Aryl binaphthyl indolyl pyrrole carboxylic ester derivative and preparation method thereof

Abstract

The aryl binaphthyl indolyl pyrrole carboxylate derivative disclosed by the invention is a levorotatory or dextrorotatory optical active body or racemate with the following structural formula, and the preparation method of the aryl binaphthyl indolyl pyrrole carboxylate derivative comprises the following steps: taking a benzyl alcohol pyrrole carboxylate compound and an indole compound as raw materials, taking 3, 5-bis (trifluoromethyl) phenyl spirocyclic phosphoric acid as a catalyst, and carrying out a reaction at the room temperature to obtain the aryl binaphthyl indolyl pyrrole carboxylate derivative. And reacting in an organic solvent to obtain the aryl binaphthyl indolyl pyrrole carboxylic ester derivative. The aryl binaphthyl indolyl pyrrole carboxylic ester derivative is synthesized by utilizing a cascade reaction method of catalyzing two components by organic phosphoric acid, the reaction condition is mild, the process is simple, the operation is convenient, and the yield is high. The obtained indole-pyrrole heterotriaryl structure is a core skeleton of a series of natural products with important biological activity, such as reserpine (with an antihypertensive effect), ergoline (which can be used for postpartum hemostasis, migraine research and the like) and the like, so that the indole-pyrrole heterotriaryl structure has important significance on synthesis of analogues of the natural products. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to an aryl binaphthyl indole pyrrole carboxylate derivative and a preparation method thereof. Background Art

[0002] Pyrrole carboxylates hold a crucial position in the biopharmaceutical field. Their diverse structures and unique chemical properties make them the core of numerous active ingredients. For example, Lamellarin, isolated from marine invertebrates, contains a pyrrole-2-carboxylate backbone and exhibits significant anti-tumor and anti-HIV activity, providing guidance for related drug development. Ningalin, extracted from the sea squirt of Western Australia, is cytotoxic and serves as a precursor for important anti-tumor agents. The bacterial coenzymes methoxatin and lycogarubin play a key role in protecting against herpes simplex virus type 1 (HSV-1), offering new opportunities for antiviral drug development.

[0003]

[0004] Therefore, the research and synthesis of arylbinaphthyl indole pyrrole carboxylate derivatives with chiral centers and axial chirality has become an important goal in drug synthesis. Furthermore, indole and its derivatives also possess important pharmacological activities. Compounds containing indole ring structural units are widely present in nature and are the most abundant class of alkaloids discovered to date, accounting for one-fifth of all alkaloids. Arylbinaphthyl-indole pyrrole carboxylate derivatives with multiple chiral centers may exhibit significant biological activity due to their complex stereochemical configurations and structural diversity. This class of molecules has important basic research value and potential application prospects in the discovery of new drug lead compounds and the development of synthetic processes for drug intermediates. Summary of the Invention

[0005] The present invention aims to provide an aryl binaphthyl indole pyrrole carboxylate derivative and a preparation method thereof.

[0006] The arylbinaphthyl indole pyrrole carboxylate derivative of the present invention is a levorotatory or dextrorotatory optically active form or racemic form having the following structural formula:

[0007]

[0008] In the formula: R1 is selected from methyl, ethyl, benzyl, propyl, butyl, trifluoromethyl, R2 is selected from hydrogen, fluorine, methyl, phenyl, or forms a naphthyl with the phenyl group, R3 is selected from hydrogen, phenyl, methoxy, fluorine, naphthyl, substituted phenyl, and the substituent is halogen, methyl or ethyl.

