DD246110A5 - METHOD FOR THE PRODUCTION OF 10-METHOXY-6-METHYLLERGOLIN DERIVATIVES AND THEIR SAEUREADDITIONAL SALTS - Google Patents

Abstract

The invention relates to a novel process for the preparation of partially known 10a-methoxy-6-methyl-ergoline derivatives of the general formula (I) in which R is hydrogen or a methyl group, X is hydrogen, chlorine, bromine or iodine and R is hydrogen or a 5-bromo nicotinoyl group, and their acid addition salts. The compounds are prepared according to the invention by reacting 2-halo-lysergols of the general formula (II), wherein X is chlorine, bromine or iodine, by a photochemical reaction to give 2-halo-lumilysergolen of the general formula (I) and these if desired converted by subsequent reactions into other compounds also covered by the general formula (I). The compounds of the general formula (I) have valuable pharmacological effects and are also important intermediates. Formulas I and II

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a novel process for the preparation of partially known 10a-methoxy-6-methylergoline derivatives and their acid addition salts. The compounds to be prepared correspond to the general formula (I) in which R is hydrogen or a methyl group,

X is hydrogen, chlorine, bromine or iodine and

R 'is hydrogen or a 5-bromo-nicotinoyl group.

The above compounds are in part valuable intermediates in the preparation of the niceroline known as peripheral vasodilator, and the other are the new 2-halo-Iumilysergols containing R, R ', X, chlorine, bromine or iodine, and R is a methyl group, as R'. Hydrogen and as X chlorine, bromine or iodine-containing new i-methyl-2-hallumilysergole also pharmacologically active itself.

Characteristic of the known technical solutions

For the production of nicergoline several methods are known from the literature. The preparation of esterified derivatives of 10-methoxy-1-dimethyl-ergoline-S-methanol, including nicergoline, have been described for the first time in DE-PS 2112273 and US Pat. No. 3,228,943. According to said US-PS is based on lumilysergic acid or 1-methyllumilysergic acid and reduces the carboxyl group in the 8-position with lithium aluminum hydride in an ether to the OH group. This is then esterified with the anhydride or chloride of the corresponding alcohol in the presence of a tertiary amine. When using lumilysergic acid as starting material, the methylation is carried out with a methyl halide, in liquid ammonia and in the presence of metallic potassium. To produce the corresponding luminescent compounds, the respective acids are dissolved in a dilute mineral acid and irradiated with UV light. According to DE-PS 2112273 is assumed by lumilysergol and methylated after esterification.

According to DE-PS 2752533, the nicergoline is obtained by esterifying 1-methyl-lumilysergol with 5-bromonicotinic acid. The esterification is carried out with an imidazole-triphenylphosphite complex in the presence of hexamethylenephosphortriamide.

A process described in EP-PS 4664 is based on the production of the nicergoline from lysergol. The lysergol is methoxylated with UV light in the presence of methanol to lumilysergol. The N-indole methylation is then carried out in dimethyl sulfoxide in the presence of potassium hydroxide with methyl iodide. The resulting 1-methyl-lumilysergol is then esterified in tetrahydrofuran in the presence of dicyclohexyl-carbodiimide as a condensing agent with 5-bromo-nicotinic acid to nicergoline.

As can be seen from the literature, the connection of the methoxy group with the carbon atom in the 10-position of the Ergolingerüstes so far only succeeded in photochemical way. The attempts to circumvent the photochemical reaction (US Pat. No. 3,814,765) did not lead to success, because ergole derivatives were formed from which the desired starting compounds could not be prepared.

It has only been possible to optimize the methoxy group-introducing reaction carried out in the presence of UV light in the case of lysergic acid (CA 95 43434y).

For carrying out the indole-N-methylation is described in addition to the methods described in the three abovementioned patents from EP-PS 0533 still running as a phase transfer reaction methylation.

The processes described above for the production of the nicergoline have the common disadvantage that significant amounts of byproducts are formed in the photochemical step, with the result that, to recover the product and separate the resulting structural isomers and unwanted dyes, complicated chromatographic procedures required are.

Object of the invention

The aim of the invention is to reduce the stated deficiencies of the prior art.

