A method for preparing 1,2-dihydroquinoline compounds

Abstract

The application belongs to the technical field of pharmaceutical chemical intermediates and related chemistry, and relates to a method for preparing 1,2-dihydroquinoline compounds. Specifically, 1,3- or 1,4-cycloalkenone and arylamine are used as raw materials, an organic acid or an inorganic acid is used as a catalyst, and the 1,2-dihydroquinoline compound is generated by heating and stirring in an organic solvent for a certain time. The application has the following advantages: 1,3-cycloalkenone and arylamine are both commercially available chemicals, which are stable in chemical properties and widely available; the catalytic reaction has excellent selectivity and can efficiently generate 1,2-dihydroquinoline compounds; the reaction step is high in economy and atom economy, and the byproduct is only water; the 1,2-dihydroquinoline compound synthesized by the method can be further functionalized to obtain various derivative compounds, and can be applied to the development and research of natural products, functional materials and fine chemicals.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical intermediates and related chemical technologies, and relates to a method for preparing 1,2-dihydroquinoline compounds. Specifically, using 1,3- or 1,4-cycloenone and aromatic amine as reactants, a skeleton rearrangement reaction occurs with excellent chemoselectivity under the action of a catalytic amount of acid, generating substituted 1,2-dihydroquinoline products. The reaction has extremely high atom economy. Background Technology

[0002] 1,2-Dihydroquinolines are an important class of organic skeletal structures, widely found in natural compounds and biologically active molecules [(a) JV Johnson, et al. J. Med. Chem. 1989, 32, 1942; (b) C.S. Reid, et al. Bioorg. Med. Chem. 2011, 19, 513; (c) B. Lockhart, et al. Eur. J. Pharmacol. 2001, 416, 59; (d) N. Yamada, S. et al. Biochem. Pharmacol. 1992, 44, 1211.]. Furthermore, 1,2-Dihydroquinolines are also important organic synthesis raw materials, used in the processing and synthesis of many metal ligands, drug molecules, functional materials, and other fine chemical products. Therefore, research on the efficient preparation of 1,2-dihydroquinoline compounds is of significant research importance.

[0003] Traditionally, the Skraup reaction is a common method for preparing 1,2-dihydroquinoline compounds [ME Theoclitou, et al. Tetrahedron Lett. 2002, 43, 3907.]. Transition metal-catalyzed arylamine-alkyne coupling reactions are also one of the efficient methods for synthesizing 1,2-dihydroquinoline compounds [Y MLuo, et al. Org. Lett. 2005, 7, 2675.]. However, these methods are generally only applicable to the synthesis of common 1,2-dihydroquinoline compounds, and the synthesis of cyclically substituted 1,2-dihydroquinoline compounds remains a challenging task. In this regard, using pre-functionalized substrates, 3,4-cyclic-1,2-dihydroquinoline compounds can be successfully synthesized under Lewis acid catalysis [C. Zhu, et al. Angew. Chem. Int. Ed. 2014, 53, 13532.]. For 1,2-phenocytic-1,2-dihydroquinoline compounds, gold-catalyzed coupling reactions can also be used [X.-Y. Liu, et al. Angew. Chem. Int. Ed. 2008, 47, 3805.]. However, there are currently few synthetic methods for 2,3-phenocytic-1,2-dihydroquinoline compounds. In 2006, Hartwig's group discovered that in the palladium-catalyzed coupling reaction of aromatic amines with cycloheptatriene, in addition to generating the expected tropane products, a small amount of 2,3-phenocytic-1,2-dihydroquinoline byproducts were also generated [N. Sakai, et al. J. Am. Chem. Soc. 2006, 128, 8134.]. However, this method requires the use of expensive metal catalysts and has poor selectivity for 2,3-phenocytic-1,2-dihydroquinoline products, resulting in low yields and limited practical value. Summary of the Invention

[0004] This invention provides a novel method for preparing 2,3-phenanthrocyclo-1,2-dihydroquinoline compounds. This method uses aromatic amines as raw materials, requires no transition metals or equivalent reaction promoters, and reacts with 1,3- or 1,4-cycloenones under the action of a catalytic amount of acid to obtain 2,3-phenanthrocyclo-1,2-dihydroquinoline compounds. The reactants are readily available, the catalytic system is simple, the reaction efficiency is high, and the reaction is economical.

[0005] The technical solution of the present invention:

[0006] The purpose of this invention is to develop an acid-catalyzed reaction system using inexpensive and readily available 1,3- or 1,4-cycloenones and aromatic amines as reactants, enabling the efficient synthesis of 2,3-fused-cyclo-1,2-dihydroquinoline via skeletal rearrangement. The synthetic route is as follows:

[0007]

[0008] The specific operating steps are as follows:

[0009] Under an atmosphere of argon, nitrogen, or air, an acid catalyst, an aromatic amine, and a cycloenone were added sequentially to a 10 mL sealed tube. A certain amount of solvent was then added to dissolve them. After sealing, the tube was stirred at a specific temperature for a certain period of time. After the reaction was complete, the reaction solvent was evaporated, and the target product 3 was obtained by column chromatography (mobile phase: petroleum ether / ethyl acetate).

