An indolocyclopentane compound and its synthesis method

Abstract

The invention discloses an indole cyclopentane compound and a synthesis method thereof, and belongs to the technical field of indole compounds. Synthesis method: methyl-substituted 2-indole methanol and 3-substituted 2-indole methanol are added to an organic solvent as a reaction raw material, stirred and reacted under the catalysis of chiral phosphoric acid and at 10-50°C, TLC tracking reaction to completion, filtration, concentration, purification to obtain. The indole cyclopentane compound synthesized by the present invention is tested by biological activity, showing that the derivative has high sensitivity and strong cytotoxic activity to human prostate cancer cells PC-3. The reaction conditions of the present invention are relatively conventional, the reaction process is mild, simple, and low-cost, suitable for industrial large-scale production, and the scope of application of the method is broadened; a variety of substrates are used as reactants to obtain products with diverse structures, and the yield, diastereoselectivity, and enantioselectivity are high.

Description

Technical Field

[0001] The present invention belongs to the technical field of indole compounds, and particularly relates to an indolocyclopentane compound and a synthesis method thereof. Background Art

[0002] Indolocyclic compounds widely exist in anti-cancer drug molecules and natural products, and have broad application prospects in the field of life sciences. Combining indole and cyclopentane skeletons is expected to have good anti-tumor activity. However, at present, indolocyclopentane compounds are a class of compounds that have never been studied, and no one has studied the synthesis methods of these compounds and their cytotoxicity to human prostate cancer cells PC-3. Summary of the Invention

[0003] One of the purposes of the present invention is to provide an indolocyclopentane compound to expand the variety range of indole and cyclopentane compounds, and this derivative has good sensitivity and cytotoxic activity to human prostate cancer cells PC-3.

[0004] Another purpose of the present invention is to provide a synthesis method of the above indolocyclopentane compound. This method has a mild reaction process, is simple, safe and easy to operate, has high diastereoselectivity and enantioselectivity, and has the advantages of low cost and high yield.

[0005] To achieve the above purposes, on the one hand, the present invention provides an indolocyclopentane compound, and its chemical structural formula is as follows:

[0006]

[0007] Wherein, Ar independently selects one from phenyl, phenyl substituted by methyl, phenyl substituted by methoxy, and thiophenyl; R selects one from hydrogen, halogen, and methyl; R 1 independently selects one from phenyl substituted by halogen, phenyl substituted by methyl, phenyl substituted by methoxy, naphthyl, thiophenyl, isopropyl, and cyclohexyl; R 2 independently selects from hydrogen and methyl; R 3 independently selects one from phenyl, methyl, n-propyl, and benzyl.

[0008] On the other hand, the present invention provides a synthesis method of the above indolocyclopentane compound. The specific steps are as follows: Using methyl-substituted 2-indolemethanol and 3-substituted-2-indolemethanol as reaction raw materials, adding them into an organic solvent, stirring and reacting under the catalysis of chiral phosphoric acid and at a temperature of 10 - 50 °C. Tracking the reaction by TLC until it is complete, filtering, concentrating, and purifying to obtain the indolocyclopentane compound;

[0009] The molar ratio between the methyl-substituted 2-indolylmethanol and the 3-substituted 2-indolylmethanol is 2:(1 - 4), and the molar ratio between the methyl-substituted 2-indolylmethanol and the chiral phosphoric acid is (1 - 2):0.1;

[0010] The structural formula of the methyl-substituted 2-indolylmethanol is wherein, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, and thiophenyl; R is selected from one of hydrogen, halogen, and methyl;

[0011] The structural formula of the 3-substituted 2-indolylmethanol is wherein, R 1 is selected from one of halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, thiophenyl, isopropyl, and cyclohexyl; R 2 is selected from hydrogen and methyl; R 3 is selected from one of phenyl, methyl, n-propyl, and benzyl.

[0012] In an alternative embodiment, the chiral phosphoric acid is selected from one of binaphthyl framework derivatives and octahydrobinaphthyl framework derivatives;

[0013] The structural formula of the binaphthyl framework derivative is In the formula, G is selected from one of 4-chlorophenyl, 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, 2-naphthyl, and 1-naphthyl;

[0014] The structural formula of the octahydrobinaphthyl framework derivative is In the formula, G' is selected from one of 9-phenanthryl, 9-anthryl, 2-naphthyl, and 1-naphthyl.

[0015] In an alternative embodiment, the chiral phosphoric acid is the octahydrobinaphthyl framework derivative, and G' is selected from 9-anthryl.

[0016] In an alternative embodiment, the organic solvent is selected from acetonitrile, acetone, ethyl acetate, and 1,2-dichloroethane.

[0017] In an alternative embodiment, the ratio of the volume of the organic solvent to the molar amount of the methyl-substituted 2-indolylmethanol is (5 - 40 mL):1 mmol.

[0018] In an alternative embodiment, the organic solvent is ethyl acetate, and the ratio of the volume of the ethyl acetate to the molar amount of the methyl-substituted 2-indolylmethanol is 10 mL:1 mmol.

