CN102977098B - Aryl-substituted indolizine derivative and preparation method and applications thereof - Google Patents

Abstract

The invention discloses an aryl-substituted indolezine derivative and its preparation method and use, which is characterized in that: under stirring conditions, add indolezine compound, aryl acetate periodiodine, oxidizing agent, inorganic base and catalyst into N - In methylpyrrolidone, under the protection of nitrogen, the reaction is complete at 80-100°C. The invention adopts readily available raw materials to prepare aryl-substituted indolezine derivatives, has good reaction selectivity, mild reaction conditions, simple preparation process, low production cost, and the whole synthesis route is environmentally friendly. The synthesized aryl-substituted indoxazine derivatives are used to prepare antitumor drugs and have remarkable effects.

Description

A kind of aryl substituted indolezine derivative and its preparation method and application

Technical field:

The invention relates to the field of preparation of organic compound intermediates, in particular to an aryl-substituted indolezine derivative and its preparation method and application.

Background technique:

C-C bond construction is an important research content of organic synthetic chemistry. Transition metal-catalyzed organic synthesis reactions are an important method for the formation of C-C bonds, which have been intensively studied and become widely used tools for constructing C-C bonds. For example, transition metal-catalyzed Heck reaction, Suzuki-Miyaura coupling reaction, Stille coupling reaction and Sonogashira coupling reaction, etc. However, these reactions require preactivation steps such as halogenation or metallation of the substrate. Therefore, the method of directly constructing C-C bonds from C-H bonds catalyzed by transition metals has become an effective way to efficiently construct C-C bonds. Related researches have aroused great interest. It is of great interest and has become a research hotspot in organic synthesis. The reactivity and reaction selectivity of carbon-hydrogen bonds are the key points of related research.

Indoxazine structural units widely exist in biologically active natural products and synthetic drugs. Therefore, how to synthesize indoxazine derivatives quickly, efficiently and greenly is of great significance. At present, there are few methods for rapidly and effectively synthesizing 3-aryl substituted indolezines, Gevorgyan (Park, C.-H.; Ryabova, V.; Seregin, I.V.; Sromek, A.W.; Gevorgyan, V.Org.Lett.2004 , 6, 1159-1162.) reported in 2004 the method of using aryl bromide to arylate the 3-position carbon of indolazine. In 2009, researchers from the Shanghai Institute of Organic Chemistry used the carbon-hydrogen bond on the 3-carbon of indolezine to be converted into a carbon-chlorine bond and then synthesized a 3-aryl substituted indolezine derivative product through Suzuki reaction (Xia, J.-B .; You, S.-L. Org. Lett. 2009, 11, 1187-1190.).

Invention content:

The first aspect of the present invention is to provide an important organic intermediate - aryl-substituted indolezine derivatives.

An aryl substituted indolezine derivative, the structure of which is shown in formula (I):

In the formula (I), R ₁ is 1-naphthyl, 2-naphthyl, phenyl or a phenyl group with a substituent, wherein when _R is a phenyl group with a substituent, the substituent on the phenyl group is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylmercapto, halogen atom, trifluoromethoxy, formyl or trifluoromethyl;

R ₂ is hydrogen or methyl;

R ₃ is hydrogen or methyl;

R ₄ is a cyano group or a C ₁ -C ₄ alkoxycarbonyl group.

The compound represented by preferred formula (I) is one of the following compounds:

Another aspect of the present invention also provides a method for preparing the above-mentioned aryl-substituted indolezine derivatives. The method has a simple preparation process, is environmentally friendly and has a high yield.

A preparation method of aryl-substituted indolezine derivatives, comprising the following steps: adding indolezine compound, aryl acetate periodiodine, oxidizing agent, inorganic base and catalyst to N-methylpyrrolidone (NMP) under stirring condition , under the protection of nitrogen, the reaction is complete at 80-100°C, and the aryl-substituted indoleazine derivatives are obtained after post-treatment. The structure is shown in formula (I). The above reaction process is shown in the following formula:

In formula (I), R ₁ is phenyl, 1-naphthyl, 2-naphthyl or phenyl with substituent, wherein R ₁ is phenyl with substituent, the substituent on its phenyl is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylmercapto, halogen atom, trifluoromethoxy, formyl or trifluoromethyl; R ₂ is hydrogen or Methyl; R ₃ is hydrogen or methyl; R ₄ is cyano or C ₁ -C ₄ alkoxycarbonyl.

