Polycyclic nitrogen heterocyclic compound and preparation method thereof

Abstract

The invention belongs to the field of organic compounds, and particularly relates to a polycyclic nitrogen heterocyclic compound and a preparation method thereof. According to the specific technical scheme, the method for synthesizing the polycyclic nitrogen heterocyclic compound comprises the following steps: dissolving N-(o-chloromethyl) aryl amide or a derivative thereof, dihydro-beta-carboline or 3, 4-dihydroisoquinoline in an organic solvent, adding alkali, and stirring at 0-40 DEG C for more than 3 hours to obtain the polycyclic nitrogen heterocyclic compound. The one-step synthesis method provided by the invention is simple and mild in reaction condition and high in product yield, and has a relatively great application prospect.

Description

Technical Field

[0001] The invention belongs to the field of organic compounds, and in particular relates to a class of polycyclic nitrogen heterocyclic compounds and a preparation method thereof. Background Art

[0002] Fused polycyclic N-heterocyclic compounds, especially indolopyridinequinazolines, are widely found in nature (e.g., evodiamine and rutaecarpine). Their analogs have shown potential as targeting ligands for antitumor drugs, TMEM16A inhibitors, G-quadruplexes, and are candidates for pesticides. Isoquinolinoquinazoline derivatives also exhibit antitumor activity in a variety of cancer cell lines and are used as radiotracers in positron emission tomography for butyrylcholinesterase imaging.

[0003] These compounds are usually synthesized through the condensation reaction of o-aminobenzaldehyde and secondary amines or metal-catalyzed intramolecular redox reactions or multi-step reactions, which generally have problems such as complex operating procedures, dependence on metals, and harsh reaction conditions.

[0004] Therefore, developing new synthetic strategies is an important research direction. Summary of the invention

[0005] The purpose of the present invention is to provide a class of polycyclic nitrogen heterocyclic compounds and a preparation method thereof.

[0006] To achieve the above-mentioned purpose, the technical solution adopted by the present invention is: a method for synthesizing polycyclic nitrogen heterocyclic compounds, which is carried out through the following reaction equation:

[0007]

[0008] Preferably, the method comprises the following steps: dissolving N-(o-chloromethyl)arylamide or its derivative, dihydro-β-carboline or 3,4-dihydroisoquinoline in an organic solvent, adding a base, and stirring at 0-40° C. for more than 3 hours to obtain the polycyclic nitrogen heterocyclic compound.

[0009] Preferably, the organic solvent is any one of dichloromethane, toluene, ether, acetonitrile, tetrahydrofuran or chloroform.

[0010] Preferably, the base is any one of cesium carbonate, potassium bicarbonate, potassium carbonate and sodium bicarbonate.

[0011] Preferably, the molar ratio of N-(o-chloromethyl)arylamide or its derivative:dihydro-β-carboline or 3,4-dihydroisoquinoline:base=(1-2):1:2.

[0012] Correspondingly, the polycyclic nitrogen heterocyclic compound is prepared by the method.

[0013] Preferably, the polycyclic nitrogen heterocyclic compounds are compound 3 and compound 6; the general structural formulas are as follows:

[0014]

[0015] Preferably, the compound 3 is any one of compounds 3a-3t, and the compound 6 is any one of compounds 6a-6c, 6e, 6h, 6u-6y (see Tables 3 and 4 for specific compound structural formulas).

[0016] The present invention has the following beneficial effects: The present invention provides a novel method for synthesizing polycyclic nitrogen heterocyclic compounds, which is synthesized by a [4+2] cyclization reaction between cyclic imine and N-(o-chloromethyl)arylamide. The one-step synthesis method provided by the present invention has simple and mild reaction conditions, high product yield, and great application prospects. DETAILED DESCRIPTION

[0017] The present invention provides a series of novel polycyclic nitrogen heterocyclic compounds: Compound 3 and Compound 6; the general structural formula of the polycyclic nitrogen heterocyclic compounds is as follows:

[0018]

[0019] The preferred scheme is: the polycyclic nitrogen heterocyclic compound includes: compounds 3a-3t, and compounds 6a-6c, 6e, 6h, 6u-6y (specific compound structures are shown in Tables 3 and 4). The numbers or the combination of numbers and letters below the chemical structure represent the compound number; the combination of numbers and letters represents the series of specific compounds under the structural formula corresponding to the number. For example, compounds 1a, 1b, etc. all belong to compound 1.