[0019] In an alternative embodiment, the molar ratio between the methyl-substituted 2-indolylmethanol and the 3-substituted 2-indolylmethanol is 1:2.

[0020] In an alternative embodiment, the reaction temperature is 30 °C.

[0021] In an alternative embodiment, the purification is carried out by silica gel column chromatography, and the eluent is a petroleum / dichloromethane mixed solution with a volume ratio of 1:1.

[0022] Compared with the prior art, the present invention has at least the following beneficial effects:

[0023] The indolocyclopentane compounds synthesized by the present invention, through bioactivity tests, show that these derivatives have high sensitivity and strong cytotoxic activity against human prostate cancer cell line PC-3, indicating that the indolocyclopentane compounds synthesized by the present invention are expected to be applied in the pharmaceutical field;

[0024] The reaction conditions for synthesizing indolocyclopentane compounds in the present invention are relatively conventional, the reaction process is mild, simple, easy to operate, and low in cost, suitable for large-scale industrial production, and broaden the scope of application of this method; the present invention uses a relatively large variety of substrates as reactants, obtaining products with diverse and complex structures, and high yields as well as high diastereoselectivity and enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The drawings are used to provide a further understanding of the present application and form a part of the specification, and are used together with the following specific embodiments to explain the present application, but do not constitute a limitation to the present application. In the drawings:

[0026] Figure 1 It is a synthetic route diagram of the indolocyclopentane compound of formula 3aa in Exemplary Embodiment 1 of the present invention;

[0027] Figure 2 It is a synthetic route diagram of the indolocyclopentane compounds in Exemplary Embodiments 2-15 of the present invention;

[0028] Figure 3 It is a synthetic route diagram of the indolocyclopentane compounds in Exemplary Embodiments 16-21 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] The present invention will be further described in detail below with reference to the embodiments.

[0030] In the following embodiments, unless otherwise specified, methyl-substituted 2-indolylmethanol, 3-substituted-2-indolylmethanol, chiral phosphoric acid and other reagents can be obtained through commercial purchase or according to the methods reported in known literature; the experimental methods are generally carried out under conventional conditions or the conditions recommended by the manufacturer.

[0031] Example 1

[0032] The synthetic route of indolocyclopentane compounds of formula 3aa is as follows Figure 1 As shown, 0.05 mmol of methyl-substituted 2-indolylmethanol of formula 1a and 0.1 mmol of 3-substituted-2-indolylmethanol of formula 2a were added as reactants in a solvent, and under the action of 0.005 mmol (10 mol% of methyl-substituted 2-indolylmethanol) of chiral phosphoric acid of formula 4 or formula 5, the reaction was stirred at 30 °C for 5 h. The reaction was monitored by TLC until completion. After filtration and concentration, it was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and dichloromethane with a volume ratio of 1:1), and indolocyclopentane compounds of formula 3aa were obtained. The diastereoselectivity, yield, and enantioselectivity are shown in Table 1.

[0033] Table 1 Effects of different types of chiral phosphoric acids, solvents, temperatures, solvent volumes, and equivalent ratios on the diastereoselectivity, enantioselectivity, and yield of the reaction a

[0034]

[0035] Note: ee in Table 1 is the enantiomeric excess ratio.

[0036] From the data in Table 1, the optimal reaction conditions can be obtained as follows: chiral phosphoric acid is formula 5d, the solvent is ethyl acetate, the volume of the organic solvent is 0.5 mL, and the reaction temperature is 30 °C.

[0037] The structural characterization data of the product of formula 3aa obtained under the optimal reaction conditions in Example 1 are as follows:

[0038] 95% yield (42.9 mg) as a white solid. m.p. 122.6–122.9 °C; >95:5 dr; [α] D 20 =39.5 (c=0.86, acetone); 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.39–7.33 (m, 4H), 7.25–7.17 (m, 5H), 7.14–7.08 (m, 4H), 6.93–6.88 (m, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 4.63–4.56 (m, 1H), 3.61–3.54 (m, 1H), 3.25–3.14 (m, 1H), 2.36 (s, 3H), 2.00 (s, 3H); 13 C NMR (100 MHz, CDCl 3)δ 141.6, 141.1, 139.3, 136.5, 135.9, 133.6, 132.9, 130.6, 128.6, 128.0, 127.9, 127.0, 126.9, 126.6, 122.5, 121.3, 120.8, 120.1, 119.2, 118.8, 111.2, 110.6, 104.4, 103.1, 68.0, 56.6, 38.8, 19.7, 8.7; IR(KBr): 3566, 3055, 1558, 1540, 1489, 1455, 1338, 1312, 1298, 746 cm -1 ; ESI FTMS exact mass calcd for (C 33 H 28 N 2 -H) - requires m / z 451.2179, found m / z 451.2199; The enantiomeric excess: 93%, determined by HPLC (Daicel Chiralpak IB, hexane / isopropanol = 90 / 10, flow rate 1.0 mL / min, T = 30 °C, 254 nm): t R = 4.877 (minor), t R = 11.777 (major).

