RU2439071C1 - METHOD OF PRODUCING 11H-INDOLO[2,3-c]QUINOLINE DERIVATIVES - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to novel synthesis of 11H-indolo[2,3-c]quinoline derivatives of formula I, which can be used in synthesis of novel preparations for pharmaceutical purposes. In the method of producing 11H-indolo[2,3-c]quinoline derivatives of general formula I

index R R¹ R² Iа Н Н Н Ib Cl Н Н Ic Cl ОСН₃ ОСН₃ Id СН₃ Н Н Ie Н ОСН₃ Н

, the corresponding 4-[2-(2-nitrophenyl)-1H-indol-3-yl]-but-3-en-2-ones II are boiled in acetic acid in the presence of twenty-fold molar excess of carbonyl iron for 5 minutes.

EFFECT: method widens the range of obtained products and simplifies the process owing to use of other initial compounds and conditions.

1 cl, 4 ex, 2 tbl

Description

The invention relates to the field of organic chemistry - the synthesis of heterocyclic compounds - derivatives of 11H-indolo [2,3-c] quinoline, which can be used in the synthesis of new pharmaceutical preparations.

The invention relates to the development of a method for producing 11H-indolo [2,3-c] quinoline derivatives of general formula I, which are of interest as substances having anti-cancer activity [Helissey P., Giorgi-Renault S., Renault J., Cros S., Chem . Pharm. Bull., 1989, 37, 675], and also which can be used in the synthesis of antimalarial drugs analogues of the isocryptolepine alkaloid [Hostyn S., Maes BUW, Pieters L., Lemiere GLF, Matyus P., Hajos G., Dommisse RA, Tetrahedron, 2005, 61, 1571].

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

Various approaches to the synthesis of 11H-indolo [2,3-c] quinoline derivatives are described in the literature. Thus, upon boiling of 3-phenylquinoline azides in o-dichlorobenzene, regioselective thermal cyclization to 11H-indolo [2,3-c] quinoline derivatives occurs [Trecourt F., Mongin F., Mallet M., Quéguiner G., Synthetic Communications, 1995 , 25, 4011], also these compounds are obtained by oxidative photochemical cyclization of 4- (N-phenyl) aminoquinolines in a mixture of benzene, methanol and sulfuric acid when irradiated with ultraviolet light in the presence of traces of iodine [Dhanabal T., Sangeetha R., Mohan PS, Tetrahedron, 2006, 62, 6258].

Another method of preparation is the Fisher reaction, the interaction of 2,3-dihydro-1-H-quinolin-4-one with phenylhydrazines in acetic acid in the presence of sulfuric acid [Rousseil O., Buu-Hoi NP, Jacquignon P., Journal of the Chemical Society, 1965, 5458; He L., Chang H., Chou T., Savaraj N., Cheng C. C., European Journal of Medicinal Chemistry, 2003, 38, 101].

There are also methods based on the palladium-catalyzed cyclization reaction of 4-N- (2-halogenophenyl) aminoquinoline [Meyers C., Rombouts G., Loones K.T.J., Coelho A., Maes B.U.W., Adv. Synth. Catal., 2008, 350, 465; Jonckers T.H.M ,. Maes B.U.W., Lemiere G.L.F., Rombouts G, Pieters L., Haemers A., Dommissea R.A., Synltett, 2003, 5, 615], resulting in 11H-indolo [2,3-c] quinoline derivatives.

The disadvantage of the described methods is either low selectivity or the use of expensive palladium-based catalysts.

The objective of the invention is the development of a method for producing derivatives of 11H-indolo [2,3-c] quinoline I, which allows to expand the range of potentially biologically active substances and constitute convenient starting compounds for the synthesis of analogues of the isocryptolepine alkaloid.

The technical result is the provision of the introduction of the required substituents in the target product while the formation of the quinoline core.

The technical result is achieved by the fact that in the method for producing derivatives of 11H-indolo [2,3-c] quinoline, 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2- Ones II [Butin AV, Uchuskin MG, Pilipenko AS, Tsiunchik FA, Cheshkov DA, Trushkov IV, Eur. J. Org. Chem., 2010, 920] are boiled in acetic acid in the presence of carbonyl iron for 5 minutes.

Index R R ¹ R ² Ia N N N Ib Cl N N Ic Cl OCH ₃ OCH ₃ Ig CH ₃ N N Id N OCH ₃ N

The basis of the proposed method is the interaction of an electrophilic carbon atom with a nucleophilic nitrogen atom while forming a quinoline skeleton, described in [MacPhillamy H.B., Dziemam R.L., Lucas R.A., Kuehne M.E., J. Am. Chem. Soc., 1958, 2172].

Melting points, elemental analysis data and spectral characteristics of 11H-indolo [2,3-c] quinoline Ia-d are shown in Table 1.

The technical result obtained allows us to expand the range of derivatives of 11H-indolo [2,3-c] quinoline Ia-d, and thereby 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 11H-indolo [2,3-c] quinoline.