[0020] The present invention also provides a method for preparing the polycyclic nitrogen heterocyclic compound, which is carried out according to the following equation:

[0021]

[0022] The reaction mechanism is as follows:

[0023]

[0024] Taking compound 1a as an example, the reaction mechanism is as follows: activation of N-(o-chloromethyl)aryl amide (compound 1a) is achieved through Cs2CO3 to form nitrogen-o-methylene benzoquinone (compound A); cyclic imine (compound 2) or (compound 5) undergoes a [4+2] cyclization reaction with compound A; and then a fused polycyclic N-heterocyclic skeleton (compound 3a or 6a) is transferred through the continuous formation of CN bonds.

[0025] The method specifically comprises the following steps: dissolving N-(o-chloromethyl)arylamide (compound 1) and dihydro-β-carboline (compound 2) or 3,4-dihydroisoquinoline (compound 5) in an organic solvent, adding a base, and stirring at 0-40° C. for more than 3 hours to obtain a polycyclic product (compound 3 or compound 6).

[0026] Preferably, the organic solvent is dichloromethane; and the base is cesium carbonate.

[0027] Preferably, the benzene ring of the N-(o-chloromethyl)arylamide is connected to an electron-withdrawing substituent, such as Cl or Br.

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. The data obtained are all average values ​​obtained after at least 3 repetitions, and all the data obtained in each repetition are valid data.

[0029] Example 1: Effect of reaction conditions on the reaction

[0030] 1. According to the following reaction equation, compound 1a (0.15 mmol) and compound 2 (0.1 mmol) were added to CH2Cl2 solvent (3 mL), and KOH (0.2 mmol) was added. The mixture was stirred at room temperature for 3 hours to obtain a polycyclic product with a yield of 49%: compound 3a, which was a white solid.

[0031]

[0032] Compound 3a: 1 H NMR(400MHz, CDCl3)δ9.47(s,1H),7.59(d,J=8.1Hz,1H),7.46(t,J=9.2Hz,2H),7.34–7.16(m,7H),7.09(t, J=7.5Hz,1H),6.98(d,J=7.4Hz,1H),6.05(s,1H),3.46–3.08(m,2H),2.87–2.54(m,3H),2.53–2.18(m,4H). 13C NMR (100MHz, CDCl3) δ144.25,136.52,134.65,134.35,132.72,130.25,129.56,128.20,128.14,127.26,126 .92,126.38,125.77,122.64,119.31,118.72,111.64,53.57,45.92,21.65,21.15.HRMS(ESI-TOF)Calcd.for C 25 H 23 N3O2S[M+H] + :430.1584; found:430.1587.

[0033] 2. Effect of the type of base on the reaction. Keeping the other conditions in step 1 unchanged, other bases were used to replace KOH according to Table 1, and the reaction was carried out for 3 hours (reaction was complete). The results are shown in Table 1.

[0034] Table 1 Comparison of the effects of base types on final product yield

[0035] Group Alkali Dosage of alkali Yield (3a) 1 NaOH 0.2mmol 31％ 2 TEA(Triethylamine) 0.2mmol Trace 3 <![CDATA[K2CO3]]> 0.2mmol 69％ 4 <![CDATA[Cs2CO3]]> 0.2mmol 86％ 5 <![CDATA[NaHCO3]]> 0.2mmol 57％ 6 <![CDATA[Na2CO3]]> 0.2mmol 48％ 7 <![CDATA[KHCO3]]> 0.2mmol 71％ 8 \ \ NR

[0036] The results show that the formation of the product depends on the alkaline environment and is closely related to the type and strength of the base. Cs2CO3 is the best choice for this transformation. When other inorganic bases such as KOH, NaOH and Na2CO3 are used, the yield is low; when an organic base (triethylamine) is used, the product obtained is trace. This shows that Cs2CO3 not only provides the alkaline environment required for the reaction, but may also provide certain substances or conditions that can promote the forward reaction, playing a catalytic role.

[0037] 3. Effect of solvent type on the reaction: According to the steps and methods of Group 4 in Table 1, Cs2CO3 was selected as the base, the solvent was adjusted according to Table 2, and the reaction was carried out for 3 hours (the reaction was complete). The results are shown in Table 2.

