CS247100B2 - Production method of 2-(trialkylsilyl)-ergoline - Google Patents

Abstract

A novel process for the preparation of 2-(trialkylsilyl)ergoline derivatives of the general formula <IMAGE> in which C8---C9 and C9---C10 denote a CC single bond or a C=C double bond, but not a cumulated double bond, and the substituent in the 8-position is a- or b- if C8---C9 denotes a CC single bond, R denotes C1-4-alkyl, R<6> denotes C1-3-alkyl, and R<8> denotes methyl or the group NH-CO-NEt2 or NH-CS-NEt2 and their salts is described by rearrangement of a 2-bromo-1-(trialkylsilyl)ergoline. The compounds according to the invention have biological activity in the central nervous system field.

Description

The present invention relates to a novel process for the preparation of 2- (trialkylsilyl) ergoline derivatives having valuable pharmacological properties and which can be used as active ingredients of medicaments.

The 2- (trialkylsilyl) ergoline derivatives can be prepared by electrophilic substitution of compounds metallized at the 2-position. This procedure has not been described so far for ergoline derivatives.

However, the process proceeds only with unsatisfactory yields.

SUMMARY OF THE INVENTION It was therefore an object of the present invention to provide a process for the preparation of 2- (trialkylsilyl) ergoline derivatives which provides better yields.

Surprisingly, it has now been found that the production of 2- (trialkylsilyl) ergoline derivatives is doing well when 2-bromo-1- (trialkylsilyl) ergoline derivatives are treated in the cyclic ether with alkyl lithium and the reaction product is switched to the corresponding 2- ( trialkylsilyl) ergoline.

Accordingly, it is an object of the present invention to provide a process for the preparation of 2- (trialkylsilyl) ergoline derivatives of formula (I) wherein:

means a carbon-carbon single bond or a carbon-carbon double bond but not a cumulative double bond, and the substituent at position 8 occupies an α- or (β-position) if

means a carbon-carbon single bond,

R is C 1 -C 4 alkyl,

R ^e represents an alkyl group of 1 to 3. carbon atoms and

R ⁸ represents a methyl group or an NH-CO-NE 12 or NH-CS-NE 8 group, as well as their physiologically tolerated acid addition salts, characterized in that the 2-bromo-1- (trialkylsilyl )ergoline of the formula II

R, R ⁶ and R 8 are as defined above, treated with an alkyllithium at temperatures below 0 ° C, optionally in the presence of a tertiary amine and the reaction product is optionally converted with an acid into a physiologically compatible acid addition salt.

The process of the invention is carried out by reacting 2-bromo-1- (trialkylsilyl) ergoline at low temperatures in a cyclic ether solvent with alkyl lithium and then, over an extended reaction time, switching to the corresponding 2-silylergoline derivative.

Suitable alkyllithium are, in particular, tert-butyllithium. It is used in an amount of from 1 to 5 equivalents.

Low temperatures are understood to be temperatures below 0 ° C, in particular temperatures in the range of -70 to -20 ° C, which are achieved, for example, by cooling means such as solid carbon dioxide in methanol and / or methylene chloride.

Tetrahydrofuran and dioxane are particularly suitable as cyclic ethers. The solvent is used in large excess, i.e. in about 10 to 500 times the amount.

Depending on the chemical structure of the ergoline used as starting material, a tertiary amine such as tetramethylenediamine may be added to the reaction mixtures.

Isomerization is complete after several hours, ie after 2 to 8 hours.

The process of the invention was surprising in that the rearrangement reactions did not take place in other solvents useful in silylation reactions such as toluene or benzene.

This fact is illustrated by the following example.