In formula (II), R ₂ is hydrogen or methyl; R ₃ is hydrogen or methyl; R ₄ is an electron-withdrawing group, such as cyano or C ₁ -C ₄ alkoxycarbonyl;

In formula (III), R ₁ is phenyl, 1-naphthyl, 2-naphthyl or phenyl with substituent, and when R ₁ is phenyl with substituent, the substituent on the phenyl C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylmercapto, halogen, trifluoromethoxy, formyl or trifluoromethyl;

The oxidizing agent is a peroxide reagent, and the preferred oxidizing agents are benzoyl peroxide (PhCO ₂ ) ₂ , tert-butanol peroxide (t-BuCO ₃ H), di-tert-butyl peroxide (t-BuCO ₂ ) _2. Potassium persulfate or (K ₂ S ₂ O ₈ ) sodium persulfate (Na ₂ S ₂ O ₈ ).

The catalyst is metal palladium catalyst, and the preferred catalyst is palladium acetate (Pd(OAc) ₂ ), palladium chloride (PdCl ₂ ), bistriphenylphosphine palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), bis(dibenzylideneacetone)palladium (Pd(dba) ₂ ) or tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ).

The inorganic base is a common inorganic base, the preferred inorganic base is potassium acetate (KOAc), potassium carbonate (K ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ) or sodium acetate (NaOAc), the preferred inorganic base Is KOAc or NaOAc. Commercially available products can be used for the above reagents.

The preferred molar ratio of the indolezine compound, periodiodonium aryl acetate, oxidant, inorganic base and catalyst in the above preparation method is: 1:1.1-1.5:1.1-1.5:1-2:0.1-0.2. The preferred reaction time is 12 to 19 hours.

Preferably, the compound represented by formula (II) is selected from 1-cyanindolezine, 1-n-butyl indolezine carboxylate, 2-methyl-1-cyanindolezine or 6-methyl-1 - cyanindorazine. The compound represented by the preferred formula (III) is selected from periodic iodine p-methoxyphenyl acetate, periodic iodine p-methylmercaptophenyl acetate, periodic iodine p-tert-butylphenyl acetate, periodic iodine p-chlorophenyl acetate, p- Periodic trifluoromethoxyphenyl acetate, periodic iodine p-trifluoromethylphenyl acetate, periodic iodine m-methylphenyl acetate, periodic iodine m-chlorophenyl acetate, periodic iodine m-fluorophenyl acetate, m-formyl Periodic phenyl acetate, periodic iodine m-trifluoromethylphenyl acetate, periodic iodine o-methylphenyl acetate, periodic iodine o-bromophenylacetate, periodic iodine phenylacetate, periodic iodine 1-naphthyl acetate or 2- Periodic iodine naphthyl acetate.

The invention adopts readily available raw materials to prepare the 3-aryl-substituted indolezine, has good reaction selectivity, mild reaction conditions, simple preparation process, low production cost, and the whole synthesis route is environmentally friendly.

The purpose of the third aspect of the present invention is to provide the use of an aryl-substituted indolezine derivative in the preparation of antitumor drugs. The aryl-substituted indoxazine derivatives prepared by the invention have good anti-tumor proliferation activity, and have remarkable effect on synthesizing new anti-tumor drugs.

The present invention will be further described below in combination with specific embodiments.

Detailed ways:

Embodiment 1～18:

According to the raw materials and feed ratio of Table 1, the NMP of indolezine compound, aryl acetate periodiodine, oxidizing agent, inorganic base, catalyst and 2ml is added in the round bottom flask of 25ml, under nitrogen protection, according to the reaction condition of Table 2 The reaction is complete, and then the solvent is spin-dried, and the obtained crude product is purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain the final product as shown in Table 2, and the reaction process is shown in the following formula:

Table 1: Reaction raw materials and feed ratios of different embodiments.

Note: Me means methyl, ^tBu means tert-butyl, Ph means phenyl, o- means ortho-position substitution, m- means meta-position substitution, p- means para-position substitution.

Table 2: Reaction conditions and products of different examples.

