α-Indolepyrrolo[1,2-a]indole derivatives and their preparation methods

Abstract

This invention discloses an α-indolylpyrrolo[1,2-a]indole derivative and its preparation method. The derivative is a levorotatory or dextrorotatory optically active form or racemate with the following structural formula: The preparation involves using α-indolylpropynyl alcohols and indole compounds as raw materials, and 3,5-bis(trifluoromethyl)phenylbinaphthylphosphonic acid as a catalyst, reacting in an organic solvent to obtain the α-indolylpyrrolo[1,2-a]indole derivative. This invention utilizes an organophosphate-catalyzed tandem reaction of two components to synthesize the α-indolylpyrrolo[1,2-a]indole derivative. The reaction conditions are mild, the process is simple, and the operation is convenient. The obtained product is the core skeleton of the indole bases of the natural products isoborreverine and dimethyl isoborreverine, which is of great significance for the synthesis of analogs of these natural products.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to α-indolylpyrrolo[1,2-a]indole derivatives and their preparation methods. Background Technology

[0002] α-Indolepyrrolo[1,2-a]indole derivatives are an important class of organic compounds and the core skeleton of the indole bases in the natural products of the antimalarial drugs isoborreverine and dimethyl isoborreverine.

[0003] Antimalarial natural product: isoborreverine anddimethylisoborreverine

[0004]

[0005] Therefore, the synthesis of chiral α-indolylpyrrolo[1,2-a]indole derivatives has become an important goal in drug synthesis. In addition, indoles and their derivatives also possess significant pharmacological activities. Compounds containing indole ring structural units are widely distributed in nature and constitute the most abundant class of alkaloids discovered to date, accounting for one-fifth of all alkaloids. Due to the unique biological properties of indole compounds, they have extremely wide applications in organic synthesis, materials science, agricultural chemistry, and pharmacology. Therefore, it can be expected that chiral α-indolylpyrrolo[1,2-a]indole derivatives are likely to also possess high biological activity and have potential research value in the development and synthesis of drug intermediates. Summary of the Invention

[0006] The purpose of this invention is to provide an α-indolylpyrrolo[1,2-a]indole derivative and its preparation method.

[0007] The α-indolylpyrrolo[1,2-a]indole derivative of the present invention is a levorotatory or dextrorotatory optically active form or racemate having the following structural formula:

[0008]

[0009] In the formula: R 1 ~R 4 Each element is independently selected from H, halogen, methyl, ethyl, phenyl, cyclohexyl, methoxy, and Ar. 1 Ar 2 Each of the components is independently selected from phenyl, phenyl with substituents, naphthyl, thiophene, and the substituents are selected from halogen, methyl, ethyl, phenyl, cyclohexyl, methoxy, ethoxy, propoxy, and butoxy.

[0010] The preferred structural formula of the above-mentioned α-indolylpyrrolo[1,2-a]indole derivative is one of the following structural formulas:

[0011]

[0012] The method for preparing the α-indolylpyrrolo[1,2-a]indole derivative of the present invention includes: using α-indolylpropynyl alcohol and indole compound as raw materials, using 3,5-bis(trifluoromethyl)phenylnaphthyl phosphate as catalyst, reacting at low temperature in an organic solvent for 10-24 hours, and purifying to obtain the α-indolylpyrrolo[1,2-a]indole derivative;

[0013] The 3,5-bis(trifluoromethyl)phenylnaphthylphosphonic acid is a compound having the structural formula (1), and can be a levorotatory or dextrorotatory optically active form or a racemic mixture:

[0014]

[0015] The structure of the α-indolylpropynyl alcohols is shown in formula (2) below:

[0016]

[0017] The structure of the indole compounds is shown in formula (3) below:

[0018]

[0019] In this invention, the α-indolylpropynyl alcohol compound is preferably one of the following compounds:

[0020]

[0021] In this invention, the indole compound is preferably one of the following compounds:

[0022]

[0023] In this invention, the organic solvent is one or more of the following: dichlorofluoroethane, dichloromethane, 1,2-dichloroethane, toluene, benzene, chloroform, tetrahydrofuran, fluorobenzene, chlorobenzene, or acetone.

