A dihydroindole compound and a synthetic method and application thereof

Abstract

The application discloses a dihydroindole compound and a synthesis method and application thereof, and relates to a dihydroindole compound obtained by taking o-aminobenzaldehyde and allyl carbonate as reaction raw materials and under the mediation of an organic phosphine reagent. Advantages of the application include: high reaction efficiency, high yield, cheap, stable, and non-irritating smell of the organic phosphine reagent, no need to add an oxidizing or reducing agent, relatively mild conditions, no need to use a transition metal as a catalyst in the reaction, economy and practicability, environmental friendliness, easy preparation of a reaction substrate, high reaction efficiency after reaction amplification, and practical value. The compound has significant anti-proliferation effect on all tested human pancreatic cancer cells (PANC-1) in a growth period, and has certain anticancer activity.

Description

Technical Field

[0001] This invention belongs to the field of organic compound process application technology, specifically involving dihydroindole compounds and their efficient and convenient synthesis methods, as well as their application in producing anti-proliferative effects on PANC-1 cells. Background Technology

[0002] Dihydroindole, obtained by adding hydrogen at the 2,3 positions of indole, is an aromatic bicyclic organic heterocyclic compound whose core skeleton is widely found in natural products and drug molecules. For example, in the development of new energy sources, dyes containing the dihydroindole structure can be used as photosensitizers for solar cells. Y. Chen et al. used electron-rich fluorenylindole groups as donors for organic dyes. The strong electron-donating properties of the fluorenylindole group in the dye give it excellent panchromatic absorption and light-harvesting properties. Ren and his colleagues overcame the limitations of current commercial dyes for LD imaging and developed the tict-based fluorescent probe DCQTB. Meanwhile, dihydroindole derivatives also have good pharmacological and physiological activities. In addition to anticonvulsant and anti-inflammatory activities, C. Bao and Radchenko et al. also described that perindopril containing the dihydroindole structure can significantly inhibit the pressor response of exogenous angiotensin I and can be used to treat hypertension and chronic heart failure. Yahiya Y. Syed et al. also found that daily single-tablet perindopril / indapamide / amlodipine provided very good blood pressure control in patients with uncontrolled hypertension, and was generally well tolerated. L. Fan and Mahdavi et al. confirmed that dihydroindole derivatives also have good hypoglycemic activity, and Morris et al. synthesized dihydroindole derivatives and found that they had certain antibacterial effects. Kawahara et al. reported that Silodosin can inhibit the growth of bladder cancer cells by inactivating ELK1, while enhancing the cytotoxic activity of gemcitabine.

[0003]

[0004] Developing a simplified synthetic strategy for this skeleton has been a topic of great interest in the organic synthesis community. However, mediated methods for synthesizing this skeleton are rarely reported, and its synthesis remains highly challenging. The goal of this invention is to design a simple and practical route to construct this skeleton. Organophosphines are characterized by the initial nucleophilic addition of phosphine to electrophilic initiators containing carbon-carbon multiple bonds, typically under mild conditions, to generate reactive zwitterionic intermediates. These intermediates can then be used to construct functionalized carbocyclic and heterocyclic structures through ylide formation, which has important applications in drug design and natural product synthesis. Therefore, this invention resolves the parent structure into anthranilaldehyde and allyl carbonate, and constructs the parent structure via phosphine-mediated synthesis. Summary of the Invention

[0005] This invention innovatively provides an efficient method for constructing dihydroindole skeletons. The inventors discovered that dihydroindole is a unique class of compounds containing an indole skeleton, possessing characteristics such as stability and ease of preparation. Therefore, this invention designs a reaction method for preparing dihydroindole compounds by reacting o-aminobenzaldehyde with allyl carbonate.

[0006] This invention proposes a method for synthesizing dihydroindole compounds. Under organophosphorus conditions, o-aminobenzaldehyde and allyl carbonate are used as reactants in a reaction solvent, effectively achieving the corresponding transformation to prepare dihydroindole compounds as shown in formula (III). The reaction process is shown in the following reaction formula (a):

[0007]

[0008] In the above reaction equation, R 1 It is methyl, benzene ring, naphthalene ring, or substituted benzene ring; R 2 It is a hydrogen or halogen atom, methyl, methoxy, nitro, or cyano substitution; R 2 The position on the benzene ring is not fixed; R 3 It is a C1-C10 chain alkyl or aryl alkane.

