The method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h - imidazol-1-yl)-methyl]-4h-carbazole-4-it


(57) Abstract:

The method of obtaining 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it formula I, which is the cyclization of compounds of formula II under conditions of acylation by Friedel-Crafts by activating the carboxyl group of the acid catalyst in the environment of a suitable solvent and the final selection of the desired product in a common manner. 4 C.p. f-crystals.

The invention relates to a method for 1, 2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl] -4H - carbazole-4-one with formula 1;

which is a selective antagonist of 5-HT3receptors and exhibits interesting properties as antiemetics in the chemotherapy as well as in the treatment of headaches, schizophrenia, anxiety, obesity, and manic syndrome.

A method of obtaining 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it reaction carbosilane with formula III with 2-methylimidazole.



V is a methylene radical or halogenmethyl radical (Patent EP 548430)

Also known is a method of obtaining 1, 2, 3, 9-tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl)methyl-4H-carbazole-4-it oxidized the

Patent ES 539852 describes obtaining 1,2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it alkylation carbazole formula V



R1and/or R2are hydrogen atoms.

Patent ES 2000935 describes receiving 1, 2, 3, 9-tetrahydro-9-methyl-3- [(2-methyl-1H-yl)methyl] -4H-carbazole-4-it-cyclization phenylhydrazine derivative of formula VI.


Known to produce 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4 - it is the cyclization of aniline derivative with formula VII [1]



X is a hydrogen atom or a halogen.

The invention relates to a method for 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it formula I.


which involves the cyclization of 2-[(2-methyl-1H-imidazol-1-yl)-methyl]-4-(1-methylindol-2-yl)butterboy acid of formula II


the reaction conditions for the acylation according to Friedel-Crafts, through the activation of the carboxyl group in the presence of an acidic catalyst, passing the solvent environment and the further allocation of the necessary product standard methods.

Activation of the carboxylic acid is carried out by transforming it into atzinganoi Sunny anhydride.

The acidic catalyst may be an inorganic acid such as hydrochloric, sulfuric or phosphoric, or a Lewis acid such as boron TRIFLUORIDE, zinc chloride or trichloride aluminum, preferably phosphoric acid.

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

The cyclization reaction can be carried out quite effectively in the temperature range from -60 to 50oC, preferably at 0oC.

After completion of the reaction the desired product stands out in a common manner, preferably from methanol, to obtain chemically pure 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-it.

The compound of formula II can be prepared by reaction of 2-methylene-4-(3-carboxyl-1-methylindol-2-yl)butyric acid of the formula VIII c 2-methylimidazole.


Accepted to carry out the reaction in the temperature range of 100 - 200oC, preferably at 150oC.

The reaction is carried out in high-boiling solvents, such as toluene, xylene or Brabanthal, or their mixture, or without solvent that p is recrystallization of the organic solvent, such as methanol, toluene, dimethoxyethane, methoxyethanol, preferably from dimethoxyethane.

Decollato formula III is obtained by hydrolysis of 2-methylene-4-(3-etoxycarbonyl-1-methylindol-2-yl) butyric acid with the formula IX.


which in turn can be prepared by reaction of ethyl 1,2-dimethylindole-3-carboxylate anion with the formula X


(prepared according to John E. Macor, Kewin Ryan, Michael E. Newman in J. Org. Chem. 54, 4785 (1989)) (Bromeliaceae) acid with fomrula XI.


The following examples illustrate but do not limit the scope of the invention.

Example 1. 2-Methylene-4-(3-etoxycarbonyl-1-methylindol-2-yl) butyric acid.

To a solution of lithium salt prepared from 4,34 g (20 mmol) of ethyl 1,2-dimethylindole-3-carboxylate in 150 ml of tetrahydrofuran, stored at -60oC add for 10 with a solution to 4.98 g (30 mmol) -(Bromeliaceae) acid in 20 ml of tetrahydrofuran. The temperature should not exceed -50oC. After 2 h shaking at -60oC the solution is poured into a mixture containing 400 g of ice and 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After separation of the phases are separated and the aqueous layer was extracted with ethyl acetate (2200 ml). SWAT is lizovyvatj from toluene and then from methanol, thus obtain 3.0 g (50%) of analytically pure titled compound in the form of white crystals.

So square 138 - 140oC.