[0024] In this invention, the molar ratio of α-indolylpropynyl alcohol and indole compound is 1:1, the molar ratio of 3,5-bis(trifluoromethyl)phenylbinaphthyl phosphate catalyst and α-indolylpropynyl alcohol is 1:10, and the reaction temperature is -10 to 60°C.

[0025] After the reaction is completed, the final product is separated and the catalyst is recovered by column chromatography. The eluent for column chromatography is a mixture of dichloromethane / petroleum ether or ethyl acetate / petroleum ether. More preferably, the volume ratio of dichloromethane / petroleum ether is 1:3 and the volume ratio of ethyl acetate / petroleum ether is 1:10 to 30.

[0026] The reaction equation of this invention is as follows:

[0027]

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] 1) No metal catalysis is required; the reaction can be carried out under mild conditions.

[0030] 2) Substituent-containing indole is widely available as a reaction substrate; α-indole propynyl alcohols can be easily prepared from α-indolecarboxylic acid and its derivatives, which reduces the preparation cost of the final product.

[0031] 3) Highly optically active chiral α-indolylpyrrolo[1,2-a]indole derivatives can be obtained;

[0032] 4) The product is the core framework of a natural product analog with antimalarial pharmacological activity.

[0033] In summary, this invention utilizes a catalytic two-component tandem reaction method to synthesize α-indolylpyrrolo[1,2-a]indole derivatives. The reaction conditions are mild, the process is simple, and the operation is convenient. The obtained products are the core skeletons of the antimalarial drugs isoborreverine and dimethyl isoborreverine. References can be found in Organic Letters. 2009, 11(2), 329-332; Chirality. 2013, 27, 14–17. This will be of great significance for the synthesis of analogues of this class of drugs. Detailed Implementation

[0034] The following examples will help to understand the present invention, but are not limited to the content of the present invention.

[0035] Example 1

[0036] Substrate synthesis

[0037] The α-indolylpropynyl alcohols are synthesized as follows:

[0038]

[0039] Under N2 conditions at 0 °C, a solution of carbodiimide hydrochloride (EDCI, 5.27 g, 27.5 mmol, 1.2 equivalents) in DCM (20 mL) was added dropwise to a round-bottom flask containing indole-2-carboxylic acid S1 (25 mmol, 1.0 equivalent), 1-hydroxybenzotriazole (HOBt, 336 mg, 2.5 mmol, 0.1 equivalent), N,O-dimethylhydroxylamine hydrochloride (2.42 g, 25 mmol, 1.0 equivalent), Et3N (7.0 mL, 50 mmol, 2.0 equivalent), and DCM (50 mL). The mixture was stirred at room temperature for 12 hours, then quenched with water (50 mL), the organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The desired Weinreb amide S2 was obtained by silica gel column chromatography.

[0040] Under -78°C and N2 conditions, a hexane solution of n-butyllithium (2.5 M, 8 mL, 20.0 mmol, 2.0 equivalent) was added dropwise to a round-bottom flask containing aryl bromide (20 mmol, 2.0 equivalent) and THF (20 mL). The mixture was stirred at -78°C for 30 min, and then a THF solution of the above-mentioned Weinreb amide S2 (10 mmol, 1.0 equivalent) was slowly added via syringe. The resulting mixture was heated to room temperature and stirred for 1 h. The reaction was then quenched with an aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate (30 mL × 3). The mixture was washed with water (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography yielded the desired ketone derivative S3.

[0041] Under -78°C and N2 conditions, a hexane solution of n-butyllithium (2.5 M, 2.4 mL, 6.0 mmol, 3.0 equivalent) was slowly added to a THF (10 mL) solution of arylynylene (6 mmol, 3.0 equivalent). The resulting mixture was stirred at -78°C for 30 minutes. Then, a THF (10 mL) solution of ketone derivative S3 (2 mmol, 1.0 equivalent) was added. The mixture was slowly heated to room temperature and then stirred overnight. The reaction was quenched by adding saturated NH4Cl aqueous solution (10 mL). The reaction mixture was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification by silica gel column chromatography yielded the desired substrate, α-indolylpropynyl alcohol S4.