[0009] Preferably, R 1 It is selected from any one of methyl, phenyl, mesitylene, 4-tolyl, 4-biphenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, and 1-naphthalene.

[0010] R 2 It is selected from any one of hydrogen, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-methylphenyl, 5-fluorophenyl, 5-chlorophenyl, 5-bromophenyl, 5-trifluoromethylphenyl, 5-methoxyphenyl, 5-methylphenyl, 5-nitrophenyl, 4-cyanophenyl, and 4-tert-butylphenyl.

[0011] R 3 It is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclohexyl, and benzyl.

[0012] As shown in reaction formula (a) above, the present invention utilizes o-aminobenzaldehyde as shown in formula (I) and allyl carbonate as reaction raw materials, and reacts in a reaction solvent under the action of organophosphorus reagent to obtain dihydroindole compounds as shown in formula (III).

[0013] In this invention, the ratio of the starting material o-aminobenzaldehyde (as shown in formula (I)) to the raw material allyl carbonate (as shown in formula (II)) is 1:1.5-1:3. Preferably, the ratio is 1:1.5.

[0014] In this invention, the solvent is any one or any combination of dichloromethane, dichloroethane, trichloromethane, tetrahydrofuran, and toluene. Preferably, the solvent is toluene.

[0015] The reaction temperature is 20-30℃.

[0016] The organophosphorus reagent is Ph3P, Bu3P, PhMe2P, PhEt2P, PhCy2P, Ph2CyP, Ph2MeP, Ph2EtP, or Ph2PrP. The acid is any one of benzoic acid, anthranilic acid, 2-iodobenzoic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, 4-nitrobenzoic acid, 2,5-dinitrobenzoic acid, phenol, p-nitrophenol, or acetic acid.

[0017] The synthetic reaction of this invention includes the following steps:

[0018] The reaction described in equation (a) includes the following steps: adding o-aminobenzaldehyde, organophosphine, acid, toluene, and allyl carbonate to a reaction vessel, stirring the reaction at 20-30°C to obtain the dihydroindole compound shown in formula (III).

[0019] In a specific example, as shown in equation (a), the synthesis reaction of this invention involves adding o-aminobenzaldehyde, an organophosphorus compound, an acid, an allyl carbonate, and a solvent to reaction flask A. The reaction system is stirred at 20-30°C for 4-8 hours. After the reaction is complete, the mixture is concentrated and separated by column chromatography to obtain the target product.

[0020] This invention also proposes dihydroindole compounds of formula (III) prepared according to the above-described synthetic method of this invention.

[0021]

[0022] Among them, R 1 It is methyl, benzene ring, naphthalene ring, or substituted benzene ring; R 2 It is a hydrogen or halogen atom, methyl, methoxy, nitro, or cyano substitution; R 3 It is an alkyl or aryl-containing alkane.

[0023] The present invention also proposes a method for using the dihydroindole compounds represented by formula (III) above in the synthesis of potential drugs containing an indole skeleton.

[0024] The present invention has the following advantages: a) high efficiency and high yield; b) organophosphorus compounds are inexpensive, readily available, stable, and odorless; c) no additional oxidizing or reducing agents are required in the reaction, and the conditions are relatively mild; d) no transition metals are required as catalysts in the reaction, making it economical, practical, and environmentally friendly; e) the reaction substrates are easy to prepare; f) the reaction efficiency is high after scale-up, making it practically valuable.

[0025] The reaction sequence of this invention may begin with the in-situ formation of allyl phosphorus ylide from organophosphorus and allyl carbonate, followed by a sterically favorable α-addition to the aldehyde group on o-aminobenzaldehyde. Ring closure is ultimately achieved via a Michael addition-elimination process through proton transfer and double bond migration to produce the cyclized product of formula (III). In this process, benzoic acid facilitates the departure of the OBoc anionic group from the allyl carbonate, which then forms a new hydrogen bond with the hydrogen on the amino group. If the acidity is too strong, acid-base neutralization is readily achieved to tert-butanol.