[0009] The structural formula is preferably one of the following structural formulas:

[0010]

[0011] The preparation method of an aryl binaphthyl indole pyrrole carboxylate derivative comprises: using a benzyl alcohol pyrrole carboxylate compound and an indole compound as raw materials, using 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid as a catalyst, reacting in an organic solvent for 10-24 hours, and purifying to obtain the aryl binaphthyl indole pyrrole carboxylate derivative;

[0012] The 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid catalyst is a compound having the structural formula (1), which can be a left-handed or right-handed optically active form or a racemic form:

[0013]

[0014] The structure of the benzyl alcohol pyrrole carboxylate compound is shown in the following formula (2):

[0015]

[0016] The structure of the indole compound is shown in the following formula (3):

[0017]

[0018] The benzyl alcohol pyrrole carboxylate compound is preferably one of the following compounds but is not limited to the following compounds:

[0019]

[0020] The indole compound is preferably one of the following compounds but is not limited to the following compounds:

[0021]

[0022] The organic solvent is ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, benzene, chloroform, tetrahydrofuran, n-hexane, methanol, acetone or monofluorodichloroethane.

[0023] The molar ratio of the benzyl alcohol pyrrole carboxylate compound to the indole compound is 1.2:1, and the molar ratio of the 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid catalyst to the indole compound is 1:10; and the reaction temperature is -20°C.

[0024] After the reaction is completed, the final product is separated and the catalyst is recovered by column chromatography. The eluent for column chromatography is ethyl acetate / petroleum ether or a mixed solvent of dichloromethane / petroleum ether, and the corresponding volume ratio is preferably 1:10-15.

[0025] Reaction equation of the present invention is as follows:

[0026]

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] 1) No metal catalysis is required and the reaction can be carried out under mild conditions;

[0029] 2) Substituted indoles are widely available as reaction substrates; benzyl alcohol pyrrole carboxylates can be easily prepared from benzaldehyde pyrrole carboxylates, which reduces the cost of preparing the final product.

[0030] 3) Obtaining highly optically active multichiral aryl binaphthyl indole pyrrole carboxylate derivatives;

[0031] 4) The product has potential application in the field of anti-tumor or neuropharmacological activity.

[0032] In summary, the present invention utilizes an organophosphoric acid-catalyzed two-component tandem reaction method to synthesize aryl binaphthyl indole pyrrole carboxylate derivatives. The reaction conditions are mild, the process is simple, and the operation is convenient. The resulting indole-pyrrole heterotriaryl structure is the core skeleton of a series of important biologically active natural products, such as reserpine (which has antihypertensive effects) and ergot alkaloids (which can be used for postpartum hemostasis and migraine research, etc.). This will be of great significance for the synthesis of analogues of these natural products. DETAILED DESCRIPTION

[0033] The following examples will help to understand the present invention, but are not intended to limit the present invention.

[0034] Example 1

[0035] Substrate synthesis

[0036] The synthesis method of the benzyl alcohol pyrrole carboxylate compound is as follows:

[0037]

[0038] Under N2 atmosphere, 1,1-dichlorodimethyl ether (60 mmol, 1.5 eq, 6.9 g) was added dropwise to a mixture of 1H-pyrrole-2-carboxylate derivative S1 (40 mmol, 1 eq, 5.58 g) and aluminum chloride (120 mmol, 3 eq, 16.04 g) dissolved in 80 ml of anhydrous dichloromethane, which was placed in a three-necked flask. The reaction mixture was stirred at 0°C for 2 hours. Ice water was slowly added to the mixture under ice bath conditions until no more bubbles were generated. The reaction mixture was then extracted with dichloromethane (3 × 90 ml). The combined organic layers were washed with 60 ml of saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and then purified by flash column chromatography (petroleum ether: ethyl acetate = 1:8) to obtain product S2.

[0039] In a three-necked flask, at -78 ° C, a Grignard reagent (1M in THF, 66 mmol, 3 eq, 66 ml, wherein R is R2 in the present invention, which can be selected from hydrogen, fluorine, methyl, phenyl, or forming a naphthyl group with the phenyl group) was added dropwise to an anhydrous tetrahydrofuran solution (20 ml, mmol) containing 1H-pyrrole-3-carboxaldehyde. Subsequently, the mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. After cooling in an ice bath, a saturated aqueous ammonium chloride solution (80 ml) was added to the resulting mixture to terminate the reaction. Then, the reaction mixture was extracted with ethyl acetate (3×80 ml). The organic layers were combined, washed with saturated brine (60 ml), and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and then purified by flash column chromatography (petroleum ether: ethyl acetate = 1:6) to obtain product S3.

