RU2041876C1 - Process for preparing 1,2,3,9-tetrahydro -9-methyl -3-[(2-methyl-1h-imidazol -1-yl)methyl]-4h- carbazol-4-one or salts thereof or hydrates thereof, and intermediate products of synthesis thereof - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: the product is 1,2,3,9,-tetrahydro -9-methyl- (3- [(2-methyl- 1H-imidazol 1-yl) methyl]-4H-carbazol-4-one of the formula I, or salts thereof, or hydrates thereof. Reagent 1: 3-[(N-dialkylamino)methyl] -1,2,3,9-tetrahydro- 9-methyl-4H-carbazol-4-one of the formula II. Reagent 2: 2-methylimidazole. Reaction conditions: in a solvent of heating in the presence of catalytic amounts of iodine. The structure of the formulae I and II:

wherein NAlk₂ is N(C₂H₅)₂ or N(CH₂)₅.. EFFECT: improved properties of the title product, 4 cl

Description

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

^N(CH3⁾2^__→

Недостатком известного способа является длительность проведения процесса.A known method for producing 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] 4H-carbazol-4-one or its salts, or their hydrates of the formula I, which consists in the fact that the hydrochloride or iodomethylate 3 - [(N-dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one is reacted with 2-methylimidazole in a medium solvent during prolonged (20 h) heating. The desired product is isolated in the form of a base or salt.

^{N (CH} 3 ⁾ 2 ^{__ →}

The disadvantage of this method is the duration of the process.

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

 The goal is achieved by the proposed method for producing 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] 4H-carbazol-4-one or its salts, or their hydrates, namely that 3 - [(N-dialkylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one or its hydrochloride is reacted with 2- methylimidazole in an aqueous medium when heated in the presence of catalytic amounts of iodine.

^NAlk2^__→

Дополнительным преимуществом предлагаемого способа является использование новых промежуточных продуктов общей формулы II

где NAlk₂ представляет собой N(C₂H₅)₂ или N(CH₂)₅, или их солей с кислотами, являющихся промежуточными продуктами синтеза 1,2,3,9-тетрагидро-9-метил-3-[(2-метил-1Н-имидазол-1-ил)метил]-4Н-карбазол-4 -она или его солей. Особенно следует отметить 3-[(N-диэтиламино)метил]-1,2,3,9-тетрагидро-9-метил-4Н-карбазол-4-он, при использовании которого легко вернуть в процесс, применяемый в синтезе диэтиламин. Получение новых 3-[(N-диалкиламино)метил] -1,2,3,9-тетрагидро-9-метил-4Н- карбазол-4-онов общей формулы II основано на известной в литературе реакции Манниха.

^NAlk 2 ^{__ →}

An additional advantage of the proposed method is the use of new intermediate products of General formula II

where NAlk ₂ represents N (C ₂ H ₅ ) ₂ or N (CH ₂ ) ₅ , or 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-carbazol-4 -one or its salts. Particularly noteworthy is 3 - [(N-diethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, when used it is easy to return diethylamine to the process used in the synthesis. The preparation of the new 3 - [(N-dialkylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-ones of general formula II is based on the Mannich reaction known in the literature.

 It should be noted that in the proposed method, as the starting compound, Mannich base can be used both in the form of hydrochloride (similar to the known production method) and in the form of a free base. The advantage of this variant of the method is the ability to use Mannich base immediately after its preparation without converting it to a salt with acids or a quaternary base.

 It is also significant that when using the proposed method, not only dimethylamino derivative, but also heavier Mannich bases, for example, diethylaminomethyl or piperidylmethyl, the synthesis of which is somewhat simpler and, in addition, their use allows you to return the used amine to the process as the Mannich base, when using the proposed method.

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

 The advantages of the preferred process options are the ability to control the process and return for further use of the secondary amine, as well as the ability to use Mannich base in the form of a free base.

The target product is an antagonist of serotonin receptors (5-HT ³ ) and is used in medical practice, in particular, as an antiemetic, including in cancer patients.

Example 1. A mixture of 28.4 g (0.1 mol) of 3 - [(N-diethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole 4-one, 25.0 g (0.3 mol) of 2-methylimidazole, 250 ml of water and 0.05 g (0.0002 mol) of iodine are boiled for 5 hours with vigorous stirring. First, the precipitate dissolves, then the cloudiness after which a precipitate begins to precipitate. The reaction mass is cooled, the precipitate is filtered off, washed thoroughly with water, dried and 27.9 g of technical product are obtained with a melting point of 207-210 ^{° C} (yield 95%). The resulting product (3 g) is converted by the action of hydrochloric acid into hydrochloride, which after crystallization and drying is obtained in the form of a white crystalline powder (1.7 g), so pl. 177.5 178.5 ^about S. [literary data: so pl. 178.5-179.5 ^about C]
Analysis. Found, Cl 9.70, water 9.92. C ₁₈ H ₁₉ N ₃ ˙ HCl ˙ 2H ₂ O. Calculated, Cl 9.69, water 9.85.

Example 2. A suspension of 28.4 g (0.1 mol) of 3 - [(N-diethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole 4-one, 12.5 g (0.15 mol) of 2-methylimidazole and 0.05 g of iodine in 250 ml of water are stirred at the boil for 5 hours, cooled, the precipitate is filtered off, washed with water, dried and 26.9 g are obtained (90%) technical product with so pl. 207-210 ^about C. Hydrochloride receive analogously to example 1.