[0026] This invention uses readily prepared o-aminobenzaldehyde and allyl carbonate compounds as reactants to yield dihydroindole compounds under organophosphorus-mediated reaction. The reaction is simple to operate, the reaction conditions are relatively mild, and it is suitable for large-scale industrial production. Detailed Implementation

[0027] The present invention will be further described in detail below with reference to specific embodiments. However, the scope of protection of the present invention is not limited to these embodiments. All variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention and are protected by the appended claims. The processes, conditions, reagents, experimental methods, etc., used to implement the present invention, except as specifically mentioned below, are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations. The data given in the following embodiments include specific operations, reaction conditions, and products. Product purity was determined by NMR.

[0028] The synthesis reaction of the aryl alkyl sulfide compound of the present invention includes the following steps:

[0029] As shown in equation a: o-aminobenzaldehyde, organophosphorus compounds, acid, toluene, and allyl carbonate are added to a reaction vessel and stirred at 20-30°C to obtain dihydroindole compounds as shown in formula (III). The product is then concentrated and separated by column chromatography.

[0030] The dihydroindole compounds shown in Table 1 are all products synthesized by the method of this invention, and no published literature has disclosed these compounds.

[0031] Table 1 Novel dihydroindole compounds of the present invention

[0032]

[0033]

[0034]

[0035] Example 1

[0036]

[0037] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 1 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 87.7%; 1 H NMR (400MHz, CDCl3) δ7.73(d,J=8.1Hz,1H),7.60–7.54(m,2H),7.25–7.20(m,1H),7.18(d,J=8.1Hz,2H),7.05–6.97(m,2H),6.34(s,1H),6.04 (s,1H),5.17–5.11(m,1H),4.30–4.16(m,2H),3.10(dd,J=16.5,10.2Hz,1H),2.61(dd,J=16.5,3.0Hz,1H),2.36(s,3H),1.29(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.77,144.05,141.55,140.10,134.68,131.09,129.65,127.82,127.09 ,125.66,125.21,124.88,116.96,61.27,60.96,36.21,21.54,14.13.HRMS(ESI)m / z:calcd.for C 20 H 21 NNaO4S + [M+Na] + :394.1083.Found:394.1098.

[0038] Example 2

[0039]

[0040] Benzyl-protected o-aminobenzaldehyde (26.1 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 2 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 66.1%; 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=8.1Hz, 1H), 7.76–7.72 (m, 2H), 7.56–7.50 (m ,1H),7.44–7.37(m,2H),7.25–7.19(m,1H),7.07–7.01(m,1H),7.01–6.96(m ,1H),6.34(s,1H),6.03(s,1H),5.21–5.10(m,1H),4.30–4.16(m,2H),3.08( dd,J=16.6,10.2Hz,1H),2.62(dd,J=16.6,3.0Hz,1H),1.29(t,J=7.1Hz,4H). 13 C NMR (100MHz, CDCl3) δ165.71,141.40,139.99,137.58,133.17,131.06,129.03,127.85,1 27.04,125.67,125.25,125.00,116.91,61.32,60.98,36.15,14.11.HRMS(ESI)m / z:Calcd for C 19 H 19 NNaO4S + [M+Na] + :380.0927.Found:380.0935.

[0041] Example 3

[0042]

[0043] o-Aminobenzaldehyde (33.7 mg, 0.1 mmol, 1.0 equiv.) protected by biphenylbenzenesulfonate and toluene (2.0 mL) were added to a reaction tube. Then, organophosphorus reagent Ph₂CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.) were added, followed by ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 3 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 51.2%; 1 H NMR (400MHz, CDCl3) δ7.80–7.73(m,3H),7.63–7.59(m,2H),7.56–7.52(m,2H) ,7.47–7.43(m,2H),7.42–7.37(m,1H),7.29–7.24(m,1H),7.07–7.00(m,2H), 6.36(s,1H),6.06(d,J=1.5,1H),5.22–5.17(m,1H),4.31–4.17(m,2H),3.16( dd,J=16.6,10.2Hz,1H),2.65(dd,J=16.6,3.1Hz,1H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.76,145.96,141.46,140.07,138.99,136.17,131.09,129.01,128.53,127.89,1 27.59,127.58,127.23,125.71,125.32,125.01,116.91,61.35,61.00,36.25,14.14.HRMS(ESI)m / z:Calcd for C 25 H 23 NNaO4S + [M+Na] + :456.1240.Found:456.1240.

