A method for preparing bis(indolyl)methane

Abstract

The present invention discloses a preparation method of diindolylmethane, belonging to the technical field of organic synthesis, and solves the problem that the preparation process of diindolylmethane in the prior art is not environmentally friendly enough. The preparation method of diindolylmethane is as follows: in the presence of trivalent iodide and a base, an indole derivative and methanol undergo a coupling reaction, and after purification, diindolylmethane is obtained. The method provided by the present invention expands the substrate range, has a relatively high yield, avoids the use of formaldehyde and expensive catalysts, and has low pollution.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more particularly to a method for preparing diindolylmethane. Background Art

[0002] 3,3 - Diindolylmethane (DIM) widely exists in natural products and has a series of biological activities. DIM is an effective radiation protector and reliever, which can regulate signal pathways to inhibit the invasion, angiogenesis, proliferation of tumor cells and induce their apoptosis. It can also inhibit estrogen - induced gene expression and cause endoplasmic reticulum stress response. The latest research also finds that DIM has the effect of regulating the intestinal flora against Staphylococcus aureus pneumonia. In particular, it has a protective effect on radiation - induced lung injury. It can be seen that DIM has broad application prospects.

[0003] Traditional DIM is synthesized from indole and its derivatives with aldehydes or ketones under acidic conditions, and usually uses Ln(OTf) 3 , Yb(III) - resin, LiClO 4 , In(OTf) 3 , PPhl·HClO 4 , HY - zeolite or montmorillonite K - 10, etc. as catalysts for the catalytic synthesis of diindolylmethane. Traditional methods for preparing diindolylmethane all use formaldehyde or other aldehyde or ketone compounds as raw materials. As is well known, formaldehyde has strong irritation to mucous membranes and a lacrimatory effect, can coagulate proteins, and is likely to make the skin hard or even cause local tissue necrosis when touching the skin. Ketone compounds are highly toxic to the respiratory and digestive systems, and also have medium toxicity after skin absorption. Aldehyde or ketone compounds also have a certain degree of environmental pollution. In summary, the traditional preparation methods of diindolylmethane are not environmentally friendly enough. Summary of the Invention

[0004] The present invention provides a method for preparing diindolylmethane to solve the problem that the preparation process of diindolylmethane in the prior art is not environmentally friendly enough.

[0005] In a first aspect, the present invention provides a method for preparing diindolylmethane, including the following steps: in an environment where trivalent iodide and a base exist, an indole derivative and methanol undergo a coupling reaction to obtain the diindolylmethane. The reaction equation is as shown in Formula II,

[0006]

[0007] The diindolylmethane has a structural formula as shown in Compound 2 in Formula II.

[0008] As a possible implementation manner, the indole derivative is an indole compound.

[0009] As a possible implementation manner, the chemical formula of the indole compound is shown as Compound 1 in Formula II. In Formula II, R is one of H, methyl, and ethyl.

[0010] As a possible implementation manner, the trivalent iodide is Ph 2 I·OTf, (m-CF 3 Ph) 2 I·OTf, (p-ClPh) 2 I·OTf; and the base is a weak base or a basic salt.

[0011] As a possible implementation manner, the trivalent iodide is Ph 2 I·OTf; the base is one of sodium acetate, lithium acetate, and cesium pivalate, and the base is a weak base or a basic salt. When the trivalent iodide is diaryliodonium methanesulfonate (Ph 2 I·OTf), the yield is very high. Other trivalent iodides such as iodobenzene diacetate can also promote the reaction, but the yield is very low. When the base is a moderately strong base or a strong base, the yield decreases.

[0012] As a possible implementation manner, the trivalent iodide is Ph 2 I·OTf; the base is one of sodium acetate, lithium acetate, and cesium pivalate.

[0013] As a possible implementation manner, the molar ratio of Compound 1, the trivalent iodide, and the base is 1:0.8 - 1.2:1 - 1.5.

[0014] As a possible implementation manner, the reaction is carried out in an air or nitrogen atmosphere at a temperature of 80 - 150 °C.

[0015] As a possible implementation manner, it further includes: after the coupling product is washed, a mixed solution of ethyl acetate and petroleum ether is used as the eluent, and silica gel column chromatography is used to separate the target product.

[0016] As a possible implementation manner, in the eluent, the addition ratio of ethyl acetate and petroleum ether by volume is 1:10 - 60.