[0010] The reactant cycloenone 1 can be a 1,3-cycloenone or a 1,4-cycloenone, and can be a seven-membered ring or an eight-membered ring;

[0011] The reactant aromatic amine 2 can be aniline, fused-ring aromatic amine, heterocyclic aromatic amine, wherein the substituent on the aryl group can be one or more of hydrogen, C1-C8 alkyl, cyano, ester, acyl, alkoxy, amino, thioether, halogen, and trifluoromethyl.

[0012] The amount of reactant aromatic amine 2 is 0.5-10 times the molar amount of cycloenone; the reaction temperature is between 60-140℃; and the reaction time is between 1-36h.

[0013] The acid catalyst used in the reaction is selected from one or more of the following: formic acid, acetic acid, pentanoic acid, benzoic acid, trifluoroacetic acid, diphenyl phosphate, dibenzyl phosphate, benzyl sulfonic acid, alkyl or halogen substituted benzyl sulfonic acid, camphor sulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, and phosphoric acid. P-Toluenesulfonic acid is preferred. The molar ratio of acid to cycloenone is 0.01-3, preferably 0.05-0.5.

[0014] The solvent used in the reaction is selected from one or more of the following solvents: methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, toluene, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide. The concentration of the cycloenone is preferably in the range of 0.05-5.0 mol / L.

[0015] The present invention has the following advantages:

[0016] This invention has the following advantages: aromatic amines are simple and readily available chemicals with wide sources; cycloenones are commercially available reagents with stable chemical properties; the reaction exhibits excellent selectivity, requires no transition metal catalyst, has a simple reaction system, and is easy to operate; the 1,2-dihydroquinoline compound synthesized by this reaction has a 2,3-fused ring structure, which is difficult to synthesize by other methods; the 1,2-dihydrofused ring quinoline compound synthesized by this method can be conveniently functionalized in one step to obtain various derivative compounds, which can be applied to the development and research of natural products, functional materials, and fine chemicals. Detailed Implementation

[0017] The present invention will be described below with specific embodiments, but the scope of protection of the present invention is not limited to these examples.

[0018] 1: Acid-catalyzed rearrangement reaction of aromatic amines with cycloenones

[0019] In an air atmosphere, acid (20 mol% relative to the amount of 1,3-cycloheptenone), 1,3-cycloheptenone (0.2 mmol, i.e., 1.0 molar equivalent), and 4-fluoroaniline (3.0 molar equivalent relative to the amount of 1,3-cycloheptenone) were added sequentially to a 10.0 mL sealed tube, followed by the addition of 1.0 mL of solvent. After sealing, the tube was stirred at 80°C to 120°C for 24 hours.

[0020] After the reaction was complete, 0.1 mmol (0.5 molar equivalent) of 4-fluorobiphenyl was added to the reaction solution as an internal standard, the solvent was evaporated, and the solution was analyzed by... 19 The yield of target product 3a was determined by FNMR, as detailed in Table 1.

[0021]

[0022] Table 1. Effects of catalyst, temperature, and solvent on the reaction

[0023]

[0024]

[0025] As shown in Table 1, the acid catalysts with stronger acidity exhibit better activity, with hydrochloric acid (HCl) showing the best performance (Examples 1-4). Isopropanol was the optimal solvent (Examples 4-9). The optimal reaction temperature was 100-120 degrees Celsius; decreasing the temperature resulted in a decrease in yield (Examples 9-11).

[0026] 2. Aromatic amine substrate types

[0027] Under a nitrogen atmosphere, hydrochloric acid (20 mol% relative to the amount of 1,3-cycloheptenone), 0.2 mmol (1.0 molar equivalent) of 1,3-cycloheptenone, and an aromatic amine (3.0 molar equivalent relative to the amount of 1,3-cycloheptenone) were added sequentially to a 10.0 mL sealed tube, followed by the addition of 1.0 mL of solvent. The tube was then sealed and stirred at 100 °C for 24 hours. After the reaction was complete, the solvent was evaporated to dryness, and the mixture was directly separated by column chromatography using a mobile phase of petroleum ether / ethyl acetate with a volume ratio of 10:1 to 20:1.

[0028]

[0029] 7-Fluoro-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3a)

[0030] 33.2mg,82%yield,yellow solid,melting point:80–81℃,R f =0.38(PE / EA=20 / 1).

[0031] 1 H NMR(400MHz,CDCl3)δ6.67–6.61(m,2H),6.42(dd,J=8.1,4.7Hz,1H),6.08(t,J=2.2Hz,1H),3.89(brs,1H),2.54-2.50(m,2H),2.00–1.72(m,4H),1.15(s,3H).

[0032] 13 C NMR(100MHz,CDCl3)δ156.4(d,J=234.2Hz),147.0,138.4(d,J=1.8Hz),123.9(d,J=7.8Hz),115.9(d,J=2.2Hz),113.9(d,J=7.8Hz),113.2(d,J=22.7Hz),112.3(d,J=22.8Hz),60.0,41.5,28.6,24.7,21.9.

