CS247570B1 - Process for preparing N, alkylated dihydrolysergol derivatives - Google Patents

Abstract

Method for preparing N1 alkylated derivatives of dihydrolysergol of the general formula I where R1 means C^ - alkyl R2 means a residue of an organic carboxylic acid including aliphatic, alicyclic or aromatic carboxylic acids containing up to 10 carbon atoms and or heterocyclic carboxylic acids containing one heterocyclic ring with one nitrogen atom, optionally substituted by halogen. These are active substances, in particular with antiserotonin and adrenolytic effects. According to the method of the solution, these substances are produced from elymoclavine, which is available by fermentation. Elymoclavine is isomerized to lysergol, which is converted to mesyl or tosyl ester. The tosylate or mesylate of lysergol is subjected to photochemical methoxylation and the resulting 10-alpha-methoxy derivative is alkylated to under conditions of phase transfer catalysis. the alkylated derivative of 10-alpha-methoxydihydrolysergol is then converted into a substance of general formula I by reaction with the sodium, potassium or tetraalkylammonium salt of the corresponding carboxylic acid.

Description

The invention relates to a process for the preparation of alkylated dihydrolysergol derivatives of the general formula I

H _(>> CH ₂ -O-CO-R ₂

CH 3 -O, fl pA 2 -CH 2

Η, —N— “(I) wherein R ^ represents alkyl

R 1 represents a residue of an organic carboxylic acid comprising 1-6 carboxylic acid; aliphatic, alicyclic or aromatic carboxylic acids containing 2-carboxylic acid; at most 10 carbon atoms and / or heterocyclic carboxylic acids containing one heterocyclic ring with one nitrogen atom optionally substituted by halogen.

The compounds of the formula I have very interesting pharmacological properties, in particular adrenolytic and antiserotonin activity. A therapeutically important representative of these compounds is D-1,6-dimethyl-8-beta- (5-bromonicotinoyloxymethyl) -10-alpha-methoxyergoline referred to as Nicergoline.

The processes known to date for the preparation of the compounds of the formula I are based on lysergic acid VIIa (U.S. Pat. No. 144,540), lumilysergic acid VIII (U.S. Pat. No. 3,228,943), lysergol VIIb (RP 4,664) or 1-methyllysergic acid VII. c (cf. AO 229 086).

(VII a) - COOH CH (VII b) - CH 3 OH H (VII c) - COOH CH 3

These methods have some disadvantages. According to U.S. Pat. No. 3,228,943, 10-alpha-methoxy lasergic acid methyl ester, prepared by esterification and etherification of lumilysergic acid or photoaddition of methanol to lysergic acid, e.g. according to Cs. No. 144,540 reduces lithium aluminum hydride to 10-alpha-methoxydihydrolysergol. The methyl alcohol obtained with methyl iodide in liquid ammonia in the presence of potassium amide gives 1-methyl-10-alpha-methoxydihydrolysergol which is acylated with an organic acid chloride in pyridine to give a compound of formula I. However, this process has the disadvantage of O-alkyl ether formation by alkylation a derivative of a dihydrolysergol having an unprotected hydroxyl group which is difficult to remove from the reaction product, low yields in the esterification of the alcohol, and use for industrial production of less suitable reagents such as lithium aluminum hydride and liquid ammonia.

According to Swiss patent 553 185, the acylation of 10-alpha-methoxydihydrolysergol with an organic acid chloride is first carried out, which gives higher yields of the 10-alpha-methoxydihydrolysergol ester and then methylation of the obtained ester with methyl iodide in liquid ammonia. However, the alkylation is accompanied by undesirable side reactions such that the desired compound of formula I is obtained in low yield.

The alkylation can also be carried out in the 10-alpha-methoxydihydrolysergic acid ester phase either in liquid ammonia in the presence of potassium amide / L. Bernardi et al. IL Farmaco Ed.