Explanation of the essence of the invention

The invention has for its object to reduce the amount of by-products obtained in the photochemical process step.

It has now surprisingly been found that in the preparation of the 10-methoxy-ergoline derivatives ausin2-position of Ergolengerüstes halogenated derivatives in the photochemical reaction significantly fewer by-products and structural isomers are formed, as in the lysergol or lysergic emanating from the photochemical reactions of Case is. Therefore, the resulting 2-halo-lumiverbindungen need not be purified by chromatography, but their purification is sufficient for a simple crystallization, and the yield is higher than those achieved with the known methods so far. , ,

The compounds of the general formula (I) and their pharmacologically acceptable acid addition salts are prepared according to the invention by reacting 2-halo-lysergols (2-halo-6-methyl-8-hydroxymethylergol-9-enes) of the general formula (II) in which X. is chlorine, bromine or iodine, by a photochemical reaction to 2-Halogenlumilysergolen the general formula (I) is reacted, in which R and R 'are hydrogen and the meaning of X is chlorine, bromine or iodine, if desired, the resulting 2-halogen -lumilysergole, if desired, from obtained 1-methyl-2-halo-lumilysergolen of the general formula (I) in which R stands for a methyl group, while the meaning of X and R 'is the same as above, that in the 2-position of Ergolingerüstes If desired, 1-methyl-lumilysergole of the general formula (I), in which R 'is hydrogen, by esterification to that falling under the formula (I), is removed by removal of chlorine, bromine or iodine atom ners nicergoline (10α-methoxy-1-dimethyl-ergoline-SjS-methanol-S-bromo-nicotinate) in which X is hydrogen, R 'is a 5-bromo-nicotinoyl group and R is a methyl group, reacting in each step of the method, the IOa-methoxy-6-methyl-ergoline derivatives, if desired, in their physiologically acceptable acid addition salts implement. ·

The introduction of an activating group into the center C-2 is associated with further unexpected advantages. In addition to the desired N-methyl compound, the known methylation process always produces a significant proportion of O-methyl derivative, from which the desired product must then be separated off. It has now been found that the N-methylation carried out with halogenated ergoline derivatives proceeds within a shorter time and is more selective than the known processes, and this leads to significantly higher yields. Another advantage is that the N-methyl-2-halogenlumiverbindungen are much less soluble than the non-halogen corresponding compounds. As a result, they can be isolated more easily, for example without extraction with chloroform, which also leads to higher yields.

The preparation of the 2-halo-lysergols of the general formula (II) which are used as starting material for the process according to the invention can be carried out in accordance with Examples 1-3. According to these examples, lysergol is halogenated or 2-halo-elimoclavines are isomerized

In the first step of the process according to the invention, the 2-halo-lysergols of the general formula (II) are reacted in a photochemical reaction to 2-halo-lumilysefgolen.

The photochemical reaction is carried out in sulfuric acid methanol by irradiation with a UV light source. The reaction is monitored by thin-layer chromatography. After completion of the photochemical reaction, the reaction mixture is poured into ice-water, the mixture is adjusted with ammonium hydroxide to a pH of 6 and with a water-immiscible solvent such as chloroform, dichloromethane, benzene, carbon tetrachloride or toluene, but preferably with chloroform, extracted. The extract is dried and evaporated. The evaporation residue containing the 2-halo-lumilysergol is crystallized from an aprotic solvent, for example acetone, ethyl acetate, benzene or acetonitrile. For methylation, the 2-halo-lumilysergol in a dipolar aprotic solvent, preferably in a 15-20 ° C warm mixture of anhydrous dimethyl sulfoxide and potassium hydroxide, dissolved. After stirring the mixture for 30-35 minutes, the methyl iodide is added. Then, the reaction mixture is poured into ice-water and the precipitated 1-methyl-2-halo- | umilysergol filtered off and dried in vacuo. The product is recrystallized from one of the solvents mentioned in the photochemical reaction, preferably acetone, or, if desired, the halogen atom is removed from the 1-methyl-2-halo-lumilysergol by dehalogenation. For dehalogenation, the 1-methyl-2-halo-lumilysergol is dissolved in a protic or aprotic solvent, for example in ethanol, methanol, ether, ethyl acetate, acetonitrile, tetrahydrofuran, benzene or toluene, but preferably in ethanol. This solution is added to pre-moistened palladium activated carbon, the amount of which should be 10% based on the amount of the substance.