[0044] Example 4

[0045]

[0046] o-Aminobenzaldehyde (29.1 mg, 0.1 mmol, 1.0 equiv.) protected by p-methoxybenzenesulfonate and toluene (2.0 mL) were added to a reaction tube. Then, organophosphorus reagent Ph₂CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.) were added, followed by ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 4 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 88%; 1 H NMR(400MHz, CDCl3)δ7.73(d,J=8.1Hz,1H),7.65–7.60(m,2H),7.25–7.20(m,1H) ),7.06–6.98(m,2H),6.88–6.83(m,2H),6.34(s,1H),6.05(s,1H),5.16–5.10((m 1H), 4.24 (m, 2H), 3.81 (s, 3H), 3.11 (dd, J=16.6, 10.2Hz, 1H), 2.62 (dd, J=16.6, 3.1Hz, 1H), 1.30 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ165.80,163.26,141.64,140.14,131.15,129.27,129.20,127.79,125.65,1 25.21,124.88,117.03,114.17,61.24,60.95,55.53,36.25,14.13,1.01.HRMS(ESI)m / z:Calcdfor C 20 H 21 NNaO5S + [M+Na] + :410.1033.Found:410.1025.

[0047] Example 5

[0048]

[0049] 1-Naphthylbenzenesulfonated o-aminobenzaldehyde (31.1 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 5 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 61.7%; 1 H NMR (400MHz, CDCl3) δ8.56(d,J=8.4Hz,1H),8.26–8.19(m1H),8.02(d,J=8.1Hz,1H),7.88–7.83(m 1H),7.66(d,J=8.1Hz,1H),7.53–7.45(m,3H),7.24–7.16(m 1H),7.02–6.91(m,2H),6.27(s,1H),5.99(d,J=1.4Hz,1H),5.36–5.29(m 1H), 4.26–4.13 (m, 2H), 3.01 (dd, J=16.4, 9.9Hz, 1H), 2.60 (dd, J=16.4, 2.2Hz, 1H), 1.27 (t, J=7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ165.60,141.59,139.51,134.60,134.26,133.78,130.68,130.35,128.75,128.69,128.03 ,127.64,126.85,125.67,125.31,124.68,124.03,116.62,61.64,60.93,36.09,14.09.HRMS(ESI)m / z:Calcdfor C 23 H 21 NNaO4S + [M+Na] + :430.1083.Found:430.1087.

[0050] Example 6

[0051]

[0052] o-Aminobenzaldehyde (30.3 mg, 0.1 mmol, 1.0 equiv.) protected by trimethylbenzenesulfonate and toluene (2.0 mL) were added to a reaction tube. Then, organophosphorus reagent Ph₂CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.) were added, followed by ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 8 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 6 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 70%. 1 H NMR (400MHz, CDCl3) δ7.21(d,J=7.6Hz,1H),7.13–7.07(m,2H),6.99–6.94(m,1H),6.92(s,2H),6.19(s,1H),5.86(s,1H),5.30–5.25(m ,1H),4.25–4.12(m,2H),3.52(dd,J=16.3,10.0Hz,1H),2.76(dd,J=16.3,2.4Hz,1H),2.57(s,6H),2.28(s,3H),1.26(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.57,142.98,142.39,140.39,139.49,132.90,132.18,130.08,127. 56,125.37,123.79,115.17,61.04,60.89,36.53,23.02,20.96,14.07.HRMS(ESI)m / z:Calcd for C 22 H 25 NNaO4S + [M+Na] + :422.1397.Found:422.1387.

[0053] Example 7

[0054]

[0055] 2-Bromobenzenesulfonated o-aminobenzaldehyde (33.9 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 7 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 54.9%; 1 H NMR (400MHz, CDCl3) δ8.23 (dd, J=7.9, 1.7Hz, 1H), 7.67 (d, J=7.7Hz, 1H), 7.47–7. 41(m,1H),7.39–7.33(m,1H),7.28(s,1H),7.12–7.04(m,1H),6.97–6.91(m,1H), 6.32(s,1H),6.02(d,J=1.4Hz,1H),5.75(d,J=10.0Hz,1H),4.32–4.17(m,2H),3. 62(dd,J=16.3,10.0Hz,1H), 2.81(dd,J=16.3,2.0Hz,1H), 1.31(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.58,140.67,139.83,137.95,135.68,134.01,133.30,129.94,127.50,1 27.41,125.57,125.31,123.92,120.10,114.17,63.11,60.98,35.96,14.14.HRMS(ESI)m / z:Calcd for C 19 H 18 BrNNaO4S + [M+Na] + :458.0032.Found:458.0035.