1H - NMR (CDCl3): of 1.46 (t, J=7,1, 3H, -CH2-CH3), 2,62 - a 2.71 (m, 2H, -CH2-C=C), 3,36 - of 3.48 (m, 2H, indole-CH2), 3,76 (s, 3H, N-CH3), to 4.41 (K, J = 2,1, 2H, -CH2-CH3), of 5.81 (d, J=1,2, 1H, -C=CH), 6,37 (d, J=1,2, 1H, -C=CH), 7,15 - and 4.40 (m, 3H, aromatics), of 8.1 to 8.2 (m, 1H, aromatics).

Example 2. 2-Methylene-4-(3-carboxyl-1-medicinal-2-yl) butyric acid. To a suspension of 5.7 g (of 18.9 mmol) of compound 1 in 15 ml methanol and 15 ml of water is added 19 g of potassium hydroxide and the resulting mixture is heated to boiling for 30 minutes Then pour in a mixture of 200 g of ice and 200 ml of water, acidified with 30 ml of concentrated hydrochloric acid. The product distinguish filtration and suspended it in 250 ml of toluene, take 10 ml) and then distilled and after cooling to 20oC and further filtering obtain 4.5 g (87%) of analytically pure titled product as white crystals.

So pl. 194 - 196oC

1H-NMR (CDCl3): 2,40 - 2,60 (m, 2H, indole-CH2-CH2-),3,20 - to 3.50 (m, 2H, indole-CH2-CH2-), of 3.77 (s, 3H, N-CH3), 5,59 (d, J=1,5, 1H, -C=C-H), 6,07 (d, J=1,5, 1H, -C=C-H), 7,10 - 7,25 (m, 2H, aromatics), 7,46 - rate of 7.54 (m, 1H, aromatics), of 7.96 - with 8.05 (m, 1H, aromatics).

oC for 2 min. After cooling to room temperature, the mixture is dissolved in chloroform, passed through a chromatographic column filled with silica gel, elute the system methylene chloride/methanol in the ratio of 70:30. Thus, the gain of 2.21 g (71%) of target compound in the form of yellowish crystals, analytically pure.

So pl. 198 - 199oC

1H-NMR (DMCO): 1,65 - 2,05 (m, 2H, indole-CH2-CH2-), and 2.27(s, 3H, C-CH3), 2,65 - 2,95 (m, 3H, indole-CH-CH-COOH), 3,63 (s, 3H, N-CH3), 3,95 - of 4.25 (m, 2H, imidazole-CH2-), x 6.15 (s, 1H, indole-H), 6,79 (d, J=1,6, 1H, imidazole-H), 6.90 to - 7,10 (m, 3H), including 7,06 (d, J=1,6, 1H, imidazole-H), 7,30 was 7.45 (m, 2H, aromatics).

Example 4. 1,2,3,9-Tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1 - yl)-methyl]-4H-carbazol-4-one.

To a suspension 311 ml (1 mmol) of the compound of example 3 in 10 ml of acetonitrile, add 28 μl (0.28 mmol) of 85% phosphoric acid. The reaction mixture was cooled to 0oC and added dropwise 353 μl (2.5 mmol) triperoxonane anhydride. After 15 min the reaction mixture was passed through a mixture of 50 g of ice and 50 ml of saturated solution of monocarbonate sodium and extracted with methylene chloride (310). The combined organic extracts dried (MgSO4) and evaporated. The solid precipitate perekristallizatsiya from methanol - 228oC.

1H - NMR (CDCl3): 1,70 - 2,05 (m, 1H, H-C(2)), 2,10 - of 2.30 (m, 1H, H-C (2 , of 2.45 (s, 3H, CH3), a 2.75 - 3.15 in (m, 3H, H-C(1) and H-C(3)), and 3.72 (s, 3H, N-CH3), 4,10 (DD, J=8,15, 1H, N-CH2), 4,70 (DD, J=4,15, 1H, N-CH2), 6,85 - 7,05 (m, 2H, aromatics), 7,20 - 7,40 (m, 3H, imidazole-H and aromatics), 8,20 - 8,30 (m, 1H, aromatics). dt

1. The method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl - 1H-imidazol-1-yl) methyl]-4H-carbazole-4-it formula I

< / BR>
the cyclization of a derivative of imidazole, wherein the cyclization is subjected to 2-[2-(methyl-1H - imidazol-1-yl)methyl] - 4-(1-methylindol-2-yl) butyric acid II

< / BR>
and the process is conducted in the presence of acid catalyst in the solvent environment.

2. The method according to p. 1, characterized in that the solvent used aprotic organic solvent, preferably acetonitrile.

3. The method according to PP.1 and 2, characterized in that as the acid catalyst used phosphoric acid.

4. The method according to PP.1 to 3, characterized in that the cyclization reaction is carried out at temperatures from -60 to + 50oC, preferably at 0oC.


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