[0040] Based on the above method, benzyl alcohol pyrrole carboxylate compounds including but not limited to the following can be obtained: 4-(phenyl hydroxymethyl)-1H-pyrrole-2-carboxylic acid ethyl ester structural formula:

[0041]

[0042] Appearance: Yellow oily liquid

[0043] The eluent for silica gel column chromatography was petroleum ether / ethyl acetate = 15:1-8:1. The yield was 86%. The product was characterized as follows:

[0044] 1 H NMR(400MHz, CDCl3)δ9.87(s,1H),7.33(d,J=7.0Hz,2H),7.29–7.17(m,3H),6.75(d,J=1.8H z,1H),6.65(d,J=2.1Hz,1H),5.68(s,1H),4.18(q,J=7.1Hz,2H),1.23(t,J=7.1Hz,3H)ppm.

[0045] Ethyl 4-(3-fluorophenylhydroxymethyl)-1H-pyrrole-2-carboxylate Structural formula:

[0046]

[0047] Appearance: Yellow oily liquid

[0048] The eluent for silica gel column chromatography was petroleum ether / ethyl acetate = 15:1-8:1. The yield was 89%. The product was characterized as follows:

[0049] 1H NMR(400MHz, CDCl3)δ9.54(s,1H),7.32–7.23(m,1H),7.19–7.08(m,2H),6.94(tt,J=8.7,1.8Hz,1 H), 6.82–6.74 (m, 2H), 5.76 (s, 1H), 4.26 (q, J = 7.1Hz, 2H), 2.87 (s, 1H), 1.31 (t, J = 7.1Hz, 3H) ppm.

[0050] Ethyl 4-(hydroxy(p-tolyl)methyl)-1H-pyrrole-2-carboxylate Structural formula:

[0051]

[0052] Appearance: Yellow oily liquid

[0053] The eluent for silica gel column chromatography was petroleum ether / ethyl acetate = 15:1-8:1. The yield was 85%. The product was characterized as follows:

[0054] 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.

[0055] 1 H NMR(400MHz, CDCl3)δ9.09(s,1H),7.37–7.27(m,0H),7.23–7.14(m,2H),7.08(dd,J=12.4,6.7Hz,1 H),6.83(dt,J=10.5,2.2Hz,1H),5.77(s,1H),4.28(q,2H),2.35(s,2H),1.32(t,J=7.1Hz,2H)ppm.

[0056] Example 2

[0057] 3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(phenylhydroxymethyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1), Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indole pyrrole carboxylate derivative with a yield of 87%. The product was characterized as follows:

[0058] Structural formula:

[0059]

[0060] Appearance: white solid;

[0061] mp110-112℃;

[0062] Optical purity: 84% ee;

[0063] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)12.002min,t R (major)10.437min;

[0064] Optical rotation: [α] D 20 =-11.563°(c 1.00,CH2Cl2);

[0065] 1 H NMR (400MHz, CDCl3) δ8.98 (s, 1H), 8.09 (s, 1H), 7.86 (d, J = 9.0Hz, 1H), 7.8 1(d,J=8.0Hz,1H),7.54(d,J=8.3Hz,1H),7.36–7.27(m,2H),7.24–7.11(m, 11H),7.07(d,J=7.8Hz,1H),7.01–6.95(m,1H),6.64(s,1H),6.43(s,1H), 5.28(s,1H),4.23(q,J=7.1Hz,2H),3.51(s,2H),1.28(t,J=7.1Hz,3H)ppm.

[0066] HRMS m / z (ESI + ):Calculated value C 33 H 28 N2NaO3([M+Na] + )523.1948, detected value 523.1993.

