An indolizidine lactam compound and a method for synthesizing the same

Abstract

The application discloses an indole and medium ring lactam compound and a synthesis method thereof, and a chemical structural formula of the indole and medium ring lactam compound is shown as formula 3; the synthesis method comprises the following steps: adding a compound 2-indole acetate of formula 1 and an o-chloromethyl aniline compound of formula 2 as reaction raw materials into an organic solvent, adding a base, stirring and reacting under a temperature condition of 0-40 DEG C, tracking the reaction to completion through TLC, and filtering, concentrating and purifying to obtain the indole and medium ring lactam compound. The indole and medium ring lactam compound synthesized by the application has high sensitivity and strong cytotoxicity to human prostate cancer cell PC-3 through a biological activity test. The reaction condition is very conventional, the reaction is carried out near room temperature, no metal is needed, and the operation is simple; the method can be used for large-scale amplification reaction of a gram level, and proves the potential of practical application; a plurality of kinds of substrates are used as reactants in the application, the indole and medium ring lactam compound with diversified structure is efficiently constructed, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to an indole-containing cyclic lactam compound and its synthesis method. Background Technology

[0002] Indole-medium-cyclic lactams are skeletal structures of extremely high value to both academia and industry. They are widely found in natural products, agrochemicals, and pharmaceuticals, and can also be used as synthetic intermediates, thus occupying an important position in modern organic chemistry. Indole derivatives and medium-cyclic lactams are widely present in antitumor drug molecules and natural products, showing broad application prospects in the life sciences. Combining indole and medium-cyclic lactam skeletons is expected to have good antitumor activity. However, indole-medium-cyclic lactams are a class of compounds that have never been studied before, and their synthetic methods and cytotoxicity against human prostate tumor cells (PC3) have not been investigated. Summary of the Invention

[0003] One of the objectives of this invention is to provide an indole-1,000 cyclic lactam compound, thereby expanding the range of indole-1,000 derivatives. This derivative exhibits good sensitivity and cytotoxic activity against human prostate cancer cells PC-3.

[0004] The second objective of this invention is to provide a method for synthesizing the above-mentioned indole-containing cyclic lactam compounds. This method is simple to operate, has good substrate universality, and has the advantages of low cost and high yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: an indole-containing cyclic lactam compound, the chemical structural formula of which is shown in Formula 3: Formula 3; In Formula 3, R1 is selected from hydrogen, methyl, halogen, and 5,6-methylenedioxy; R2 is selected from methyl, p-methylphenyl, propyne, and allyl; R3 is selected from hydrogen, methyl, methoxy, and halogen; and n is any integer from 1 to 4.

[0006] The present invention also provides a method for synthesizing the above-mentioned indole-containing cyclic lactam compound, the specific steps of which are as follows: 2-indole acetate of formula 1 and o-chloromethylaniline of formula 2 are added to an organic solvent as reaction raw materials, an alkali is added, the reaction is stirred at a temperature of 0-40°C, the reaction is monitored by TLC until complete, and the product is obtained by filtration, concentration and purification. The structural formula of compound 2-indoleacetate of formula 1 is as follows: In this context, R1 is selected from hydrogen, methyl, halogen, and 5,6-methylenedioxy; R2 is selected from methyl, p-methylphenyl, propargyl, and allyl; and n is any integer from 1 to 4.

[0007] The structural formula of compound o-chloromethylaniline of formula 2 is as follows: R3 is selected from hydrogen, methyl, methoxy, and halogen.

[0008] Preferably, the molar ratio between compound 2-indoleacetic acid of formula 1 and compound o-chloromethylaniline of formula 2 is 1:1.2.

[0009] Preferably, the organic solvent is selected from one of tetrahydrofuran, dichloromethane, toluene, acetonitrile, hexafluoroisopropanol, and ethyl acetate; the volume ratio of the organic solvent to the molar amount of the compound 2-indoleacetic acid ester of Formula 1 is (20~40) mL: 1 mmol.

[0010] Preferably, the organic solvent is tetrahydrofuran, and the volume ratio of the tetrahydrofuran to the molar amount of the compound 2-indoleacetic acid ester of Formula 1 is 40 mL: 1 mmol.

[0011] Preferably, the reaction temperature is 25°C and the reaction time is 12 hours.

[0012] Preferably, the base is one of cesium carbonate, triethanolamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylenediamine, sodium carbonate, and potassium carbonate, and the molar ratio between the base and compound 2-indoleacetic acid ester of Formula 1 is 2:1.

[0013] Preferably, the alkali is cesium carbonate.

[0014] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of n-hexane and ethyl acetate with a volume ratio of 5:1.