Sci 30, 789 (1975)], or using phase transfer catalysts with an alkyl halide or dialkyl sulfate (EP 533). In the first process, unwanted side reactions occur whose products reduce the yield and make product isolation more difficult. The disadvantage of the second method is the large volume of solvents and the use of an excess of alkylating agent which causes the quaternization of the tertiary nitrogen atom of the ergoline backbone and thus the yield reduction. Most of the above-mentioned disadvantages are eliminated by Cs. AO 234 498, according to which the alkylation is carried out in dichloromethane with an alkyl halide or dialkyl sulfate in the presence of a small cup of an aqueous solution of sodium hydroxide and tetraethylammonium hydroxide. The degree of conversion is greater than 95% and the tertiary nitrogen quaternization is minimized. The recoverable product of the reaction is converted to the well-crystallized 1-alkyl-10-alpha-methoxydihydrolysergol by reduction with sodium borohydride.

European patent 4,664 discloses the preparation of compounds of formula I by a process starting from lysergol. Photoaddition of methanol yielded 10-alpha-methoxydihydrolysergol, which is alkylated with methyl iodide in dimethylsulfoxide and in the presence of powdered potassium hydroxide and esterification of the 1-methyl derivative is carried out with an organic acid in the presence of dicyclohexylcarbodiimide. The disadvantage of the process is the formation of by-products in methylation, in particular the O-methyl derivative, and the difficult removal of dicyclohexylurea from the product after esterification of the alcohol.

In the process of the synthesis of D-6-methyl-8-beta- (5-bromonicotinoyl) -10-.alpha.-methoxydihydrolysergol, the authors used AO 229 086 using 1-methyllysergic acid as the starting material. Prepare methanol by photoaddition in the presence of a strong acid. A 10-alpha-methoxy derivative that is reduced with a complex hydride such as sodium borohydride or bis- (2-methoxy-ethoxy) aluminum sodium hydride. The thus obtained 1-methyl-10-alpha-methoxydihydrolyserogol is esterified in an inert solvent in the presence of triethylamime, bromonicotinic chloride.

Another method of esterification of lysergol derivatives is dealt with in German Patent 2,752,533. The esterification of the alcohol is carried out with 5-bromonicotinic acid using an imidazole complex with a triphenylphosphine item. However, the process uses more expensive auxiliary raw materials and the esterification product must be isolated by ion exchange chromatography.

The present inventors have found a new preferred process for the preparation of the compounds of formula (I) using the formula (I). elymoclavin, fermentatively available as a starting material. The proposed procedure overcomes some of the disadvantages of the above methods. According to the process of the invention, the compounds of formula (1) are prepared by:

a) elymoclavin of formula II isomerized in an inert solvent in the presence of Al 2 O 4 to lysergol III ch ₂ -oh

H, CH ₂ OH

(II)

(b) the presence of lysergol by reaction with p-toluenesulfonic acid or methanesulfonic acid chloride in the tertiary base to convert to tosyl - respectively. lysergol mesylester IV a, b,

(IV a) R 1 is CH 2 -C 6 H 2 -SO 2 (IV b) R 1 is CH 2 -SO 2 c) compound IVa, b is converted by photoaddition of methanol in the presence of a strong acid to the 10-alpha-methoxydihydrolysergol tosyl (mesyl) ester b.

H. CH ₂ -OA ₃

N-CH,

Η -N (V)

d) the obtained hydroxyl-protected 10-alpha-methyl ether of formula (a), (b) is alkylated with an alkyl halide or dimethyl sulphate in methylene chloride in the presence of an aqueous sodium hydroxide solution and a phase transfer catalyst to tosyl (mesyl) ester 1-alkyl-10-alpha-methoxy · dihydrolysergol VI a, b.

e) converting VIa, b by reaction with an organic acid salt in an inert solvent to form a compound of formula I.

In step a) of the process of the invention, the double bond isomerization at position 8, 9 to position 9, 10 is carried out by boiling elymoclavin II in a solution of benzene or pyridine in the presence of Al 2 O 4. The double bond isomerization product at the 9, 10 position is isolated by washing the filtered alumina with methanol. The combined washings were concentrated to crystallize.

