EP0000533A1 - N-Substituted 9,10-dihydrolysergic acid esters and a method for their preparation - Google Patents

Abstract

N-substituted 9,10-dihydrolysergic esters of the formula <IMAGE> in which R1 is alkyl with 1-5 C atoms, alkenyl with 2-5 C atoms or cycloalkyl with 3-5 C atoms, R2 is hydrogen or alkoxy with 1-3 C atoms and X are hydrogen or halogen, the compound in which R1 is methyl or ethyl and R2 and X are hydrogen, and the compound in which R1 is a methyl radical, R2 is a methoxy radical and X is hydrogen, except as intermediates for the Synthesis of therapeutically highly effective compounds and processes for their preparation by reacting optionally esterified 9,10-dihydrolylsergic acids of the general formula <IMAGE> in which R is hydrogen or an organic radical which can be hydrolyzed in alkaline medium and X and R2 have the meanings indicated above, with a Compound of the general formula R1Y (III) in which R1 has the meaning given under the formula I and Y is halogen or sulfate, in Presence of a phase transfer catalyst, an inert organic solvent immiscible with water and an alkaline aqueous phase. Compared to known processes, this process is distinguished by good selectivity, a simple and rapid course of the reaction, the reaction being easy to control, the use of customary solvents from which the water does not need to be removed, and, above all, by reaction conditions which are safe Enable work. The compounds are important intermediates for the synthesis of therapeutic, highly effective compounds with an N-substituted group in the 1-position.

Description

The present invention relates to N-substituted 9,10-dihydrolysergic acid esters and a process for their preparation.

worin

• R₁ Alkylreste mit 1-5 C-Atomen, Alkenylreste mit 2-5 C-Atomen oder Cycloalkylreste mit 3-5 C-Atomen;
• R₂ Wasserstoff oder Alkoxyreste mit 1-3 C-Atomen und
• X Wasserstoff oder Halogen bedeuten,

wobei die Verbindung, worin R₁ Methyl- oder Äthylresteund R₂ und X Wasscrstoff bedeuten, sowie die Verbindung, worin R₁ einen Methylrest, R₂ einen Methoxyrest und _X Wasserstoff bedeuten, ausgenommen sind,
sind wichtige Zwischenverbindungen für die Synthese von therapeutisch hochwirksamen Verbindungen.New N-substituted 9,10-dihydrolysergic esters of the general formula according to the invention

wherein

• R ₁ alkyl radicals with 1-5 C atoms, alkenyl radicals with 2-5 C atoms or cycloalkyl radicals with 3-5 C atoms;
• R _{2 is} hydrogen or alkoxy radicals with 1-3 C atoms and
• X is hydrogen or halogen,

with the exception of the compound in which R _{1 is} methyl or ethyl and R ₂ and X are hydrogen, and the compound in which R _{1 is} methyl, R _{2 is} methoxy and _{X is} hydrogen,
are important intermediates for the synthesis of therapeutically highly effective compounds.

The previously known process of N-alkylation of lysergic acids or other compounds of this basic structure is based on the metallization of indole nitrogen with potassium or lithium in liquid ammonia at -50 ° C. and the subsequent introduction of the alkyl group. According to this The alkyl group is only introduced into the 1-stelluna, since the reaction is not particularly selective, especially when the excess of alkyl halide is necessary, it is also accompanied by the substitution of the activated hydrogen at the chiral center 8 with an alkyl group, so that the yield increases N-alkyl compound decreases (F. Troxler and A. Hofmann, Helv. Chim. Acta 40, 1957, 1721). Working under the specified reaction conditions is complex, anhydrous solvents are required and, under unfavorable conditions, explosions can also occur. The reaction product has to be purified by column chromatography.

worin

• R Wassarstoff oder einen in alkalischem Medium hydrqlisierbaren organischen Rest be- deutet, und
• X und R₂ die unter Formel I angegebene Bedeutung haben,
  mit einer Verbindung der allgemeinen Formel
  
  worin
• R₁ die unter Formel I angegebene Bedeutung hat, und
• Y Halogen oder Sulfat bedeutet,

in Anwesenheit eines Katalysators zur Pha- ,senübertragung, eines,mit Wasser nicht mischbaren inerten organischen Lösungsmittels und einer alkalischen wässerigen Phase umgesetzt werden.The process according to the invention for the preparation of N-alkylated 9,10-dihydrolysergic esters of the general formula I is characterized in that the optionally esterified 9,10-dihydrolysergic esters of the general formula

wherein

• R is hydrogen or an organic radical which can be hydrolyzed in an alkaline medium, and
• X and R _{2 have} the meaning given under formula I,
  with a compound of the general formula
  
  wherein
• R _{1 has} the meaning given under formula I, and
• Y is halogen or sulfate,

in the presence of a catalyst for phase transfer, a water-immiscible inert organic solvent and an alkaline aqueous phase.