Note: T is the reaction temperature, t is the reaction time.

Structure confirmation data:

The structural detection data of the aryl-substituted indolezine derivatives prepared by Examples 1-18 are respectively:

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data and high resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.19(d, J=6.8Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.41(d, J=8.4Hz, 2H), 7.02 -7.08(m, 3H), 6.98(s, 1H), 6.72(t, J=7.2Hz, 1H), 3.88(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 159.8, 138.2, 130.2, 126.8, 123.7, 122.4, 122.0, 118.1, 115.6, 114.7, 112.9, 81.8, 55.4.

HRMS (EI) calculated for C ₁₆ H ₁₂ N ₂ O [M ⁺ ]: 248.0950; detected: 248.0957.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR ) detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) 8.25(d, J=7.2Hz, 1H), 7.71(t, J=9.6Hz, 1H), 7.38-7.45(m, 4H), 7.09(t, J= 7.6Hz, 1H), 7.04(s, 1H), 6.76(t, J=6.8Hz, 1H), 2.56(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.6, 138.4, 129.0, 126.8, 126.6, 126.5, 123.7, 122.3, 118.2, 116.7, 116.1, 113.1, 82.2, 15.5.

HRMS (EI) calcd for _C16H12N2S [M ⁺ ] _: 264.0721; found _: 264.0725.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data and high resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.29(d, J=7.6Hz, 1H), 7.68(d, J=8.8Hz, 1H), 7.54(d, J=8.0Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 7.06(t, J=7.6Hz, 1H), 7.02(s, 1H), 6.72(t, J=6.8Hz, 1H), 1.39(s, 9H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 151.8, 138.3, 130.6, 129.1, 128.4, 127.2, 127.0, 126.2, 125.4, 123.9, 122.2, 118.1, 116.0, 113.0, 82.0, 34.8, 31.3.

HRMS (EI) calcd for _C19H18N2 [M ⁺ ]: 274.1470; found _{: 274.1479} .

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR ) of the aryl-substituted indolezine derivative 1-cyano-3-(4-chlorophenyl)-indolezine (I-4) prepared in Example 4 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.17(d, J=7.2Hz, 1H), 7.65(d, J=8.8Hz, 1H), 7.40-7.46(m, 4H), 7.06(t, J=8.0Hz, 1H), 7.00(s, 1H), 6.73(t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.6, 138.3, 129.9, 128.6, 127.2, 127.0, 123.8, 122.1, 118.1, 117.0, 115.9, 113.0, 82.0.

HRMS (EI) _calcd for _Ci5H9N2Cl [M ⁺ ] _: 252.0454; found: 252.0452.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data and high resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.26(d, J=6.8Hz, 1H), 7.69(d, J=9.6Hz, 1H), 7.55(t, J=8.4Hz, 1H), 7.46 (d, J=7.6Hz, 1H), 7.37(s, 1H), 7.28(t, J=8.8Hz, 1H), 7.12(t, J=8.0Hz, 1H), 7.08(s, 1H), 7.80 (t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 149.81, 149.79, 138.7, 132.1, 131.8, 126.8, 125.2, 123.4, 122.8, 120.9, 120.8, 118.3, 116.9, 113.6, 82.7.

HRMS ( _EI ) calcd for _C16H9N2OF3 [ _M ⁺ ]: 302.0667; found _: 302.0664.

NMR of the aryl-substituted indolezine derivative 1-cyano-3-(4-trifluoromethylphenyl)-indolezine (I-6) prepared in Example 6 ( ¹ H NMR and ¹³ C NMR) detection data and high resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.29(d, J=6.8Hz, 1H), 7.77(d, J=8.4Hz, 2H), 7.68(d, J=8.8Hz, 1H), 7.65 (d, J=8.4Hz, 2H), 7.13(t, J=6.4Hz, 1H), 7.10(s, 1H), 6.81(t, J=6.8Hz, 1H).

¹³ C NMR (100MHz, CDCl ₃ ) δ138.8, 133.8, 130.3 (q, J=32Hz), 128.6, 126.3 (q, J=4.0Hz), 125.3, 125.2, 123.5, 122.9, 122.5, 118.4, 117.1, 116.4, 113.7, 82.9.