800 mg of 2-bromo- (1-tert-butyldimethylsilyl) -8,9-didehydro-6,8-dimethylergoline are dissolved in 50 ml of anhydrous toluene, the solvent is distilled off in vacuo and the residue is taken up in 75 ml of anhydrous, freshly distilled toluene under atmosphere. To this solution was added 1 mL of anhydrous tetramethylethylenediamine and the solution was cooled to -90 [deg.] C. Then 6.0 mL of a 1.4 M solution of tert-butyllithium in hexane (8.4 mmol) was added and the reaction mixture was stirred for After 5 hours, water is added, the mixture is extracted with methylene chloride, the organic phase is dried over sodium sulphate and evaporated and 8,9-dihydro-6,8-dimethylergoline is isolated in quantitative yield. 8-dimethyl-2-trimethylsilylergoline could no longer be detected by NMR spectrum.

The starting compounds required for carrying out the process of the invention are either known or can be prepared by methods known to the person skilled in the art.

Production of starting materials: .................

A solution of lithium diisopropylamide was prepared from 27 ml of 15% n-butyllithium in hexane (67 mmol), 9.1 ml of anhydrous diisopropylamine and 40 ml of anhydrous tetrahydrofuran. This solution was cooled to -20 ° C and a solution of 12.7 g of bromagroclavin (30 mmol) in 115 mL of anhydrous tetrahydrofuran was added dropwise, the mixture was stirred for 15 minutes at this temperature and then 7.3 mL of was added. tert-butyldimethylsilyl chloride (48 mmol) in 15 mL of anhydrous tetrahydrofuran. The mixture was allowed to warm to room temperature and then stirred for 2 days. The mixture was then partitioned between ethyl acetate and bicarbonate solution, the organic phase was dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel using methylene chloride as the eluent, followed by methylene chloride / methanol. 2-Bromo-1- (tert-butyldimethylsilyl) -8,9-didehydro-6,8-dimethylergoline was obtained in 83% yield.

[ _.alpha. ] _D = -161 DEG (0.5% in chloroform).

The following compounds were prepared in an analogous manner:

3- (2-bromo-1- (tert-butyldimethylsilyl) -9,105)

-1,1-diethylurea;

Yield: 72%.

3- (2-bromo-1- [tert-butyldimethylsilyl) -6-methyl-Baergolinyl] -1,1-diethylthio;

Yield: 63% of theory (from diisopropyl ether) [α] D = + 6 ° (0.5% in chloroform).

3- (2-bromo-1- (tert-butyldimethylsilyl) -9,10-didehydro-6-methyl-88-ergolinyl) -1,1-diethylthiourea; *

3- [2-bromo-1- (tert-butyldimethylsilyl) -6-methyl-8'-ethyl] -1,1-diethylthiourea;

3- (2-bromo-1- (tert-butyldimethylsilyl) -6-methyl- N -golinyl) -1,1-diethylurea;

Yield: 65% of theory = -80 ° [0.5% in chloroform].

3- [2-bromo-1- (tert-butyldimethyisilyl) -n-propyl-8 (α-ergolinyl) -1,1-diethylurea;

Yield: 77% of theory [α] D = -5 ° (0.5% in chloroform).

The compounds obtained by the process of the invention are purified by recrystallization and / or chromatography, either in the form of the free bases or in the form of their acid addition salts, optionally obtained by reaction with a physiologically tolerated acid, such as tartaric acid or maleic acid. '

To form salts, the compounds of formula (I ') are dissolved in a small amount of methanol or methylene chloride and to this solution is added a concentrated solution of the desired acid in methanol at room temperature.

The salts of the compounds of formula I which are produced by the process of the invention are acid addition salts and are derived from physiologically acceptable acids. Such physiologically acceptable acids are inorganic acids such as:

hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, or organic acids such as:

aliphatic monocarboxylic or dicarboxylic acids, phenylsubstituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids or alkanedicarboxylic acids, aromatic acids or.

aliphatic or aromatic sulfonic acids.

Thus, the physiologically acceptable salts of these acids are, for example, the following: sulfate, pyrosulfate, hydrogen sulfate, sulfite, hydrogensulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, capanoate acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, ........ lactate, (-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate or naphthalene-2-sulfonate.

The novel compounds produced by the process of the invention are biologically active compounds in the central nervous system. In particular, these compounds have central antidopaminergic and / or α 2 receptor blocking effects and can therefore be used in medicine as neuroleptics for the treatment of schizophrenic-type psychoses or as antidepressants.