[0042] The above method can be used to prepare a series of α-indolylpropynyl alcohols, as shown in the following examples:

[0043] 1-(1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol structural formula:

[0044]

[0045] Appearance: Yellow solid

[0046] Silica gel column chromatography with petroleum ether / ethyl acetate eluent of 20:1-8:1 yielded 92% product. The product characterization is as follows:

[0047] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),7.76(d,J=8.0Hz,2H),7.61(d,J=7.8Hz,1H),7.58–7.50(m,2H),7.37( ddt,J=18.5,12.5,7.5Hz,7H),7.20(t,J=7.6Hz,1H),7.12(t,J=7.4Hz,1H),6.62(s,1H),3.11(s,1H)ppm.

[0048] 3-(4-bromophenyl)-1-(1H-indol-2-yl)-1-phenyl-prop-2-yn-1-ol structural formula:

[0049]

[0050] Appearance: White solid

[0051] Silica gel column chromatography with petroleum ether / ethyl acetate eluent of 20:1-8:1 yielded 93% product. The product characterization is as follows:

[0052] 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.72(d,J=7.9Hz,2H),7.60(d,J=7.8Hz,1H),7.49(d,J=7.9Hz,2H),7.44–7 .34(m,5H),7.32(d,J=8.1Hz,1H),7.20(t,J=7.6Hz,1H),7.12(t,J=7.4Hz,1H),6.60(s,1H),3.10(s,1H)ppm.

[0053] 1-(1H-indol-2-yl)-1-phenyl-3-(thien-2-yl)-prop-2-yn-1-ol structural formula:

[0054]

[0055] Appearance: Brown solid

[0056] Silica gel column chromatography with petroleum ether / ethyl acetate eluent of 20:1-8:1 yielded 83% product. The product characterization is as follows:

[0057] 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),7.74(d,J=7.9Hz,2H),7.60(d,J=7.8Hz,1H),7.57–7.49(m,1H),7.40(td,J=11 .2,9.4,4.5Hz,3H),7.33–7.26(m,2H),7.19(d,J=5.1Hz,2H),7.12(t,J=7.4Hz,1H),6.59(s,1H),3.11(s,1H)ppm.

[0058] Example 2

[0059] 1-(1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of dichlorofluoroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 70% yield. The product was characterized as follows:

[0060] Structural formula:

[0061]

[0062] Appearance: White solid;

[0063] mp221-223℃;

[0064] Optical purity: 90% ee, 99% ee (after recrystallization);

[0065] HPLC analysis conditions: (Cyclone chiral column, same below) Chiralpak AD-H (n-hexane / i-PrOH = 90 / 10, 1.0 mL / min), t R (minor) 6.427 min, t R (major) 11.035min;

[0066] Optical rotation: [α] D 20 = +13° (c 1.00, CH2Cl2);

[0067] 1H NMR(400MHz, CDCl3)δ7.90(s,1H),7.72–7.67(m,2H),7.65(d,J=7.7Hz,1H),7.57(d,J=7.7Hz,1H),7.51–7.42(m,3H),7.37(dq, J=7.2,3.9Hz,5H),7.23(d,J=8.1Hz,1H),7.17–7.12(m,1H),7.12–7.02(m,4H),6.67(s,1H),6.55–6.49(m,1H),2.41(s,3H)ppm;

[0068] HRMS m / z(ESI + ): Calculated value C 32 H 25 N2([M+H)) + )437.2012, detected value 437.2010.

[0069] Example 3

[0070] 1-(5-bromo-1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of dichlorofluoroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 84% yield. The product was characterized as follows:

[0071] Structural formula:

[0072]

[0073] Appearance: White solid;

[0074] mp161-163℃;

[0075] Optical purity: 93% ee;

[0076] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (major) 6.227min,t R (minor) 7.373 min;

[0077] Optical rotation: [α] D 20= +20° (c 1.00, CH2Cl2);

[0078] 1 H NMR(400MHz, CDCl3)δ7.93(s,1H),7.71–7.62(m,4H),7.52–7.42(m,3H),7.40–7.32(m,5H),7.21(d d,J=8.7,1.9Hz,1H),7.13–7.00(m,4H),6.64(s,1H),6.45(dd,J=2.2,0.9Hz,1H),2.40(s,3H)ppm;

[0079] HRMS m / z(ESI + ): Calculated value C 32 H 24 BrN2([M+H] + 517.1097, detected value 517.1095.