HRMS (EI) calcd for _Ci6H9N2F3 [M ⁺ ] _{: 286.0718} ; found _: 286.0713.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR ) detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.34(d, J=7.2Hz, 1H), 7.74(d, J=9.2Hz, 1H), 7.46(d, J=7.6Hz, 1H), 7.31 -7.38(m, 3H), 7.14(t, J=8.0Hz, 1H), 7.09(s, 1H), 6.80(d, J=6.8Hz, 1H), 2.50(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.1, 138.3, 130.1, 129.4, 129.3, 129.1, 127.1, 125.6, 123.8, 118.1, 116.1, 113.0, 82.1, 21.4.

HRMS (EI) calcd for _C16H12N2 [M+]: 232.1000; found _{: 232.0998} .

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) of the aryl-substituted indolezine derivative 1-cyano-3-(3-chlorophenyl)-indolezine (I-8) prepared in Example 8 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.21(d, J=7.2Hz, 1H), 7.64(d, J=8.8Hz, 1H), 7.45(s,1H), 7.35-7.42(m, 3H), 7.06(t, J=8.0Hz, 1H), 7.01(s, 1H), 6.74(t, J=7.2Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.6, 135.2, 131.9, 130.5, 128.6, 128.5, 126.6, 125.4, 123.5, 122.7, 118.3, 116.7, 113.5, 82.6.

HRMS (EI) _calcd for _Ci5H9N2Cl [M ⁺ ]: 252.0454; found: _252.0448 .

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) of the aryl-substituted indolezine derivative 1-cyano-3-(3-fluorophenyl)-indolezine (I-9) prepared in Example 9 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.35(d, J=6.8Hz, 1H), 7.75(d, J=9.2Hz, 1H), 7.52-7.58(m, 1H), 7.37(d, J=7.6Hz, 1H), 7.28(d, J=9.6Hz, 1H), 7.15-7.22(m, 2H), 7.12(s, 1H), 6.85(t, J=6.8Hz, 1H).

¹³ C NMR (100MHz, CDCl ₃ ) δ164.3, 161.9, 138.6, 132.2(d, J=7.7Hz), 130.9(d, J=8.0Hz), 125.6, 124.2(d, J=3.2Hz), 123.6 , 122.7, 118.3, 116.7, 115.6 (d, J=8.9Hz), 115.3 (d, J=9.0Hz), 113.4, 82.5.

HRMS (EI) calcd for _C15H9N2F [M ⁺ ] _: 236.0750; found _: 236.0745.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR ) detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ10.04(s, 1H), 8.01(s, 1H), 7.95(d, J=6.8Hz, 1H), 7.82-7.85(m, 3H), 7.52- 7.61 (m, 2H), 7.18 (d, J=6.8Hz, 1H), 6.93-6.99 (m, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 192.0, 140.6, 137.0, 132.9, 129.7, 129.4, 127.9, 126.4, 122.3, 117.8, 116.8, 113.9, 117.4, 112.9.

HRMS (EI) calcd for _C16H10N2O [M ⁺ ] _: 246.0793; found _: 246.0796.

NMR of the aryl-substituted indolezine derivative 1-cyano-3-(3-trifluoromethylphenyl)-indolezine (I-11) prepared in Example 11 ( ¹ H NMR and ¹³ C NMR) detection data and high resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.22(d, J=6.8Hz, 1H), 7.72(s, 1H), 7.63-7.72(m, 4H), 7.13(t, J=6.4Hz, 1H), 7.10(s, 1H), 6.80(t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.7, 131.8, 131.0, 129.9, 125.3 (q, J=4.6 Hz), 123.3, 122.8, 118.4, 117.0, 116.5, 113.7, 82.8.

HRMS (EI) calcd for _C16H9N2F3 [M ⁺ ] _{: 286.0718} ; found _: 286.0721.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR ) detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ7.77(d, J=9.2Hz, 1H), 7.70(d, J=6.8Hz, 1H), 7.37-7.50(m, 4H), 7.15(t, J=8.0Hz, 1H), 7.05(s, 1H), 6.78(t, J=6.8Hz, 1H), 2.17(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.4, 137.4, 131.3, 130.7, 129.5, 129.2, 126.3, 125.9, 124.0, 122.0, 118.0, 116.5, 112.9, 120.0, 81.4, 19.5.

