SK278786B6 - -1h-imidazole-1-yl)methyl|-4h-carbazol-4-one - Google Patents

Abstract

This patent describes the procedure closed to 1,2,METHOD FOR PRODUCING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL- 3,9- -tetrahydro-9-methyl-3-[(2-methyl-1H-imidazole-1-yl)methyl]- -4H-carbazol-4-one with a general formula (I) with the use of cyclization of the compound with a general formula (II), while the conditions closed to Friedel-Craft's acylation are respected, however this acylation is provided via activation of carboxyl group based on the acid catalysis, in the suitable solvent, the requested product is isolated, after having finished this activation.

Description

Technical field

The invention relates to a process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbosol-4-one of formula (I), 5

a synthetic compound that selectively antagonizes 5-HT ₃ receptors and exhibits interesting properties as antiemetics in chemotherapy, as well as in the treatment of headaches, schizophrenia, anxiety, obesity and mania.

BACKGROUND OF THE INVENTION

EC patent 2000936 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by cyclization of the aniline derivative of formula (VII)

wherein X represents a hydrogen or halogen atom.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one of formula (I). )

ES 548430 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by reaction of a carbazolone of formula (III) o

(III),

characterized in that 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4- (1-methylindol-2-yl) butyric acid of formula (II) ch ₃ wherein Y is methylene or halomethyl , with 2-methylimidazole.

The EC patent 556101 describes the preparation of 1,2,3,9-tetra-35 hydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one oxidation of carbazole of formula (IV)

wherein A is hydrogen or hydroxy.

The preparation of 1,2,3,9-tetra-45 hydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4- by alkylation of the carbazolone of formula (V)

wherein R 1 and / or R ₂ represents a hydrogen atom.

EC Patent 2000935 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by cyclization of phenylhydrazine. derivative of formula (VI)

ch ₃ h

cyclization under Friedel-Crafts acylation reaction conditions by activation of the carboxyl group by acid catalysis, in a suitable solvent medium, whereupon the desired product is isolated in the usual manner.

Activation of the carboxyl group is effected by converting the carboxylic acid to an acid halide or mixed anhydride with trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid, preferably to mixed trifluoroacetic anhydride.

As the acid catalyst, an inorganic acid such as hydrochloric, sulfuric or phosphoric acid or a Lewis acid such as boron trifluoride, zinc chloride or aluminum chloride may be used. Phosphoric acid is preferably used.

The reaction is carried out in an aprotic organic solvent such as chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran or acetonitrile, preferably acetonitrile.

The cyclization is conveniently carried out at a temperature ranging from -60 to +50 ° C, preferably at 0 ° C.

Upon completion of the reaction, the desired product is conventionally isolated and recrystallized from an organic solvent, preferably methanol. Chemically pure 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is obtained.

The compound of formula (II) can be produced by reacting 2-methylene-4- (3-carboxy-1-methylindol-2-yl) butyric acid of formula (VIII).

COOH

with 2-ethylimidazole. The reaction is conveniently carried out at a temperature in the range of from 100 to 200 ° C, preferably at 150 ° C.

The reaction is carried out in a high boiling solvent such as toluene, xylene or bromobenzene or mixtures thereof, or without solvent.

Upon completion of the reaction, the desired product is isolated by conventional means and recrystallized from an organic solvent such as methanol, toluene, dimethoxyethane or methoxyethanol, preferably dimethoxyethane.

The dicarboxylic acid of formula (VIII) is obtained by hydrolyzing 2-methylene-4- (3-ethoxycarbonyl-1-methylindol-2-yl) butyric acid of formula (IX)

This compound can then be produced by reacting ethyl 1,2-dimethylindole-3-carboxylate of formula (X);

N CH ₃ k

CH-j (which is obtained by the method described in John E. Macor, Kewin Ryan, Michael E. Newman, J. Org. Chem. 54, 4785, 1989) with α-bromomethylacrylic acid of formula (XI)

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2-Methylene-4- (3-ethoxycarbonyl-1-methylindol-2-yl) butyric acid

To a solution of the lithium salt, which was made from 4.34 g (20 mmol) of ethyl 1,2-dimethylindole-3-carboxylate, in 150 mL of tetrahydrofuran, maintained at -60 ° C, was added a solution of 4.98 over 10 s. g (30 mmol) of α-bromomethylacrylic acid in 20 ml of tetrahydrofuran. The temperature should not exceed -50 ° C. After stirring at -60 ° C for two hours, the solution was poured into a mixture containing 400 g of ice, 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After separation, the phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried (MgSO 4) and evaporated. The resulting solid was recrystallized from toluene and then from methanol. 3.0 g (50%) of an analytically pure title compound are obtained as a white solid.