[0015] Compared with the prior art, the present invention has the following beneficial effects: (1) The indole-1,000-ring lactam compounds synthesized in this invention, through bioactivity testing, show that these derivatives have high sensitivity and strong cytotoxic activity against human prostate cancer cells PC-3, indicating that the indole-1,000-ring lactam compounds synthesized in this invention are expected to be applied in the pharmaceutical field. (2) By controlling the chain length of compound 2-indoleacetic acid ester of formula 1, this invention can easily synthesize indole-containing eight-membered and eleven-membered ring compounds. The reaction conditions are very conventional, the reaction is carried out near room temperature, no metal is required, and the operation is simple. This method can be scaled up to gram scale, demonstrating its potential for practical application. This invention uses a variety of substrates as reactants to efficiently construct structurally diverse indole-containing medium-ring lactam compounds with high yields. Detailed Implementation

[0016] The present invention will be further described in detail below with reference to the embodiments.

[0017] In the examples below, unless otherwise stated, 2-indoleacetic acid ester, o-chloromethylaniline, and other reagents are commercially available or obtained in accordance with known literature; the experimental methods described are generally performed under standard conditions or conditions recommended by the manufacturer. Example 1

[0018] The synthetic route for the indole-8-membered ring lactam compound of formula 3aa is as follows: 0.1 mmol of 2-indole acetate (formula 1a) and 0.12 mmol of o-chloromethylaniline (formula 2a) were added as reactants to an organic solvent (the molar ratio of 2-indole acetate to o-chloromethylaniline was 1:1.2). 0.2 mmol of base was added, and the reaction was stirred at 0–40°C for 12 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (using a 5:1 mixture of petroleum ether and ethyl acetate as eluent) to obtain the indole-3-membered ring lactam compound (formula 3aa). The yields are shown in Table 1.

[0019] Table 1. Effects of different types of alkali, different types of solvent, solvent dosage, and temperature on yield. The optimal reaction conditions can be determined from the data in Table 1 as follows: the base is cesium carbonate, the solvent is tetrahydrofuran, the volume of the organic solvent is 4 ml, and the reaction temperature is 25°C.

[0020] The steps for obtaining product formula 3aa under optimal reaction conditions in Example 1 are as follows: 0.1 mmol of 2-indoleacetic acid (formula 1a) and 0.12 mmol of o-chloromethylaniline (formula 2a) were added to tetrahydrofuran (4.0 mL) as reactants, followed by the addition of 0.2 mmol of cesium carbonate. The mixture was stirred at 25°C for 12 hours. After the reaction was completed by TLC, the reaction solution was directly concentrated, and the residue was purified by silica gel column chromatography (using a 5:1 mixture of petroleum ether and ethyl acetate as eluent) to give the indole-3-membered octagonal lactam compound (formula 3aa).

[0021] The structural characterization data of product formula 3aa obtained under the optimal reaction conditions in Example 1 are as follows: 89% yield (76.6 mg); white solid; mp 206.2 - 207.7 ℃; 1 H NMR (400MHz, CDCl3) δ 8.00 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.54 (d, J= 6.8 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.33 - 7.28 (m, 3H), 7.23 - 7.08 (m, 3H), 4.00 (d, J = 15.2 Hz, 1H), 3.72 (d, J = 15.2 Hz, 1H), 3.60 (d, J = 14.0 Hz, 1H), 3.55 (s, 3H), 3.35 (d, J = 14.0 Hz, 1H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 167.5, 145.5, 137.0, 136.5, 135.8, 135.6, 131.1, 130.9, 129.7,129.6, 129.5, 128.7, 127.8, 126.4, 121.8, 119.5, 117.7, 110.3, 109.3, 34.7,29.5, 27.6, 21.8; IR (KBr): 3045, 2920, 1687, 1364, 1163, 755 cm -1 ; ESI FTMSexact mass calcd for (C 25 H 22 N2O3S+Na) + requires m / z 453.1243, found m / z453.1238. Example 2-12

[0022] The synthesis methods of Examples 2-12 are the same as those of the product formula 3aa obtained under optimal reaction conditions in Example 1, except that 2-indole acetate with a different structure is used as the starting material.

[0023] The reaction synthesis route is shown below: The products and yields are shown in Table 2 below: Table 2. Reactants and yields of Examples 1-12 Examples 13-19

[0024] The synthesis methods of Examples 13-19 are the same as those of the product formula 3aa obtained under optimal reaction conditions in Example 1, except that o-chloromethylaniline with a different structure is used as the starting material.

[0025] The reaction synthesis route is shown below: The products and yields are shown in Table 3 below: Table 3. Reactants, yields, and reaction rates for Examples 1, 13-19 Examples 20-24

[0026] The synthesis methods of Examples 20-24 are the same as those of Example 6, except that o-chloromethylaniline with a different structure is used as the raw material.