[0067] Example 3

[0068] 3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(3-fluorophenylhydroxymethyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1), Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indolyl pyrrole carboxylate derivative in a yield of 93%. The product was characterized as follows:

[0069] Structural formula:

[0070]

[0071] Appearance: white solid;

[0072] mp109-110℃;

[0073] Optical purity: 86%ee;

[0074] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)7.019min,t R (major) 5.992min; optical rotation: [α] D 20 =-7.840°(c 1.00,CH2Cl2);

[0075] 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 9.0Hz, 1H), 7.82–7.76 (m ,1H),7.46–7.39(m,1H),7.38–7.33(m,2H),7.33–7.27(m,1H),7.24–7.14(m,2H),7 .06(dq,J=7.8,2.5,1.8Hz,2H),7.02–6.97(m,1H),6.85–6.71(m,4H),6.66(d,J=2. 5Hz,1H),5.32(s,1H),4.28(q,J=7.1Hz,2H),3.69(s,3H),1.32(t,J=7.1Hz,3H)ppm.

[0076] HRMS m / z (ESI+): calculated value C 33 H27 N2NaO3([M+Na]+)541.1898, detected value 541.1821.

[0077] Example 4

[0078] 3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(hydroxy(p-tolyl)methyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethylphenyl)spirophosphoric acid (0.005 mmol) represented by the above structural formula (1) were added to the reaction flask. Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indole pyrrole carboxylate derivative with a yield of 96%. The product was characterized as follows:

[0079] Structural formula:

[0080]

[0081] Appearance: white solid;

[0082] mp115-117℃;

[0083] Optical purity: 92%ee;

[0084] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)6.266min,t R (major) 5.557min; optical rotation: [α] D 20 =-11.459°(c 1.00,CH2Cl2);

[0085] 1H NMR (400MHz, CDCl3) δ8.84(s,1H),8.05(s,1H),7.87(d,J=9.0Hz,1H),7.81(d,J =8.1Hz,1H),7.53(d,J=8.4Hz,1H),7.33(dt,J=17.2,8.1Hz,3H),7.25–7.22(m, 1H),7.15(q,J=7.0Hz,2H),7.09–6.95(m,5H),6.64(s,1H),6.46(s,1H),5.26(s ,1H),4.24(q,J=7.0Hz,2H),3.57(s,3H),2.27(s,3H),1.30(t,J=7.0Hz,3H)ppm;

[0086] HRMS m / z (ESI + ):Calculated value C 34 H 30 N2NaO3([M+Na] + )537.2104, detected value 537.2147.

[0087] Example 5

[0088] 5-(3-chlorophenyl)-3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), 4-(p-tolylhydroxymethyl)-1H-pyrrole-2-carboxylic acid methyl ester (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1) were added to the reaction flask. Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indole pyrrole carboxylate derivative with a yield of 85%. The product was characterized as follows:

[0089] Structural formula:

[0090]

[0091] Appearance: white solid;

[0092] mp118-120℃;

[0093] Optical purity: 83%ee;

[0094] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R(minor)10.950min,t R (major)8.693min;

[0095] Optical rotation: [α] D 20 =4.688°(c 1.00,CH2Cl2);

[0096] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.14(s,1H),7.91(d,J=8.9Hz,1H),7.84(d,J=7.9Hz,1H),7.55(d,J=8.3Hz,1H),7.47(s,1H),7.45–7 .26(m,6H),7.25–7.14(m,3H),7.09(q,J=7.8Hz,4H),6.67(s,1H),6.49(s,1H),5.27(s,1H),3.79(s,3H),3.60(s,3H),2.32(s,3H)ppm;

[0097] HRMS m / z (ESI + ):Calculated value C 39 H 31 ClN2NaO3([M+Na] + )633.1871, detected value 633.1904.