Example 1

A mixture of 0.5 g (1.6 mmol) of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2-one Ia, 1.83 g (32 mmol) of carbonyl iron and 25 ml of acetic acids are heated until the starting compound is completely dissolved and boiled for 5 minutes. Then the reaction mixture was poured into 500 ml of water, neutralized with NaHCO ₃ , extracted with ethyl acetate (20 × 15 ml), the combined organic fractions were dried with sodium sulfate, filtered with activated carbon and evaporated under reduced pressure. The residue was recrystallized from 1,4-dioxane. Yield 68% (0. 24 g).

T _pl. > 250 (decomposition).

Found C ₁₈ H ₁₄ N ₂ O ₃ ,% C, 82.60; H 4.70; N, 12.80.

Calculated: C 82.55; H 4.62; N, 12.83.

Spectrum ¹ H NMR (CDCl ₃ ), (δ, ppm, and KSSB, J, Hz): 7.32-7.37 (m, 1H, H _Ar ), 7.48-7.53 (m, 1H, H _Ar ), 7.68- 7.78 (m, 3H, H _Ar ), 8.13-8.16 (m, 1H, H _Ar ), 8.31-8.34 (m, 1H, H _Ar ), 8.52-8.55 (m, 1H, H _Ar ), 9.61 (s, 1H, H _Py ), 12.75 (s, 1H, NH).

¹³ C NMR Spectrum (CDCl ₃ ), (δ, ppm): 111.9, 114.3, 117.0, 120.1, 120.6, 121.9, 122.1, 125.6, 125.7, 128.1, 129.2, 138.8, 139.9, 144.6, 145.1.

Example 2

A mixture of 0.5 g (1.6 mmol) of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2-one Ia, 0.183 g (3.2 mmol) of carbonyl iron and 25 ml of acetic acids are heated until the starting compound is completely dissolved and boiled for 10 minutes. Then the reaction mixture was poured into 500 ml of water, neutralized with NaHCO ₃ , extracted with ethyl acetate (20 × 15 ml), the combined organic fractions were dried with sodium sulfate, filtered with activated carbon and evaporated under reduced pressure. The residue was recrystallized from 1,4-dioxane. Yield 25% (0.09 g).

Example 3

A mixture of 0.5 g (1.6 mmol) of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2-one Ia, 3.66 g (64 mmol) of carbonyl iron and 25 ml of acetic acids are heated until the starting compound is completely dissolved and boiled for 5 minutes. Then the reaction mixture was poured into 500 ml of water, neutralized with NaHCO ₃ , extracted with ethyl acetate (20 × 15 ml), the combined organic fractions were dried with sodium sulfate, filtered with activated carbon and evaporated under reduced pressure. The residue was recrystallized from 1,4-dioxane. Yield 67% (0.238 g).

Example 4

A mixture of 0.5 g (1.6 mmol) of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2-one Ia, 1.83 g (32 mmol) of carbonyl iron and 25 ml of acetic acids are heated until the starting compound is completely dissolved and boiled for 20 minutes. Then the reaction mixture was poured into 500 ml of water, neutralized with NaHCO ₃ , extracted with ethyl acetate (20 × 15 ml), the combined organic fractions were dried with sodium sulfate, filtered with activated carbon and evaporated under reduced pressure. The residue was recrystallized from 1,4-dioxane. Yield 55% (0.2 g).

Table 2 shows the effect of the reaction time, excess carbonyl iron on the yield of 11H-indolo [2,3-c] quinoline Ia (examples 1-4).

table 2 Effect of reaction conditions on the yield of 11H-indolo [2,3-s] quinoline Ia Example Ratio Reaction time, min Exit, % compound Ia, mol Carbonyl iron, moth one one twenty 5 68 2 one 2 10 25 3 one 40 5 67 four one twenty twenty 55

As can be seen from table 2, the optimal condition for the synthesis of the target product 11H-indolo [2,3-c] quinoline I is the boiling of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-ene -2-ones II, in acetic acid with a twenty-fold excess of carbonyl iron for 5 minutes. An increase in the excess of carbonyl iron does not lead to an increase in the yield of the reaction product, and when doubled, resinification is observed and the yield does not exceed 25%.

Longer boiling leads to resinification and, as a result, to a decrease in the yield of the target product.

The inventive method obtained a number of derivatives of 11H-indolo [2,3-s] quinoline Ia-e.

Claims (1)

The method of obtaining derivatives of 11H-indolo [2,3-c] quinoline of General formula I

Index R R ¹ R ² Ia N N N Ib Cl N N Ic Cl OCH ₃ OCH ₃ Ig CH ₃ N N Id N OCH ₃ N
characterized in that the derivatives of 4- [2- (2-nitrophenyl) -1H-indol-3-yl] -but-3-en-2-one II are boiled in acetic acid in the presence of a twenty-fold molar excess of carbonyl iron for 5 minutes .