HRMS (EI) calcd for _C16H12N2 [M ⁺ ]: 232.1000; found _{: 232.0999} .

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) of the aryl-substituted indolezine derivative 1-cyano-3-(2-bromophenyl)-indolezine (I-13) prepared in Example 13 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ7.77(d, J=9.2Hz, 1H), 7.70(d, J=6.8Hz, 1H), 7.37-7.50(m, 4H), 7.15(t, J=8.0Hz, 1H), 7.05(s, 1H), 6.78(t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.4, 137.4, 131.3, 130.7, 129.5, 129.2, 126.3, 125.9, 124.0, 122.0, 118.0, 116.5, 112.9, 120.0, 81.4.

HRMS (EI) calcd for _Ci5H9N2Br [M ⁺ ] _: 295.9949; found _: 295.9944.

The nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) detection data and high Resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.28(t, J=7.2Hz, 2H), 7.55(d, J=8.0Hz, 2H), 7.50(t, J=7.6Hz, 2H), 7.40 (t, J=7.2Hz, 1H), 7.32(s, 1H), 7.07(m, 1H), 6.70(t, J=7.6Hz, 1H), 4.36(t, J=6.8Hz, 2H), 1.80 (m,2H), 1.53(m,2H), 1.01(t, J=7.6Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.1, 136.3, 131.2, 129.1, 128.6, 128.0, 126.4, 123.3, 122.2, 120.1, 116.1, 114.9, 112.6, 104.3, 63.5, 31.1, 19.4, 13.8.

HRMS (EI) calcd for _C19H19NO2 [M ⁺ ] _: 293.1416; found: _293.1424 .

NMR ( ¹ H NMR and ¹³ C NMR ) detection of the aryl-substituted indolezine derivative 1-cyano-3-(2-naphthyl)-indolezine (I-15) prepared in Example 15 Data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.35(d, J=7.2Hz, 1H), 7.95-7.98(m, 2H), 7.86-7.91(m, 2H), 7.71(d, J=8.4 Hz, 1H), 7.54-7.59(m, 3H), 7.12(s, 1H), 7.10(t, J=8.0Hz, 1H), 6.75(t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.5, 133.5, 133.0, 129.0, 128.0, 127.8, 127.7, 126.9, 126.8, 126.0, 123.7, 122.5, 118.2, 116.6, 113.2, 82.4.

HRMS (ESI) calcd for _C19H12N2 [M ⁺ ] _{: 268.1000} , found: 268.1002.

NMR ( ¹ H NMR and ¹³ C NMR ) detection of the aryl-substituted indolezine derivative 1-cyano-3-(1-naphthyl)-indolezine (I-16) prepared in Example 16 Data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.03-8.09(m, 2H), 7.83(d, J=8.8Hz, 1H), 7.60-7.69(m, 4H), 7.45-7.53(m, 2H ), 7.24(s, 1H), 7.18(t, J=8.0Hz, 1H), 6.71(t, J=6.8Hz, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 138.2, 133.8, 132.1, 129.9, 129.5, 128.8, 127.3, 127.1, 126.5, 125.6, 125.0, 124.8, 124.5, 122.3, 118.0, 117.7, 112.8, 81.9.

HRMS (ESI) calculated for ₁₉ H ₁₂ N ₂ [M ⁺ ]: 268.1000, found: 268.0992.

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) of the aryl-substituted indolezine derivative 1-cyano-2-methyl-3-phenyl-indolezine (I-17) prepared in Example 17 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.03(d, J=7.2Hz, 1H), 7.62(d, J=9.2Hz, 1H), 7.56(t, J=7.6Hz, 2H), 7.48 (t, J=8.0Hz, 1H), 7.43(d, J=8.0Hz, 2H), 7.05(t, J=8.0Hz, 1H), 6.67(t, J=6.8Hz, 1H), 2.39(s , 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 137.1, 130.1, 129.5, 129.2, 128.6, 126.1, 123.8, 122.1, 117.3, 116.8, 112.5, 83.4, 10.9.

HRMS (EI) calcd for _C16H12N2 [M ⁺ ]: _232.1000 , found: _232.0998 .

