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

 

(57) Abstract:

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-she of the formula (I). The method consists in the interaction of tetrahydrocarbazole formula (IV) with morpholine at a temperature of from 110oWith up to temperature phlegmy, with the addition of formaldehyde or paraformaldehyde and obtaining the compounds of formula (III), which is then subjected to interaction with 2-methyl-imidazole with the formation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1 H-imidazol-yl)methyl] -4H-carbazole-4-she of the formula (I). The technical result increased efficiency and process safety. The invention can be used in the synthesis of chemical products, which are the active ingredients in pharmaceutical preparations.

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The invention concerns a method of obtaining derivatives of imidazole, mainly product 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-it is known as the active component of the pharmaceutical drug Ondansetron (Ondansetron) or its pharmacologically acceptable salts.

"Ondansetron" known as the electoral antagonist "neuronic" 5-HT recipe the ways of obtaining mentioned derivatives of imidazole, in particular from EP 595111, which describes a process for their preparation by the reaction of N-methylcarbazole with dialkyl oxalate with the aim of obtaining a new intermediate product, which is then converted into the target product.

In EP 2211629 described the process of obtaining the same imidazole derivatives by cyclization imidazolidine intermediates in the presence of palladium catalyst.

In EP 219929 described the process of obtaining these compounds by cyclization of phenyl hydrazine to obtain an intermediate product in the presence of Lewis acid as a catalyst.

In the Patent of the Russian Federation 1528319, describes the synthesis of imidazole derivatives of the formula (I),

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by reaction of the intermediate compounds of formula (II)

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where Y represents =CH2or CH2Z, where Z is chlorine, dimethylamino or methanimidamide,

with 2-methyl-imidazole with obtaining the compounds of formula (I).

The present invention concerns a method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -4H-carbazole-4-she of the formula (I), by creating a new intermediate compounds of formula III.

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by using the reaction of tetrahydrocarbazole as intermediate compounds is uly III then directly reacted with 2-methyl-imidazole, resulting in the receive connection of the formula (I).

If necessary, the target product is transferred in the form of salt.

Example 1

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

A mixture of 10 g of 1,2,3,9-tetrahydro-9-methyl-4H-1-carbazole-4-she and 4.5 ml of the research in 60 ml of N,N-dimethyl of formamide was heated to 110oC. To it was added paraformaldehyde in the amount of 5.0 g in small portions over 4 hours. After the reaction was completed, the solvent was removed under vacuum, the residue was rapidly cooled in water, extracted with ethyl acetate and the organic layer was concentrated to obtain compound III.

Compound III was placed in a mixture of 50 ml toluene and 6.5 g of 2-methyl-imidazole, person to distil the mixture under reflux for 5 hours. The reaction mass was then cooled to room temperature and filtered to obtain a solid of the desired product in the amount of 8.5 g so pl. 155-156oC.

Example 2

The method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazolyl)methyl]-4H-carbazole-4-she hydrochloride(I)

A mixture of 10 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-she and 4.5 ml of the research in 80 ml of ethanol was heated to temperate reaction solvent was removed under vacuum, the residue was rapidly cooled in water, extracted with ethyl acetate and the organic layer was concentrated to obtain compound III.

Compound III was then added to a mixture of 70 ml of dioxane with 6.5 GM of 2-methyl-imidazole, next person to distil under reflux for 7 hours. Then the reaction mass was cooled to room temperature and filtered to obtain an 8.0 GM of a solid compound (I).

The product was placed in a mixture of 30 ml of methanol and 40 ml of isopropanol, which was added 2.5 ml of 30% hydrochloric acid and was obtained the hydrochloride dihydrate in the form of 7.5 g of a white solid precipitate with so pl. 186-187oC.

Toxicity tests were conducted on laboratory mice. After intravenous injection of target products of examples 1 and 2 was determined by the maximum permissible dose for 50% survival of test animals. For compounds of example 1 MPC50was 10.2 mg/kg-1and the connection according to example 2 and 10.3 mg/kg-1.

Standard methods were determined, the antagonism of responses, caused by 5-HT in "neuronic" 5-HT receptors in vitro and in vivo the compounds of examples 1 and 2.

Tests revealed no abnormalities in the effectiveness of the compounds obtained way the ptx2">

The proposed method has the following advantages at least in relation to the method described in the patent of the Russian Federation 1528319.

The proposed scheme for 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazolyl)methyl]-4H-carbazole-4-it allows you to:

- to reduce the purely technological stage of the process;

- using the new intermediate products making it more efficient;

- exclude the formation of toxic side products;

- do not use these dangerous solvents in extraction and purification as diethyl ether;

to make the production process more technologically comfortable.

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

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using 2-methyl-imidazole and an organic solvent, characterized in that tetrahydrocarbazole formula (IV)

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subjected to interaction with morpholine at a temperature of from 110oWith up to temperature phlegmy, then add formaldehyde or paraformaldehyde obtaining compound (III)

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which, in turn, is subjected to the interaction with 2-methyl-imidazole and produce the target product in the

 

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