[0098] Example 6

[0099] 5-Methoxy-3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(hydroxy(phenyl)methyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethylphenyl)spirophosphoric acid (0.005 mmol) represented by the above structural formula (1) were added to the reaction flask. Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indole pyrrole carboxylate derivative in a yield of 65%. The product was characterized as follows:

[0100] Structural formula:

[0101]

[0102] Appearance: white solid;

[0103] mp124-126℃;

[0104] Optical purity: 73%ee;

[0105] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)8.402min,t R (maJor)6.635min;

[0106] Optical rotation: [α] D 20 =-12.766°(c 1.00,CH2Cl2);

[0107] 1 H NMR(400MHz, CDCl3)δ8.86(s,1H),7.95–7.79(m,3H),7.58–7.54(m,1H),7.34–7.31(m,1H) ),7.31–7.28(m,1H),7.27(d,J=1.4Hz,0H),7.25–7.22(m,2H),7.19(d,J=7.4Hz,3H),6.81 (dd,J=8.8,2.5Hz,1H),6.63(t,J=2.2Hz,1H),6.52(d,J=2.5Hz,1H),6.45(t,J=2.5Hz,1H ),5.25(s,1H),4.25(q,J=7.1Hz,2H),3.63(s,3H),3.53(s,3H),1.30(t,J=7.1Hz,3H)ppm;

[0108] HRMS m / z (ESI + ):Calculated value C 34 H 29 N2NaO4([M+Na] + )553.2054, detected value 553.2102.

[0109] Example 7

[0110] 5-Fluoro-3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(p-tolylhydroxymethyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1), Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indole pyrrole carboxylate derivative in a yield of 94%. The product was characterized as follows:

[0111] Structural formula:

[0112]

[0113] Appearance: white solid;

[0114] mp107-109℃;

[0115] Optical purity: 84% ee;

[0116] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)7.687min,t R (major)5.968min;

[0117] Optical rotation: [α] D 20 =-5.313°(c 1.00,CH2Cl2);

[0118] 1 H NMR (400MHz, CDCl3) δ8.89(s,1H),8.04(s,1H),7.87(d,J=9.0Hz,1H),7.83–7.77(m,1H),7.49(dd, J=8.4,1.3Hz,1H),7.33–7.30(m,1H),7.30–7.27(m,1H),7.26–7.21(m,2H),7.10–7.02(m,4H),6.87 (td,J=9.1,2.5Hz,1H),6.72(d,J=2.5Hz,0H),6.69(d,J=2.5Hz,0H),6.64(t,J=2.1Hz,1H),6.48–6 .42(m,1H),5.24(s,1H),4.24(q,J=7.1Hz,2H),3.59(s,3H),2.30(s,3H),1.29(t,J=7.2Hz,3H)ppm;

[0119] HRMS m / z (ESI + ):Calculated value C 34 H 29 FN2NaO3([M+Na] +)555.2010, detection value 555.2055.

[0120] Example 8

[0121] 3-(2-methoxynaphthalen-1-yl)-6-phenyl-1H-indole (0.05 mmol), ethyl 4-(phenylhydroxymethyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1) were added to the reaction flask. Molecular sieves (50 mg) were injected with 1 mL of monofluorodichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indolyl pyrrole carboxylate derivative in 83% yield. The product was characterized as follows:

[0122] Structural formula:

[0123]

[0124] Appearance: white solid;

[0125] mp117-119℃;

[0126] Optical purity: 94%ee;

[0127] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)12.585min,t R (major)10.522min;

[0128] Optical rotation: [α] D 20 =-9.650°(c 1.00,CH2Cl2);

[0129] 1H NMR(400MHz, CDCl3)δ8.92(s,1H),8.14(s,1H),7.88(d,J=9.0Hz,1H),7.85– 7.81(m,1H),7.64–7.55(m,4H),7.41(t,J=7.7Hz,2H),7.34–7.26(m,4H),7.2 5–7.16(m,4H),7.13(d,J=8.2Hz,1H),6.67(t,J=2.1Hz,1H),6.54–6.44(m,1H ),5.30(s,1H),4.25(q,J=7.1Hz,2H),3.55(s,3H),1.30(t,J=7.1Hz,4H)ppm;

[0130] HRMS m / z (ESI + ): Calculated value for C39H31N2NaO3+([M+H] + )599.2261, detected value 599.2309.

