydroxide and 100 g of ice. The precipitate was filtered off, washed three times with 50 ml of water and dried. Product weight: 9.0 g, 9,10-dihydro-ergotamine content by HPLC: 7.6 g, 94.4% alkaloid utilization, HPLC by 9,10-dihydro -ergotaminine content not detectable.

Example 7

9.10-Dihydro-ergotamine

10.0 g of ergotamine base (measured by HPLC: ergotamine content 4.1 g, ergotamine content 3.9 g) are dissolved in 125 ml glacial acetic acid and 50 ml water. To the reaction mixture was added 1.5 g of monochloroacetic acid and 5.0 g of palladium on charcoal, and the mixture was stirred under a hydrogen atmosphere at 35 ° C for 3 hours. The catalyst was filtered off and the mixture was added dropwise to a mixture of 250 ml of 20% ammonium hydroxide and 100 g of ice. The precipitated 9,10-dihydro-ergotamine base is filtered off, washed three times with 50 ml of water and dried.

Product weight: 9.2 g

9,10-Dihydro-ergotamine content (HPLC): 7.81 g (97.6% HPLC) of the 9,10-dihydro-ergotamine content was undetectable.

Claims (2)

PATENT CLAIMS A process for the preparation of ergoline backbone compounds free from inin-type isomers (left-rotating) by catalytic hydrogenation of ergoline backbone compounds with hydrogen gas in a solvent, wherein the starting compound is a 9,10-double bonded ergolene backbone. A mixture containing up to 60 wt.% (Right-rotating) -inin derivative with compound (s) -4193129 is treated with a monovalent acid having a pK of less than 3.5 and / or a polyhydric acid having a pKi of less than 3.5. Hydrogenation is carried out in the pH ₅ system obtained ₅ , and the resultant inin-free (reversible) ergoline compound is isolated. Process according to Claim 1, characterized in that the monobasic acid used is mono chloroacetic acid and the preferred acid is sulfuric acid, maleic acid and tartaric acid.