[0033] 19 F NMR(376MHz,CDCl3)δ-127.40.

[0034] HRMSCalculated for C 13 H 15 FN[M+H] + 204.1183,found 204.1188.

[0035]

[0036] 7-Chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3b)

[0037] 30.8mg,70%yield,yellow solid,melting point:85-86℃,R f =0.30(PE / EA=20 / 1).

[0038] 1 H NMR(400MHz,CDCl3)δ6.89–6.85(m,2H),6.42(d,J=8.2Hz,1H),6.06(t,J=2.1Hz,1H),3.99(brs,1H),2.52(t,J=7.8Hz,2H),1.98–1.92(m,1H),1.90–1.74(m,3H),1.15(s,3H).

[0039] 13 C NMR(100MHz,CDCl3)δ146.6,140.9,126.8,125.6,124.1,122.5,115.7,114.5,59.9,41.5,28.5,25.1,21.7.

[0040] HRMSCalculated for C 13 H 15 ClN[M+H] + 220.0888,found 220.0884.

[0041]

[0042] 3a-Methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline-7-carbonitrile(3c)

[0043] 18.1mg,43%yield,yellow solid,melting point:93–94℃,R f =0.38(PE / EA=5 / 1).

[0044] 1 H NMR(400MHz,CDCl3)δ7.19(dd,J=8.3,1.9Hz,1H),7.12(s,1H),6.45(d,J=8.2Hz,1H),6.08(s,1H),4.46(brs,1H),2.54(td,J=7.6,6.9,2.0Hz,2H),2.05–1.73(m,4H),1.20(s,3H).

[0045] 13 C NMR(100MHz,CDCl3)δ146.0,146.0,131.9,129.7,122.3,120.5,115.3,113.1,99.6,60.1,41.3,28.3,26.3,21.0.

[0046] HRMSCalculated for C 14 H 15 N2[M+H] + 211.1230,found 211.1229.

[0047]

[0048] Ethyl 3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline-7-carboxylate(3d)

[0049] 19.3mg,38%yield,yellow solid,melting point:145–146℃,R f =0.75(PE / EA=3 / 1).

[0050] 1 H NMR(400MHz,CDCl3)δ7.66(dd,J=8.3,2.0Hz,1H),7.59(d,J=1.9Hz,1H),6.46(d,J=8.3Hz,1H),6.15(s,1H),4.43(brs,1H),4.31(q,J=7.1Hz,2H),2.53(ddd,J=8.9,6.7,2.1Hz,2H),2.05–1.72(m,4H),1.36(t,J=7.1Hz,3H),1.19(s,3H).

[0051] 13 C NMR(100MHz,CDCl3)δ167.0,146.6,144.7,129.9,127.8,121.5,119.5,116.2,112.5,60.2,60.0,41.3,28.3,26.1,21.3,14.5.

[0052] HRMSCalculated for C 16 H 20 NO2[M+H] + 258.1489,found 258.1481.

[0053]

[0054] 3a-Methyl-7-phenyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3e)

[0055] 37.7mg,72%yield,yellow oil,R f =0.65(PE / EA=10 / 1).

[0056] 1 H NMR(400MHz,CDCl3)δ7.54–7.51(m,2H),7.37(t,J=7.7Hz,2H),7.26–7.19(m,2H),7.16(d,J=2.1Hz,1H),6.56(d,J=8.1Hz,1H),6.19(s,1H),4.07(brs,1H),2.56–2.52(m,2H),2.01–1.95(m,1H),1.92–1.74(m,3H),1.20(s,3H).

[0057] 13 C NMR(100MHz,CDCl3)δ145.3,142.0 141.4,131.1,128.6,126.3,126.1,126.0,124.8,122.9,116.6,113.8,60.0,41.6,28.6,25.4,21.7.

[0058] HRMSCalculated for C 19 H 20 N[M+H] + 262.1590,found 262.1591.

[0059]

[0060] 7-(tert-Butyl)-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3f)

[0061] 35.6mg,74%yield,yellow oil,R f =0.62(PE / EA=20 / 1).

[0062] 1H NMR(400MHz,CD3CN)δ7.00–6.94(m,2H),6.46(d,J=8.2Hz,1H),6.11(t,J=2.1Hz,1H),4.64(brs,1H),2.53–2.48(m,2H),1.93–1.89(m,2H),1.83–1.77(m,2H),1.28(s,9H),1.12(s,3H).

[0063] 13 C NMR(100MHz,CD3CN)δ145.7,141.3,140.5,124.6,123.4,122.6,116.9,113.4,60.0 41.9,34.0,31.5,28.7,24.7,22.0.

[0064] HRMSCalculated for C 17 H 24 N[M+H] + 242.1903,found 242.1901.

[0065]

[0066] 3a-Methyl-7-phenoxy-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3g)

[0067] 39.5mg,71%yield,yellow oil,R f =0.36(PE / EA=20 / 1).

[0068] 1 H NMR(400MHz,CDCl3)δ7.27–7.23(m,2H),6.98(t,J=7.4Hz,1H),6.94–6.92(m,2H),6.68–6.64(m,2H),6.48(d,J=8.2Hz,1H),6.08(s,1H),3.93(brs,1H),2.51(t,J=6.4Hz,2H),2.02–1.72(m,4H),1.18(s,3H).

