RU2439073C1 - METHOD OF PRODUCING INDOLIZINO[7,6-b]INDOLE DERIVATIVES - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to a method of producing indolizino[7,6-b]indole derivatives of formulae Ia-f

, where Ia: R=R¹=R²=H; Ib: R-R²=H, R¹=CH₃; Ic: R=H, R¹=CH₃, R²=Cl; Id: R=Cl, R¹=R²=H; Ie: R=CH₃, R¹=H, R²=Cl; If: R=OCH₃, R¹=H, R²=Cl, which involves reaction of 3-alkyl-5-tosyl-5H-pyrido[4,3-b]indole II and phenacyl bromide in a mixture of benzene and toluene.

EFFECT: novel heterocyclic backbone - indolizino[7,6-b]indole derivatives.

1 cl, 2 tbl, 2 ex

Description

The invention relates to the field of organic chemistry - the synthesis of a new heterocyclic system indolisino [7,6-b] indole, since substances possessing such a framework can be used in the synthesis of new pharmaceutical preparations.

The invention relates to the development of a method for the preparation of indolisino [7,6-b] indole derivatives of the general formula I, which are analogues (isomers) of the known indolisino [8,7-b] indoles exhibiting anticancer activity [Yoshino H., Koike K., Nikaido T., Heterocycles, 1999, 51, 281].

Index R R ¹ R ² Ia H H H Ib H CH ₃ H Ic H CH ₃ Cl Ig Cl H H Id CH ₃ H Cl Ie Och ₃ H Cl

The literature does not describe methods for the preparation of indolisino [7,6-b] indole derivatives. On the other hand, methods for the synthesis of the isomeric structure, indolisino [8,7-b] indole, are known in which β-carboline derivatives are used as starting compounds, due to the availability of tryptamine derivatives, β-carboline precursors.

Thus, the 1,3-dipolar addition of acetylene carboxylates to the β-carboline azomethine ylide generated by thermal decomposition of] N - [(trimethylsilyl) methyl] β-carboline trphthalates in boiling dimethoxyethane in the presence of cesium fluoride leads to indolisino derivatives [8,7-b] indole [Poissonnet G., Theret-Bettiol MH., Dodd RH, J. Org. Chem., 1996, 61, 2273; Grigg R., Poissonnet G., Potier P., Dodd R. H., Tetrahedron Lett., 1989, 30, 3423].

Another way to obtain an isomeric structure is the interaction of β-carboline derivatives with phenacyl bromide or bromoacetone followed by treatment with a soda solution [Yoshino H., Koike K., Nikaido T., Heterocycles, 1999, 51, 281].

These compounds can also be obtained by oxidative regioselective cyclization of N-allyl-tetrahydro-β-carbolines in boiling xylene in the presence of silver carbonate [Grigg R., Myers P., Somasunderam A., Sridharan V., Tetrahedron, 1992, 44, 9735].

We have proposed the synthesis of a new heterocyclic system indolisino [7,6-b] indole based on derivatives of γ-carboline.

The objective of the invention is the development of a method for producing a new heterocyclic framework - derivatives of indolisino [7,6-b] indole I,

Index R R ¹ R ² Ia H H H Ib H CH ₃ H Ic H CH ₃ Cl Ig Cl H H Id CH ₃ H Cl Ie Och ₃ H Cl

allowing to expand the range of potentially biologically active substances.

The technical result is the synthesis of a new, not previously studied, heterocyclic system - indolisino [7,6-b] indole, as well as ensuring the introduction of the required substituents in the target product while forming an indolysin core.

The technical result is achieved by the fact that in the method for producing indolisino [7,6-b] indole derivatives, available 3-alkyl-5-tosyl-5H-pyrido [4,3-b] indoles II and phenacyl bromides are boiled in a mixture of benzene and toluene for 72 h, the precipitate was filtered off and treated with a solution of NaHCO ₃ .

Index R R ¹ R ² Ia H H H Ib H CH ₃ H Ic H CH ₃ Cl Ig Cl H H Id CH ₃ H Cl Ie Och ₃ H Cl

Available 3-alkyl-5-tosyl-5H-pyrido [4,3-b] indoles II were obtained and described in [Butin A.V., Pilipenko A.S., Milich A.A., Finko A.V. Chemistry of heterocyclic compounds, 2009, 5, 774].

The claimed method is based on the interaction of β-carboline derivatives with phenacyl bromides with the formation of the corresponding salts, further intramolecular aldol condensation of the alkyl group in the second position of the β-carboline pyridine ring with the N-methylene carbonyl group, leading to the formation of the indolysinium cation, and subsequent deprotonation to indolysines [Yosh H., Koike K., Nikaido T., Heterocycles, 1999, 51, 281].

Melting points, elemental analysis data, and spectral characteristics of indolisino [7,6-b] indoles Ia-e are shown in Table 1.

The technical result obtained allows us to synthesize a new heterocyclic system — indolisino [7,6-b] indole Ia-e, not previously studied, and thereby expand the range of potentially biologically active compounds.

Thus, the set of essential features set forth in the claims, allows to achieve the desired technical result.