The reduction is carried out with hydrogen gas flowing through and monitored by thin-layer chromatography. After the reduction has taken place, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The evaporation residue is crystallized from an aprotic solvent, for example acetone. From the resulting 1-methyllumilysergol the nicergol is prepared by esterification. This is done in two stages. In the first stage, an active ester is prepared, and in the second stage, it is used for esterification.

To prepare the active ester, N-hydroxysuccinimide is dissolved in an aprotic solvent, for example tetrahydrofuran or ethyl acetate (preferably in the latter), and the solution is first treated with an excess of 5-bromonicotinic acid, then with N-hydroxysuccinimide. molar equivalent amount of N, N-dicyclohexyl-carbodiimid added. The mixture is stirred at room temperature, the deposited precipitate is filtered off and the filtrate is evaporated under reduced pressure. The active ester obtained in the form of a white amorphous substance may, if necessary, be crystallized from ethanol.

In the second step, the esterification with the active ester at 20-60 ⁰ C, preferably at room temperature, in an aprotic solvent, for example tetrahydrofuran, benzene or acetonitrile, but preferably in tetrahydrofuran, (in the presence of an organic base such as triethylamine or pyridine, preferably Pyridine). The organic base can simultaneously serve as a solvent. The 1-methyl-lumilysergol is dissolved in a suitable solvent or excess of the organic base and added to the solution of active esters. The reaction will. followed by thin layer chromatography. When the esterification is complete, the solvent is removed in vacuo, the final product is separated from the organic base by Estrahieren and crystallized after drying and in vacuo evaporation of the extract of diethyl ether. If necessary, the product can be purified by column chromatography.

Of the compounds of the general formula (I) prepared by the process according to the invention, those which contain hydrogen as R and R 'and chlorine, bromine or iodine as X (2-halo-lumilysergols) and those which as R are a methyl group are novel , as R'hydrogen and as X chlorine, bromine or iodine (1-methyl-2-halo-lumilysergole). These compounds also have valuable pharmacological effects per se, in particular they have a blocking effect on the D ₂ receptors.

The studies on the blocking of the D ₂ receptors were carried out according to the method of Seeman (P. Seeman: Dopamine receptor measurment with [3 _H ] Ligands, Methods in Biogenic Amines Ftesearch, Ed., By S.Parvez, T. Nagatsu, I.Nagatsu and H. Parvez, p. 591-622 [1983], Elsevier). The studies involved rat striatum membranes and ligand [3H] -spiroperidol.

The IOa-methoxy-6-methyl-ergoline derivatives of the general formula (I) prepared by the process according to the invention are isolated as base, if desired purified by recrystallization or, if desired, to a physiological. reacted acceptable acid addition salt. , · ...

For recrystallization, an aprotic or protic solvent, preferably acetone or ether, may be used.

To prepare the acid addition salts, the compound is dissolved in an inert solvent, for example an aliphatic alcohol of 1-6 carbon atoms, and the solution is treated with the appropriate acid or solution of this acid prepared with the same solvent until the mixture becomes acidic. The precipitated acid addition salt is then separated in a suitable manner, for example by filtration, from the reaction mixture.

The novel 2-halo-lumilysergols or i-methyl-2-halo-lumilysergols of the general formula (I) can be mixed with the usual non-toxic inert solid or liquid carrier, stretching, parenteral or enteral administration which is conventional in the pharmaceutical industry. and / or excipients and formulated into pharmaceutical preparations. Suitable carriers are, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils (for example peanut oil and olive oil). The active compounds may be formulated in the form of the usual pharmaceutical preparations, for example in solid form (rounded or square tablets, dragées, capsules of gelatin capsules, pills, suppositories). The amount of solid carrier can vary widely and is generally from 25 mg to 1 g for a dosing unit. The preparations may optionally contain the usual adjuvants, for example preservatives, stabilizers, wetting and emulsifying agents, etc. The preparation of the preparations is carried out in a conventional manner, for example - in the case of solid preparations - by sieving, mixing, granulation and pressing of the components. The preparations may be subjected to further operations customary in the manufacture of medicaments, for example sterilized.