[0038] Table 2 Comparison of the effects of solvent types on final product yield

[0039] Group Solvents Amount of solvent Yield (3a) 1 Toluene 3mL 54％ 2 Ether 3mL 27％ 3 Acetonitrile 3mL 72％ 4 Tetrahydrofuran 3mL 65％ 5 Chloroform 3mL 76％ 6 Methanol 3mL Trace

[0040] The results showed that using CH2Cl2 as solvent had the best effect, while other solvents would reduce the product yield, and using methanol as solvent would hardly produce the desired product.

[0041] 4. Effect of the amount of reactants on the reaction. According to the steps and methods of Group 4 in Table 1, the base is Cs2CO3 and the solvent is CH2Cl2. Adjust compound 1: compound 2: Cs2CO3 = 1:1:2 (molar ratio). After sufficient reaction, the yield of compound 3a is 82%. Adjust compound 1: compound 2: Cs2CO3 = 2:1:2 (molar ratio). After sufficient reaction, the yield of compound 3a is 61%.

[0042] 5. Effect of reaction temperature and time. According to the steps and methods of Group 4 in Table 1, Cs2CO3 was selected as the base, CH2Cl2 was selected as the solvent, the reaction temperature was raised to 40°C, and after sufficient reaction for 3 hours, the yield of compound 3a was 83%; the reaction temperature was lowered to 0°C, and after sufficient reaction for 8 hours, the yield of compound 3a was 64%.

[0043] According to the steps and methods of Group 4 in Table 1, Cs2CO3 was selected as the base, CH2Cl2 was used as the solvent, and the reaction time was extended to 6 h. The yield of compound 3a was 80%; if the reaction time was only 1 h, the yield of compound 3a was 63%.

[0044] Example 2: Effect of reaction raw materials on the reaction

[0045] 1. Synthesis of series compound 1 (aza-o-methylene benzoquinone precursor). The reaction equation is as follows:

[0046]

[0047] Thionyl chloride (2.5 mmol) was dissolved in chloroform (4 mL), and a solution of compound S1 (1 mmol) in chloroform (10 mL) was added within 5 minutes. The mixture was heated to 40 ° C and reacted overnight. After the reaction was completed, it was cooled to room temperature and the mixture was poured into ice water (5 mL). The aqueous layer was extracted with chloroform (50 mL). The combined organic layer was washed with brine (10 mL) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography to obtain compound 1.

[0048] Depending on the different substituent groups of compound S1, different compounds 1 are obtained, as shown below.

[0049]

[0050] 2. Synthesize compound 4 (azadiene) and replace compound 1. The reaction equation for synthesizing compound 4 is as follows:

[0051]

[0052] Under nitrogen atmosphere, 4-methylbenzenesulfonamide (compound S5, 250mg, 1.5mmol) and heterocyclic ketone (compound S4, 1.5mmol) were added to a round-bottom flask, 15mL of toluene was added, and cooled to 0°C. Triethylamine (0.43mL, 3.0mmol) and titanium tetrachloride (1.0M in toluene solution, 1.6mL, 1.6mmol) were added successively. The mixture was heated to 120°C and refluxed overnight under nitrogen. The solution was then cooled to room temperature, quenched with water (50mL), and extracted with dichloromethane (60mL). The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 4.

[0053] Compound 4 was used to replace compound 1, and the reaction was attempted according to the steps and methods of Group 4 in Table 1 of Example 1, with Cs2CO3 as the base and CH2Cl2 as the solvent. The reaction time was extended to 24 h, but no reaction occurred.

[0054] 3. Synthesis of compound 2 (dihydro-β-carboline). The reaction equation is as follows:

[0055]

[0056] Tryptamine (compound S2, 6.0 g, 37.4 mmol) was dissolved in 80 mL of ethyl formate and heated under gentle reflux (oil bath temperature 65 ° C) for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the residual ethyl formate was removed in vacuo. The residue was dissolved in dichloromethane and washed with 1N hydrogen chloride, saturated sodium bicarbonate solution and brine in sequence. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The crude product S3 (5.42 g) obtained was used in subsequent steps without further purification.