[0080] Example 4

[0081] 1-(3-methyl-1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), and (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1) were added to a reaction flask. 1 mL of monofluorodichloroethane was injected, and the reaction was carried out at 0 °C for 24 hours. After the reaction was complete, the product was directly precipitated by silica gel column chromatography with ethyl acetate / petroleum ether at a ratio of 1:30 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 85% yield. The product was characterized as follows:

[0082] Structural formula:

[0083]

[0084] Appearance: White solid;

[0085] mp155-157℃;

[0086] Optical purity: 91% ee;

[0087] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 90 / 10, 1.0 mL / min), t R (major) 5.075 min, t R (minor) 6.921 min;

[0088] Optical rotation: [α] D 20= +212° (c 1.00, CH2Cl2);

[0089] 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.67–7.57 (m, 3H), 7.51 (dd, J = 6.9, 1.9Hz, 1H), 7.45–7.33 (m, 5H), 7.33–7. 24(m,3H),7.17–7.13(m,1H),7.13–7.03(m,3H),7.03–6.94(m,2H),6.69(s,1H),2.35(s,3H),2.01(s,3H)ppm;

[0090] HRMS m / z(ESI + ): Calculated value C 33 H 27 N2([M+H)) + 451.2169, detected value 451.2168.

[0091] Example 5

[0092] 1-(1H-indol-2-yl)-1-phenyl-3-(thiophen-2-yl)-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of dichlorofluoroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 72% yield. The product was characterized as follows:

[0093] Structural formula:

[0094]

[0095] Appearance: White solid;

[0096] mp>300℃;

[0097] Optical purity: 90% ee;

[0098] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 6.321 min, t R (major) 10.095min;

[0099] Optical rotation: [α] D 20 = +55° (c 1.00, CH2Cl2);

[0100] 1 H NMR (400MHz, CDCl3) δ7.88(s,1H),7.65(d,J=7.7Hz,2H),7.56(d,J=7.7Hz,1H),7.43(dd,J=4.9,3.0Hz,1H),7. 39(d,J=12.3Hz,6H),7.21(d,J=7.9Hz,1H),7.17–7.03(m,5H),6.69(s,1H),6.53–6.48(m,1H),2.50(s,3H)ppm;

[0101] HRMS m / z(ESI + ): Calculated value C 30 H 23 N2S([M+H)) + 443.1576, detected value 443.1577.

[0102] Example 6

[0103] 1-(4-bromophenyl)-1-(1H-indol-2-yl)-3-phenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of difluorodichloroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 80% yield. The product was characterized as follows:

[0104] Structural formula:

[0105]

[0106] Appearance: White solid;

[0107] mp275-277℃;

[0108] Optical purity: 95% ee;

[0109] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 7.302 min, t R(major) 11.101 min;

[0110] Optical rotation: [α] D 20 = -45° (c 1.00, CH2Cl2);

[0111] 1 H NMR(400MHz, CDCl3)δ7.89(s,1H),7.71–7.62(m,3H),7.58(d,J=7.7Hz,1H),7.48(td,J=8.6,6.4Hz,5H),7.26–7.20(m,3H),7.18–7 .13(m,1H),7.11(ddd,J=7.9,3.8,1.5Hz,2H),7.04(td,J=7.9,7.4,3.7Hz,2H),6.60(s,1H),6.51(d,J=2.2Hz,1H),2.40(s,3H)ppm;

[0112] HRMS m / z(ESI + ): Calculated value C 32 H 24 BrN2([M+H] + 515.1117, detected value 515.1110.