[0017] The preparation method of bis(indolyl)methane provided by the present invention uses indole derivatives as raw materials, and under the action of a trivalent iodide and a base, a bis(indolyl)methane compound is obtained through the coupling reaction of indole derivatives and alcohols. This preparation method avoids the use of formaldehyde and expensive catalysts, has a low cost in the process of preparing bis(indolyl)methane, and causes low pollution.

[0018] The preparation method provided by the present invention expands the substrate range, has a high yield; and is simple to operate, has a low production cost, and has a wide substrate applicability.

[0019] The bis(indolyl)methane prepared by the preparation method provided by the present invention is used as a raw material for the preparation of indolocarbazole phenol, and the yield of the product indolocarbazole phenol is relatively high, providing a material basis for the preparation of anti-tumor and anti-leukemia chemotherapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0021] Figure 1 1H NMR spectrum of product 2a provided by the embodiment of the present invention 1 1H NMR spectrum.

[0022] Figure 2 13C NMR spectrum of product 2a provided by the embodiment of the present invention 13 13C NMR spectrum.

[0023] Figure 3 1H NMR spectrum of product 2b provided by the embodiment of the present invention 1 1H NMR spectrum.

[0024] Figure 4 13C NMR spectrum of product 2b provided by the embodiment of the present invention 13 13C NMR spectrum.

[0025] Figure 5 1H NMR spectrum of product 2c provided by the embodiment of the present invention 1 1H NMR spectrum.

[0026] Figure 6 13C NMR spectrum of product 2c provided by the embodiment of the present invention 13 13C NMR spectrum.

[0027] Figure 7 1H NMR spectrum of product 4 provided by the embodiment of the present invention 1 1H NMR spectrum.

[0028] Figure 8 13C NMR spectrum of product 4 provided by the embodiment of the present invention 13 13C NMR spectrum. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0030] To solve the problem that the preparation process of diindolylmethane in the prior art is not environmentally friendly enough, the present invention provides a method for preparing diindolylmethane, including: The reaction equation is shown in Formula I,

[0031]

[0032] The structural formula of diindolylmethane is shown as Compound 2 in Formula I; in Formula I, R is one of H, methyl, and ethyl.

[0033] The method for preparing diindolylmethane provided by the present invention uses indole derivatives as raw materials, and under the action of trivalent iodide and a base, a diindolylmethane compound is obtained through the coupling reaction of indole derivatives and methanol. This preparation method avoids the use of formaldehyde and expensive catalysts, and has low pollution during the preparation of diindolylmethane.

[0034] Next, the technical solutions of the present invention will be further elaborated in conjunction with specific embodiments.

[0035] Example 1

[0036] This example provides an experiment for preparing diindolylmethane using indole as a raw material.

[0037]

[0038] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv), diaryliodonium methanesulfonate (Ph 2 I·OTf, 94.6 mg, 0.22 mmol, 1.1 equiv) and sodium acetate (NaOAc, 18.0 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol; the mixture is reacted at 120 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 85%. Nuclear magnetic resonance is performed on the product 2a to obtain the Figure 1 as shown 1 1H NMR spectrum of 2a and asFigure 2 as shown in 2a 13 13C NMR spectrum. The results were obtained, and the nuclear magnetic resonance data of 2a are as follows:

[0039] 1 1H NMR (600 MHz, CDCl 3 3): δ = 7.89 (s, 2H), 7.64 (d, J = 6.6 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.20 (s, 2H), 7.10 (s, 2H), 6.93 (s, 2H), 4.25 (s, 2H) ppm.

[0040] 13 13C NMR (101 MHz, CDCl 3 3): δ = 136.6, 127.7, 122.3, 122.0, 119.4, 119.3, 115.8, 111.2, 21.3 ppm.

[0041] Example 2

[0042] This example provides an experiment for preparing diindolylmethane using methylindole as a raw material.

[0043]

[0044] In a reaction tube, 1b of methylindole (25.0 μL, 0.2 mmol, 1.0 equiv), Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were accurately added. After evacuating and replacing with nitrogen three times, 1.0 mL of methanol was added; the mixture was reacted at 120 °C for 24 hours. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, and silica gel was added to the flask, and the solvent was evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:60) as the eluent, purification was carried out by silica gel column chromatography to obtain the corresponding product 2b with a yield of 82%. Nuclear magnetic resonance was performed on product 2b to obtain the Figure 3 1H NMR spectrum of 2b as shown in 1 and the Figure 4 13C NMR spectrum of 2b as shown in 13 The results were obtained, and the nuclear magnetic resonance data of 2b are as follows:

[0045] 1 1H NMR (600 MHz, CDCl 3):δ = 7.65 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.26 - 7.23 (m, 2H), 7.11 (t, J = 7.2 Hz, 2H), 6.81 (s, 2H), 4.24 (s, 2H), 3.72 (s, 6H) ppm.