[0056] Example 8

[0057]

[0058] 3-Bromobenzenesulfonated o-aminobenzaldehyde (33.9 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 8 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 55.17%; 1 H NMR(400MHz, CDCl3)δ7.85(t,J=1.8,1H),7.71(d,J=8.1Hz,1H),7.67–7.60(m,2H),7.30–7.22(m,2H),7.09–7.01(m,2H),6.35(s,1H),6.0 1(d,J=1.5,1H),5.19–5.12(m,1H),4.31–4.17(m,2H),3.16(dd,J=16.6,10.2Hz,1H),2.67(dd,J=16.6,3.0Hz,1H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.61,141.08,139.95,139.57,136.21,130.98,130.52,130.03,128.03,125 .72,125.54,125.44,125.28,123.06,116.67,61.56,61.05,36.22,14.12.HRMS(ESI)m / z:Calcdfor C 19 H 18 BrNNaO4S + [M+Na] + :458.0032.Found:458.0038.

[0059] Example 9

[0060]

[0061] o-Aminobenzaldehyde (30.6 mg, 0.1 mmol, 1.0 equiv.) protected by p-nitrobenzenesulfonate and toluene (2.0 mL) were added to a reaction tube. Then, organophosphorus reagent Ph₂CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.) were added, followed by ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 9 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 62.7%; 1 H NMR (400MHz, CDCl3) δ8.32–8.21(m,2H),7.94–7.85(m,2H),7.74(d,J=8.1 Hz,1H),7.30–7.26(m,1H),7.11–7.05(m,1H),7.05–7.01(m,1H),6.36(s, 1H),6.02(d,J=1.4Hz,1H),5.20–5.11(m,1H),4.32–4.16(m,2H),3.12(dd ,J=16.7,10.2Hz,1H),2.68(dd,J=16.7,3.1Hz,1H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.51,150.38,143.16,140.54,139.68,130.89,128.30,128.19 ,125.82,125.68,124.29,116.61,61.58,61.17,36.15,14.12.HRMS(ESI)m / z:Calcdfor C 19 H 18 N2NaO6S + [M+Na] + :425.0778.Found:425.0787.

[0062] Example 10

[0063]

[0064] Methanesulfonated o-aminobenzaldehyde (19.9 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 10 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 61.7%; 1 H NMR (400MHz, CDCl3) δ7.52(d,J=8.0Hz,1H),7.26–7.21(m,1H),7.17(d,J=7.4Hz,1H),7.11–7.04(m,1H),6.34(s,1H), 5.99(s,1H),5.30–5.18(m,1H),4.33–4.17(m,2H),3.70(dd,J=16.7,10.5Hz,1H),2.87(m,4H),1.30(t,J=7.1Hz,3H). 13 CNMR(100MHz, CDCl3)δ165.66,141.39,140.41,130.23,128.18,125.57,124.83,115.51,61.57,61.07,36.63,36.18,14.15.HRMS(ESI)m / z:Calcdfor C 14 H 17 NNaO4S + [M+Na] + :318.0770.Found:318.0770.

[0065] Example 11

[0066]

[0067] 4-Fluoro-o-aminobenzaldehyde (29.3 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph₂CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 11 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 50.6%;1 H NMR(400MHz, CDCl3)δ7.62(d,J=8.2Hz,1H),7.50–7.44(m,1H),7.22(d,J=8.0Hz,1H),7.03–6.87(m,1H),6.75–6.67(m,1H),6.35(s,1H),6.01 (s,1H),5.20–5.14(m,1H),4.37–4.11(m,1H),3.10(dd,J=16.3,10.4Hz,1H),2.60(dd,J=16.3,3.2Hz,1H),2.38(s,3H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.63,162.61(d,J=242Hz),144.38,142.94(d,J=11Hz),140.02,134.57,129.80,127.11,126.23(d,J=3H z),125.82,125.72(d,J=3Hz),111.45(d,J=23Hz),104.73(d,J=28Hz),62.24,61.02,35.62,21.56,14.11.HRMS(ESI)m / z:Calcd for C 20 H 20 FNNaO4S + [M+Na] + :412.0989.Found:412.0989.