Nuclear magnetic resonance ( ¹ H NMR and ¹³ C NMR) of the aryl-substituted indolezine derivative 1-cyano-6-methyl-3-phenyl-indolezine (I-18) prepared in Example 18 The detection data and high-resolution mass spectrometry (HRMS) detection data are:

¹ H NMR (400MHz, CDCl ₃ , TMS) δ8.17(d, J=7.2Hz, 1H), 7.47-7.52(m, 4H), 7.41-7.45(m, 2H), 6.97(s, 1H), 6.57(d, J=7.2Hz, 1H), 2.39(s, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 139.1, 133.4, 130.4, 129.2, 128.5, 128.3, 127.1, 126.2, 123.2, 116.5, 115.9, 115.7, 80.5, 21.1.

HRMS (EI) calcd for _C16H12N2 [M ⁺ ]: _232.1000 , found: _232.0996 .

Application example:

The compounds prepared in the present invention can be used to prepare antitumor drugs. The following examples I-1 to I-9 are used as examples to test their antiproliferative activity on intestinal cancer cells.

Samples to be tested: compounds of Examples I-1 to I-9.

Experimental object: intestinal cancer cells.

Experimental steps:

Take a bottle of cells that have just grown into a complete monolayer, collect the cells after trypsinization, blow evenly with a pipette, take two drops of cell suspension for trypan blue (Trypan Blue) staining, and count the number of living cells (dead cells) under a microscope. The number of cells should not exceed 5%), adjust the number of cells to 1×10 ⁵ cells/mL with complete culture medium. Add 100 μL of cell suspension to each well of a 96-well cell culture plate, place the culture plate in a CO ₂ incubator and incubate for 12 hours, take out the culture plate, and add 11 μL of solutions containing different concentrations of tested samples to each well, so that the final drug The concentrations were 40.0, 20.0, 10.0, 5.0, 1.0, and 0.1 μg/mL, respectively, and 3 parallel wells were set up for each concentration, and the cells in 3 wells were not added with the tested drug as normal control wells. After adding the medicine, the culture plate was shaken and mixed on a microplate shaker, and placed in a CO ₂ incubator to continue culturing for 48 hours. Take out the culture plate, add 25 μL of 4 mg/mL MTT solution to each well, shake and mix well, and continue to incubate for 6 h. Add 100 μL SDS lysate (90 mL triple distilled water + 10 g SDS + 5 mL isopropanol + 2 mL concentrated hydrochloric acid) to each well and incubate for 12 h. Measure the light absorption (OD value) of each well in a microplate reader, the measurement wavelength is 570nm, and the reference wavelength is 630nm. The inhibitory rate of drugs on cell proliferation was calculated according to the OD value of each well.

In the experiment, the light absorption (OD value) of each well was measured by a microplate reader, and the inhibitory rate of the drug on cell proliferation was calculated:

Inhibition rate=[1-(OD value of test sample-OD value of blank)/(OD value of negative control-OD value of blank)]×100

Calculate the IC ₅₀ value of the tested sample according to the following formula (Courtesy method):

lgIC ₅₀ =Xm-I[P-(3-Pm-Pn)/4]

Among them, Xm: the logarithmic value of the maximum concentration designed; I: the logarithmic value of the ratio of the maximum dose to the adjacent dose; P: the sum of positive reaction rates; Pm: the maximum positive reaction rate; Pn the minimum positive reaction rate.

The statistical results are shown in Table 3:

Table 3: Pharmaceutical activity data of the compounds of each example.

Compd. _IC50 (μg/mL) Compd. _IC50 (μg/mL) I-1 2.3±0.1 I-10 6.2±0.5 I-2 31±0.6 I-11 21±0.3 I-3 3.4±0.6 I-12 1.9±0.09 I-4 22±0.8 I-13 2.8±0.2 I-5 27±0.4 I-14 2.6±0.3 I-6 33±0.9 I-15 4.1±0.2 I-7 3.9±0.2 I-16 3.5±0.3 I-8 13±0.3 I-17 2.2±0.09 I-9 15±0.3 I-18 3.9±0.3

Claims (4)