[0046] 13 C NMR (101 MHz, CDCl 3 ):δ = 137.3, 128.1, 127.1, 121.5, 119.4, 118.7, 114.5, 109.2, 32.7, 21.1 ppm.

[0047] Example 3

[0048] This example provides an experiment for preparing diindolylmethane using ethylindole as a raw material.

[0049]

[0050] In a reaction tube, accurately add ethylindole 1c (29.3 μL, 0.2 mmol, 1.0 equiv), Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv), evacuate and replace with nitrogen three times and then add 1.0 mL of methanol; the mixture is reacted at 120 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:60) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2c with a yield of 84%.

[0051] The synthesis steps of N-ethylindole 1c used in this example: At room temperature, dissolve indole (1 g, 8.54 mmol) and KOH (1.44 g, 25.61 mmol) in dimethylformamide (DMF, 8 mL), add bromoethane (1.27 mL, 17.07 mmol), and stir the reaction at room temperature for 3 h; after the reaction is completed, add ethyl acetate (EtOAc, 20 mL) and water (20 mL) for extraction three times; the combined organic phases are washed successively with water and brine, and then dried over anhydrous Na 2 SO 4Dry it, concentrate by rotary evaporation to obtain the crude product; purify the crude product by silica gel column chromatography to obtain the product N-ethylindole 1c. (For the synthetic process reference: Wu, Y.; Peng, X.; Luo, B.; Wu, F.; Liu, B.; Song, F.; Huang, P.; Wen, S. Palladium catalyzed dual C–H functionalization of indoles with cyclic diaryliodoniums, an approach to ring-fused carbazole derivatives. Org. Biomol. Chem. 2014, 12, 9777-9780.)

[0052] Perform nuclear magnetic resonance on the product 2c to obtain the Figure 5 1H NMR spectrum of 2c as shown in 1 and the Figure 6 13C NMR spectrum of 2c as shown in 13 . The results are as follows: The nuclear magnetic resonance data of 2c are as follows:

[0053] 1 1H NMR (400 MHz, CDCl 3 3): δ = 7.65 - 7.63 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 - 7.20 (m, 2H), 7.11 - 7.07 (m, 2H), 6.88 (s, 2H), 4.25 (s, 2H), 4.11 (q, J = 7.2 Hz, 4H), 1.42 (t, J = 7.2 Hz, 6H) ppm.

[0054] 13 13C NMR (101 MHz, CDCl 3 3): δ = 136.3, 128.3, 125.4, 121.4, 119.6, 118.6, 114.5, 109.3, 40.9, 21.2, 15.7 ppm.

[0055] Example 4

[0056] Accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 and (m-CF 3 3Ph) 2I·OTf (124.3 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were added after evacuating and replacing nitrogen three times, and then 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 h. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, silica gel was added to the flask, and the solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 33%.

[0057] Example 5

[0058] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 was accurately added, (p-ClPh) 2 I·OTf (109.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were added after evacuating and replacing nitrogen three times, and then 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 h. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, silica gel was added to the flask, and the solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 45%.

[0059] Comparing Example 1 with Examples 4 to 5, it can be seen that when the trivalent iodide is Ph 2 I·OTf, the yield is higher; when the trivalent iodide is other iodides ((m-CF 3 Ph) 2 I·OTf, (p-ClPh) 2 I·OTf), the yield is lower.

[0060] Example 6

[0061] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 was accurately added, Ph 2I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and lithium acetate (LiOAc, 14.5 mg, 0.22 mmol, 1.1 equiv) were added. After evacuating and replacing with nitrogen three times, 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 hours. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, and silica gel was added to the flask. The solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 65%.

[0062] Example 7

[0063] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 and Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and cesium pivalate (C(CH 3 ) 3 COOCs, 51.5 mg, 0.22 mmol, 1.1 equiv) were accurately added. After evacuating and replacing with nitrogen three times, 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 hours. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, and silica gel was added to the flask. The solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 60%.