[0068] Example 12

[0069]

[0070] 4-Chloro-o-aminobenzaldehyde (30.90 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.), and finally ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 9 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 12 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 48.2%; 1H NMR (400MHz, CDCl3) δ7.75 (d, J = 1.9 Hz, 1H), 7.63–7.58 (m, 2H), 7.23 (d, J = 8. 0Hz,2H),7.00(dd,J=8.0,1.9Hz,1H),6.91(d,J=8.0Hz,1H),6.35(s,1H),6.0 1(d,J=1.5Hz,1H),5.18–5.11(m,1H),4.30–4.15(m,2H),3.08(dd,J=16.7,1 0.4Hz, 1H), 2.60 (dd, J = 16.7, 3.2Hz, 1H), 2.38 (s, 3H), 1.29 (t, J = 7.1Hz, 3H). 13 C NMR (100MHz, CDCl3) δ165.60,144.41,142.83,139.86,134.51,133.49,129.84,129.48,127. 09,125.94,125.81,124.86,116.99,61.91,61.05,35.78,21.58,14.12.HRMS(ESI)m / z:Calcd for C 20 H 20 ClNNaO4S + [M+H] + :406.0874.Found:406.0863.

[0071] Example 13

[0072]

[0073] 4-Bromo-o-aminobenzaldehyde (35.3 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 9 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 13 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 36.7%; 1H NMR (400MHz, CDCl3) δ7.90 (d, J=1.8Hz, 1H), 7.63–7.59 (m, 2H), 7.23 (d, J=8. 1Hz,2H),7.15(dd,J=7.9,1.8Hz,1H),6.86(d,J=7.9Hz,1H),6.35(s,1H),6.0 1(d,J=1.5Hz,1H),5.16–5.11(m,1H),4.30–4.16(m,2H),3.06(dd,J=16.8,1 0.3Hz, 1H), 2.59 (dd, J = 16.8, 3.2Hz, 1H), 2.38 (s, 3H), 1.30 (t, J = 7.1Hz, 3H). 13 CNMR (100MHz, CDCl3) δ165.62,144.47,143.05,139.85,134.49,130.10,129.88,127.83,127. 10,126.42,125.87,121.20,119.81,61.82,61.09,35.86,21.62,14.15.HRMS(ESI)m / z:Calcd for C 20 H 20 BrNNaO4S + [M+Na] + :472.0189.Found:472.0185.

[0074] Example 14

[0075]

[0076] 5-Bromo-o-aminobenzaldehyde (35.3 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, ethyl allyl carbonate (34.52 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the product 14 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 47.2%; 1H NMR (400MHz, CDCl3) δ7.60(d,J=8.5Hz,1H),7.57(d,J=8.1Hz,2H),7.36–7.31(m,1H),7.21(d,J=8.0Hz,2H),7.11(s,1H),6.34(s,1H),6.01( s,1H),5.47–4.92(m,1H),4.30-4.15(m,1H),3.08(dd,J=16.8,10.3Hz,1H),2.61(dd,J=16.8,3.1Hz,1H),2.38(s,2H),1.29(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.58,144.39,140.87,139.80,134.39,133.46,130.82,129.82,128. 32,127.07,125.85,118.23,117.67,61.58,61.05,35.95,21.57,14.12.HRMS(ESI)m / z:Calcd forC 20 H 20 BrNNaO4S + [M+Na] + :472.0189.Found:472.0193.