[0113] Example 7

[0114] 3-(4-bromophenyl)-1-(1H-indol-2-yl)-1-phenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of monofluorodichloroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 87% yield. The product was characterized as follows:

[0115] Structural formula:

[0116]

[0117] Appearance: White solid;

[0118] mp273-275℃;

[0119] Optical purity: 93% ee;

[0120] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 5.987 min, t R (major) 14.842 min;

[0121] Optical rotation: [α] D 20 = +10° (c 1.00, CH2Cl2);

[0122] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.61 (ddd, J = 26.2, 16.7, 8.1Hz, 6H), 7.39 (s, 5H), 7.22(d,J=7.9Hz,1H),7.19–7.04(m,5H),6.67(s,1H),6.52(s,1H),2.41(s,3H)ppm;

[0123] HRMS m / z(ESI + ): Calculated value C 32 H 24 BrN2([M+H] + 517.1097, detected value 517.1132.

[0124] Example 8

[0125] 1-(1H-indol-2-yl)-3-(naphth-2-yl)-1-phenyl-prop-2-yn-1-ol (0.05 mmol), 3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of difluorodichloroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 58% yield. The product was characterized as follows:

[0126] Structural formula:

[0127]

[0128] Appearance: White solid;

[0129] mp182-184℃;

[0130] Optical purity: 90% ee;

[0131] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 5.296 min, t R (major) 7.825min;

[0132] Optical rotation: [α] D 20 = +15° (c 1.00, CH2Cl2);

[0133] 1 H NMR (400MHz, CDCl3) δ8.19(s,1H),8.01–7.88(m,4H),7.79(dd,J=8.4,1.3Hz,1H),7.68(d,J=7.5Hz,1H),7.63–7.52(m,3H),7.41(dt,J= 14.3,7.1Hz,5H),7.24(d,J=8.1Hz,1H),7.20–7.15(m,1H),7.10(dt,J=9.0,6.9Hz,4H),6.78(s,1H),6.60–6.52(m,1H),2.45(s,3H)ppm;

[0134] HRMS m / z(ESI + ): Calculated value C 36 H 27 N2([M+H)) + 487.2169, detected value 487.2174.

[0135] Example 9

[0136] 1-(1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol (0.05 mmol), 6-bromo-3-methylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to a reaction flask. 1 mL of dichlorofluoroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 68% yield. The product was characterized as follows:

[0137] Structural formula:

[0138]

[0139] Appearance: White solid;

[0140] mp>300℃;

[0141] Optical purity: 94% ee;

[0142] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 6.135 min, t R (major) 7.140min;

[0143] Optical rotation: [α] D 20 = +95° (c 1.00, CH2Cl2);

[0144] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.65 (d, J = 7.7Hz, 2H), 7.58 (d, J = 7.9Hz, 1H), 7.46 (q, J = 7.4, 6.8Hz, 4H), 7.38 (t, J = 6.8Hz, 3H),7.34(d,J=7.8Hz,2H),7.28(s,1H),7.20–7.14(m,3H),7.10(t,J=7.4Hz,1H),6.64(s,1H),6.50(s,1H),2.35(s,3H)ppm;

[0145] HRMS m / z(ESI + ): Calculated value C 32 H 24 BrN2([M+H] + 517.1097, detected value 517.1148.

[0146] Example 10

[0147] 1-(1H-indol-2-yl)-1,3-diphenyl-prop-2-yn-1-ol (0.05 mmol), 3-ethylindole (0.05 mmol), (R)-3,5-bis(trifluoromethylphenyl)naphthyl phosphate (0.005 mmol) as shown in the aforementioned structural formula (1), and 3A molecular sieve (50 mg) were added to the reaction flask. 1 mL of dichlorofluoroethane was injected, and the reaction was carried out at -10 °C for 24 hours. After the reaction was completed, the product was directly precipitated by silica gel column chromatography with dichloromethane / petroleum ether as the eluent at a ratio of 1:3 to obtain the corresponding optically active α-indolylpyrrolo[1,2-a]indole derivative in 76% yield. The product was characterized as follows:

[0148] Structural formula:

[0149]

[0150] Appearance: White solid;

[0151] mp139-141℃;

[0152] Optical purity: 92% ee;

[0153] HPLC analysis conditions: Chiralpak AD-H (n-hexane / i-PrOH = 80 / 20, 1.0 mL / min), t R (minor) 5.044 min, t R (major) 5.941 min;

[0154] Optical rotation: [α] D 20 = +72° (c 1.00, CH2Cl2);