[0064] Example 8

[0065] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 and Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and potassium fluoride (KF, 12.8 mg, 0.22 mmol, 1.1 equiv) were accurately added. After evacuating and replacing with nitrogen three times, 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 hours. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, and silica gel was added to the flask. The solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 45%.

[0066] Example 9

[0067] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and sodium hydroxide (NaOH, 8.8 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol; the mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 40%.

[0068] Example 10

[0069] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and dipotassium hydrogen phosphate (K 2 HPO 4 , 38.3 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol; the mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 42%.

[0070] Comparing Example 1 with Examples 6 to 10, it can be seen that when the base is a basic salt with relatively weak alkalinity (NaOAc, LiOAc, C(CH 3 ) 3 COOCs), the yield is relatively high; when the base is a basic salt with relatively strong alkalinity (KF, K 2 HPO 4 ) or a strong base (NaOH), the yield is relatively low.

[0071] Example 11

[0072] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were added after evacuating and replacing nitrogen three times, and then 1.0 mL of methanol was added. The mixture was reacted at 80 °C for 24 h. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, silica gel was added to the flask, and the solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 20%.

[0073] Example 12

[0074] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 and Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were added after evacuating and replacing nitrogen three times, and then 1.0 mL of methanol was added. The mixture was reacted at 100 °C for 24 h. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, silica gel was added to the flask, and the solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 47%.

[0075] Example 13

[0076] In a reaction tube, indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1 and Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv) were added after evacuating and replacing nitrogen three times, and then 1.0 mL of methanol was added. The mixture was reacted at 150 °C for 24 h. The reaction mixture was passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents were transferred to a round-bottom flask, silica gel was added to the flask, and the solvent was evaporated under vacuum. Purification was carried out by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent to obtain the corresponding product 2a with a yield of 77%.

[0077] Comparing Example 1 with Examples 11 to 13, it can be seen that when the reaction temperature of the mixture reaction is in the range of 80 to 120 °C, the yield is positively correlated with the reaction temperature. When the reaction temperature is 80 °C, the product yield is low; when the reaction temperature of the mixture reaction is in the range of 120 to 150 °C, the yield is negatively correlated with the reaction temperature. When the reaction temperature is 150 °C, the product yield is high.

[0078] Example 14

[0079]

[0080] In a reaction tube, accurately add 1-methyl-1H-indole-2-carbaldehyde 1b (25.0 μL, 0.2 mmol, 1.0 equiv) shown in Example 2, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of ethanol. The mixture is reacted at 120 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:60) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2d with a yield of 77%.

[0081] Example 15

[0082]

[0083] In a reaction tube, accurately add 1-methyl-1H-indole-2-carbaldehyde 1b (25.0 μL, 0.2 mmol, 1.0 equiv) shown in Example 2, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of propanol. The mixture is reacted at 120 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:60) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2e with a yield of 75%.

[0084] Comparing Example 1 with Examples 14 to 15, it can be seen that when the alcohol added is other alcohols, the corresponding products obtained are other diindolylalkanes.

[0085] Example 16

[0086] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (68.8 mg, 0.16 mmol, 0.8 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol. The mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask. The solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 52%.

[0087] Example 17

[0088] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (103.2 mg, 0.24 mmol, 1.2 equiv) and NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol. The mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask. The solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 36%.

[0089] Example 18

[0090] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (16.4 mg, 0.2 mmol, 1.0 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol. The mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask. The solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 45%.

[0091] Example 19

[0092] In a reaction tube, accurately add indole 1a (23.4 mg, 0.2 mmol, 1.0 equiv) shown in Example 1, Ph 2 I·OTf (94.6 mg, 0.22 mmol, 1.1 equiv) and NaOAc (24.5 mg, 0.3 mmol, 1.5 equiv). After evacuating and replacing with nitrogen three times, add 1.0 mL of methanol. The mixture is reacted at 150 °C for 24 hours. The reaction mixture is passed through a thin layer of diatomaceous earth and washed with ethyl acetate. All the washing solvents are transferred to a round-bottom flask, and silica gel is added to the flask, and the solvent is evaporated under vacuum. Using ethyl acetate / petroleum ether (v / v, 1:10) as the eluent, purification is carried out by silica gel column chromatography to obtain the corresponding product 2a with a yield of 30%.

[0093] Comparing Example 1 with Examples 16 to 19, it can be seen that the feeding ratio of the reactants affects the product yield.