[0077] Example 15

[0078]

[0079] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, tert-butylallyl carbonate (38.72 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 9 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 15 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 84.6%; 1H NMR(400MHz, CDCl3)δ7.74(d,J=8.1Hz,1H),7.60–7.54(m,2H),7.26–7.21(m,1H) ),7.18(d,J=8.0Hz,2H),7.06–6.98(m,2H),6.33(s,1H),6.04(s,1H),5.17–5.11 (m,1H),4.23–4.12(m,2H),3.09(dd,J=16.6,10.2Hz,1H),2.61(dd,J=16.6,3.1H z,1H),2.36(s,3H),1.70–1.62(m,2H),1.43–1.37(m,2H),0.95(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ165.49,143.73,141.23,139.78,134.32,130.75,129.32,127.49,126.77,125 .29,124.89,124.57,116.66,64.52,60.95,35.89,30.23,21.22,18.88,13.40.HRMS(ESI)m / z:Calcd for C 22 H 25 NO4S + [M+Na] + :422.1397.Found:422.1381.

[0080] Example 16

[0081]

[0082] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, benzyl allyl carbonate (43.85 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 16 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 46.6%; 1H NMR(400MHz, CDCl3)δ7.73(d,J=8.0Hz,1H),7.59–7.54(m,2H),7.39–7.32(m, 5H),7.25–7.20(m,1H),7.17(d,J=8.0Hz,2H),7.05–7.00(m,1H),7.00–6.97(m ,1H),6.39(s,1H),6.08(d,J=1.6Hz,1H),5.22(d,J=2.9Hz,2H),5.18–5.13(m, 1H), 3.09 (dd, J=16.6, 10.1Hz, 1H), 2.62 (dd, J=16.6, 3.1Hz, 1H), 2.36 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.59,144.08,141.52,139.89,135.60,134.61,130.99,129.65,128.58,128.29,1 28.10,127.85,127.10,126.23,125.23,124.93,116.99,66.71,61.22,36.22,21.54.HRMS(ESI)m / z:Calcd for C 25 H 23 NNaO4S + [M+Na] + :456.1240.Found:456.1242.

[0083] Example 17

[0084]

[0085] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, isopropyl allyl carbonate (36.62 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 17 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 51.2%; 1H NMR (400MHz, CDCl3) δ7.73(d,J=8.1Hz,1H),7.60–7.55(m,2H),7.26–7.20(m,1H),7.18(d,J=8.1Hz,2H),7.05–6.98(m,2H),6.31(s,1H),6.01(s, 1H),5.17–5.12(m,1H),5.11–5.04(m,1H),3.09(dd,J=16.5,10.2Hz,1H) ,2.62(dd,J=16.5,3.1Hz,1H),2.36(s,3H),1.26(dd,J=6.3,2.9Hz,6H). 13 C NMR (100MHz, CDCl3) δ165.25,144.03,141.61,140.43,134.75,131.18,129.63,127.78,127.10, 125.43,125.18,124.85,116.98,68.51,61.39,36.19,21.78,21.75,21.53.HRMS(ESI)m / z:Calcd forC 21 H 23 NNaO4S + [M+Na] + :408.1240.Found:408.1234.

[0086] Example 18

[0087]

[0088] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, benzyl allyl carbonate (42.62 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 18 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 52.7%; 1H NMR(400MHz, CDCl3)δ7.74(d,J=8.1Hz,1H),7.64–7.54(m,2H),7.26–7.21( m,1H),7.19(d,J=8.1Hz,2H),7.07–6.97(m,2H),6.33(s,1H),6.02(s,1H), 5.20–5.11(m,1H),4.94–4.82(m,1H),3.09(dd,J=16.6,10.2Hz,1H),2.63( dd,J=16.6,3.1Hz,1H),2.37(s,3H),1.90–1.69(m,4H),1.57–1.37(m,6H). 13 C NMR (100MHz, CDCl3) δ165.14,144.07,141.62,140.48,134.71,131.21,129.67,127.83,127.13,125.44 ,125.23,124.91,117.07,73.23,61.41,36.24,31.51,31.45,25.38,23.60,21.58.HRMS(ESI)m / z:Calcd for C 24 H 27 NNaO4S + [M+Na] + :448.1553.Found:448.1551.