[0131] Example 9

[0132] 3-(2-methoxynaphthalen-1-yl)-5-(naphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(phenylhydroxymethyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethyl)phenyl spirophosphate (0.005 mmol) represented by the above structural formula (1), Molecular sieves (50 mg) were injected with 1 mL of 1,2-dichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indolyl pyrrole carboxylate derivative in a yield of 93%. The product was characterized as follows:

[0133] Structural formula:

[0134]

[0135] Appearance: white solid;

[0136] mp116-118℃;

[0137] Optical purity: 96%ee;

[0138] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)8.198min,t R (major)6.888min;

[0139] Optical rotation: [α] D 20 =-19.375°(c 1.00,CH2Cl2);

[0140] 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 8.13 (s, 1H), 7.89 (d, J = 9.8Hz, 2H), 7.84–7.72 (m, 4H),7.65(dd,J=8.5,1.8Hz,1H),7.55(d,J=8.3Hz,2H),7.47–7.33(m,5H),7.30(t,J= 7.4Hz,1H),7.22(d,J=6.8Hz,1H),7.19–7.08(m,5H),6.77–6.73(m,1H),6.65(d,J=2 .8Hz,1H),5.32(s,1H),4.27(q,J=7.1Hz,2H),3.70(s,3H),1.31(t,J=7.1Hz,3H)ppm;

[0141] HRMS m / z (ESI + ):Calculated value C 43 H 34 N2NaO3([M+Na] + )649.2417, detected value 649.2465.

[0142] Example 10

[0143] 3-(2-methoxynaphthalen-1-yl)-1H-indole (0.05 mmol), ethyl 4-(hydroxy(naphthalen-1-yl)methyl)-1H-pyrrole-2-carboxylate (0.06 mmol), (S)-3,5-bis(trifluoromethylphenyl)spirophosphoric acid (0.005 mmol) represented by the above structural formula (1) were added to the reaction flask. Molecular sieves (50 mg) were injected with 1 mL of monofluorodichloroethane and reacted at -20°C for 24 hours. After the reaction was complete, silica gel column chromatography was performed directly using dichloromethane / petroleum ether = 1:10 as the eluent to obtain the corresponding optically active aryl binaphthyl indolyl pyrrole carboxylate derivative in a yield of 91%. The product was characterized as follows:

[0144] Structural formula:

[0145]

[0146] Appearance: white solid;

[0147] mp126-128℃;

[0148] Optical purity: 83%ee;

[0149] HPLC analysis conditions: (Dasero chiral column, the same below) Chiralpak IB-3 (n-hexane / i-PrOH=85 / 15, 1.0mL / min), t R (minor)8.285min,t R (major)7.212min;

[0150] Optical rotation: [α] D 20 =-20.572°(c 1.00,CH2Cl2);

[0151] 1 H NMR (400MHz, CDCl3) δ8.87(s,1H),8.07(s,1H),7.89(d,J=8.5Hz,1H),7.81–7.74(m,3H ),7.71(dd,J=7.7,1.8Hz,1H),7.49–7.45(m,1H),7.42–7.34(m,3H),7.32–7.21(m,3H) ,7.20–7.06(m,4H),6.98(ddd,J=7.9,6.9,1.0Hz,1H),6.60(t,J=2.1Hz,1H),6.32(t,J =2.3Hz,1H),6.00(s,1H),4.21(q,J=7.1Hz,2H),3.32(s,3H),1.27(t,J=7.1Hz,3H)ppm;

[0152] HRMS m / z (ESI + ):Calculated value C 37 H 30 N2NaO3([M+Na] + )573.2149, detected value 573.2051.

