HU210775B - Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazol-1-yl)methyl-4h-carbazol-4-one - Google Patents

Description

Λ description length: 6 pages (within 2 pages figure)

HU 210 775 Β

The present 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-carbazol-4-one of formula (I). The synthetically produced compound of formula (I) selectively antagonizes the 5HT ₃ receptors and, due to its pharmaceutically valuable properties, is useful in the chemotherapeutic treatment of nausea, and in the treatment of patients with headaches, cognitive or manic dementia, and anxiety or obesity.

No. 548,430. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is prepared according to the Spanish patent, reacting with 2-methylimidazole a carbazolone wherein Y is a methylene group or a halomethyl group.

No. 556,101. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is prepared according to the procedure described in oxidizing a carbazole derivative wherein A is hydrogen or hydroxy in formula IV.

No. 539,852. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is prepared according to the Spanish patent, to alkylate carbazolone derivatives wherein R 1 and / or R ₂ are hydrogen.

No. 2,000,935. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one according to the procedure described in Spanish Patent ring closure of the phenylhydrazine derivative of formula (VI).

No. 2,000,936. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, by ring closure of aniline derivatives wherein X is halogen.

The process of the invention provides the compound of formula (I) at a cheaper and higher purity than the known processes because the ring closure of the process according to the invention is carried out at a lower temperature and in a shorter time than the known processes. As a result, the final product does not contain the impurities that are present in the final product in the known processes, thus eliminating the need for purification of the final product or the purification process being carried out in fewer steps and using less energy.

The present invention provides a novel process for preparing 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole of formula (I). 4-on that the carboxyl group of 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4- (1-methylindol-2-yl) butanoic acid of formula II in a solvent in the presence of an acidic catalyst and then cyclization under standard reaction conditions for Friedel-Crafts acylation and isolation of the product of formula (I) in a known manner.

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

The acid used as the catalyst is an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid or a Lewis acid such as boron trifluoride, zinc chloride or aluminum trichloride, preferably phosphoric acid.

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

The ring closure can be carried out at a temperature in the range of (-60) to -50 'C, with the preferred reaction temperature being 0' C.

After completion of the reaction, the desired product is isolated by conventional means and recrystallized from an organic solvent, preferably methanol. 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is obtained in this way.

The compound of formula (Π) is 2-methylene-4- (3-carboxy-methyl-indol-2-yl) -butyric acid (compound of formula VIII) and

It can be prepared by reacting 2-methylimidazole.

The reaction is carried out at 100-200 'C, preferably 150' C.

The reaction is conveniently carried out in a high-boiling solvent, such as toluene, xylene, bromobenzene, or a mixture of these solvents, or in the absence of a solvent, preferably without a solvent.

After 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 (VIH) is prepared by hydrolyzing 2-methylene-4- [3- (ethoxycarbonyl) -1-methyl-indol-2-yl] -butyric acid of formula (IX).

The 2-methylene [3- (ethoxycarbonyl) -1-methylindol-2-yl] butanoic acid of formula IX can be prepared from 1,2-dimethylindole-3-carboxylic acid ethyl ester [compound X] ] and alpha (bromomethyl) acrylic acid (compound of formula XI). Preparation of the compound of formula X from John E. Macor, Kewin Ryan and Michael E. Newman, J. Org. Chem., 54, 4785 (1989)].

The following examples are intended to illustrate the invention in more detail and are not intended to limit the scope of the invention in any way.

Example 1

Preparation of 2-Methylene-4- [3- (ethoxycarbonyl)] -methylindol-2-yl] butanoic acid

A lithium salt was prepared from 4.34 g (20 mmol) of 1,2-dimethylindole-3-carboxylic acid ethyl ester and dissolved in 150 ml of tetrahydrofuran. To the resulting solution at -60 ° C was added a solution of 4.98 g (30 mmol) of alpha-bromomethyl acrylic acid in 20 ml of tetrahydrofuran over 10 seconds, while

The stool was not allowed to rise above -50 ° C. After stirring for 2 hours at -60 ° C, the resulting solution was poured into a mixture of 400 g of ice, 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After partitioning, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over magnesium sulfate and evaporated. The solid evaporation residue was recrystallized from toluene then methanol to give the title compound (3.0 g, 50%) as a white solid, m.p. 138-140 ° C.