[0057] Under nitrogen, phosphorus oxychloride (1.0 ml, 8.8 mmol, 1.1 eq.) was added dropwise to a solution of compound S3 (1.5 g, 8.0 mmol, 1.0 eq.) in anhydrous dichloromethane (15 mL) at 0°C by syringe. Stir for 1 hour at 0°C and then for 1 hour at 25°C. After evaporating the solvent in vacuo, the residue was dissolved in 1N hydrogen chloride and washed with ether. The pH of the aqueous layer was adjusted to pH = 10 by adding ammonium hydroxide. The resulting solution was extracted four times with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. After exposure to high vacuum overnight, a yellow foamy crude product was obtained, which was compound 2 (1.7 g).

[0058] 4. Synthesis of compound 5 (3,4-dihydroisoquinoline), the reaction equation is as follows:

[0059]

[0060] Tetrahydroisoquinoline (compound S6, 2.6 g, 20 mmol, 1 eq.) was dissolved in 100 mL of anhydrous dichloromethane, and N-bromosuccinimide (NBS, 3.8 g, 24 mmol, 1.2 eq.) was added and stirred at room temperature for 6 hours. Then 45 mL of 30% sodium hydroxide solution was added to promote the elimination reaction. The biphasic system was vigorously stirred overnight at room temperature. After phase separation, the organic layer was washed three times with 30 mL of water. The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain compound 5.

[0061] 5. Adjust the substituent of compound 1, and according to the steps and methods of group 4 in Table 1 of Example 1, select cesium carbonate as the base and dichloromethane as the solvent to prepare series of compounds 3. The specific compound 1 used, the prepared compound 3 and the yield of the corresponding compound 3 are shown in Table 3.

[0062] Table 3 Comparison of the effects of the substituents of compound 1 on the product

[0063]

[0064]

[0065]

[0066] The results showed that the presence of electron-withdrawing substituents (such as Cl, Br, CF3) on the benzene ring of compound 1 could promote the reaction and obtain indole pyridine quinazolines (compounds 3b-3f) with a yield of 57%-92%. Among them, amides with strong electron-withdrawing groups (compound 1e) showed lower reactivity and obtained compound 3e in a moderate yield. The change in the position of the electron-withdrawing group had little effect on the product yield.

[0067] When chlorine and methyl substituents coexist on the benzene ring of compound 1, the yield of compound 3g is significantly reduced. At the same time, the electron-donating substituted aza-o-methylene benzoquinone (the substituent CH3 on aza-o-methylene benzoquinone) effectively participates in the [4+2] cycloaddition reaction to produce the corresponding products in good yields: compounds 3h-3k. By comparing compounds 3h with 3k, the position of the electron-donating group plays a significant role in affecting the reaction progress and product yield. The low yield of compound 3j may be attributed to the steric hindrance effect.

[0068] Compounds 3l-3t reflect the effects of different protecting groups on nitrogen atoms. Compounds 3l-3q can be prepared by the method of the present invention using compound 1 containing benzoyl (Bz), methanesulfonyl (Ms), benzyloxycarbonyl (COOBn) and ethoxycarbonyl (COOEt); however, it is difficult or impossible to observe the expected products when using compound 1r protected by tert-butyloxycarbonyl, N-(4-chloro-2-(chloromethyl)-6-methylphenyl)benzamide compound 1s or N-(2-(chloro(phenyl)methyl)phenyl)benzamide compound 1t as reactants.

[0069] The NMR data of each compound 3 synthesized in this step are as follows:

[0070] 3b: white solid (40.7mg, 88% yield), 1 H NMR (400MHz, CDCl3) δ9.37(s,1H),7.53(dd,J=5.5,3.6Hz,1H),7.46(dd,J=13.7,8.0Hz,2H),7.34(dd,J=8.3,1.6Hz,2H),7 .27–7.19(m,5H),7.10(t,J=7.5Hz,1H),6.02(s,1H),3.96(d,J=15.7Hz,1H),2.77–2.52(m,4H),2.42(s,3H),2.34(s,1H). 13 C NMR (100MHz, CDCl3) δ144.63,136.45,136.17,134.18,132.08,130.88,129.84,129.69,128.32,127.23,126.97,126 .90,125.75,122.70,119.38,118.72,111.61,110.51,71.11,50.06,45.78,21.68,20.98.HRMS(ESI-TOF)Calcd.forC 25 H 22 ClN3O2S[M+H] + :464.1194; found:464.1199.