[0069] 13C NMR(100MHz,CDCl3)δ159.2,148.2,146.4,138.9,129.5,123.9,121.8,119.1,118.0,117.1,116.2,114.3,60.0,41.6,28.6,24.9,21.9.

[0070] HRMSCalculated for C 19 H 20 NO[M+H] + 278.1539,found 278.1542.

[0071]

[0072] 3a-Methyl-7-(methylthio)-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3h)

[0073] 30.5mg,66%yield,yellow oil,R f =0.39(PE / EA=10 / 1).

[0074] 1 H NMR(400MHz,CDCl3)δ6.99–6.94(m,2H),6.45(d,J=8.1Hz,1H),6.10(s,1H),4.00(brs,1H),2.52(s,2H),2.40(s,3H),2.01–1.72(m,4H),1.17(s,3H).

[0075] 13 C NMR(100MHz,CD3CN)δ146.7,142.6,129.5,127.9,124.5,123.8,116.1,114.4,60.1,41.7,28.7,24.8,21.8,18.5.

[0076] HRMSCalculated for C 14 H 18 NS[M+H] + 232.1154,found 232.1163.

[0077]

[0078] Ethyl 2-(3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinolin-7-yl)acetate(3i)

[0079] 27.2mg,50%yield,yellow oil,R f =0.56(PE / EA=5 / 1).

[0080] 1 H NMR(400MHz,CDCl3)δ6.85(dd,J=8.0,2.0Hz,1H),6.81(s,1H),6.45(d,J=8.0Hz,1H),6.10(t,J=2.4Hz,1H),4.12(q,J=7.1Hz,2H),3.98(brs,1H),3.45(s,2H),2.51(t,J=7.9Hz,2H),2.01–1.70(m,4H),1.23(t,J=7.1Hz,3H),1.16(s,3H).

[0081] 13 C NMR(100MHz,CDCl3)δ172.4,145.2,141.4,128.0,126.9,123.6,122.8,116.4,113.6,60.6,59.8,41.6,40.7,28.5,25.2,21.8,14.2.

[0082] HRMSCalculated for C 17 H 22 NO2[M+H] + 272.1645,found 272.1642.

[0083]

[0084] 6-Bromo-3a,7-dimethyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3j)

[0085] 27.3mg,49%yield,yellow solid,melting point:97–98℃,R f =0.67(PE / EA=10 / 1).

[0086] 1H NMR(400MHz,CDCl3)δ6.73(s,1H),6.70(s,1H),6.05(t,J=2.1Hz,1H),3.91(brs,1H),2.49(t,J=7.8Hz,2H),2.24(s,3H),1.98–1.70(m,4H),1.14(s,3H).

[0087] 13 C NMR(100MHz,CDCl3)δ145.8,141.5,127.8,126.6,122.4,122.2,116.8,115.8,59.8,41.4,28.6,25.1,21.74,21.72.

[0088] HRMSCalculated for C 14 H 17 BrN[M+H] + 278.0539,found 278.0538.

[0089]

[0090] 3a,5,7-Trimethyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3k)

[0091] 31.2mg,73%yield,yellow solid,melting point:86–87℃,R f =0.42(PE / EA=20 / 1).

[0092] 1 H NMR(400MHz,CDCl3)δ6.68(s,1H),6.62(s,1H),6.10(t,J=1.8Hz,1H),3.82(brs,1H),2.54–2.49(m,2H),2.19(s,3H),2.09(s,3H),2.04–1.97(m,1H),1.95–1.72(m,3H),1.14(s,3H).

[0093] 13 C NMR(100MHz,CDCl3)δ144.5,137.9,129.5,126.5,124.7,122.1,120.5,116.8,59.9,41.8,28.6,25.4,22.0,20.5,16.9.

[0094] HRMSCalculated for C 15 H 20 N[M+H] + 214.1590,found 214.1583.

[0095]

[0096] 7-Methoxy-3a,5-dimethyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3l)

[0097] 33.8mg,74%yield,yellow solid,melting point:113–114℃,R f =0.34(PE / EA=10 / 1).

[0098] 1 H NMR(700MHz,CDCl3)δ6.49(d,J=2.8Hz,1H),6.42(d,J=2.8Hz,1H),6.11(t,J=1.3Hz,1H),3.73(s,4H),2.54–2.52(m,2H),2.11(s,3H),2.03–1.98(m,1H),1.94–1.91(m,1H),1.89–1.84(m,1H),1.80–1.75(m,1H),1.13(s,3H).

[0099] 13 C NMR(176MHz,CDCl3)δ151.9,145.9,134.3,123.1,121.8,116.7,114.8,109.4,60.0,55.9,41.7,28.6,25.0,22.1,17.2.

[0100] HRMSCalculated for C 15 H 20 NO[M+H] + 230.1539,found 230.1532.