In the process according to the invention, the alkyl group is simultaneously introduced into the 1-position of the compound of the general formula II and the group in the 8-position is esterified by the same alkyl group which was introduced into the 1-position.

In the compound of the general formula II, R denotes hydrogen or an organic radical which can be hydrolyzed in an alkaline medium. For this reason, 9,10-dihydrplysergic acid esters can also be used for the process according to the invention, in which R denotes any organic radical which is higher than the introduced group R ₁ is. This organic radical R is replaced by a lower group R ₁ by the intermediate alkaline hydrolysis.

The compounds of all my formulas II and III are known and described in the literature or can be prepared by processes known per se.

The starting materials of formula II are alkylated by compounds of general formula III in the presence of a phase transfer catalyst. This catalyst is an ammonium or phosphonium compound of the general formula Z ₄ QA, where Z is the same or different alkyl, cycloalkyl, aryl, arylalkyl or alkylaryl groups with 1-16 C atoms, Q is a quaternary nitrogen or phosphorus atom and A is an anion such as chloride, bromide, iodide, hydrogen sulfate, acetate, tosylate, etc. Thus, for example, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, tetrabutylphosphonium bromide, etc. can be used as the catalyst for phase transfer.

The phase transfer catalyst is used in an amount of 0.1 to 3 moles to 1 mole of 9,10-dihydroloysergic acid. The amount of the catalyst within these limits has a great influence on the reaction rate. Since 9,10-dihydrolysergic acid and its derivatives are very sensitive compounds, a rapid course of the reaction is desirable. Therefore, the use of the catalyst in an amount close to the above upper limit is advantageous.

The water-immiscible inert organic solvent can e.g. Benzene, Toluok, xylene or a saturated hydrocarbon such as pentane, hexane, heptane or cyclohexane.

The alkaline aqueous phase is a 20-50% aqueous alkali hydroxide solution, e.g. Sodium hydroxide solution.

The inventive method is carried out at room temperature or moderately elevated temperature.

The substitution of the 9,10-dihydrolysergic acids in the 8-position is faster than in the 1-position. Therefore, the esters and the N-substituted esters can be isolated from the reaction mixture at the beginning of the reaction. By continuing the reaction, the concentration of the ester is reduced until it completely disappears at the end of the reaction and only the N-substituted ester is obtained. For this reason, when an alkyl or alkenyl and cycloalkyl group is introduced into a 9,10-dihydrolysergic acid alkyl or alkenyl and cycloalkyl ester, a 1- (alkyl or alkenyl or cycloalkyl) -9,10-dihydrolyseric acid alkyl can be obtained in high yield -, -Alkenyl or -cycloalkyl esters can be obtained.

The advantages of the method according to the invention over the known method are good selectivity, simple and fast reaction course, the reaction being easily controlled, use of conventional solvents from which the water cannot be removed needs, but above all the reaction conditions that make driving possible.

The compounds according to the invention are important intermediate compounds for the synthesis of therapeutically highly effective compounds with N-substituted groups in the 1-position. The further reactions of the synthesis proceed primarily in the direction of the reduction of the ester group in the 8-position to a primary alcohol group, to which a suitable acid residue, for example 5-bromnicotinic acid, is then bound. Therefore, the simultaneous introduction of the group R ₁ in the 1 position and esterification of the carboxy group in the 8 position, which is thereby more accessible for the reduction into the alcohol group, is very advantageous.

example 1

= -61,1° (c = 0,5,Chloroform) erhalten.2.7 g (10 mmol) of 9,10-dihydrolysergic acid and 7 g (20 mmol) of tetrabutylammonium hydrogen sulfate are suspended in 200 ml of 45% sodium hydroxide. A solution of 4.2 g (.30 mmol) of methyl iodide in 300 ml of benzene is added and the mixture is stirred intensively for 1 hour. The organic phase is then separated and the aqueous phase is extracted in the same way twice with 150 ml of benzene, which contains 2.1 g (15 mmol) of methyl iodide. The benzene extracts are combined, washed with water until neutral and the solvent is evaporated. 2.62 g or 88% of theory are used. Theor. pure, crystalline 1-methyl-9,10-dihydrolysergic acid methyl ester with mp. 116-119 ° C and a specific rotation of

= -61.1 ° (c = 0.5, chloroform) obtained.