[0071] 3c: yellow solid, (46.6mg, 92% yield), 1 H NMR (400MHz,CDCl3)

[0072] δ9.43(s,1H),7.52–7.42(m,4H),7.36(d,J=8.2Hz,2H),

[0073] 7.23(t,J=8.0Hz,3H),7.15–7.08(m,2H),6.00(s,1H),3.35(s,1H),2.86–2.63(m,3H),2.71–2.32(m,5H). 13 C NMR(100MHz,CDCl3)δ144.56,136.50,134.75,134.18,133.89,131.20,129.85,129.83,129.81,129.76,127.25,125.72,122.74,120.07,119.41,118.76,111.64,110.51,71.14,53.15,45.98,21.67,21.12.HRMS(ESI-TOF)Calcd.forC 25 H 22 BrN3O2S[M+H] + :508.0689;found:508.0688.

[0074] 3d:yellow solid,(38.9mg,84%yield), 1 H NMR(400MHz,CDCl3)

[0075] δ9.41(s,1H),7.52(d,J=8.6Hz,1H),7.45(dd,J=13.8,

[0076] 8.1Hz,2H),7.34(d,J=7.7Hz,2H),7.28–7.17(m,4H),7.08(t,J=7.5Hz,1H),6.96(d,J=2.7Hz,1H),6.00(s,1H),3.30(s,1H),2.87–2.57(m,3H),2.52–2.27(m,5H). 13 CNMR(100MHz,CDCl3)δ144.54,136.51,134.41,134.20,133.34,132.04,129.88,129.74,129.51,128.22,127.26,126.94,125.73,122.74,119.40,118.75,111.64,110.51,71.14,53.23,45.96,21.66,21.12.HRMS(ESI-TOF)Calcd.for C 25 H 22 ClN3O2S[M+H] + :464.1194;found:464.1192.

[0077] 3e:white solid,(28.3mg,57%yield), 1 H NMR(400MHz,CDCl3)δ9.41(s,1H),7.89(s,1H),7.52–7.41(m,3H),7.34(d,J=8.1Hz,2H),7.22(dd,J=15.3,7.9Hz,3H),7.10(d,J=7.5Hz,2H),6.06(s,1H),3.45(s,1H),2.97–2.67(m,3H),2.56–2.32(m,5H). 13 C NMR(100MHz,CDCl3)δ144.69,136.51,135.49,134.20,130.72,130.39,129.76,129.62,127.31,127.24,125.66,125.15,125.11,124.99,122.99,122.95,122.81,122.28,119.44,118.74,111.65,110.52,71.28,53.23,45.95,21.65,21.07.HRMS(ESI-TOF)Calcd.forC 26 H 22 F3N3O2S[M+H] + :498.1458;found:498.1456.

[0078] 3f:white solid,(36.1mg,78%yield), 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.61(d,J=8.3Hz,1H),7.48–7.31(m,6H),7.24(d,J=8.0Hz,1H),7.10(d,J=7.4Hz,2H),6.95(t,J=7.5Hz,1H),6.06(s,1H),2.95(s,2H),2.47(s,2H),2.37(s,3H),2.24(s,2H). 13CNMR(100MHz,DMSO-d6)δ144.99,138.60,137.43,134.79,133.52,132.29,130.29,130.07,128.62,128.21,127.01,125.70,122.59,119.29,118.82,113.01,110.93,52.61,46.14,21.56,20.54.HRMS(ESI-TOF)Calcd.for C 25 H 22 ClN3O2S[M+H] + :464.1194;found:464.1197.

[0079] 3g:yellow solid,(36.1mg,61%yield), 1 H NMR(400MHz,CDCl3)δ9.29(s,1H),7.46(t,J=9.5Hz,4H),7.30–7.19(m,4H),7.10(t,J=7.5Hz,1H),6.86(d,J=2.3Hz,1H),5.94(s,1H),3.22(d,J=15.2Hz,1H),2.73–2.48(m,3H),2.45(s,4H),2.35(s,3H),2.06–1.98(m,1H). 13 C NMR(100MHz,CDCl3)δ144.69,141.47,137.12,136.67,134.18,132.28,131.68,130.74,130.07,129.86,127.82,125.83,124.86,122.61,119.32,118.68,111.62,110.57,70.63,53.55,45.95,21.70,21.15,19.70.HRMS(ESI-TOF)Calcd.forC 26 H 24 ClN3O2S[M+H] + :478.1351;found:478.1352.

