CS229086B1 - Method of preparing d-1,6-dimethyl-8 beta-/5-bromonicotinoyl/oxymethyl-10 alphametohoxyergoline - Google Patents

Description

The present invention relates to a process for the preparation of D-1,6-dimethyl-8 beta- (5-bromonicotinoyl) oxymethyl-10 alpha-methylergoline of the formula I

The compound of formula I is a potent α-adrenergic blocker, has a potent vasodilator and antiserotonin effect, and increases blood flow in the brain of animals. It has found wide application in human therapy in the treatment of various brain diseases and in geriatrics.

The prior art processes described for the preparation of the compound of formula I have some disadvantages. In the method according to MS. No. 144,540 and U.S. Pat. No. 3,228,943, starting with D-lysergic acid, is converted by photoaddition of methanol to 10 alpha-methoxydihydrolysergic acid (II) methyl ester to give 10 alpha-methoxydihydrolysergol (III) by reduction with lithium aluminum hydride. Methylation of alcohol (III) with methyl iodide in liquid ammonia in the presence of potassium amide affords 1-methyl-10 alpha-methoxydihydro-lysergol (IV), which is acylated with 5-bronmicotinic acid chloride in pyridine to give compound I. low yields in esterification of alcohol IV, as well as the use of lithium aluminum hydride to reduce ester II is less suitable for industrial purposes.

According to French patent 2,084,678 it is possible to carry out the esterification of the alcohol IXI with 5-bromonicotinic acid chloride first and then 1-methylation of the obtained D-6-methyl-8β- (5-bromonicotinoyl) -10rt-methoxydihydrolysergol (V) to give I. III proceeds better than the acylation of the above-described 1-methyl derivative IV, but methylation of ester V in liquid ammonia is accompanied by undesirable side reactions so that the desired compound I is obtained in low yield (about 60%).

According to another method (German Pat. No. 2,752,533 »Yugoslavian Proirita 22.12.76), esterification of alcohol IV can be accomplished with 5-bromonicotinic acid using an imidazole-triphenyl phosphite complex; The disadvantages of this process are the more expensive auxiliary raw materials and the need to isolate the desired product by column chromatography on cation exchangers.

1-Methylation can also be carried out in the ester phase II, a cell with methyl iodide in liquid ammonia in the presence of potassium amide (L. Bernardi et al., II Farmaco Ed. Sci. 30, 789 (1975)), or using phase transfer catalysts (cf. AO No. 216 231). The disadvantage of the first process is low yields due to side reactions, in the second process large volumes of reaction solvents used.

According to European patent 0 004 664, lysergol VI is used as a starting material in the preparation of a compound of formula I. The photoaddition of methanol to VI gives alcohol III which is methylated with methyl iodide in a mixture of dimethylsulfoxide with powdered potassium hydroxide to give the 1-methyl derivative IV; The esterification of the alcohol IV is carried out with 5-bromonicotinic acid in the presence of dicyclohexylcarbodiimide. The disadvantage of this process is the formation of the O-methyl derivative in the methylation of III and the difficult removal of the dioyclohexylurea resulting from the esterification of alcohol IV.

We have now found a novel process for the preparation of a compound of formula (I) using the available 1-methyl-D-lysergic acid as a starting material which overcomes most of the above-mentioned disadvantages of the described processes.

According to the invention, the compound of formula I is preferably produced by the process of:

a) 1-methyl-D-lysergic acid of formula VII

H

_N-CH3

Ή

COOH (VII) CH ₃ indicate for irradiation in the presence of a strong acid is reacted with methanol to give methyl 1-methyl-10 alpha-methoxyčihydrolysergové VIII

H

_N-CH3

H cooch ₃ (VIII) ch ₃

b) reducing the methyl ester VIII obtained with a complex hydride, preferably sodium borohydride, to t-methyl-10 < 6 > -methoxydihydrolysergol of formula IV

c) compound IV is esterified in an inert medium, in the presence of triethylamine, with 5-bromonicotinic acid chloride of formula IX

Br COCI

to form a compound of formula I.

In step a), the photoaddition of methanol is carried out by irradiating a methanolic solution of 1-methyl-D-lysergic acid in the presence of a strong acid. Sunlight or preferably ultraviolet light, preferably with a maximum radiated energy at about 320 nm, can be used as a light source, such as low-pressure or high-pressure mercury ultraviolet lamps.