embodiments

The invention will be explained in more detail with reference to the following embodiments, but is not limited to these examples.

example 1

2-Chloro-lysergol

1 g of lysergol is dissolved in 400 ml of anhydrous dimethylsulfoxide and the solution saturated with dry hydrochloric acid gas, wherein the eighth daraufzu that the temperature of the reaction mixture does not rise above 3O ⁰ C. The progress of the reaction is monitored by thin-layer chromatography. If no more starting material is detectable, the mixture is poured onto 200 ml of ice water and its pH adjusted to 7 with ammonium hydroxide. The precipitate is filtered off and dried in vacuo. If necessary, the compound may be further purified on a silica gel column with a 80:20 mixture of chloroform and methanol as the eluent. This gives 1 g (60%) of the title compound, which melts at 207 ⁰ C.

Example 2

2-Chloro-lysergol

1 g of 2-chloro-elimoclavin is suspended together with 10 g of Brockman I aluminum oxide in 70 ml of toluene. The reaction mixture is boiled for 15 minutes, then cooled to room temperature, whereupon the aluminum oxide is filtered off. The filtered catalyst is slurried three times with 50 ml of methanol at a temperature of 40-50 ⁰ C and filtered off. The combined organic phases are evaporated in vacuo. This gives 0.8 g (80%) of the title compound, which melts at 207 ⁰ C.

Example 3

2-Chloro-lysergol phosphate

1 g of 2-chloro-elimoclavin is isomerized according to the manner described in Example 2 and the product isolated without crystallization. After evaporation, the solvent-free evaporation residue (0.8 g) is dissolved at 80-90 ⁰ C in 70ml of 4% phosphoric acid. The solution is cooled to 0-5 ⁰ C, whereby the title compound äuskristallisiert. This gives 0.8 g (75%) of the substance, which melts at 248 ⁰ C. Eutectic melting point in dicyandiamide: 189 ^° C.

Example 4

2-Chloro-lysergol phosphate

0.5 g of 2-chloro-elimoclavin are isomerized according to the manner described in Example 2. From the cooled reaction mixture, the Aluniiniumoxyd is filtered off. The filtered catalyst is slurried at 80-90 ⁰ C three times with 15 ml of 4% phosphoric acid and stirred for 15 minutes, after which the solution is filtered hot. The filtrate is cooled to 0-5 ⁰ C, whereby the title compound crystallizes. This gives 0.4 g (60%) of the phosphate, which melts at 248 ° C.

Example 5

2-bromo-lysergol

3 g of anhydrous lysergol are dissolved in 6O ⁰ CJn 500 ml of anhydrous dioxane. While stirring, a solution of 2.3 g of N-bromo-succinimide prepared by dioxane is added dropwise to the solution. The reaction mixture is stirred at 60 ° C for 30 minutes, then adjusted to pH 8 with triethylamine and evaporated under reduced pressure. The product is chromatographed on a silica gel 60 column with a 80:20 mixture of chloroform and methanol and then recrystallized from acetonitrile. This gives 2.2 g (55%) of the title compound, which melts at 193 ⁰ C.

Example 6

2 Iodine lysergol

3 g of anhydrous lysergol are dissolved at 60 ⁰ C in 600 ml of anhydrous dioxane and reacted according to the manner described in Example 5 with 3.0 g of N-iodo-succi η in id. The mixture is worked up in the manner described in Example 5. 2.15 g (48%) of the title compound are obtained.

¹ H-NMR (CDCl ₃ + DMSOd ₆ ): 2.46 (b, 3H, N-CH ₃ ), 3.97 (b, sH, CH ₂ -OH), 6.29 (b., 1 H, olefinic), 6.96 (m, 3H, arom.