[0094] Example 20

[0095] This example provides an application experiment of the prepared diindolylmethane.

[0096] Taking the preparation process provided by Patent CN105218552B as an example, using the diindolylmethane 2a prepared in any one of Example 1 or Examples 4 to 12 or Examples 16 to 19 as the raw material, dihydroindolocarbazole phenol is prepared. Here, taking Example 1 as an example, the specific process is as follows:

[0097]

[0098] To a 50 mL round-bottom flask, add 2a (49.2 mg, 0.2 mmol, 1.0 equiv) of diindolylmethane and 3 (14.6 mg, 0.12 mmol, 1.67 equiv) of p-hydroxybenzaldehyde, and dissolve them by stirring in 30 mL of absolute ethanol. Add 5 drops of concentrated sulfuric acid dropwise under an ice bath and stir well for 5 minutes. After reacting at room temperature for 24 hours, monitor the reaction by TLC until the starting material spot of diindolylmethane disappears, then stop the reaction and concentrate the reaction solution under reduced pressure. Dissolve the residue in 30 mL of ethyl acetate, transfer it to a separatory funnel, wash it successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry the ethyl acetate layer over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify it by silica gel column chromatography using ethyl acetate / petroleum ether (v / v, 1:5) as the eluent to obtain the corresponding product 4, dihydroindolocarbazole phenol, with a yield of 62%. The yield of dihydroindolocarbazole phenol in this example is significantly higher than that of the prior art (Patent CN105218552B) (10.2% - 37%). The inventors speculate that the reason for the higher yield is that, compared with the prior art, the purity of the diindolylmethane prepared in this example of the present invention is higher and the influence of impurity types on the reaction to obtain dihydroindolocarbazole phenol is smaller. However, due to time constraints, no experimental verification has been carried out. Perform nuclear magnetic resonance on the prepared dihydroindolocarbazole phenol 4 to obtain the Figure 7 HNMR spectrum of dihydroindolocarbazole phenol 4 as shown in 1 and the Figure 8 C NMR spectrum of dihydroindolocarbazole phenol 4 as shown in 13 . The results show that the nuclear magnetic resonance data of dihydroindolocarbazole phenol 4 are as follows:

[0099] 1 H NMR (400 MHz, DMSO): δ = 10.65 (s, 2H), 9.69 (s, 1H), 8.77 (s, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.58 - 7.57 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.16 - 7.12 (m, 2H), 7.09 - 7.07 (m, 2H) ppm.

[0100] 13 C NMR (101 MHz, DMSO): δ = 156.9, 140.8, 137.8, 130.8, 125.5, 124.3, 123.4, 119.2, 118.3, 117.6, 116.3, 110.9, 109.9, 105.9 ppm.

[0101] Indoline carbazole phenol (4) can significantly reduce the ROS level in leukemia cells, induce apoptosis and autophagy in leukemia cells, and inhibit their proliferation. This example provides the reaction process for synthesizing indoline carbazole phenol (4) from diindolylmethane, and in the reaction provided in this example, the yield of indoline carbazole phenol (4) is significantly higher, providing a material basis for the preparation of anti-tumor and anti-leukemia chemotherapeutic agents.

[0102] Although the preferred embodiments of the present invention have been described, additional changes and modifications can be made to these embodiments by those skilled in the art once they learn the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments as well as all changes and modifications that fall within the scope of the present invention.

[0103] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A method for preparing diindolylmethane, characterized in that: The following steps are involved: In the presence of Ph2I·OTf and a base, the indole compound and methanol undergo a coupling reaction to obtain the diindolylmethane; The chemical formula of the indole compound is shown in Formula I, In formula I, R is one of H, methyl and ethyl.

2. The method according to claim 1, characterized in that The base is a weak base or a basic salt.

3. The method according to claim 2, characterized in that The base is one of sodium acetate, lithium acetate and cesium pivalate.

4. The method according to claim 1, characterized in that The molar ratio of the compound 1, the trivalent iodide and the base is 1:0.8-1.2:1-1.

5.

5. The method according to claim 1, characterized in that The reaction is carried out in air or nitrogen atmosphere at a temperature of 80 to 150°C.

6. The method according to claim 1, characterized in that Also includes: After the coupling product is washed, the target product is separated by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent.

7. The method according to claim 6, characterized in that In the eluent, the ratio of ethyl acetate to petroleum ether added is 1:10-60 by volume.

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