[0039] Example 2 - 15

[0040] The synthesis method of Example 2 - 15 is the same as that of Example 1, except that 3 - substituted - 2 - indolemethanol with different structures is used as the raw material.

[0041] The reaction synthesis route is as Figure 2 shown, and the products, diastereoselectivity, enantioselectivity, and yields are shown in Table 2 below:

[0042] Table 2 Reaction raw materials, products, diastereoselectivity, enantioselectivity, and yields of Example 1 and 2 - 15

[0043]

[0044] Examples 16 - 21

[0045] The synthesis method of Examples 16 - 21 is the same as that of Example 1, except that methyl - substituted 2 - indolemethanol with different structures is used as the raw material.

[0046] Its reaction synthesis route is as Figure 3As shown, the product, diastereoselectivity, enantioselectivity, and yield are as shown in Table 3 below.

[0047] Table 3 Reaction raw materials, products, diastereoselectivity, yield, and enantioselectivity of Examples 16 - 21

[0048]

[0049] [a] The catalyst is of formula (R)-4e, the catalytic amount is 20 mol%, and the ratio of formula 1:formula 2 is 2:1.

[0050] It can be seen from Table 2 and Table 3 that the method of the present invention can not only achieve the synthesis of indolocyclopentane compounds in one step, obtain extremely high diastereoselectivity, enantioselectivity, excellent yield, high atom economy, environmental friendliness, and wide applicability, but also has easily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diverse product structures. Therefore, it has great implementation value and potential social and economic benefits.

[0051] For the indolocyclopentane compounds of the examples of the present invention, the cytotoxic activity of the compound synthesized in Example 1 against human prostate cancer cell line PC-3 was tested by the MTT method, and the results are shown in Table 4. The results show that the compounds synthesized by the present invention have relatively high cytotoxic activity against human prostate cancer cell line PC-3.

[0052] Table 4 Cytotoxic activity of the compounds in the present invention against human prostate cancer cell line PC-3

[0053]

[0054] Note: IC in Table 4 50 refers to the half-maximal inhibitory concentration.

Claims

1. An indole cyclopentane compound, characterized in that: Its chemical structure is as follows: Wherein, Ar is independently selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, and thienyl; R is selected from one of hydrogen, halogen, and methyl; R 1 is independently selected from one of halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, thienyl, isopropyl, and cyclohexyl; R 2 are independently selected from hydrogen and methyl; R 3 Independently selected from one of phenyl, methyl, n-propyl and benzyl.

2. A method for synthesizing the indolecyclopentane compound as claimed in claim 1, characterized in that: The specific steps are: adding methyl-substituted 2-indolemethanol and 3-substituted-2-indolemethanol as reaction raw materials into an organic solvent, stirring and reacting under the catalysis of chiral phosphoric acid and at a temperature of 10-50° C., tracking the reaction by TLC until completion, filtering, concentrating and purifying to obtain the indolecyclopentane compound; The molar ratio of the methyl-substituted 2-indole methanol to the 3-substituted-2-indole methanol is 2:(1-4), and the molar ratio of the methyl-substituted 2-indole methanol to the chiral phosphoric acid is (1-2):0.1; The structural formula of the methyl-substituted 2-indolemethanol is Wherein, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, and thienyl; R is selected from one of hydrogen, halogen, and methyl; The structural formula of the 3-substituted-2-indolecarbinol is Among them, R 1 is selected from the group consisting of halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, thienyl, isopropyl, and cyclohexyl; R 2 is selected from hydrogen and methyl; R 3 One selected from phenyl, methyl, n-propyl and benzyl; The chiral phosphoric acid is selected from one of a binaphthyl skeleton derivative and an octahydrobinaphthyl skeleton derivative; The structural formula of the binaphthyl skeleton derivative is Wherein G is selected from one of 4-chlorophenyl, 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, 2-naphthyl and 1-naphthyl; The structural formula of the octahydrobinaphthyl skeleton derivative is In the formula, G' is selected from one of 9-phenanthrenyl, 9-anthryl, 2-naphthyl and 1-naphthyl.

3. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The chiral phosphoric acid is the octahydrobinaphthyl skeleton derivative, and the G' is selected from 9-anthryl.

4. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The organic solvent is selected from one of acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene and tetrahydrofuran.

5. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The ratio of the volume of the organic solvent to the molar amount of the methyl-substituted 2-indolemethanol is (5-40 mL): 1 mmol.

6. The method for synthesizing indolecyclopentane compounds according to claim 4, characterized in that: The organic solvent is ethyl acetate, and the ratio of the volume of the ethyl acetate to the molar amount of the methyl-substituted 2-indolemethanol is 10 mL:1 mmol.

7. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The molar ratio between the methyl-substituted 2-indolecarbinol and the 3-substituted-2-indolecarbinol is 1:

2.

8. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The reaction temperature is 30°C.

9. The method for synthesizing indolecyclopentane compounds according to claim 2, characterized in that: The purification is performed by silica gel column chromatography, and the eluent is a petroleum / dichloromethane mixture with a volume ratio of 1:1.

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