[0080] 3h:whitesolid,(26.1mg,69%yield), 1H NMR(400MHz,CDCl3)δ9.40(s,1H),7.47(dd,J=13.3,8.0Hz,3H),7.33(d,J=8.0Hz,2H),7.20(dd,J=14.7,7.7Hz,4H),7.10(t,J=7.5Hz,1H),7.04(d,J=7.6Hz,1H),6.03(s,1H),3.68(d,J=15.4Hz,1H),2.76–2.53(m,4H),2.40(s,4H),2.16(s,3H). 13 C NMR(100MHz,CDCl3)δ144.15,136.45,134.66,134.46,131.36,130.44,129.42,127.96,127.34,127.31,126.05,125.89,122.52,119.27,118.67,111.60,110.29,70.53,49.51,45.85,21.65,20.99,18.34.HRMS(ESI-TOF)Calcd.forC 26 H 25 N3O2S[M+H] + :444.1740;found:444.1741.

[0081] 3i:whitesolid,(34.6mg,78%yield), 1 H NMR(400MHz,CDCl3)δ9.44(s,1H),7.50–7.42(m,3H),7.34(d,J=8.0Hz,2H),7.25–7.17(m,3H),7.12–7.06(m,2H),6.78(d,J=2.0Hz,1H),5.98(s,1H),3.34(d,J=15.0Hz,1H),2.77–2.51(m,4H),2.40(s,3H),2.33(s,4H). 13 C NMR(100MHz,CDCl3)δ144.12,136.45,136.22,134.34,132.45,131.86,130.40,129.53,128.71,127.99,127.55,127.32,125.81,122.52,119.23,118.66,111.59,110.31,70.77,53.53,45.95,21.64,21.18,21.16.HRMS(ESI-TOF)Calcd.forC 26 H 25N3O2S[M+H] + :444.1740;found:444.1746.

[0082] 3j:white solid,(23.7mg,52%yield), 1 H NMR(400MHz,CDCl3)δ9.34(s,1H),7.47(d,J=8.1Hz,2H),7.40(d,J=7.9Hz,2H),7.24(d,J=7.9Hz,3H),7.12–7.07(m,1H),7.03(d,J=7.5Hz,1H),6.76(d,J=7.4Hz,1H),5.96(s,1H),3.23(d,J=15.0Hz,1H),2.70–2.54(m,2H),2.43(s,5H),2.27(s,3H),2.24(s,3H),2.02(dt,J=11.9,5.7Hz,1H). 13 C NMR(100MHz,CDCl3)δ144.32,138.22,138.04,136.66,134.43,132.70,130.54,129.64,127.85,125.94,124.15,122.42,119.18,118.63,111.58,110.48,70.40,53.78,45.88,21.67,21.19,20.52,17.13.HRMS(ESI-TOF)Calcd.for C 27 H 27 N3O2S[M+H] + :458.1897;found:458.1894.

[0083] 3k:yellow solid,(35.3mg,80%yield), 1 H NMR(400MHz,CDCl3)δ9.32(s,1H),7.44(dd,J=19.3,8.0Hz,4H),7.27–7.19(m,4H),7.11(dt,J=17.1,7.5Hz,2H),6.84(d,J=7.2Hz,1H),5.97(s,1H),3.26(d,J=15.0Hz,1H),2.74–2.41(m,7H),2.37(s,3H),2.04–1.96(m,1H). 13C NMR(100MHz,CDCl3)δ144.41,139.48,136.66,135.53,134.40,132.93,130.99,130.45,129.70,127.84,126.56,125.90,124.79,122.47,119.21,118.63,111.60,110.48,70.49,53.82,45.89,21.68,21.19,19.67.HRMS(ESI-TOF)Calcd.for C 26 H 25 N3O2S[M+H] + :444.1740;found:444.1742.

[0084] 3l:yellow solid,(21.9mg,58%yield), 1 H NMR(400MHz,CDCl3)δ10.05(s,1H),7.48(dd,J=12.4,8.0Hz,2H),7.36–7.31(m,3H),7.23(dt,J=7.6,4.0Hz,4H),7.16–7.07(m,3H),6.62(s,1H),6.52(s,1H),4.32(d,J=15.0Hz,1H),4.07(d,J=15.0Hz,1H),2.89–2.82(m,1H),2.74–2.64(m,2H),2.29–2.22(m,1H). 13 C NMR(100MHz,CDCl3)δ171.54,137.38,135.98,135.18,134.97,130.69,130.50,128.27,128.17,127.27,125.35,123.89,122.63,121.87,119.27,118.66,111.54,110.40,70.18,54.03,46.12,20.95.HRMS(ESI-TOF)Calcd.for C 25 H 21 N3O[M+H] + :380.1757;found:380.1754.