In step b), lysergol is reacted with tosyl chloride, or more preferably mesyl chloride (providing higher yields and a uniform reaction product) in an inert solvent such as methylene chloride, chloroform, or benzene in the presence of a tertiary base, e.g. triethylamine. The reaction can also be carried out in pyridine, which also binds the resulting hydrogen chloride. The reaction is carried out at a temperature in the range of -10 to + 30 ° C. After completion of the reaction, the product is isolated by known methods.

In step c), the methanolic solution of IVa, b is irradiated in the presence of a strong acid. High-pressure mercury lamps or germicidal lamps with luminoflor, preferably with a maximum energy emission of about 320 nm, are used as ultraviolet radiation sources. Simax glass can preferably be used as a radiation filter of lower wavelength. The strong acid used is sulfuric acid, phosphoric acid, or strong organic acids such as methanesulfonic acid, respectively. p-toluenesulfonic acid. The reaction is carried out in a temperature range of 0 to +50 ° C, preferably at room temperature. In the above reaction configuration, the course is highly stereospecific and the undesired 10-beta isomer is less than 10%. The reaction time depends on the intensity of the radiation, the concentration of the irradiated substance and the purity of the raw materials used. The reaction product is isolated after alkalization of the mixture by extraction into an organic solvent such as methylene chloride, chloroform or toluene. After evaporation of the solvent under vacuum, the product is crystallized from an organic solvent, preferably acetone.

In step d) according to the process of the invention, a solution of V a, b in an inert solvent, preferably dichloromethane, is treated with an alkyl halide or dialkyl sulfate equivalent in the presence of an aqueous solution of sodium hydroxide and a quaternary ammonium salt or base, preferably in the presence of tetraethylammonium hydroxide. The alkylation is carried out at temperatures of -20 ° C to +30 ° C, preferably at 0 ° C, and is completed in 2 to 10 minutes. Under the above reaction conditions, a high degree of conversion is achieved and the nitrogen atom in the 6-position of the ergoline backbone is quaternized to a minimum extent. A major benefit of the process of the invention is the prevention of the formation of the O-alkyl derivative by protection of the hydroxyl group with a tosyl or mesyl group. After completion of the reaction, the reaction mixture is preferably worked up by pouring it into an aqueous solution of an organic acid such as acetic acid, taking up the organic solvent, and the crude product obtained after evaporation of the solvents is purified by column chromatography or or crystallization.

In step e), the product VIa, b obtained from the preceding step is condensed with the sodium, potassium or tetraalkylammonium salt of the carboxylic acid. The reaction must be carried out at a minimum of 70 ° C. When working with sodium or potassium salt, a polar solvent (dimethylformamide or dimethylsulfoxide) must be used, while working with tetraalkylammonium salt the solvent is less polar (in case of tetraethylammonium salt - dioxane and in case of tetrabutylammonium salt sufficient toluene). Especially preferred is the use of the tetraethylammonium salt in dioxane. The reaction mixture is worked up by evaporation and the tetraethylammonium salt is easily removed from the reaction mixture by extraction of the methylene chloride solution with water. The ester of formula I obtained is then isolated by conventional methods. The process according to the invention is explained in more detail by the following non-limiting example.

Example

Dissolve 100 g of elymoclavin in 4 000 ml of pyridine. 1000 g of alumina are added to the solution and the suspension is stirred at 70 ° C for 48 hours. The alumina was then filtered off and the pyridine solution was concentrated to a residue. The aluminum oxide was then washed with 30 L of methanol.

The pyridine residue is added to the methanolic eluate, the solution is decolorized with activated carbon and concentrated to a volume of about 200 ml. After cooling, a lysergol crystal is obtained which is isolated. 87 g of lysergol are obtained, which contains 2 as well as elymoclavin.

g of lysergol is stirred in 870 ml of methylene chloride and 100 ml of triethylamine are added to the suspension. The suspension is cooled to 0 ° C and 65 ml of methanesulfonyl chloride are added at a rate such that the temperature of the reaction mixture does not exceed + 5 ° C. The reaction mixture was stirred at room temperature for 2 hours and then 500 ml of 10% aqueous sodium hydroxide solution was added. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated to a volume of about 200 ml. The solution thus concentrated is purified by passage through a column of 260 kg of alumina: eluting with methylene chloride. The functions containing lysergol mesylate are concentrated to a residue which is crystallized from acetone. 74 g of the mesylate are obtained (m.p. 280 DEG C., decomposition: [.alpha.] D @ 20 = 12.1 DEG (1%, chloroform + 10% methanol).