Hydrogen)

UV: X _max = 312nm

Example 7

2-chloro-lumilysergol

2.0 g (0.007 mol) of 2-chloro-lysergol are dissolved in 200 ml of a 40:75 ratio mixture of methanol and sulfuric acid. At 25-30 ⁰ C, the mixture is irradiated with a TUNGSRAM mercury vapor lamp with a power of 250W. The reaction is monitored by thin-layer chromatography (Kieselgel 60 F254, chloroform and methanol in the ratio 80:20). After the reaction, the mixture is clarified with 0.2 g of activated carbon, poured after filtering on 300 ml of ice water and adjusted with ammonium hydroxide to a pH of 8. The mixture is extracted three times with 70 ml of chloroform, the combined organic phases are dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue is crystallized from acetone. This gives 2.0 g (90%) of the title compound, which melts at 227 ° C.

¹ H-NMR (DMSOd ₆ H-CDCl ₃ ) PPm: 2.50 (b, 3H ₁ N-CH ₃ ), 2.85 (b, 3H, -O-CH ₃ ), 3.55 (m , 2H, -CH ₂ -OH), 7.13-7.24 (m, 3H, arom. H) IR (in KBr) cm ^-1 : 2910 (-OCH ₃ ), 780 (dry halogen).

Example 8

2-chloro-lumilysergol-maleate

0.8 g (2.46 mmol) of 2-chloro-lumilysergol are dissolved in a mixture of 40 ml of methanol and 30 ml of dichloromethane, whereupon 0.3 g (2.58 mmol) of maleic acid are added to the solution. After everything has dissolved, the solvent is removed under reduced pressure. The dry residue is triturated with 50 ml of diethyl ether, filtered, washed with ether and then dried. Yield: 0.92 g (84.9%).

Example 9 - -

i-methyl-2-chloro-lumilysergol

1.54 g of finely powdered potassium hydroxide are added to 12.7 ml of dimethyl sulfoxide. The mixture is stirred at room temperature for 10 minutes, then heated to 15-2O ⁰ C and treated with 2.0 g of 2-chloro-lumilysergol. The mixture is stirred for 35 minutes, then warmed to room temperature, treated with 0.6 g of methyl iodide and, after stirring for a further 10 minutes, poured onto 400 ml of ice water. The precipitate is filtered off. The filtrate is evaporated in vacuo and the residue is crystallized from acetone. This gives 1.77 g (85%) of the title compound, which melts at 252 ° C.

¹ H-NMR (DMSOd ₆ + TFA) ppm: 2.50 (b, 3H, N-CH ₃ ), 2.85 (b, 3H, -O-CH ₃ ), 3.55 (m, 2H , -CH ₂ OH), 3.73 (b., 3H, indole-N-CH ₃ ),

7.13 to 7.44 (m, 3H, arom.H)

IR (in KBr) cm ^-1 : 2910 (OCH ₃ ), 2820 (indole-CH ₃ ), 780 (Arom. Cl)

Example 10

1-methyl-2-chloro-lumilysergol hydrochloride

0.3 g (0.89 mmol) of 1-methyl-2-chloro-lumilysergoi are dissolved in 40 ml of absolute ethanol. To the solution is added 10% hydrochloric acid ethanol in molar amount. (The exact acid content of the hydrochloric ethanol is previously determined by titration with sodium hydroxide.) The resulting solution is evaporated to a volume of 10 ml and allowed to stand at ⁰ C overnight. The precipitated crystals are filtered off and washed with cold ethanol. Yield: 0.28 g (83.8%).

Example 11

2-bromo-lumilysergol

The procedure is as in Example 8, but using as starting material 2.0 g (5.98 mmol) of 2-bromo-lysergol. Yield: 1.86 g (85%) of eutectic melting point with dicyandiamide: 206 ^° C.

¹ H-NMR (CDCI ₃₎ ppm: 2.47 (b, 3H, N-CH _3.), 2.87 (b, 3H, O-CH _3.), 3,4T (m72H7CH2-OH), 7 , 07- (m, 3H, arom. H)

IR (in KBr) cm ^-1 : 3400 (OH), 2910 (-OCH ₃ , 3150 (indole-NH).