[0101]

[0102] 5a-Methyl-5a,6,7,8-tetrahydro-5H-cyclopenta[b]furo[2,3-g]quinoline(3m)

[0103] 24.8mg,55%yield,yellow oil,R f =0.28(PE / EA=20 / 1).

[0104] 1 H NMR(400MHz,CDCl3)δ7.51(d,J=2.1Hz,1H),7.09(d,J=8.5Hz,1H),6.70(s,1H),6.51(d,J=8.5Hz,1H),6.41(s,1H),3.91(brs,1H),2.61–2.57(m,2H),2.04–1.99(m,1H),1.92–1.85(m,2H),1.83–1.76(m,1H),1.17(s,3H).

[0105] 13 C NMR(100MHz,CDCl3)δ149.6,145.5,145.0,137.4,124.4,114.3,113.4,111.8,109.4,104.3,59.9,41.7,29.0,24.2,22.3.

[0106] HRMSCalculated for C 15 H 16 NO[M+H] + 226.1226,found 226.1219.

[0107]

[0108] 5a-Methyl-5a,6,7,8-tetrahydro-5H-cyclopenta[b]thieno[2,3-g]quinoline(3n)

[0109] 30.3mg,63%yield,yellow solid,melting point:82–83℃,R f =0.40(PE / EA=10 / 1).

[0110] 1H NMR(400MHz,CDCl3)δ7.43(d,J=8.4Hz,1H),7.35(d,J=5.5Hz,1H),7.31(d,J=5.5Hz,1H),6.63(d,J=8.4Hz,1H),6.58(t,J=2.2Hz,1H),4.03(brs,1H),2.63–2.57(m,2H),2.06–1.98(m,1H),1.95–1.75(m,3H),1.17(s,3H).

[0111] 13 C NMR(100MHz,CDCl3)δ144.9,139.0,136.6,130.3,126.5,120.7,120.6,116.3,113.6,113.5,59.7,41.7,29.1,24.5,22.2.

[0112] HRMSCalculated for C 15 H 16 NS[M+H] + 242.0998,found 242.0999.

[0113]

[0114] 5a-Methyl-5a,6,7,8-tetrahydro-5H-cyclopenta[b]thiazolo[5,4-g]quinoline(3o)

[0115] 20.9mg,43%yield,yellow solid,melting point:111–112℃,R f =0.51(PE / EA=5 / 1).

[0116] 1 H NMR(700MHz,CDCl3)δ8.65(s,1H),7.70(d,J=8.5Hz,1H),6.72(d,J=8.5Hz,1H),6.26(t,J=2.2Hz,1H),4.24(brs,1H),2.66–2.54(m,2H),2.07–1.99(m,1H),1.97–1.91(m,1H),1.92–1.84(m,1H),1.86–1.77(m,1H),1.20(s,3H).

[0117] 13C NMR (176MHz, CDCl3) δ148.8,146.8,146.1,140.0,131.9,121.8,114.8,114.6,114.3,60.2,41.5,28.8,25.0,21.9.

[0118] HRMS Calculated for C 14 H 15 N2S[M+H] + 243.0950, found 243.0946.

[0119] 20 mol%), 1,3-cycloheptenone (

[0120] 3. Cycloenone substrate types

[0121] Under air atmosphere, hydrochloric acid (20 mol% relative to the amount of cycloheptenone), cycloheptenone (0.2 mmol, i.e., 1.0 molar equivalent), and 4-fluoroaniline (3.0 molar equivalent relative to the amount of cycloheptenone) were added sequentially to a 10.0 mL sealed tube, followed by the addition of 1.0 mL of solvent. The tube was then sealed and stirred at 100 °C for 24 hours. After the reaction was complete, the mixture was directly separated by column chromatography using a 1:1 volume ratio of petroleum ether / ethyl acetate as the mobile phase.

[0122]

[0123] 7-Fluoro-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline(3a)

[0124] 21.5mg,53%yield,yellow solid,melting point:80–81℃,R f =0.38 (PE / EA = 20 / 1).

[0125] 1 H NMR (400MHz, CDCl3) δ6.67–6.61(m,2H),6.42(dd,J=8.1,4.7Hz,1H),6.08(t,J =2.2Hz,1H),3.89(brs,1H),2.54-2.50(m,2H),2.00–1.72(m,4H),1.15(s,3H).

[0126] 13C NMR(100MHz,CDCl3)δ156.4(d,J=234.2Hz),147.0,138.4(d,J=1.8Hz),123.9(d,J=7.8Hz),115.9(d,J=2.2Hz),113.9(d,J=7.8Hz),113.2(d,J=22.7Hz),112.3(d,J=22.8Hz),60.0,41.5,28.6,24.7,21.9.

[0127] 19 F NMR(376MHz,CDCl3)δ-127.40.

[0128] HRMSCalculated for C 13 H 15 FN[M+H] + 204.1183,found 204.1188.

[0129]

[0130]

[0131] 7-Fluoro-4a-methyl-1,2,3,4,4a,10-hexahydroacridine(4)

[0132] 27.0mg,62%yield,yellow solid,melting point:71–72℃,R f =0.43(PE / EA=10 / 1).