[0085] 3m:white solid,(26.3mg,75%yield), 1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.54(d,J=8.0Hz,1H),7.38(d,J=7.9Hz,2H),7.24–7.13(m,3H),7.05(t,J=7.7Hz,1H),6.96(t,J=7.4Hz,1H),6.28(s,1H),4.03(s,2H),3.08(d,J=5.9Hz,2H),3.00(s,3H),2.74(d,J=6.1Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ136.51,133.73,130.74,130.22,127.83,127.37,127.21,126.62,126.59,121.94,119.12,118.52,112.39,109.42,69.46,48.61,47.68,38.31,17.81.HRMS(ESI-TOF)Calcd.for C 19 H 19 N3O2S[M+H] + :354.1271;found:354.1273.

[0086] 3n:white solid,(33.7mg,80%yield), 1 H NMR(400MHz,CDCl3)δ9.53(s,1H),7.52(d,J=7.9Hz,1H),7.46–7.31(m,6H),7.26–7.21(m,1H),7.14(dt,J=15.2,7.9Hz,3H),7.01(d,J=7.3Hz,1H),6.33(s,1H),5.46(d,J=12.5Hz,1H),5.26(d,J=12.5Hz,1H),4.20(d,J=15.1Hz,1H),3.99(d,J=15.1Hz,1H),2.86(ddd,J=16.3,11.5,5.5Hz,1H),2.69(dt,J=16.3,5.0Hz,2H),2.37(s,4H). 13C NMR(100MHz,CDCl3)δ156.15,135.95,135.91,135.37,134.69,131.71,129.04,128.69,128.30,127.87,126.52,126.34,125.62,124.08,122.39,119.25,118.70,111.40,109.95,69.15,67.97,50.44,45.54,21.00,18.65.HRMS(ESI-TOF)Calcd.for C 27 H 25 N3O2[M+H] + :424.2020;found:424.2021.

[0087] 3o:yellow solid,(16.3mg,47%yield), 1 H NMR(400MHz,CDCl3)δ9.66(s,1H),7.50(d,J=7.9Hz,1H),7.41(d,J=8.1Hz,1H),7.29–7.08(m,6H),6.28(s,1H),4.44(dq,J=10.7,7.2Hz,1H),4.28–4.17(m,2H),3.88(d,J=14.8Hz,1H),2.89–2.80(m,1H),2.72–2.63(m,2H),2.35(td,J=12.1,11.7,4.0Hz,1H),1.35(t,J=7.1Hz,3H). 13 C NMR(100MHz,CDCl3)δ156.38,135.84,135.66,131.82,130.10,127.19,126.81,126.06,125.56,124.47,122.35,119.18,118.68,111.36,109.84,69.24,62.45,54.54,45.68,21.12,14.49.HRMS(ESI-TOF)Calcd.forC 21 H 21 N3O2[M+H] + :348.1707;found:348.1704.

[0088] 3p:yellow solid,(35.1mg,85%yield), 1H NMR(400MHz,CDCl3)δ10.06(s,1H),7.48(dd,J=15.0,8.0Hz,2H),7.37(t,J=7.4Hz,1H),7.22(ddd,J=29.0,14.3,7.8Hz,6H),7.08(q,J=8.6,8.0Hz,2H),6.47(s,1H),6.40(d,J=1.9Hz,1H),4.25(d,J=14.8Hz,1H),3.99(d,J=14.7Hz,1H),2.84(td,J=11.0,5.8Hz,1H),2.75–2.64(m,2H),2.28(dt,J=11.7,5.7Hz,1H). 13 C NMR(100MHz,CDCl3)δ171.31,137.90,136.04,135.10,132.51,130.91,130.60,130.02,128.50,128.19,127.91,127.02,125.48,125.46,122.57,119.23,118.69,111.55,110.44,70.16,53.82,46.12,20.98.HRMS(ESI-TOF)Calcd.for C 25 H 20 ClN3O[M+H] + :414.1368;found:414.1365.