[0089] Example 19

[0090]

[0091] o-Aminobenzaldehyde (27.5 mg, 0.1 mmol, 1.0 equiv.) and toluene (2.0 mL) were added to a reaction tube, followed by organophosphorus reagent Ph2CyP (32.2 mg, 1.2 equiv.) and benzoic acid (2.4 mg, 0.2 equiv.). Finally, tert-butylallyl carbonate (38.72 mg, 0.15 mmol, 1.5 equiv.) was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product 19 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 20:1:1). Yield: 86.9%; 1H NMR (400MHz, CDCl3) δ7.72(d,J=8.2Hz,1H),7.60–7.53(m,2H),7.25–7.20(m,1H),7.17(d,J=8.0Hz,2H),7.05–6.97(m,2H),6.2 2(s,1H),5.96(s,1H),5.16–5.08(m,1H),3.05(dd,J=16.6,10.2Hz,1H),2.59(dd,J=16.6,3.0Hz,1H),2.35(s,3H),1.48(s,9H). 13 C NMR (100MHz, CDCl3) δ165.03,144.00,141.60,141.29,134.72,131.27,129.61,127.76,127.08 ,125.19,124.87,124.78,117.10,81.42,61.41,36.21,28.05,21.53.HRMS(ESI)m / z:calcd.for C 22 H 25 NNaO4S + [M+Na] + :422.1397.Found:422.1409.

[0092] Example 20

[0093] Anticancer activity experiment

[0094] Human pancreatic cancer cells (PANC-1) at 5×10 3 Cells were seeded in wells and incubated overnight at 37°C in a 5% CO2 incubator. Cells were then treated with different concentrations of the compound, ranging from 5 to 150 μg / mL, for 48 hours. After treatment, cells were stained with 10 μL (5 mg / mL) MTT solution. The optical density (OD) of each well was measured at 570 nm using a microplate reader (reference wavelength: 620 nm). Cell viability was determined using the following formula: [(OD treated - OD blank) / (OD untreated - OD blank)] × 100%. Table 1 shows the results of the compound assay.

[0095] Table 1: Results of compound determination

[0096]

[0097] As can be seen from the table above, compound 11 exhibits the best anti-proliferative effect, with a concentration of 86.2144 μg / mL when the PANC-1 cell viability is 50%. Other compounds also show significant anti-proliferative effects. In the above embodiments of this application, compounds 2, 3, 4, 5, 6, 7, 8, 9, and 10 are structurally similar to compound 1; compounds 12, 13, and 14 are structurally similar to compound 11; and compounds 15, 16, 17, and 18 are structurally similar to compound 19. Therefore, those skilled in the art can predict that compounds with structures similar to 1, 11, and 19 will have significant anti-proliferative effects on PANC-1 cells.

Claims

1. A method for synthesizing dihydroindole compounds, characterized in that, Using o-aminobenzaldehyde of formula (1) and allyl carbonate of formula (II) as reactants, in the presence of acid and mediated by organophosphorus compounds, a dihydroindole compound as shown in formula (III) is obtained by reacting in a reaction solvent; the reaction process is shown in reaction formula (a). ； Among them, R 1 It is 4-MeOC6H4, 4-MeC6H4; R 2 It is hydrogen or F; R 3 It is ethyl or tert-butyl; The organophosphorus reagent is any one of Ph3P, Bu3P, PhMe2P, PhEt2P, PhCy2P, Ph2CyP, Ph2MeP, Ph2EtP, and Ph2PrP; The acid is any one of benzoic acid, anthranilic acid, 2-iodobenzoic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, 4-nitrobenzoic acid, 2,5-dinitrobenzoic acid, phenol, p-nitrophenol, and acetic acid.

2. The synthesis method according to claim 1, characterized in that, The reaction solvent is selected from any one or any combination of dichloromethane, dichloroethane, trichloromethane, tetrahydrofuran, and toluene.

3. The synthesis method as described in claim 1, characterized in that, In the reaction, the molar ratio of the raw material o-aminobenzaldehyde to allyl carbonate is 1:1.5-1:

3.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature is 20-30℃.

5. A dihydroindole compound prepared by the synthetic method according to any one of claims 1-4, characterized in that, Its structure is shown in equation (Ⅲ): Formula (Ⅲ); Among them, R 1 It is 4-MeOC6H4, 4-MeC6H4; R 2 It is hydrogen or F; R 3 It is ethyl or tert-butyl.

6. The use of the dihydroindole compound according to claim 5 in the preparation of a drug for treating pancreatic cancer, wherein the pancreatic cancer cells are pancreatic cancer ductal cells PANC-1.

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