[0153] Example 11

[0154] Pharmacological activity test, cytotoxicity assay.

[0155] 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. The cells were cultured in an incubator at 37°C containing 5% carbon dioxide.

[0156] The cytotoxicity of the compounds was assessed using an MTT assay using PC-3 cells. Human prostate cancer cells (PC-3) were seeded in 96-well plates at a density of 10,000 cells per well, with 200 μL of full culture medium added to each 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 dead control group, 200 μL of PEI aqueous solution (25 kD, 2 mg / mL) was added, while for the live control group, 200 μL of serum-free culture medium was added. The cell plates were incubated in a 37°C incubator with 5% CO2 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 incubated in a 37°C incubator with 5% CO2 for an additional 4 hours. The supernatant was then removed, and 100 μL of DMSO was added to each well. The culture plate was shaken for 2 min and the optical density (OD) value was read at a wavelength of 570 nm using a microplate reader.

[0157] Viability=([OD] experimenta l-[OD] blank ) / ([OD] control -[OD] blank )×100%

[0158] The test results showed that the half-inhibitory concentration IC of the compound prepared in Example 7 on PC-3 was 50 =12 μg / ml, showing potential anti-cancer value. Furthermore, the compounds produced by the present invention all have an indole-pyrrole triaryl structure, which is the core skeleton of a series of important biologically active natural products, such as reserpine (which has antihypertensive effects) and ergot alkaloids (which can be used for postpartum hemostasis and migraine research). This will have important implications for the synthesis of analogs of these natural products.

Claims

1. An aryl binaphthyl indole pyrrole carboxylate derivative, characterized in that: It is a left-handed or right-handed optically active compound or its racemate having the following structural formula: In the formula: R1 is selected from methyl, ethyl, benzyl, propyl, butyl, trifluoromethyl; R2 is selected from hydrogen, fluorine, methyl, phenyl, or forms a naphthyl group with the phenyl group; R3 is selected from hydrogen, phenyl, methoxy, fluorine, naphthyl, substituted phenyl, and the substituent is selected from halogen, methyl or ethyl.

2. The aryl binaphthyl indole pyrrole carboxylate derivative according to claim 1, characterized in that The structural formula is selected from one of the following structural formulas:

3. The method for preparing the aryl binaphthyl indole pyrrole carboxylate derivative according to claim 1, characterized in that: The method comprises using a benzyl alcohol pyrrole carboxylate compound and an indole compound as raw materials, using 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid as a catalyst, reacting in an organic solvent for 10-24 hours, and purifying to obtain an aryl binaphthyl indole pyrrole carboxylate derivative; The 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid catalyst is a compound having the structural formula (1), which can be a left-handed or right-handed optically active form or a racemic form: The structure of the benzyl alcohol pyrrole carboxylate compound is shown in the following formula (2): The structure of the indole compound is shown in the following formula (3):

4. The method for preparing an aryl binaphthyl indole pyrrole carboxylate derivative according to claim 3, wherein: The benzyl alcohol pyrrole carboxylate compound is selected from one of the following compounds:

5. The method for preparing an aryl binaphthyl indole pyrrole carboxylate derivative according to claim 3, wherein: The indole compound is selected from one of the following compounds:

6. The method for preparing an aryl binaphthyl indole pyrrole carboxylate derivative according to claim 3, wherein: The organic solvent is ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, benzene, chloroform, tetrahydrofuran, n-hexane, methanol, acetone or monofluorodichloroethane.

7. The method for preparing an arylbinaphthyl indole pyrrole carboxylate derivative according to claim 3, wherein: The molar ratio of the benzyl alcohol pyrrole carboxylate compound to the indole compound is 1.2:1, and the molar ratio of the 3,5-bis(trifluoromethyl)phenyl spirocyclic phosphoric acid catalyst to the indole compound is 1:10; and the reaction temperature is -20°C.

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