[0027] The reaction synthesis route is shown below: The products and yields are shown in Table 4 below: Table 4. Reactants, yields, and reaction rates for Examples 6, 20-24 As shown in Tables 2, 3, and 4, the reaction conditions for synthesizing indole-1,1-cyclic lactam compounds in this invention are very conventional. The reaction is carried out near room temperature, requires no metal participation, and is simple to operate. This method can be scaled up to the gram scale, demonstrating its potential for practical application. This invention uses a variety of substrates as reactants to efficiently construct structurally diverse indole-1,1-cyclic lactam compounds with high product yields.

[0028] The indole-containing cyclic lactam compounds of this invention were used to test the cytotoxic activity of compounds synthesized in Examples 1, 2, and 6 against human prostate cancer cells PC-3 using the MTT assay. The activity assay procedure was as follows: Human prostate cancer cells PC-3 were seeded at a density of 4000 cells / 100 µL of culture medium in 96-well plates. After 48 hours of cell adhesion, the test compound (Formula 3) was added to the culture medium at final concentrations of 7.81, 15.625, 31.25, 62.5, and 125 µg / mL, and the cells were cultured for another 24 hours. Cells without the test compound served as the control group, and cells with only the culture medium served as the blank group. After the compound stimulation, 20 µL of MTT was added to each well, and the cells were cultured for another 4 hours. The supernatant was removed, and 150 µL of dimethyl sulfoxide was added to each well. The cells were incubated at 37°C for 15 minutes, followed by shaking the culture plate for 2 minutes. The optical density (OD) value was read at 490 nm. Finally, the IC50 of the test compound (Formula 3) was calculated using GraphPad software. 50 The results are shown in Table 5. The experimental results indicate that these compounds have high cytotoxic activity against human prostate cancer cells PC-3.

[0029] Table 5. Cytotoxic activity of the compound of formula 3 in this invention against human prostate cancer cells PC-3. a IC in Table 5 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.

Claims

1. An indole-containing cyclic lactam compound, characterized in that, Its chemical structural formula is shown in Formula 3: Formula 3; In Formula 3, R1 is selected from hydrogen, methyl, halogen, and 5,6-methylenedioxy; R2 is selected from methyl, p-methylphenyl, propyne, and allyl; R3 is selected from hydrogen, methyl, methoxy, and halogen; and n is any integer from 1 to 4.

2. A method for synthesizing the indole-containing cyclized lactam compound according to claim 1, characterized in that, The specific steps are as follows: Compound 2-indoleacetic acid of Formula 1 and compound o-chloromethylaniline of Formula 2 are added to an organic solvent as reaction raw materials, alkali is added, and the reaction is stirred at a temperature of 0-40°C. The reaction is monitored by TLC until complete, and the product is obtained by filtration, concentration and purification. The structural formula of compound 2-indoleacetate of formula 1 is as follows: Wherein, R1 is selected from hydrogen, methyl, halogen, and 5,6-methylenedioxy; R2 is selected from methyl, p-methylphenyl, propargyl, and allyl; and n is any integer from 1 to 4. The structural formula of compound o-chloromethylaniline of formula 2 is as follows: R3 is selected from hydrogen, methyl, methoxy, and halogen.

3. The method for synthesizing an indole-containing cyclic lactam compound according to claim 2, characterized in that, The molar ratio between compound 2-indoleacetic acid of formula 1 and compound o-chloromethylaniline of formula 2 is 1:1.

2.

4. A method for synthesizing an indole-containing cyclic lactam compound according to claim 2 or 3, characterized in that, The organic solvent is selected from one of tetrahydrofuran, dichloromethane, toluene, acetonitrile, hexafluoroisopropanol, and ethyl acetate; the volume ratio of the organic solvent to the molar amount of the compound 2-indoleacetic acid ester of Formula 1 is (20~40) mL: 1 mmol.

5. The method for synthesizing an indole-containing cyclic lactam compound according to claim 4, characterized in that, The organic solvent is tetrahydrofuran, and the volume ratio of tetrahydrofuran to the molar amount of compound 2-indoleacetic acid ester of Formula 1 is 40 mL: 1 mmol.

6. A method for synthesizing an indole-containing cyclic lactam compound according to claim 2 or 3, characterized in that, The reaction temperature was 25°C and the reaction time was 12 h.

7. A method for synthesizing an indole-containing cyclic lactam compound according to claim 2 or 3, characterized in that, The base is one of cesium carbonate, triethanolamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylenediamine, sodium carbonate, and potassium carbonate, and the molar ratio between the base and compound 2-indoleacetic acid ester of Formula 1 is 2:

1.

8. The method for synthesizing an indole-containing cyclic lactam compound according to claim 7, characterized in that, The alkali is cesium carbonate.

9. A method for synthesizing an indole-containing cyclic lactam compound according to claim 2 or 3, characterized in that, The purification was performed by silica gel column chromatography, with the eluent being a mixture of n-hexane and ethyl acetate at a volume ratio of 5:1.

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