Example 12

i-methyl-2-bromo-lumilysergol

The starting material is 1.0 g (2.7 mmol) of the 2-bromo-lumilysergol prepared according to Example 11. The procedure is as described in Example 9. This gives 0.78 g (75%) of the title compound, which melts at 240-242 ⁰ C.

¹ H-NMR (PMSOd ₆ ) '2.49 (b, 3H, N-CH ₃ ), 2.9 (b, 3H, OCH ₃ ), 3.55 (m, 2H, CH ₂ OH), 3.75 (b, 3H, indole-N-CH ₃ ), 7,17-

7.31 (m, 3H, arom.H)

IR (in KBr) cm ' ¹ : 2910 (OCH ₃ ), 2920 (indole-N-CHs).

Example 13

• 1-methyl lumilysergol

0.1 g of 10% palladium activated carbon is moistened with 3 ml of ethanol. To this is added a solution of 1.0 g of i-methyl-2-chloro-lumilysergol prepared with tetrahydrofuran. Hydrogen is allowed to flow through the mixture and the course of the reduction is monitored by thin-layer chromatography. After completion of the hydrogenation, the catalyst is filtered off and washed twice with 4 ml of ethanol. The combined organic phases are evaporated in vacuo. The oily residue is crystallized from acetone. 0.85 g (95%) of the title compound is obtained, melting at 213-215T.

Example 14

N-hydroxy-succinimide-o-bromo-nicotinate (active ester)

1 g of N-hydroxy-succinimide and 5.2 g of 5-bromonicotinic acid are dissolved in 100 ml of anhydrous ethanol at 50 ° C and added to the solution of 1.77 g of N, N-dicyclohexyl-carbodiimide. The reaction mixture is stirred at room temperature for 4 hours, then cooled to 5 ° C and the precipitated white crystalline substance filtered off. The filtrate is evaporated in vacuo and the evaporation residue recrystallized from ethanol.

Example 15

nicergoline

1 g of 1-methyl-lumilysergol is dissolved in 100 ml of anhydrous pyridine. To the solution is added 0.96 g of the active ester prepared according to Example 14. The reaction mixture is stirred at room temperature for 4 hours. The progress of the reaction is monitored by thin-layer chromatography. After the esterification, the reaction mixture is evaporated under reduced pressure. The residue is poured into 200 ml of a 10% sodium carbonate solution and extracted three times with 30 ml of chloroform each time. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and then evaporated under reduced pressure. The residue is crystallized from ether and, if necessary, purified by chromatography. This gives 1.5 g (93%) of the title compound, which melts at 135 ° C.

- b-

CH ₃ O.

CHiOR ¹

N-CH

R-N-

* Χ ·

CH ₂ OH

N-CH ₃

HN

 3 9.86-371426

Claims (2)

claims: 1. Process for the preparation of preproOa-methoxy-6-methylergoline derivatives of the general formula (I) in which R is hydrogen or a methyl group, X is hydrogen, chlorine, bromine or iodine and R 'is hydrogen or a 5-bromo-nicotinoyl group, and their acid addition salts, characterized in that 2-halo-lysergols (2-halo-6-methyl-8-hydroxymethyl-ergol-9-ene) of the general formula ( II) in which X is chlorine, bromine or iodine, by a photochemical reaction to the falling below the general formula (I) 2-Halogenlumilysergolen in which R and R 'are hydrogen and X is chlorine, bromine or iodine, if desired, these 2-halo-lumilysergole methylated, if desired, the resulting i-methyl-2-hasogenlumilysergole in which R is a methyl group and X is chlorine, bromine or iodine, dehalogenated and, if desired, 1-methyl-lumilysergole of the general formula ( I), where R 'is hydrogen, esterified, wherein in each step of the process, the IOa-methoxy-6-methyl-ergoline derivatives can be converted into their physiologically acceptable acid addition salts. 2. The method according to claim 1, characterized in that 1-methyl-lumilysergol with an active ester, preferably with an N-hydroxy-succinimide, and 5-bromo-nicotinic acid produced active ester, to 10a-IVlethoxy-1,6 -dimethylergoline-8 ^ -methanol-5-bromnicotinate (nicergoline) esterified.