The method of obtaining 1,2,3,9 - tetrahydro-9-methyl-3- [(2-methyl - 1h - imidazol-1-yl) methyl]-4h - carbazole-4-or its salts or their hydrates, and intermediates for their synthesis

 

(57) Abstract:

Usage: as substances, which is an antagonist of serotonin receptors 5-HT3. The inventive product 1,2,3,9-tetrahydro -9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H - carbazole-4-one of formula I, or salts thereof, or hydrates. Reagent: 3-[(N-dialkylamino)methyl]- 1,2,3,9-tetrahydro-9-methyl-4H - carbazole-4-one of formula II. Reagent 2: 2-Mei. Reaction conditions: solvent when heated in the presence of catalytic amounts of iodine. The structure of formulas I and II: where NAlk2represents N(C2H5)2or N(CH2)5. 3 C.p. f-crystals.

The invention relates to the field of organic chemistry, specifically to an improved method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, as well as intermediates for their synthesis, which can find application in pharmaceutical industry.

A method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts, or hydrates of the formula I, namely, that the hydrochloride or iodimetric 3-[(N-dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-to the AI. The target product is isolated in the form of a base or salt

N(CH3)2__< / BR>
The disadvantage of this method is the duration of the process.

The aim of the invention is the intensification of the process.

This goal is achieved by the proposed method of obtaining 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] 4H-carbazole-4-or its salts or their hydrates, namely, that 3-[(N-dialkylamino)methyl] -1,2,3,9-then it is carbonated - draw-9-methyl-4H-carbazole-4-one or its hydrochloride is subjected to interaction with 2-methylimidazole in the aquatic environment when heated in the presence of catalytic amounts of iodine.

NAlk2__< / BR>
An additional advantage of the proposed method is the use of new intermediate products of General formula II

where NAlk2represents N(C2H5)2or N(CH2)5or their salts with acids, which are intermediate products of the synthesis of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4-or its salts. Especially note 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one, which can easily be returned to the process, -4-ones of General formula II is based on the well-known in the literature, the reaction of manniche.

It should be noted that in the proposed method as a starting compound can be used according to manniche in the form of hydrochloride (similar to the method), and in the form of free base. The advantage of this method is the possibility to use the basis of manniche directly after receiving it without transferring it in salt with acids or Quaternary base.

Significant is also the fact that when using the proposed method as Mannich bases can be used not only dimethylaminopropane, but heavier Mannich bases, such as diethylaminomethyl or piperidinedione, the synthesis of which is somewhat simpler and, in addition, they can return to the process used Amin.

Distinctive features of the proposed method is the use of a catalytic amount of iodine.

The advantages of the preferred variants of the process are the ability to control the process and return for future use secondary amine, as well as the possibility of using the Mannich bases in the form of free base.

P R I m e R 1. A mixture of 28.4 g (0.1 mol) of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 25,0 g (0.3 mol) of 2-methylimidazole, 250 ml of water and 0.05 g (is 0.0002 mol) of iodine in intensive stirring and boiled for 5 hours First dissolving the precipitate, then blurred, and then begins to fall precipitate. The reaction mass is then cooled, the precipitate is filtered off, thoroughly washed with water, dried and receive 27.9 g of a technical product with so pl. 207-210aboutWith (yield 95%). The resulting product (3 g) was transferred by the action of hydrochloric acid into the hydrochloride, which after crystallization and drying is obtained in form of white crystalline powder (1.7 g), so pl. 177,5 178,5aboutC. [literature data: so pl. 178,5-179,5aboutS]

Analysis. Found, Cl 9,70, water 9,92. C18H19N3HCl2H2O. Calculated Cl RS 9.69, water 9,85.

P R I m m e R 2. Suspension of 28.4 g (0.1 mol) of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 12.5 g (0.15 mol) of 2-methylimidazole and 0.05 g of iodine in 250 ml of water is stirred at boiling for 5 hours, cooled, the precipitate filtered off, washed with water, dried and get to 26.9 g (90% ) technical product so pl. 207-Ino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it, 184,8 g (2.25 mol) of 2-methylimidazole, 0.5 g of iodine in 1860 ml of water is boiled under stirring with simultaneous distillation of the water and diethylamine. After 6 h of boiling was autogyros 240 ml of water diethylamine. After conventional treatment get 217 g (98%) of a technical product with so pl. 207-209aboutC.