g of lysergol mesylate is dissolved in 1500 ml of a mixture of 15 volumes of methanol and 1 volume of concentrated sulfuric acid. The solution is poured into a photochemical reactor (2000 ml reactor made of SIMAX glass and equipped with one 250 H medium pressure mercury lamp) and irradiated for 20 hours. After completion of the photochemical methoxylation, the reaction mixture is diluted with 1.5 L of methylene chloride and poured into a solution of 200 ml of concentrated ammonia in 1.5 L of water with stirring. The organic phase is separated and the aqueous phase is extracted twice more with 500 ml of methylene chloride. The combined methylene chloride extracts were washed twice with 300 ml of water, dried over sodium sulfate, concentrated to a residue which was crystallized from acetone. 59 g of 10-.alpha.-methoxydihydrolysergol mesylate (m.p. 280 DEG C., decomposition; [.alpha.] D @ ₂₀ = 13.7 DEG (1%, chloroform) were obtained.

g of 10-alpha-methoxydihydrolysergol mesylate was dissolved in 1200 mL of methylene chloride and the solution was cooled to 0 ° C. A mixture of 240 ml of a 20% aqueous solution of tetraethylammonium hydroxide and 300 ml of a 50% aqueous solution of sodium hydroxide is prepared and the mixture is cooled to 0 ° C. The two solutions thus prepared are mixed and 18 ml of dimethyl sulfate are added under vigorous stirring; The reaction mixture was stirred vigorously for 4 minutes. The phases are separated, the organic phase is washed 4 times with 100 ml of water and concentrated to a residue which is crystallized from acetone to give 48 g of 1-methyl-10-alpha-methoxydihydrolysergol meaylate (m.p. 172 DEG C.). _4g = 19.8 ° (1% chloroform).

g of 1-methyl-10-.alpha.-methoxydihydrolysergol mesylate is dissolved in 250 ml of dimethylformamide and 36 g of sodium bromonicotinate are added. The reaction mixture was heated to 150 ° C for 1 hour. The solution was then cooled to 0 ° C and poured into 2500 mL of saturated aqueous sodium chloride solution. The precipitate obtained is suction filtered, washed with water and the perfectly suctioned precipitate is dissolved in methylene chloride. The methylene chloride solution is dried over sodium sulphate, concentrated to a volume of 100 ml and chromatographed on a column of 300 g of alumina using methylene chloride as eluent. The fractions containing pure product are concentrated to a residue which is dissolved in 50 l of hot acetone and 55 g of crystalline 1,6-dimethyl-8-beta- (5-bromonicotinoyloxymethyl) -10-alpha- methoxyergoline-Nicergoline (mp 137 ° C, [α] 23 D - 19.1 ° (0.5%, chloroform)).

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of N 4 -alkylated dihydrolysergol derivatives of the formula I wherein C 1 -C ₄ alkyl R 1 is a radical of an organic carboxylic acid comprising aliphatic, alicyclic or aromatic carboxylic acids; not more than 10 carbon atoms and / or heterocyclic carboxylic acids containing 1-6 carbon atoms; one heterocyclic ring with one nitrogen atom optionally substituted by halogen, characterized in that the elymoclavin of formula II isomerized to lysergol of formula III, preferably by boiling in a benzene or pyridine solution in the presence of Al ₂ Oj (III) lysergol is converted to a compound of formula IV Rj is CH3-SO3- or CH2-C8H4-SO2, converted by photochemical methoxylation to a dihydrolysergol derivative of formula V (V) wherein Rj is as hereinbefore defined, which is further alkylated to form a compound of formula VI (VI) wherein R1 | and R 1 are as defined above and provides the product of formula X by reaction with a carboxylic acid salt of formula _R2 - C00 ^(-) M ⁽⁺⁾ wherein R ₂ is as defined above and M is sodium, potassium or quaternary amonlový ion.