[0133] 1 H NMR(400MHz,CDCl3)δ6.60(td,J=8.7,2.9Hz,1H),6.52(dd,J=9.0,2.9Hz,1H),6.28(dd,J=8.5,4.5Hz,1H),5.92(d,J=1.7Hz,1H),3.38(brs,1H),2.31–2.26(m,2H),1.92(td,J=13.5,12.8,3.4Hz,1H),1.84–1.70(m,3H),1.59–1.37(m,2H).1.30(s,3H).

[0134] 13C NMR(101MHz,CD3CN)δ155.9(d,J=233.3Hz),142.2,138.6(d,J=1.6Hz),122.2(d,J=7.7Hz),118.6(d,J=2.3Hz),113.5(d,J=22.7Hz),112.5(d,J=7.7Hz),111.9(d,J=22.9Hz),55.4,42.3,31.4,26.4,25.8,23.2.

[0135] 19 F NMR(376MHz,CDCl3)δ-128.34.

[0136] HRMSCalculated for C 14 H 17 FN[M+H] + 218.1340,found 218.1346.

[0137]

[0138] 7-Fluoro-N-(4-fluorophenyl)-4a-methyl-1,2,3,4,4a,10-hexahydroacridin-3-amine(5)

[0139] 37.0mg,57%yield,yellow solid,melting point:120–121℃,R f =0.69(PE / EA=2 / 1).

[0140] 1 H NMR(400MHz,CDCl3)δ6.93–6.86(m,2H),6.63(td,J=8.6,2.8Hz,1H),6.57–6.54(m,3H),6.29(dd,J=8.5,4.5Hz,1H),5.99(d,J=1.9Hz,1H),3.47(tt,J=11.6,3.6Hz,1H),3.29(brs,2H),2.50–2.37(m,2H),2.23–2.13(m,2H),1.77(t,J=12.0Hz,1H),1.39(s,3H),1.34–1.23(m,1H).

[0141] 13C NMR (100Hz, CDCl3) δ156.1 (d, J = 235.0Hz), 155.9 (d, J = 236.5Hz), 143.0, 139.7, 138.0 (d, J = 1.5Hz), 121.9 (d, J = 7.7Hz), 119.4 (d, J = 2.2Hz), 115.8(d,J=22.4Hz), 114.4(d,J=7.3Hz), 113.9(d,J=22.8Hz), 112.7(d,J=7.7Hz), 112.2(d,J=23.1Hz), 55.8, 49.9, 48.5, 33.2, 30.0, 26.5.

[0142] 19 F NMR (376MHz, CDCl3) δ-127.54,-127.83.

[0143] HRMS Calculated for C 20 H 21 F2N2[M+H] + 327.1667, found 373.1666.

[0144] 4. Post-modification of drug molecules

[0145] Under air atmosphere, hydrochloric acid (20 mol% relative to the amount of 1,3-cycloenone), 1,3-cycloenone (0.2 mmol, i.e., 1.0 molar equivalent), and drug molecule compound 4 (3.0 molar equivalent relative to the amount of 1,3-cycloenone) were added sequentially to a 10.0 mL sealed tube. Then, 1.0 mL of solvent was added, and the tube was sealed and stirred at 100°C to 120°C for 24 hours. After the reaction was complete, the mixture was directly separated by column chromatography using a 1:1 (v / v) petroleum ether / ethyl acetate mobile phase.

[0146]

[0147] 3-Ethyl-3-(3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinolin-7-yl)piperidine-2,6-dione(6a)

[0148] 45.8mg,71%yield,yellow solid,melting point:180–181℃,R f =0.75 (DCM / MeOH = 20 / 1).

[0149] 1H NMR(700MHz,CDCl3)δ8.13(brs,1H),6.83–6.75(m,2H),6.47(s,1H),6.09(d,J=3.6Hz,1H),4.13(brs,1H),2.57–2.45(m,4H),2.31–2.27(m,1H),2.16–2.11(m,1H),2.01–1.93(m,2H),1.90–1.81(m,3H),1.79–1.73(m,1H),1.17(s,3H),0.86–0.83(m,3H).

[0150] 13 C NMR(176MHz,CDCl3)δ175.8,175.71,175.72,172.8,145.6,145.6,141.7,127.7,127.6,125.2,124.9,124.0,123.8 123.0 122.8,116.4,116.3,113.7,113.6,59.86,59.85,50.8,50.3,50.3,41.6,32.9,32.9,29.4,28.5,27.1,27.0,25.4,21.6,9.0.

[0151] HRMSCalculated for C 20 H 25 N2O2[M+H] + 325.1911,found 325.1904.

[0152]

[0153] N-(3-Methoxypyrazin-2-yl)-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline-7-sulfonamide(6b)25.6mg,34%yield,yellow solid,melting point:225–226℃,R f =0.76(DCM / MeOH=20 / 1).

[0154] 1H NMR(400MHz,CDCl3)δ7.74(d,J=3.0Hz,1H),7.69(dd,J=8.5,2.2Hz,1H),7.62(t,J=2.5Hz,2H),7.60(brs,1H),6.46(d,J=8.5Hz,1H),6.12(s,1H),4.53(brs,1H),3.96(s,3H),2.52(td,J=7.7,7.1,2.0Hz,2H),2.01–1.87(m,2H),1.85–1.73(m,2H),1.18(s,3H).