As strong acids, strong mineral acids such as sulfuric acid or organic sulfonic acids such as methanesulfonic acid can be used. The reaction time depends on the intensity of the light source, the purity of the starting materials and the concentration of the strong acid used. The higher the light intensity and acid concentration, the higher the reaction rate; colored impurities reduce the passage of light through the irradiated solution layer and slow down the reaction. The reaction may be carried out at a temperature in the range of about -10 to 50 ° C, preferably at room temperature. The photoaddition of methanol, due to the formation of a new chirality center at position 10 of the molecule, results in 2 stereoisomers, 10 alpha - and 10 beta-methoxy derivative; under the above conditions, the course of the reaction is highly stereospecific and in addition to the predominant amount of the desired 10 alpha isomer, only about 5-10 to 10 beta isomers are formed.

The progress of the reaction is expediently monitored by means of UF spectra of the samples taken; the reaction is complete when the maximum of 1-methyl-D-lysergic acid at 318 nm (in methanol) disappears.

After completion of the reaction, the product is isolated by known methods, for example by alkalizing the mixture, removing the compound of formula I in a suitable water-immiscible solvent and column chromatography of the crude product, or converting it to a suitable salt.

The starting 1-methyl-D-lysergic acid is readily accessible by methylating D-lysergic acid with methyl iodide in liquid ammonia in the presence of sodium or potassium amide (A. Cerny and M. Semonsky, Collection Czechoslovak Chem. Commun. 27, 1585 (1962)) ).

In step b) of the process according to the invention, the reduction of the ester VIII to the alcohol of the formula IV can be carried out with lithium aluminum hydride. However, the inventors have found that ester VIII can be advantageously reduced with sodium borohydride or sodium bis- (2-methoxyethoxy) aluminum hydride. Due to the absence of reactive hydrogen at the 1-position of the molecule, there is no loss of the reducing agent by reaction with this hydrogen, as is known in the art.

For reduction with sodium borohydride, 1 to 20 mol, preferably 8 to 10 mol, of reducing agent per 1 mol of ester VIII can be used. The reaction is carried out in a lower alcohol such as methanol, ethanol, propanol or isopropanol, preferably at the boiling point of the reaction mixture. The progress of the reaction is conveniently monitored by thin layer chromatography; the reaction time is usually 2 to 4 hours. The treatment of the reaction mixture after the reduction is carried out by conventional means, for example by removal of the substance in a water-immiscible organic solvent and by column chromatography and / or crystallization of the crude product.

A commercial solution of the reagent in toluene in an amount of 1 to 3 moles, preferably 1.5 to 2 moles, per 1 mol of ester is used to reduce the ester VIII with sodium bis- (2-methoxyethoxy) aluminum hydride. The reaction is preferably carried out in an anhydrous aromatic hydrocarbon such as benzene, toluene or xylene at a temperature in the range of about 50 to 120 ° C, preferably at about 80 to 100 ° C; the reaction time is usually 4 to 8 hours. After completion of the reaction, the excess reagent is quenched with aqueous methanol, the aluminum salts are taken up in 10 M sodium hydroxide solution and the crude product obtained after evaporation of the solvents is purified by column chromatography or crystallization.

In step o) according to the invention, the esterification of the alcohol of formula IV is preferably carried out with a chloride of formula IX in an inert medium in the presence of a tertiary amine to bind the liberated hydrogen chloride. It has unexpectedly been found that while carrying out this reaction in a known manner in pyridine, a large excess (about 3 mol) of chloride IX is required and the reaction proceeds slowly and with low yields (see Bernardi, 1c), using triethylamine (1-2 mol equivalents) in a suitable solvent of the reaction quickly and in high yield already using an equivalent or a small excess of chloride IX (1 to 1.1 mol equivalents). The inert medium used is preferably chlorinated aliphatic solvents such as methylene chloride, chloroform or carbon tetrachloride; the reaction is carried out at a temperature in the range of about -10 to +30 ° C, preferably +5 to +20 ° C, and the reaction time is usually 1 to 4 hours. After completion of the reaction, the triethylamine hydrochloride formed is taken up in water and, after distilling off the solvent, the crude product is purified by crystallization.

The process of the invention is explained in more detail in the following examples, which, however, do not limit its scope in any way.