1. the preparation method of an aryl substituted indole oxazine derivative; it is characterized in that; comprise the following steps: under agitation condition; indolizine compound, aryl acetic acid height iodine, oxygenant, potassium acetate or sodium acetate and catalyzer are joined in N-Methyl pyrrolidone; under nitrogen protection; react completely at 80 ~ 100 DEG C, obtain aryl substituted indole oxazine derivative through aftertreatment, its structure is such as formula shown in (I):

R in formula (I) ₁for 1-naphthyl, 2-naphthyl, phenyl or with substituent phenyl, wherein R ₁for during with substituent phenyl, the substituting group on its phenyl is C ₁~ C ₄alkyl, C ₁~ C ₄alkoxyl group, C ₁~ C ₄alkylthio, halogen atom, trifluoromethoxy, formyl radical or trifluoromethyl; R ₂for hydrogen or methyl; R ₃for hydrogen or methyl; R ₄for cyano group or C ₁~ C ₄carbalkoxy;

The structure of described indolizine compound is such as formula shown in (II):

In formula (II), R ₂for hydrogen or methyl; R ₃for hydrogen or methyl; R ₄for cyano group or C ₁~ C ₄carbalkoxy;

The structure of described aryl acetic acid height iodine is such as formula shown in (III):

In formula (III), R ₁for 1-naphthyl, 2-naphthyl, phenyl or with substituent phenyl, wherein R ₁for during with substituent phenyl, the substituting group on its phenyl is C ₁~ C ₄alkyl, C ₁~ C ₄alkoxyl group, C ₁~ C ₄alkylthio, halogen atom, trifluoromethoxy, formyl radical or trifluoromethyl;

The mol ratio of described indolizine compound, aryl acetic acid height iodine, oxygenant, mineral alkali and catalyzer is 1:1.1 ~ 1.5:1.1 ~ 1.5:1 ~ 2:0.1 ~ 0.2;

The described reaction times is 12 ~ 19 hours;

Described oxygenant is peroxide reagent; Be selected from the one of benzoyl peroxide, peroxy tert-butyl alcohol, di-t-butyl peroxide, Potassium Persulphate or Sodium Persulfate;

Described catalyzer is metal palladium catalyst, is selected from acid chloride, Palladous chloride, bi triphenyl phosphorus palladium chloride, two (dibenzalacetone) palladium or three (dibenzalacetone) two one of palladium.

2. the preparation method of aryl substituted indole oxazine derivative according to claim 1, is characterized in that: the described compound shown in formula (II) is 1-cyanoindole piperazine, 1-indolizine n-buty formate, 2-methyl isophthalic acid-cyanoindole piperazine or 6-methyl isophthalic acid-cyanoindole piperazine.

3. the preparation method of aryl substituted indole oxazine derivative according to claim 1, it is characterized in that: the described compound shown in formula (III) is p-methoxyphenyl acetic acid height iodine, to methylthio group phenyl acetic acid height iodine, to tert-butyl-phenyl acetic acid height iodine, to Trifluoromethoxyphen-l acetic acid height iodine, p-trifluoromethyl phenyl acetic acid height iodine, between aminomethyl phenyl acetic acid height iodine, between chloro-phenyl-acetic acid height iodine, between fluorophenyl acetic acid height iodine, between Fonnylphenyl acetic acid height iodine, m-trifluoromethylphenyl acetic acid height iodine, o-methyl-phenyl-acetic acid height iodine, o-bromophenyl acetic acid height iodine, phenyl acetic acid height iodine, 1-naphthyl acetic acid height iodine or 2-naphthyl acetic acid height iodine.

4. an aryl substituted indole oxazine derivative is preparing the purposes in antitumor drug, it is characterized in that: antitumor drug prepared by described aryl substituted indole oxazine derivative, have good antiproliferative activity for colon-cancer cell, the structure of aryl substituted indole oxazine derivative is such as formula shown in (I):

R in formula (I) ₁for 1-naphthyl, 2-naphthyl, phenyl or with substituent phenyl, wherein R ₁for during with substituent phenyl, the substituting group on its phenyl is C ₁~ C ₄alkyl, C ₁~ C ₄alkoxyl group, C ₁~ C ₄alkylthio, halogen atom, trifluoromethoxy, formyl radical or trifluoromethyl; R ₂for hydrogen or methyl; R ₃for hydrogen or methyl; R ₄for cyano group or C ₁~ C ₄carbalkoxy.