[0155] 13 C NMR(176MHz,CDCl3)δ148.6,146.9,145.5,138.2,133.7,133.3,128.7,126.6,126.4,121.4,115.7,112.2,60.1,53.9,41.2,28.2,26.4,20.9.

[0156] HRMSCalculated for C 18 H 21 N4O3S[M+H] + 373.1329,found 373.1335.

[0157]

[0158] 3-(9a-Methyl-3-oxo-3,7,8,9,9a,10-hexahydrocyclopenta[b]pyrrolo[3,4-h]quinolin-2(1H)-yl)piperidine-2,6-dione(6c)

[0159] 22.9mg,33%yield,1.2:1 dr,yellow solid,melting point:192–193℃,R f =0.45(DCM / MeOH=10 / 1).

[0160] 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),6.98(d,J=7.5Hz,1H,major),6.95(d,J=7.7Hz,1H,minor),6.86(d,J=7.6Hz,1H,major),6.82(d,J=7.4Hz,1H,minor),6.33–6.16(m,1H),5.09(td,J=12.8,5.1Hz,1H),4.14(brs,1H),3.33(s,2H),2.97–2.88(m,1H),2.64–2.59(m,1H),2.30–1.99(m,4H),1.94-1.90(m,2H),1.76–1.72(m,2H),1.10(d,J=3.8Hz,3H).

[0161] 13 C NMR(100MHz,DMSO-d6)δ173.4,171.8,171.7,169.2,169.1,138.2,138.1,131.1,131.1,126.3,126.3,125.1,124.4,116.5,111.3,59.6,59.6,52.1,51.9,46.0,31.8,28.5,26.0,25.9,23.3,22.0,22.0,21.3.HRMSCalculated for C 20 H 22 N3O3[M+H] + 352.1656,found 352.1671.

[0162]

[0163] 4,7a-Dimethyl-7a,8,9,10-tetrahydrocyclopenta[b]pyrano[2,3-f]quinolin-2(7H)-one(6d)

[0164] 13.1mg,25%yield,yellow solid,melting point:236–238℃,R f =0.52(DCM / MeOH=50 / 1).

[0165] 1H NMR(400MHz,CDCl3)δ7.18(d,J=8.5Hz,1H),6.71(t,J=2.2Hz,1H),6.45(dd,J=8.5,0.7Hz,1H),5.99(d,J=1.2Hz,1H),4.50(brs,1H),2.58(ddd,J=8.6,6.5,2.2Hz,2H),2.33(d,J=1.2Hz,3H),2.03–1.90(m,2H),1.88–1.77(m,2H),1.20(s,3H).

[0166] 13 C NMR(100MHz,CDCl3)δ161.9,153.3,149.9,145.8,144.7,123.2,111.3,110.2,109.8,109.6,109.2,59.8,41.3,28.6,25.8,21.4,18.8.

[0167] HRMSCalculated for C 17 H 18 NO2[M+H] + 268.1332,found 268.1321.

[0168]

[0169] 2-(Diethylamino)ethyl3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline-7-carboxylate(6e)

[0170] 23.8mg,36%yield,yellow oil,R f =0.78(DCM / MeOH=5 / 1).

[0171] 1H NMR(700MHz,CDCl3)δ7.64(dd,J=8.3,1.9Hz,1H),7.58(d,J=1.9Hz,1H),6.45(d,J=8.3Hz,1H),6.14(s,1H),4.43(brs,1H),4.35(t,J=6.3Hz,2H),2.87(t,J=6.3Hz,2H),2.67(q,J=7.1Hz,4H),2.53(td,J=7.6,6.8,2.0Hz,2H),2.01-1.97(m,1H),1.92-1.89(m,1H),1.87-1.81(m,1H),1.80–1.75(m,1H),1.19(s,3H),1.09(t,J=7.2Hz,6H).

[0172] 13 C NMR(176MHz,CDCl3)δ166.8,146.7,144.7,129.8,127.9,121.5,119.2,116.2,112.5,62.3,60.0,50.9,47.7,41.3,28.3,26.1,21.2,11.9.

[0173] HRMSCalculated for C 20 H 29 N2O2[M+H] + 329.2224,found 329.2217.

[0174]

[0175] 3-(Diethylamino)-2,2-dimethylpropyl-3a-methyl-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinoline-7-carbo xylate(6f)

[0176] 30.9mg,42%yield,yellow oil,R f =0.78(DCM / MeOH=4 / 1).

[0177] 1H NMR(400MHz,CDCl3)δ7.65(dd,J=8.3,2.0Hz,1H),7.58(d,J=1.9Hz,1H),6.47(d,J=8.3Hz,1H),6.17(s,1H),4.44(brs,1H),4.02(s,2H),2.56–2.50(m,6H),2.32(s,2H),2.04–1.75(m,4H),1.20(s,3H),0.98–0.95(m,12H).