Examples of the proposed method for producing 10-tosyl-2-phenyl-10H-indolisino [7,6-b] indole.

Example 1

A mixture of 0.5 g (1.5 mmol) of 3-methyl-5-tosyl-5H-pyrido [4,3-b] indole IIa, 0.3 g (1.7 mmol) of phenacyl bromide, 15 ml of benzene is boiled for 90 hours. Then the reaction mixture is filtered, 10 ml of water, 5 ml of 1,4-dixane and 0.5 g of NaHCO ₃ are added and boiled for 10 minutes. The precipitate is filtered off, recrystallized from a mixture of methylene chloride / petroleum ether. Yield 68% (0.44 g).

T _pl . 212-213 ° C.

Found C ₁₈ H ₁₄ N ₂ O ₃ ,% C, 74.05; H 4.77; N 6.32.

Calculated: C, 74.29; H 4.62; N, 6.42.

Spectrum ¹ H NMR (DMSO), δ, ppm and KSSV, J, Hz): 2.25 (s, 3Н, CH ₃ ), 6.83 (s, 1Н, H _Ar ), 7.09 (d, J = 8.1 Hz, 2Н, H _Ts ), 7.24-7.30 (m, 3Н , H _Ar ), 7.38-7.44 (m, 3H, H _Ar ), 7.65-7.70 (m, 5H, H _Ar ), 8.11 (s, 1H, H _Ar ), 8.15-8.18 (m, 1H, H _Ar ) 8.37 (s, 1H, H _Ar ).

¹³ C NMR Spectrum (CDCl ₃ ), (δ, ppm): 21.4, 96.3, 102.1, 108.1, 115.5, 116.5, 116.8, 119.7, 124.4, 124.8, 126.2 (2C), 126.7 (2C), 128.1, 128.8 (3С), 129.6 (2С), 131.0, 132.5, 133.4, 134.3, 135.0, 140.4, 144.9

Example 2

A mixture of 0.5 g (1.5 mmol) of 3-methyl-5-tosyl-5H-pyrido [4,3-b] indole IIa, 0.3 g (1.7 mmol) of phenacyl bromide, 10 ml of benzene and 5 ml of toluene is boiled for 72 hours. Then the reaction mixture is filtered, 10 ml of water, 5 ml of 1,4-dixane and 0.5 g of NaHCO ₃ are added and boiled for 10 minutes. The precipitate is filtered off, recrystallized from a mixture of methylene chloride / petroleum ether. Yield 82% (0.53 g).

Example 3

A mixture of 0.5 g (1.5 mmol) of 3-methyl-5-tosyl-5H-pyrido [4,3-b] indole IIa, 0.3 g (1.7 mmol) of phenacyl bromide, 10 ml of benzene and 10 ml of toluene is boiled for 30 hours. Then the reaction mixture is filtered, 10 ml of water, 5 ml of 1,4-dixane and 0.5 g of NaHCO ₃ are added and boiled for 10 minutes. The precipitate is filtered off, recrystallized from a mixture of methylene chloride / petroleum ether. Yield 55% (0.36 g).

Example 4

A mixture of 0.5 g (1.5 mmol) of 3-methyl-5-tosyl-5H-pyrido [4,3-b] indole IIa, 0.3 g (1.7 mmol) of phenacyl bromide, 15 ml of toluene is boiled for 24 hours. Then the reaction mixture is filtered, 10 ml of water, 5 ml of 1,4-dixane and 0.5 g of NaHCO ₃ are added and boiled for 10 minutes. The precipitate is filtered off, recrystallized from a mixture of methylene chloride / petroleum ether. Yield 47% (0.3 g).

Table 2 shows data on the effect of the ratio of solvents on the yield of indolisino [7,6-b] indole Ia (examples 1-4).

table 2 Effect of reaction conditions on 10H-tosyl-2-phenyl-10H-indolisino [7,6-b] indole Ia Example Solvent ratio Reaction time, hour Exit, % Toluene Benzene one - one 90 68 2 one 2 72 82 3 one one thirty 55 four one - 24 47

As can be seen from table 2, the optimal condition for the synthesis of the target product 10-tosyl-2-phenyl-10H-indolisino [7,6-b] indole Ia is the boiling of 3-methyl-5-tosyl-5H-pyrido [4,3-b ] indole IIa and phenacyl bromide in a mixture of toluene and benzene in a ratio of 1: 2, and subsequent treatment with a solution of NaHCO ₃ . The boiling of the starting compounds in toluene, as in a 1: 1 mixture of toluene and benzene, was accompanied by the grinding of the reaction mixture and, as a result, a decrease in the yield of the target product. The use of benzene led to an increase in reaction time and resinification.

The inventive method obtained a number of derivatives of indolisino [7,6-b] indole Ia-e.

Claims (1)

The method of obtaining derivatives of indolisino [7,6-b] indole of General formula I

characterized in that the available 3-alkyl-5-tosyl-5H-pyrido [4,3-b] indoles II and phenacyl bromides are boiled in a mixture of benzene and toluene for 72 hours, the precipitate is filtered off and treated with a NaHCO ₃ solution.