He did

1-Methyl-10α-methoxydihydrolysergic acid methyl ester (VIII)

A solution of 15.0 g of anhydrous 1-methyl-D-lysergic acid in a mixture of 240 ml is irradiated in a photochemical reactor under a nitrogen atmosphere, while cooling with running water, at a temperature of 20-25 ° C. of methanol with 20 ml of concentrated sulfuric acid with a high-pressure ultraviolet lamp until the maximum of the starting acid (318 nm) in the ultraviolet spectrum of the sampled samples disappeared (about 20 hours). The reaction mixture was poured into a mixture of ice water (750 g) with concentrated ammonia (50 mL), the product was taken up in chloroform, the chloroform extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform / ether (1: 3) to afford the ester VIII (10.6 g, 60%) as a viscous residue; / Λ / ² θ = + 10 ° (c = 0.5, chloroform).

Example 2

1-Methyl-10-methoxydihydrolysergol (IV)

To a solution of 32.8 g (0.1 mol) of 1-methyl-10 ° C-methoxydihydrolysergic acid methyl esters in 560 ml of ethanol, 37.8 g (1 mol) of sodium borohydride are added portionwise with stirring over about 5 minutes. The mixture was then heated at reflux for 4 hours. Most of the ethanol was distilled off under reduced pressure, the residue was dissolved in water (300 ml) and the product was taken up in chloroform (500 ml). The chloroform fraction was washed with water, dried over anhydrous stearate and the solvent was distilled off under reduced pressure. The residue was recrystallized from acetone to give compound IV (25.1 g, 83.5% yield), mp 213-215 ° C;

[.alpha.] D @ 20 -13.4 DEG (c = 0.3, pyridine)

Example 3

1-Methyl-10 d-methoxydihydrolyaergol (IV)

To a solution of 3.26 g (11 nmol) of 1-methyl-10'-methoxydihydrolysergic acid methyl ester in 90 ml of toluene was added dropwise, under nitrogen atmosphere, 11 ml of a 49.6% bis- (2-methoxyethoxy) toluene solution. sodium aluminum hydride (4.23 g, 21 nmol) and the reaction mixture was heated at 90-95 ° C for 4 hours. The solution was cooled, the excess reagent was quenched by dropwise addition of 10 mL of 80% aqueous methanol, the mixture was diluted with chloroform (100 mL) and the aluminum salts were taken up in 10 L of sodium hydroxide solution. The organic portion was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to about half. The precipitated IV is filtered off and dried under reduced pressure. 2.6 g of the desired product are obtained (yield 78.5%), m.p. 214 DEG-215 DEG C., [.alpha.] D @ 20 = -12.6 DEG (c = 0.3, pyridine). • i Example 4

6-1,6-dimethyl-8 beta- (5-bromonicotinoyl) oxymethyl-10 alpha-methoxyergoline (I)

To a suspension of 15.0 g (0.05 mol) of 1-methyl-10α-methoxydihydrolysergol in a mixture of 150 ml of methylene chloride with 6.1 g (0.06 mol) of triethylamine was stirred and cooled at 15-20 ° C. , a solution of 13.2 g (0.06 mol) of 5-bromonicotinic acid chloride in 50 ml of methylene chloride is added dropwise; the solid goes into solution. The reaction mixture was stirred at room temperature for 1 hour, then washed with sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue (24.0 g, yield 99%) was recrystallized from ether. 136 DEG-138 DEG C .; [.alpha.] D @ 20 = -16.1 DEG (c = 0.5, pyridine).

Claims (4)

Process for the preparation of D-1,6-dimethyl-8 beta- (5-bromonicotinoyl) oxymethyl-10 alpha-methoergoline of the formula I, characterized in that a) reacting 1-methyl-D-lysergic acid of formula VII under irradiation, in the presence of a strong acid, with methanol to form the methyl ester of 1-methyl-10 alpha-methoxydihydrolysergic acid of formula VIII (VIII) r b) reducing the methyl ester of formula VIII obtained with a complex hydride, preferably sodium borohydride, to 1-methyl-10 alpha-methoxy-dihydrolysergol of formula IV (IV) c) the compound of formula IV is esterified in an inert amine with bromonicotinic acid chloride of formula IX in the presence of triethylBr, COCl (ix) to give a compound of formula I. 2. Process according to claim 1, characterized in that in step a) strong mineral sulfuric acid is used. 3. The process of claim 1, wherein step b) is used to reduce 8 to 10 mol equivalents of sodium borohydride in boiling ethanol. 4. The process of claim 1 wherein step c) is esterified by treatment with 1.1 mol equivalents of the chloride of formula IX in the presence of 1.1 mol equivalents of triethylamine in methylene chloride.