P R I m e R 4. Boil a solution of 6.3 g (0,0215 mol) of the hydrochloride of 3-[(N-dimethylamino)methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it and 6.0 g (0,064 mol) of 2-methylimidazole in 65 ml of water in the presence of catalytic amounts of iodine for 2.5 h, cooled to 4aboutC, the precipitate is filtered off, washed with water, dried, yielding 5.6 g (89%) of the desired product in the form of a Foundation. To a hot solution of the base in isopropyl alcohol, add the alcohol, saturated with hydrogen chloride until acidic reaction, cooled to 0aboutC, the precipitate is filtered off and dried, yielding 4.9 g of the hydrochloride of the desired product with so pl. 175,5-176,5aboutC.

P R I m e R 5. To a solution of 11.6 g (0,039 mol) of Mannich bases in 90 ml of 3% hydrochloric acid solution was added 10 g (0,121 mol) of 2-methylimidazole and catalytic amounts of iodine, refluxed for 3 h, after cooling, the precipitate is filtered off, washed with water, dried, yielding 10.4 g of the base of the target product with so gorodom, to acid reaction. Adding ether falls hydrochloride of the desired product with so pl. 180-182aboutC.

Analysis. Found, C 62,10; N 6,18; N 12,10; Cl 9,96. WITH18H19N3OHClH2O. Calculated With 62,15; N 6,37; N 12,07; Cl 10,19.

P R I m e R 6. To a suspension of 36 g (0.18 mol) of N-methyl-1,2-dihydro-3H-carbazole-4-it 380 ml of acetic acid under stirring add 18 g of paraform, then added dropwise 25 ml (17.5 g; 0.24 mol) of diethylamine. The reaction mass is stirred at 80aboutC for 5 h, cooled, poured onto 1 l of ice water and alkalinized 48% sodium hydroxide solution to pH 6-7. The precipitation is not included in the initial reaction carbazole (8,2 g) is filtered off. To the filtrate add alkali to a pH of 10, the suspension is filtered, the precipitate washed with water and dried. Get with 37.4 g of 3-[(N-diethylamino)methyl]-1,2,3,9-tetrahed - ro-9-methyl-4H-carbazole-4-it (73% taken or 94% reacted on carbazole). After crystallization from isopropyl alcohol so pl. 134-136aboutC.

Analysis. Found, C 76,34; H Cent To 8.85; N There Is A 10.03. C18H24N2O. Calculated With 76,02; N 8,54; N 9,86.

Hydrochloride, T. pl. 174-175aboutC (isopropanol).

Analysis. Found, 67,46; N. Of 8.04; N 8,73; Cl 11,20. C18H24N2OHCl. Calculated With 67,38; N A 7.85; N is lots with stirring, add 2.0 g of paraform, then added dropwise 2.4 ml (2.1 g; 0,025 mol) of piperidine. The reaction mass is stirred at 80aboutC for 4 h, cooled, poured into ice water, alkalinized 48% sodium hydroxide solution to strongly alkaline and extracted with chloroform. After parki obtain 4.8 g of 3-[(N-piperidino)methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-it (81%). After crystallization from isopropyl alcohol so pl. 137-138aboutC.

Analysis. Found, With 77,10; N. Of 8.37; N 9,66. C19H24N2O. Calculated With 76,99; N 8,16; N 9,45.

Hydrochloride, T. pl. 177-178aboutC (isopropanol).

Analysis. Found, 68,61; N. Of 7.90; N 8,51; Cl 10,53. C19H24N2OHCl. Calculated With 68,56; N EUR 7.57; N To 8.41; Cl 10,65.

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>
or its salts or their hydrates, the interaction of 3-[(N-dialkylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one with 2-methylimidazole in a solvent under heating, wherein the process is conducted in the presence of catalytic amounts of iodine.

2. 3-[(N-dialkylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-ones of General formula II

< / BR>
where NAlk2N(C2H5)2or N(CH2)<3-[(2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazole-4-or its salts, or their hydrates.

3. The method according to p. 1, characterized in that as 3-[(N-dialkylamino) methyl] -1,2,3, 9 tetrahydro-9-methyl -4 H-carbazole-4-it uses compounds of General formula II, where NAlk2NMe2NEt2N(CH2)5or their salts.

4. The method according to PP.1 and 3, characterized in that as 3-[(N-dialkylamino) methyl] -1,2,3,9 tetrahydro-9 methyl-4H-carbazole 4-she used compounds of General formula II, where NAlk2NEt2in the form of free base.

 

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(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

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IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

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Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

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Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

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(I)< / BR>
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7 tbl, 4 ex

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2 cl, 1 tbl, 11 ex

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