[0178] 13 C NMR(100MHz,CDCl3)δ166.9,146.5,144.7,129.6,127.8,121.5,119.6,116.3,112.5,70.5,61.8,60.0,49.0,41.4,36.5,28.3,26.1,23.3,2.23,12.2.

[0179] HRMSCalculated forC 23 H 35 N2O2[M+H] + 371.2693,found 371.2699.

[0180]

[0181] 3-Ethyl-3-(10a-methyl-5,6,7,8,10,10a-hexahydroacridin-2-yl)piperidine-2,6-dione(6g)

[0182] 43.9mg,65%yield,1.0:1 dr,yellow solid,melting point:>260℃,R f =0.74(DCM / MeOH=20 / 1)

[0183] 1H NMR(400MHz,Benzene-d6)δ7.95(brs,1H),6.75(d,J=8.3Hz,1H),6.69(s,1H),6.01(d,J=8.2Hz,1H),5.72(s,1H),2.93(brs,1H),2.24-2.15(m,1H),2.09–1.90(m,4H),1.82-1.74(d,m,2H),1.59-1.48(m,3H),1.41–1.21(m,4H),1.06(s,3H),0.73(t,J=7.5Hz,3H).

[0184] 13 C NMR(176MHz,CDCl3)δ175.8,175.7,172.8,141.8,140.9,140.9,126.63,126.59,125.5,125.3,123.5,123.4,121.2,121.0,118.9,112.1,112.0,55.6,50.2,50.2,42.6,42.6,32.9,32.9,31.6,29.4,27.0,26.9,26.8,26.7,26.6,23.3,9.0.

[0185] HRMSCalculated for C 21 H 27 N2O2[M+H] + 339.2067,found 339.2064.

[0186]

[0187] N-(3-Methoxypyrazin-2-yl)-10a-methyl-5,6,7,8,10,10a-hexahydroacridine-2-sulfonamide(6h)

[0188] 24.8mg,32%yield,yellow solid,melting point:>260℃,R f =0.75(DCM / MeOH=20 / 1).

[0189] 1H NMR(700MHz,CDCl3)δ7.73(s,1H),7.62(dd,J=8.5,2.1Hz,2H),7.46(d,J=2.1Hz,1H),6.26(d,J=8.5Hz,1H),5.93(s,1H),4.00(brs,1H),3.96(s,3H),2.31(td,J=13.9,6.9Hz,1H),2.23(d,J=14.2,1H),1.97(td,J=13.2,4.1Hz,1H),1.82(d,J=12.6Hz,1H),1.77(d,J=13.3Hz,1H),1.68(d,J=11.8Hz,1H),1.55(qt,J=13.6,3.6Hz,1H),1.44–1.37(m,4H).

[0190] 13 C NMR(176MHz,CDCl3)δ148.6,146.9,141.1,138.2,133.7,133.2,129.4,126.1,125.2,119.4,117.9,110.4,56.3,53.9,42.7,31.6,27.6,27.0,23.2.

[0191] HRMSCalculated for C 19 H 23 N4O3S[M+H] + 387.1485,found 387.1473.

Claims

1. A method for preparing 1,2-dihydroquinoline compounds, characterized in that: Using cycloenones and aromatic amines as reactants, with the cycloenones being 1,3-cycloenones and / or 1,4-cycloenones, 2,3-ring-substituted 1,2-dihydroquinoline compounds are selectively generated under the action of a catalyst; the reaction formula is shown below: ； The specific operating steps are as follows: In a reactor under one or more atmospheres of argon, nitrogen, or air, a catalyst, 1,3- or 1,4-cycloenone, and an aromatic amine are added, followed by dissolution with a solvent and reaction. After the reaction is complete, the solvent is evaporated and column chromatography is performed to obtain the target product 3, where n = 1 or 2; the cycloenone is selected from 1,3-cycloenone and / or 1,4-cycloenone, and the ring of the cycloenone is a seven-membered or eight-membered carbon ring. The reactant aromatic amine is selected from one or more of substituted aniline, naphthylamine, and substituted naphthylamine; the substituent on the aryl group of the aromatic amine is selected from one or more of hydrogen, C1-C8 alkyl, cyano, halogen, and trifluoromethyl; the catalyst used in the reaction is selected from one or a mixture of two or more of diphenyl phosphate, benzenesulfonic acid, halogen-substituted benzenesulfonic acid, and hydrochloric acid.

2. The method according to claim 1, characterized in that: The amount of aromatic amine used is 0.5-10 times the molar amount of cycloenone; the reaction temperature is 60-140°C. o The reaction time is between 0.5 and 48 hours.

3. The method according to claim 2, characterized in that: The amount of aromatic amine used is 1-5 times the molar amount of cycloenone; the reaction temperature is 90-130°C. o The reaction time is between 18 and 36 hours.

4. The method as described in claim 1, characterized in that: The solvents used in the reaction are selected from methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, toluene, cyclohexane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, dichloromethane, dichloroethane, 1,4-dioxane, ethyl acetate, etc. N,N -Dimethylformamide, N One or more of the solvents selected from methylpyrrolidone and dimethyl sulfoxide, with a cycloenone concentration range of 0.05-5.0 mol / L.

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