1 H-NMR δ (CDCl ₃ ): 1.46 (t, J = 7.1, 3H, -CH ₂ -CH ₃ ), 2.62-2.71 (m, 2H, -CH ₂ -C C), 3.36-3.48 (m, 2H, indole-CH ₃ ), 3.78 (s, 3H, N-CH ₃ ), 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

Preparation of 2-Methylene-4- (3-carboxy-1-methylindol-2-yl) butanoic acid

5.7 g (18.9 mmol) of the compound prepared in Example 1 are suspended in a mixture of 15 mL of methanol and 15 mL of water. To the suspension was added 19 g of potassium hydroxide, and the resulting mixture was refluxed for 30 minutes and then poured into 200 g of ice and 200 ml of water. The resulting mixture was acidified with 30 ml of concentrated hydrochloric acid, the resulting solid was collected by filtration and suspended in 250 ml of toluene. 100 ml of the suspension were distilled off and the residue was cooled to 20 ° C. Further filtration gave the title compound (4.5 g, 87%) as a white solid, m.p. 194-196 ° C.

1 H-NMR δ (CDCl ₃ ): 2.40-2.60 (m, 2H, indole-CH ₂ CH ₂ -), 3.20-3.50 (m, 2H, indole-CH ₂ -CH ₂ ~), 3.77 (s, 3H, N-CH ₃ ), 5.59 (d, J = 1.5, 1H, -C = CH), 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

Preparation of 2- (2-Methyl-1H-imidazol-1-ylmethyl) -4- (1-methylindol-2-yl) butanoic acid From the compound prepared in Example 2, 2.73 g (10%) mmol) was added with 2.46 g (30 mmol) of 2-methylimidazole and the resulting mixture was heated at 160 ° C for 2 minutes. After cooling to ambient temperature, the reaction mixture was dissolved in chloroform and passed through a silica column. Elution was carried out with a 70:30 (v / v) mixture of methylene chloride and methanol. This gave the title compound (2.21 g, 71%) as a yellowish solid with analytical purity, m.p. 198-199 ° C. 1 H-NMR δ (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 -HC-COOH), 3.63 (s, 3H, N-CH ₃ ),

3.95-4.25 (m, 2H, imidazole-H ₂ -), 6.15 (s, 1H, indole-H), 6.79 (d, J = 1.6, 1H, imidazole-H). ), 6.907.10 (m, 3H) - at 7.06: d, J = 1.6, 1H, imidazole-H) -, 7.30-7.45 (m, 2H, aromatic).

Example 4 Preparation of 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-yl. 311 mg (1 mmol) of the prepared compound was suspended in 10 ml of acetonitrile and 28 μ 85 (0.28 mmol) of 85% phosphoric acid was added to the resulting suspension. The reaction mixture was cooled to 0 ° C and trifluoroacetic anhydride (353 μΐ, 2.5 mmol) was added dropwise. After 15 minutes, the resulting mixture was poured into a mixture of 50 g of ice and 50 ml of saturated sodium bicarbonate solution and extracted 3 times with 10 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated. The solid evaporation residue was recrystallized from methanol to give the title compound (160 mg, 55%) as a white solid, m.p. 227-228.5 ° C.

1 H-NMR δ (CDCl ₃ ): 1.70-2.05 [m, 1H, HC (2)],

2.10-2.30 [m, 1H, HC (2)], 2.45 (s, 3H, _CH3);

2.75-3.15 [m, 3H, H-C (1) and H-C (3)], 3.72 (s, 3H,

N-CH ₃ ), 4.10 (dd, J = 8.15, 1H, N-CH ₂ ), 4.70 (dd,

J = 4.15, 1H, _N-CH2), 6.85-7.05 (m, 2H, aromatic);

7.20-7.40 (m, 3H, imidazole-H and aromatic), 8.208.30 (m, 1H, aromatic).

Claims (5)

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): characterized in that the carboxyl group of 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4- (1-methylindol-2-yl) butanoic acid of formula II is activated in a solvent in the presence of an acidic catalyst; Cyclization is carried out under conventional reaction conditions for crafts acylation and finally the products of formula (I) are isolated in known manner. Process according to claim 1, characterized in that the compound of formula (II) is activated by conversion to a mixed anhydride, preferably a mixed anhydride with trifluoroacetic anhydride. Process according to claim 1 or 2, characterized in that the reaction medium is an aprotic organic solvent, preferably acetonitrile. The process according to claim 1, wherein the acid catalyst is phosphoric acid. 5. A process according to any one of claims 1 to 3, wherein the ring closure is performed at (-60) -50 'C, preferably at 0' C.