HU197006B - Process for producing ergolene derivatives by isomerization - Google Patents

Abstract

6-methyl-ergol-9-ene of general formula (I) is prepd from elymoclavine derivs. of formula (II). (II) is isomerised in an non-polar solvent, at the solvents bpt in the presence of an aluminium-oxide-hydrate catalyst, which also acts as an adsorbent. The product is dissolved off the catalyst and isolated in its unchanged as salt form. In formula (I) R1=H, short C. chain alkyl or hydroxy-methyl gp.; R2=halo, acyl-oxy-gp., or a hydroxy gp., provided R1 is not a Hydrogen atom and X=H or halo.

Description

The present invention provides a novel process for the preparation of 6-methyl-ergol-9-ene derivatives of formula (I) wherein R 1 is hydrogen, lower alkyl, or hydroxymethyl;

R ₂ is halogen or acyloxy, and hydroxy, with the proviso that when R _{2 is} hydroxy, R cannot be hydrogen,

X is hydrogen or halogen by isomerization.

In any case, the compounds of the present invention are known compounds which serve as a longing base for pharmaceutical compositions which are already present or in the process of being developed.

The role of ergolene skeletal compounds in medicine has continued to grow in recent years. In addition to the known d-lysergic acid amide compounds, d-lysergolic compounds have been formulated for pharmaceutical use. In this way, the importance of d-lysergol derivatives is enhanced.

In the literature, lysergol or lysergol. There are several methods for preparing lysergol derivatives. Thus, the reduction of the carboxyl group of d-lysergic acid to hydroxymethyl has been described (see, for example, Dutch Patent No. 7,102,982), or extraction from a plant (see, for example, British Patent No. 1,398,997) or isoclomerization of organoclavine [Bull. Ag. Chem. Soc. Japan, 20, 95 (1956)].

The latter method, the isomerization of elimoclavine, has gained increasing industrial importance.

No. 1,935,556. High activity according to the procedure described in German Patent Publication (Brockmann

l) -Aluminum oxide adsorbent was carried out in benzene or pyridine. The biggest obstacle to the application of the process on an industrial scale is that only a very poor conversion can be achieved even in a very dilute solution with prolonged boiling.

A further difficulty in industrial implementation is that there is a significant difference in the amount of conversion available and the amount of by-products used when using alumina that satisfies the desired Brockmann I activity, but with different origins. This results in uncertainty of reproducibility and high variance in the results.

Attempts have been made to reduce the reaction time and the amount of catalyst. For example, U.S. Patent No. 7,009,793. According to the Dutch patent, aluminum oxide or activated carbon containing palladium, radium, platinum or metal oxides was used. The conversion could not be increased above 50-55%.

Hungarian Patent No. 193,780 discloses the preparation of compounds wherein, in formula (I): R _; is hydrogen, R ₂ is a hydroxy group and X is halogen. These compounds were prepared from the analogous 2-halo-haloclavine derivatives in the presence of an alumina catalyst and an aromatic solvent in 50-60% yield.

Summarizing the literature data, it can be concluded that even after optimization, various methods were not used to achieve 55-

Yields greater than 60% and also with very significant variation.

It is an object of the present invention to provide a process for the industrial isomerization of the 8,9-position double bond of the elimoclavine derivatives to the 9,10-position. reproducible and with good conversion.

In our experiments, it has been found that the reaction time of isomerization is reduced to a lesser extent by the presence of boehmite [AlO (OH) j and / or gibbsite [Al (OI-1) ₃ ] or Al ₂ O ₃ containing at least 30% by weight and application. Surprisingly, muscle elution from elinoclavine derivatives results in a significantly higher chemical conversion cl than starting from elimoclavine and converting the lysergol obtained after ten isomerization to the desired derivatives.

This finding is unexpected because we have shown that the presence of a central aluminum atom with a different coordination number and valency other than Al ₂ O _{3 is} crucial for successful isomerization of the isomers. It was not foreseeable by the fact that the reaction medium as used in the substituents ergolene skeleton further facilitate the double bond on the átizomerizálódását -helyzetből ^{8 '9 91 c-position.}

In our experiments, it has been found that the processes known so far have been carried out by reacting different amounts of aluminum hydroxide and aluminum hydroxide, which are present in various amounts as impurities in the commercial products. Therefore, the procedure was in most cases not reproducible, since the A! _The "contamination" of ₂ O _{3 is} crucial to the reaction. This is proved by the experimental experience that when A !, with different Brockmann activity does not contain alumina or alumina. We are working with ₂ O ₃ , there is practically no isomerization. On the other hand, if the pure alumina is contaminated with at least 30% by weight and / or boehmite, the reactions are excellent.

It can be stated that the best results can be obtained using pure boehmite [AlQ (OH) 3 or gibbsite [A 1 (OH) ₃ ]. A commercial product having a Boehmite and / or Gibbsite content of at least 30% by weight has also proved to be suitable. in such a case, a clearly favorable transformation can already be achieved.