Example 2

In a two-phase system consisting of 200 ml of 50% sodium hydroxide, 7 g (20 mmol) of tetrabutylammonium hydrogen sulfate, 2.8 g (20 mmol) of methyl iodide and 300 ml of benzene, 2.84 g (10 mmol) of 9,10-dihydrolysergic acid methyl ester are stirred intensively admitted. The mixture is stirred for 30 minutes and then the phases are separated. 200 ml of benzene with 2.1 g (15 mmol) of methyl iodide are added to the aqueous phase and stirring is continued for 30 minutes. Then both phases are separated and the aqueous phase extracted twice with 150 ml of benzene. All four benzene extracts are washed with water until neutral and evaporated. There are 2.7 g or 91% of theory. Theor. obtained pure, crystalline 1-methyl-9,10-dihydrolysergic acid methyl ester. The compound has the same properties as in Example 1.

Example 3

2.7 g (10 mmol) of 9,10-dihydrolysergic acid and 6.44 g (20 mmol) of tetrabutylammonium bromide are suspended in 200 ml of 45% sodium hydroxide. A solution of 3.78 g (30 mmol) of dimethyl sulfate in 300 ml of benzene is added and the mixture is stirred intensively for 1 hour. The organic phase is then separated and the aqueous phase is extracted in the same way twice with 150 ml of benzene and 2.1 g (15 mmol) of methyl iodide. The benzene extracts are combined, washed with water until neutral and evaporated in vacuo. 2.36 g or 82.6% of theory. Theor. obtained pure, crystalline 1-methyl-9,10-dihydrolysergic acid methyl ester. The compound has the same properties as in Example 1.

Example 4

= -70,6° (c = 0,5, Chloroform) erhalten.2.7 g (10 mmol) of 9,10-dihydrolysergic acid and 7 g (20 mmol) of tetrabutylammonium hydrogen sulfate are suspended in 200 ml of 45% sodium hydroxide and a solution of 4.62 g (30 mmol) of diethyl sulfate in 300 ml of toluene admitted. The mixture is stirred vigorously at room temperature for 8 hours. The organic phase is then separated and the aqueous phase is extracted in the same way for 4 hours with 300 ml of toluene and 1.54 g (10 mmol) of diethyl sulfate. The toluene extracts are combined, washed with water until neutral and evaporated in vacuo. There are 2.15 g or 68.7% of theory. Theor. pure, crystalline 1-ethyl-9,10-dihydrolysergic acid ethyl ester with a melting point of 80-82 ° C and specific rotation

= -70.6 ° (c = 0.5, chloroform) obtained.

Example 5

= -69,9° (c = 0,5, Chloroform) erhalten.2.7 g (10 mmol) 9,10-dihydrolysergic acid and 7 g, (20 mmol) tetrabutylammonium hydrogen sulfate are suspended in 200 ml 45% sodium hydroxide, a solution of 4.85 g (40 mmol) allyl bromide in 300 ml benzene is added and stirred intensively for 2 hours. The phases are then separated and the aqueous phase is extracted in the same way twice with 200 ml of benzene and 2.42 g (20 mmol) of allyl bromide. The benzene extracts are combined, washed with water until neutral and evaporated in vacuo. 2.3 g or 66% of theory are used. Theor. 1-Allyl-9,10-dihydrolysergic acid allyl ester in the form of a colorless resin with specific rotation of

= -69.9 ° (c = 0.5, chloroform) obtained.

Example 7

in der Form eines farblosen Harzes mit der spezifischen Drehung

= -8.7° (c = 0,5,Chloroform) erhalten.A mixture of 4.5 g (13.22 mmol) of 10α-methoxy-lumilysergic acid methyl ester, 8.67 g (26.44 mmol) of tetrabutylammonium hydrogen sulfate, 200 ml of 45% sodium hydroxide, 300 ml of toluene and 3.33 g (26.44 mmol) of dimethyl sulfate is stirred intensively at 30 ° C. for 20 minutes. Then, the toluene phase is separated from the water phase and the water phase was extracted 3 times with 200 ml of toluene and 1.66 g (13.22 mmol) of dimethyl sulfate, in each case 20 minutes intensively stirred at 30 ° _C. The combined toluene extracts are washed with water and evaporated in vacuo. 3.8 g of 1-methyl-10α-methoxy

in the form of a colorless resin with the specific rotation

= -8.7 ° (c = 0.5, chloroform) obtained.