[0155] 1 H NMR (400MHz, CDCl3) δ7.93(s,1H),7.71(dd,J=11.4,7.9Hz,3H),7.60(d,J=7.6Hz,1H),7.49(q,J=8.0,7.2Hz,3H),7.40(s,5H),7.24(d,J=7 .9Hz,1H),7.17(t,J=7.4Hz,1H),7.10(dt,J=11.9,7.1Hz,4H),6.67(s,1H),6.54(s,1H),2.93–2.81(m,2H),1.31(dt,J=7.5,3.6Hz,3H)ppm;

[0156] HRMS m / z(ESI + ): Calculated value C 32 H 24 BrN2([M+H] + 517.1097, detected value 517.1148.

[0157] Example 11

[0158] Pharmacological activity testing and cytotoxicity assay.

[0159] Human prostate cancer cell line PC-3 was cultured in F12K medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin stock solution. Cells were cultured at 37°C in an incubator containing 5% carbon dioxide.

[0160] The cytotoxicity of the compounds was assessed using PC-3 cells via an MTT assay. Human prostate cancer cells (PC-3) were seeded into 96-well plates at a density of 10,000 cells per well, with 200 μL of total culture medium per well. After 16 hours of adhesion, the supernatant was removed from the wells, and 200 μL of culture medium containing the test sample was added to each well. For the whole-dead control cell group, 200 μL of PEI aqueous solution (25 kDa, 2 mg / mL) was added, and for the live control cell group, 200 μL of serum-free culture medium was added. The cell plates were incubated at 37°C in a 5% CO2 incubator for 4 hours. After stimulation, the supernatant was removed from the wells, and 100 μL of MTT (0.5 mg / mL) solution was added to each well. The cell plates were then incubated at 37°C in a 5% CO2 incubator for another 4 hours. The supernatant was then removed, and 100 μL of DMSO was added to each well. Shake the culture plate for 2 minutes and read the optical density (OD) value at a wavelength of 570 nm using an ELISA reader.

[0161] Viability = ([OD]) experimental -[OD] blank ) / ([OD] control -[OD] blank )×100%

[0162] Test results showed that the half-lethal concentrations (LD50) of the two compounds prepared in Examples 2 and 7 exceeded their measured concentration range, with LD50 values ​​above 300 μM.

[0163] Cytotoxicity tests on the human prostate cancer cell line PC-3 showed that the two compounds prepared in Examples 2 and 7 had weak toxicity to PC-3 cells; the compound IC prepared in Example 10... 50 [μM] is 10.0.

Claims

1. An α-indolylpyrrolo[1,2-a]indole derivative of the formula ###00001### characterized in that The structural formula is as follows: 。 2. A process for the preparation of the α-indolylpyrrolo[1,2-a]indole derivatives according to claim 1, characterized in that, The method comprises the following steps: taking α-indole propargyl alcohol compound and indole compound as raw materials, taking 3,5-bistrifluoromethyl phenyl binaphthyl phosphoric acid as a catalyst, reacting in an organic solvent for 10-24 hours, and purifying to obtain α-indole pyrrolo[1,2-a]indole derivative; The 3,5-bistrifluoromethyl phenyl binaphthyl phosphoric acid is a compound with the structural formula (1), and is optically active or racemic: Formula (1) The α-indole propargyl alcohol compound is 1-(1H-indole-2-yl)-1,3-diphenyl-prop-2-yn-1-ol. The indole compound is 3-ethyl indole.

3. The method of producing an a-indolylpyrrolo[l,2-a]indole derivative according to claim 2, characterized by, The organic solvent is one or more of monofluorodichloroethane, dichloromethane, 1,2-dichloroethane, toluene, benzene, chloroform, tetrahydrofuran, fluorobenzene, chlorobenzene or acetone.

4. The method of producing an a-indolylpyrrolo[l,2-a]indole derivative according to claim 2, characterized by, The molar ratio of the α-indole propargyl alcohol compound and the indole compound is 1:1, and the molar ratio of the 3,5-bistrifluoromethyl phenyl binaphthyl phosphoric acid catalyst and the α-indole propargyl alcohol compound is 1:10; the reaction temperature is-10-60 ℃.

Images