Accordingly, the present invention provides a process for the preparation of a compound of formula (I) wherein R 1 is hydrogen, lower alkyl, or hydroxymethyl.

R ₂ is halogen or C 2 -C 4 alkanoyloxy, and hydroxy, with the proviso that when R _{2 is} hydroxy, R 1 is not hydrogen,

X is hydrogen or halo-6-methyl-ergo! For the preparation of 9-ene derivatives by catalytic isomerization of an organoclavine derivative of formula (Π), wherein R 1, R ₂ and X are as defined above, in the presence of a solvent, followed by isolation of the resulting product by benzene or

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In a benzene derivative substituted with a C 1 -C 4 alkyl group, it is carried out at the boiling point of the system in the presence of Al ₂ O ₃ containing boehmite and / or gibbsite or 0.1 to 6% water and at least 30% by weight boehmite and / or gibbsite.

In a preferred embodiment of the invention, the catalyst used is boehmite [Al (OH)], gibbsite [Al (OH) ₃ ].

The reaction can also be carried out in good yield in the presence of Al ₂ O ₃ with a water content of less than 6% and at least 30% by weight boehmite and / or gibbsite.

The process of the invention uses benzene, toluene or xylene.

The water content of the Al ₂ O ₃ catalyst (according to Drockmann I activity) is preferably adjusted to 3.5-4.5% by weight, which can be achieved by adding water or azeotropic distillation.

Preferably, the catalyst is dissolved in a dilute aqueous acid or a mixture of a water-miscible organic solvent and a dilute aqueous acid.

The various starting compounds of the elimoclavine are prepared in a known manner. For example, according to Hungarian Patent No. 193,780, the halocellin is converted to 2-haloeliminoavin by incorporation of the halogen at the C ₂ position of the azergolene backbone; N-bromosuccinimide or dimethylsulfoxide-haloic acid system. Elimoclavine can be produced very simply, economically using fermentation technology known in the art (Gaviceps Purpurea microorganism).

Alkylation of etymoclavine or 2-halo-elloclavine derivatives is carried out in a manner known in the art (e.g., Helv. Chim, Acta. (7957) 1721]. Accordingly, the alkylation is carried out in liquid ammonia in the presence of metal potassium and alkyl iodide, or according to a method widely used in ergolene derivatives (see, for example, European Patent No. 4,664), whereby a large excess of potassium hydroxide is suspended and then adding the elloclavine or its 2-halo derivative to be alkylated and the alkylating agent. The reaction was carried out at room temperature and after pouring into water, the product was removed by simple filtration or extraction. Hydroxymethylation of the indodium nitrogen is carried out in a manner known per se, for example CA 55 17 678, whereby the elloclavine is dissolved in formaldehyde and, after boiling, is isolated by extraction from the cooled solution. The ergolene skeleton C _g -as centers esterification can be carried out with a carboxylic acid, acid halide, acid anhydride. In the case of esterification with acid anhydride, we work at room temperature using the acid anhydride or the acid derivative thereof as the solvent. Esterification is carried out at room temperature and the product is isolated by extraction after dilution. The eítmokiavin or 2 - halo - C _e elitnoklavin -as halogenation is carried out in a known manner (CoHect, Czech Chem Cornmon 39, 2819 (1969)]....

The material to be halogenated is dissolved in an apolar aprotic or dipolar aprotic solvent, such as acetonitrile, tetrahydrofuran, dimethylformamide, and at room temperature to the reflux temperature of the solvent used, with a halogen-containing phosphorous compound such as phosphorus phosphorus. After completion of the reaction, the reaction mixture was cooled, basified with ammonium hydroxide and isolated by extraction.

The product obtained by the process according to the invention can be converted, after dissolution with the catalyst, into an acid addition salt, preferably a phosphate, and the base may be liberated from the phosphate if desired. In this case, the phosphate is dissolved in an aqueous solution of tartaric acid in formamide and the basic compound of the lyscrgol is isolated with 1 N potassium hydroxide solution.

The most important advantage of the process according to the invention is that the isomerization can be carried out with very good conversion and faster than previously known processes.

A further advantage is that there is no need for a cumbersome so-called catalytic system. activation and higher reaction rates will result in less byproducts accompanying the production of the target compound.

The following examples illustrate our process:

Example 1

Preparation of 2-chloro-lysergerol Pure g boehmite is suspended in 120 ml of toluene and 20 ml of solvent are distilled off from the system at atmospheric pressure while the boiling system temperature rises to 108 ° C. To the cooled toluene solution was added 2.0 g (0.00693 mol) of 2-chloro-elloclavine having a HPLC content of 3% and a total alkaloid content of 97% based on perchloric acid titration.

The above system was refluxed for 60 minutes. The completion of the reaction is monitored by UV spectroscopy.

The boehmite is filtered off from the cooled reaction mixture and dried. The boehmite was washed with 2-chloro-lysergol in 3 x 40 mL of 4: boric acid / acetone / water (1: 3) and the combined filtrate was evaporated under reduced pressure to acetone-free.