Lower alkyl groups of up to 4 carbon atoms are those derived from aliphatic hydrocarbons such as:

methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In order to use the compounds of the present invention as medicaments, they are converted into pharmaceutical compositions which contain, in addition to the active ingredient, a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration, such as:

water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.

The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. If desired, they also contain auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers.

The following examples illustrate the process in more detail, but do not limit its scope in any way.

Example 1

800 mg of 3- [2-bromo-l- (terc.dimethylsilyl) -6-methyll8a-ergollnyl] -L-diethylmočov'iny _t l (1.5 mmol) was dissolved in 75 mL of dry, freshly distilled tetrahydrofuran under an argon atmosphere . To this solution was added 1 mL of anhydrous tetramethylethylenediamine and cooled to -80 ° C (bath temperature). Then 6.0 ml of a 1.4 M solution of tert-butyllithium in hexane (8.4 mmol) was added. A solution of 3 - [(1-tert-butyldimethylsilyl) -2-lithium-6-methyl-8,8-pyrrolidinyl] -1,1-diethylurea was obtained, which was stirred at -70 ° C for 5 hours.

After warming to room temperature, water is added, extraction is performed with methylene chloride, the organic phase is dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methylene chloride and methanol as eluent. 265 mg of 3 - [(2-tert-butyldimethylsilyl) -6-methyl-8α-ergolinyl] -1,1-diethylurea (40% of theory) were isolated.

Example 2

From 1- (tert-butyldimethylsilyl) -2-phenyl-8,9-didehydro-6,8-dimethylergoline was prepared by treatment with tert-butyllithium as described in Example 1, a 2-lithium derivative in anhydrous tetrahydrofuran. This solution was then allowed to stir for 5 hours at -70 ° C and then worked up and chromatographed in a conventional manner.

Yield:

% of theory of 2- (tert-butyldimethylsilyl) -8,9-didehydro-6,8-dimethylergoline.

[α] _D = -152 ° (0.5% in chloroform).

In the same way, the following 2-silyl derivatives are produced:

3- (2- (tert-butyldimethylsilyl) -6-methyl-1H -ergolinyl] -1,1-diethylthiourea,

3- (2- (tert-butyldimethylsilyl) -9,10-didehydro-6-methyl-8a -ergolinyl) -1,1-diethylurea,

8,9-didehydro-6,8-dimethyl-2-trimethylsilylergoline;

Yield: 60% of theory [-] d = -177 ° (0.5% in chloroform), 1,1-diethyl-3- (6-methyl-2-trimethylsilyl-8'-epsolin) urea,

3- (9,10-didehydro-6-methyl-2-trimethylsilyl-8a-ergolinyl) -1,1-diethylurea,

3- (6-n-propyl-2-trimethylsilyl-8α-ergolinyl) -1,1-diethylurea,

3- (2-tert-Butyldimethylsilyl-6-methyl-8H-ergolinyl) -1,1-diethylurea.

Claims (1)

SUBJECT Process for the preparation of 2- (trialkylsilyl) ergoline of the formula I and ^C 's ^{and C} VYNALEZU R ⁶ represents an alkyl group having 1 to 3 carbon atoms and R ⁸ represents a methyl group or an NH-CO-NEt 2 or NH-CS-NEt 2 group, as well as their physiologically tolerable acid addition salts, characterized in that the 2-biphenyl-L- (trialkylsilyl jergoline of the formula) II represents a carbon-carbon single bond or a carbon-carbon double bond, but not a cumulative double bond, and the substituent at the 8-position occupies an α- or 5 position if ^C Q- ^C— represents a carbon-carbon single bond, R is an alkyl group with 1 to 4 carbon atoms, wherein the ^C 8 's ^{and C} ^ R, R ⁶ and R ⁸ are as defined above, treated with an alkyllithium at temperatures below 0 ° C, optionally in the presence of a tertiary amine and the reaction product is optionally converted with an acid into a physiologically compatible acid addition salt.