PRI me R 3. The mixture of 211.5 g (0.75 mol) 3 - [(N-diethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole- 4-one, 184.8 g (2.25 mol) of 2-methylimidazole, 0.5 g of iodine in 1860 ml of water is boiled with stirring while distilling off water and diethylamine. After 6 hours of boiling, 240 ml of aqueous diethylamine was distilled off. After the usual treatment, 217 g (98%) of a technical product with a melting point of 207-209 ^about S.

PRI me R 4. A solution of 6.3 g (0.0215 mol) of 3 - [(N-dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazole- hydrochloride is boiled 4-it and 6.0 g (0.064 mol) of 2-methylimidazole in 65 ml of water in the presence of a catalytic amount of iodine for 2.5 hours, cooled to 4 ^° C, the precipitate is filtered off, washed with water, dried and 5.6 g are obtained (89%) of the desired product in the form of a base. To a hot solution of the base in isopropyl alcohol was added alcohol saturated with hydrogen chloride until acidic, cooled ^to 0 ° C, the precipitate was filtered off and dried, yielding 4.9 g of the hydrochloride of the title product with m. Pl. 175.5-176.5 ^about S.

Example 5. To a solution of 11.6 g (0.039 mol) of Mannich base in 90 ml of a 3% solution of hydrochloric acid, 10 g (0.121 mol) of 2-methylimidazole and catalytic amounts of iodine are added, heated to reflux 3 h, after cooling, the precipitate is filtered off, washed with water, dried and get 10.4 g of the base of the target product with so pl. 207-210 ^C. Yield 89.2% To a suspension of the base in ethanol is added alcohol saturated with hydrogen chloride until acidic. When ether is added, the hydrochloride of the target product with a mp of 180-182 ^about S.

Analysis. Found, C, 62.10; H, 6.18; N, 12.10; Cl 9.96. C ₁₈ H ₁₉ N ₃ O˙HCl˙H ₂ O. Calculated, C 62.15; H 6.37; N, 12.07; Cl 10.19.

PRI me R 6. To a suspension of 36 g (0.18 mol) of N-methyl-1,2-dihydro-3H-carbazol-4-one in 380 ml of acetic acid, 18 g of paraform is added with stirring, then dropwise 25 ml (17.5 g; 0.24 mol) of diethylamine. The reaction mass is stirred at 80 ^about C for 5 hours, cooled, poured onto 1 liter of ice water and made basic with a 48% sodium hydroxide solution to pH 6-7. The precipitate of the unreacted starting carbazolone (8.2 g) was filtered off. Alkali is added to the filtrate to pH 10, the suspension is filtered, the precipitate is washed with water and dried. 37.4 g of 3 - [(N-diethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one are obtained (73% for taken or 94% for reacted carbazolone ) After crystallization from isopropyl alcohol, mp 134-136 ^about S.

Analysis. Found, C, 76.34; H 8.85; N, 10.03. C ₁₈ H ₂₄ N ₂ O. Calculated, C 76.02; H 8.54; N, 9.86.

Hydrochloride, mp 174-175 ^C (isopropanol).

Analysis. Found, C, 67.46; H, 8.04; N, 8.73; Cl 11.20. C ₁₈ H ₂₄ N ₂ O˙HCl. Calculated, C 67.38; H 7.85; N, 8.73; Cl 11.05.

PRI me R 7. To a suspension of 4.0 g (0.02 mol) of N-methyl-1,2-dihydro-3H-carbazol-4-one in 40 ml of acetic acid, 2.0 g of paraform is added with stirring then 2.4 ml (2.1 g; 0.025 mol) of piperidine are added dropwise. The reaction mixture was stirred at ⁸⁰ ° C for 4 hours, cooled, poured into ice water, basified with 48% sodium hydroxide until strongly alkaline reaction and extracted with chloroform. After evaporation, 4.8 g of 3 - [(N-piperidino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (81%) are obtained. After crystallization from isopropyl alcohol, mp 137-138 ^about S.

Analysis. Found, C, 77.10; H 8.37; N, 9.66. C ₁₉ H ₂₄ N ₂ O. Calculated, C 76.99; H 8.16; N, 9.45.

Hydrochloride, mp 177-178 ^about C (isopropanol).

Analysis. Found, C, 68.61; H, 7.90; N, 8.51; Cl 10.53. C ₁₉ H ₂₄ N ₂ O˙HCl. Calculated, C 68.56; H 7.57; N, 8.41; Cl 10.65.

Claims (4)

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

or its salts, or their hydrates, by reacting 3 - [(N-dialkylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 2-methylimidazole in a solvent by heating, characterized in that 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-carbazol-4-ones of the general formula II

where NAlk ₂ N (C ₂ H ₅ ) ₂ or N (CH ₂ ) ₅ ,
or 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-one or its salts, or their hydrates. 3. The method according to claim 1, characterized in that as the 3 - [(N-dialkylamino) methyl] -1,2,3,9 tetrahydro-9-methyl-4 H -carbazol-4-one, compounds of the general formula II, where NAlk ₂ NMe ₂ , NEt ₂ , N (CH ₂ ) ₅ or their salts. 4. The method according to claims 1 and 3, characterized in that as compounds 3 - [(N-dialkylamino) methyl] -1,2,3,9 tetrahydro-9 methyl-4H-carbazole 4-one, compounds of the general formula II are used where NAlk ₂ NEt ₂ in the form of a free base.