The residue was triturated with charcoal (1 g), filtered off and the filtrate was basified to pH 9 with concentrated ammonium hydroxide. The precipitated base is filtered off, washed with water and dried.

Yield: 1.9 g of 2-chloro-lysergol base (1.2% unconverted 2-chloro-elimoclavine content, 0.55% 2-chloro agrocavine content and 94% total alkaloid)

Dissolve 1.9 g of crude 2-chloro-lysergol base (containing 1.2% unmodified 2-chloro-elloclavine and 0.55% 2-chloro-agro-clavin) in 40 ml of 2% aqueous phosphoric acid solution. . After dissolution, the crystallization begins immediately.

After crystallization for 1 hour at + 5 'C, the colorless crystals which formed are collected and washed with water and dried.

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Yield: 1.9 g of 2-chloro-lysergol-phosphate (0.004915 mol) (71.0% (based on the starting 2-chloro-lymeloclavine). Measured by HPLC 2-chloro-limeo clavine impurity: max. 0, 15%, other unknown impurities 0.65%. Active ingredient content 98% ₍₄ HC1O titration).

Example 2

Preparation of 2-chloro-lysergol

The amount and quality of the starting 2-chloro-elimokavavin are the same as in Example 1. In all of the procedures of Example 1, only 20 g of gibbsite was used as a catalyst.

Yield: 1.8 g (0.004657 mole) of 2-chloro-lysergol phosphate (67.2% relative to the starting 2-chloro-elimoclavine). 2 - Chlorine edge moiety: 0.2%, other unknown impurity: 0.55%. Drug content by titration with HClO ₄ added: 99%.

Example 3

Preparation of 2-chloro-lysergol

The amount and quality of the starting 2-chloro-elimokavavin are the same as in Example 1.

In each case, the procedure of Example 1 was followed, except that a 6: 4 mixture of boehmite-gibbsite (20 g) was used as a catalyst. Yield: 1.9 g (0.004915 mol) of 2-chloro-lysergol

phosphate (71.0% relative to the starting 2 - chloro elimocavin). According to HPLC measurement, 2-chlorine-elimoclavine impurity is 0.2%, other unknown impurities total: 0.45%.

Example 5 1-Methyl-2-chloro-lysergol g (0.00661 mole) was 1-methyl-2-chloro-elloclavine as isomerized as in Example 1. The catalyst used is 20 g boehmite.

Yield: 1.6 g (0.00528 mol) 80%.

Example 6

J-hydroxymethyl-lysergol

2.0 g (0.00704 µmol) of 1-hydroxymethyleneloclavine were isomerized as described in Example 1. The catalyst used is 20 g boehmite.

Yield: 1.55 g (0.00545 mol) 77.5% Melting point: 210-212 ° C.

Example 7

2-chloro-8-acetoxymethyl-lysergol

2.0 g (0.00606 mole) of 2-chloro-6-acetoxymethyleneloclavine were isomerized as described in Example 1. The catalyst used is 20 g boehmite.

Yield: 1.4 g (0.0042 mol) 70%.

Example 8

8-chloromethyl-lizcrgol

2.0 g (0.00651 mole) of 8-chloromethyl-elloclavine was isomerized as in Example 1. The catalyst used is 20 g boehmite. Yield: 1.9 g (0.00618 mol) 95%.

Melting point: 206-207 ° C.

Example 4

Preparation of 2-chloro-lysergol

The amount and quality of the starting elimoclavine dehydrate are the same as in Example 1.

In all the procedures of Example 1, 100 g of alumina with a boomite content of 30% by weight were used as catalysts only. Reaction time: 2 hours

Yield: 1.4 g (0.003622 mol) of 2-chloro-lysergol phosphate (48.5-52.2% relative to 2-chloro-elloclavine). According to HPLC measurement, the content of 2-chloro-elimoclavine is 0.9%, unknown is 0.65%.

Claims (4)

Claims A process for the preparation of a compound of formula (I) wherein: R 1 is hydrogen, lower alkyl, or hydroxymethyl, R ₂ is halogen or C 2 -C 4 alkanoyloxy and further hydroxy, provided that when R _{2 is} hydroxy, R cannot be hydrogen, X is hydrogen or halogen for the preparation of 6-methyl-ergol-9-ene derivatives of the formula (II) -halo! wherein R _1, R ₂ and X are the catalytic isomerization of the above-elimoclavine derivative in the presence of a solvent followed by 197 006, characterized in that the isomerization in benzene or a benzene derivative substituted with a C 1-4 alkyl group boils and / or gibbsite or 0.1-6 wt.% Water and at least 30 wt.% Boehmite and / or gibbsite in the presence of Al ₂ O ₃ . 2. A process according to claim 1, wherein the benzene derivative substituted with a C 1-4 alkyl group is toluene. The process according to claim 1 or 2, characterized in that the water content of the catalyst is 3.5 - 4.5% by weight.