Melting point: 138-140 ° C 1 H-NMR (CDCl 3): 1.46 (t, J = 7.1, 3H, -CH ₂ -CH ₃ ), 2.62-2.71 (m, 2H, -CH ₂ C = C), 3.36 to 3.48 (m, 2H, indole _CH2), 3.78 (s, 3H, _N-CH3), 4.41 (q, J = 7.1 , 2H, CH ₂ CH _3), 5.81 (d, J = 1.2, 1H, -C = CH), 6.37 (d, J = 1.2, 1H, C-CH ), 7.15 - 7.40 (m, 3H, aromatic), 8.10 - 8.20 (m, 1H, aromatic)

Example 2

2-Methylene-4- (3-carboxy-1-methylindol-2-yl) butyric acid

To a suspension of 5.7 g (18.9 mmol) of the compound of Example 1 in 15 ml of methanol and 15 ml of water was added 19 g of potassium hydroxide, and the resulting mixture was heated under reflux for 30 minutes. The mixture is then poured into a mixture of 200 g of ice and 200 ml of water and acidified with 30 ml of concentrated hydrochloric acid. The product is filtered off and suspended in 250 ml of toluene. Thereafter, 100 ml of toluene was distilled off from the mixture and after cooling to 20 ° C and further filtration, 4.5 g (87%) of the analytically pure title compound was obtained as a white solid.

Melting point: 194-196 ° C ¹ H-NMR 8 (CDCl ₃ ): 2.40-2.60 (m, 2H, indole-CH ₂ -CH ₂ -). 3.20 to 3.50 (m, 2H, indole-CH ₂ CH ₂ -), 3.77 (s, 3H, _N-CH3), 5.59 (d, J = 1.5, 1H, -C =C-II), 6.07 (d, J = 1.5, 1H, -C =CH), 7.10-7.25 (m, 2H, aromatic), 7.46-7.54 (m, 1H, aromatic), 7.96 - 8.05 (m, 1H, aromatic).

Example 3

2 - [(2-methyl-1H-imidazol-1-yl) -4- (1-methylindol-2-yl) butyric acid.

A mixture of 2.73 g (10 mmol) of the compound of Example 2 and 2.46 g (30 mmol) of 2-methylimidazole was heated at 160 ° C for 2 min. After cooling to room temperature, the mixture was dissolved in chloroform, applied to a silica column and eluted with methylene chloride / methanol, 70:30. This afforded 2.21 g (71%) of the title compound as an analytically pure yellowish solid.

Melting point: 198-199 ° C 1 H-NMRS (CDCl ₃ ): 1.65-2.05 (m, 2H, indole-CH ₂ -CH ₂ -), 2.27 (s, 3H, C-CH 3). ), 2.65 - 2.95 (m, 3H, indole-CH ₂ - and -CH-COOH), 3.63 (s, 3H, _N-CH3), 3.95 - 4.25 (m, 2 H, imidazole CH ₂ -), 6.15 (s, 1H, indole-H), 6.74 (d, J = 1.6, 1H, imidazole-H), 6.90 - 7.10 (m , 3H), including at 7.06 (d, J = 1.6, 1H, imidazole-H), 7.30-7.45 (m, 2H, aromatic)

Example 4 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazo-1-4-one

To a suspension of 311 mg (1 mmol) of the compound of Example 3 in 10 mL of acetonitrile was added 28 μΐ (0.28 mmol) of 85% phosphoric acid. The reaction mixture was cooled to 0 ° C and 353 μΐ (2.5 mmol) of trifluoro-acetic anhydride was added dropwise. After 15 minutes, the mixture was poured into a mixture of 50 g of ice and 50 ml of saturated sodium bicarbonate solution, and the resulting mixture was extracted with methylene chloride (3 x 10 ml). The combined organic extracts were dried (MgSO 4) and evaporated. The solid residue was recrystallized from methanol to give 160 mg (55%) of the title compound as an analytically pure white solid.

Melting point: 227-228.5 ° C 1 H-NMR (CDCl ₃ ): 1.70-2.05 (m, 1H, HC (2)), 2.10-2.30 (m, 1H, HC (2)), 2.45 (s, 3H, _CH3), 2.75 to 3.15 (m, 10

3 H, HC (I) and HC (3)), 3.72 (s, 3H, N-CII _3), 4.10 (dd, J = 8.15, 1H, N-CH _2), 4, 70 (dd, J = 4.15, 1H, N-CH _2), 6.85 to 7.05 (m, 2H, aromatic), 7.20 to 7.40 (m, 3H, imidazole-H and aromatic 8.20 - 8.30 (m, 1H, aromatic).

Claims (6)

PATENT CLAIMS A process for the preparation of 1,2,3-9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one of the formula ) characterized in that 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4- (1-methylindol-2-yl) butyric acid of formula (II) is cyclized under Friedel conditions -Crafts acylation reaction via activation of the carboxyl group by acid catalysis, in a suitable solvent environment, for which the desired product is isolated. Process according to Claim 1, characterized in that the compound of formula (II) is activated by forming a mixed anhydride, preferably a mixed anhydride with trifluoroacetic acid. Process according to claim 1 or 2, characterized in that the cyclization is carried out in a suitable solvent and in the presence of an acid catalyst. Process according to one of Claims 1 to 3, characterized in that an aprotic organic solvent, preferably acetonitrile, is used as the reaction medium. Process according to Claim 3, characterized in that phosphoric acid is used as the acid catalyst. Method according to one of claims 1 to 4, characterized in that the cyclization is carried out at a temperature in the range of -60 to +50 ° C, preferably at 0 ° C.