= -94,2° (c = 0,5,Methanol) erhalten.In a suspension of 40 ml 45% sodium hydroxide, 4.87 g (14.3 mmol) tetrabutylammonium Hydrogen sulfate, 250 ml of benzene and 3 g (21.5 mmol) of methyl iodide are added while stirring invensively at 35 ° C. 2.6 g (7.16 mmol) of 2-bromo-9,10-dihydrolysergic acid methyl ester in 65 ml of benzene. The solution is stirred for 30 minutes and then the organic phase is separated from the aqueous phase. The aqueous phase is extracted twice with 150 ml of benzene and 1.5 g (10.7 mmol) of methyl iodide. The combined benzene extracts are washed with water and evaporated in vacuo. The dry residue is crystallized from methanol. There are 2.42 g or 90% of theory. Theor. crystalline 1-methyl-2-bromo-9,10-dihydrolysergic acid methyl ester with mp. 167-168 ° C and the specific rotation

= -94.2 ° (c = 0.5, methanol) obtained.

Example 9

= -7₀° (c = 0,5, Chloroform) erhalten.In a suspension of 80 ml of 45% sodium hydroxide, 3.5 g (10 mmol) of tetrabutylammonium hydrogen sulfate, 200 ml of cyclohexane and 3.51 g (22.5 mmol) of ethyl iodide, 1.45 g (5 mmol) of 9.10- Dihydrolysergic acid ethyl ester added. The mixture is stirred intensively at 60 ° C. for 18 hours. After the two phases have been separated, the aqueous phase is extracted once more with 150 ml of cyclohexane and 1.56 g (10 mmol) of ethyl iodide. The cyclohexane fractions are combined, washed with water and evaporated. There will be 1.22 g or 80% of theory. Theor. Ethyl 1-ethyl-9,10-dihydrolysate with a melting point of 80-83 ° C and a specific rotation

= -7 ₀ ° (c = 0.5, chloroform) obtained.

Example 10

In a two-phase system consisting of 200 ml of 45% sodium hydroxide, 7 g (20 mmol) of tetrabutylammonium hydrogen sulfate, 200 ml of toluene and 2.52 g (20 mmol) of dimethyl sulfate, a solution of 3.16 g (10 mmol) 9 is stirred , 10-Dihydrolysergic acid 2'-fluoroethyl ester in 100 ml of toluene and stirred for 2 hours. The toluene extract is separated from the aqueous solution and then the aqueous solution is extracted twice with 200 ml of toluene and 0.63 g (5 mmol) of dimethyl sulfate. The combined toluene extracts are washed with water and evaporated to dryness in vacuo. There are 2.14 g or 71.8% of theory. Theor. obtained crystalline 1-methyl-9,10-dihydrolysergic acid methyl ester. The compound has the properties given in Example 1.

Claims (2)

1. N-substituted 9,10-dihydrolysergic acid esters of the general formula

wherein R ₁ alkyl residues with 1-5 C atoms, alkenyl residues with 2-5 C atoms or cycloalkyl residues with 3-5 C atoms, R _{2 is} hydrogen or alkoxy radicals with 1-3 C atoms and X is hydrogen or halogen, except for the compound in which R _{1 is} methyl or ethyl and R ₂ and X are hydrogen, and the compounds in which R _{1 is} methyl, R _{2 is} methoxy and X is hydrogen. 2. Process for the preparation of N-substituted 9,10-dihydrolysergic acid esters of the general formula

wherein R ₁ alkyl radicals. with 1-5 C atoms, alkenyl residues with 2-5 C atoms or cycloalkyl residues with 3-5 C atoms, R _{2 is} hydrogen or alkoxy radicals with 1-3 C atoms and X is hydrogen or halogen, characterized in that the optionally esterified 9,10-dihydrolysergic acids of the general formula

wherein R is hydrogen or an organic radical which can be hydrolyzed in an alkaline medium, and X and R _{2 have} the 3e interpretation given under formula I,
with a compound of the general formula

wherein R _{1 has} the meaning given under formula I and Y is halogen or sulfate,
in the presence of a phase transfer catalyst, a water-immiscible inert organic solvent and an alkaline aqueous phase.