[0089] 3q:white solid,(30.1mg,73%yield), 1 H NMR(400MHz,CDCl3)δ10.10(s,1H),7.48(dd,J=16.7,8.0Hz,2H),7.40–7.33(m,2H),7.29–7.16(m,5H),7.10(t,J=7.5Hz,1H),6.98(dd,J=8.5,2.1Hz,1H),6.48(s,1H),6.28(d,J=8.5Hz,1H),4.26(d,J=14.8Hz,1H),3.96(d,J=14.8Hz,1H),2.85(td,J=11.1,6.0Hz,1H),2.76–2.63(m,2H),2.27(td,J=12.3,11.8,4.1Hz,1H). 13C NMR (100MHz, CDCl3) δ171.17,136.01,135.93,135.34,133.59,130.96,130.43,130.29,130.01,128.57,128.35,128. 20,125.47,122.58,119.25,119.06,118.72,111.55,110.45,70.19,53.98,46.21,20.99.HRMS(ESI-TOF)Calcd.forC 25 H 20 BrN3O[M+H] + :458.0863; found:458.0861.

[0090] 6. At room temperature, compound 1 (0.15 mmol), compound 5 (0.1 mmol) and cesium carbonate (0.2 mmol) were dissolved in dichloromethane (3 mL). After 3 hours of reaction, thin layer chromatography showed that the reaction was complete. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography and eluted with (petroleum ether / ethyl acetate 10:1 or 2:1) to obtain a series of compounds 6. The specific compound 1 used, the prepared compound 6 and the yield of the corresponding compound 6 are shown in Table 4.

[0091] Table 4 Comparison of the effects of the substituents of compound 1 on the product

[0092]

[0093]

[0094] The results show that compound 5 can also successfully complete the cycloaddition reaction with compound 1 using the method of the present invention, and the yield of isoquinolinoquinazoline (compound 6a) is 74%. When the N-protecting group of compound 1a is changed from p-toluenesulfonyl (Ts) to benzyloxycarbonyl (COOBn) or p-bromobenzenesulfonyl (Bs), the reaction can also proceed normally. After a series of substitutions are performed on compound 1a, the reaction can also proceed smoothly.

[0095] The NMR data of each compound 6 synthesized in this step are as follows:

[0096] 6a: yellow solid, (28.8mg, 74% yield), 1H NMR(400MHz,CDCl3)δ7.82(d,J=8.2Hz,1H),7.69–7.62(m,1H),7.49(d,J=7.9Hz,2H),7.20–7.09(m,5H),7.03(d,J=6.8Hz,2H),6.78(d,J=7.6Hz,1H),6.32(s,1H),3.42(s,2H),3.10(t,J=6.6Hz,2H),2.83(s,2H),2.35(s,3H). 13 C NMR(100MHz,CDCl3)δ143.35,135.81,135.05,133.53,130.33,128.91,128.50,128.10,127.50,127.23,126.86,126.78,126.74,126.56,125.65,72.06,47.67,47.59,23.42,21.57.HRMS(ESI-TOF)Calcd.for C 23 H 22 N2O2S[M+H] + :391.1475;found:391.1476.

[0097] 6b:yellow solid,(35.8mg,83%yield), 1 H NMR(400MHz,CDCl3)δ7.82(dd,J=8.1,1.2Hz,1H),7.55–7.49(m,3H),7.17–7.10(m,5H),7.05(td,J=7.9,1.5Hz,2H),6.35(s,1H),3.48(s,2H),3.26(s,2H),2.85(d,J=22.5Hz,2H),2.36(s,3H). 13 C NMR(100MHz,CDCl3)δ143.75,135.69,135.10,135.01,132.94,132.16,129.12,128.91,128.23,127.80,127.76,127.28,126.73,126.41,125.04,71.50,47.73,45.60,22.37,21.70.HRMS(ESI-TOF)Calcd.for C 23 H 21 ClN2O2S[M+H] + :425.1085;found:425.1093.

[0098] 6c:white solid,(32.7mg,87%yield), 1 H NMR(400MHz,CDCl3)δ7.69(d,J=8.8Hz,1H),7.61–7.57(m,1H),7.53(d,J=7.9Hz,2H),7.28(dd,J=8.7,2.1Hz,1H),7.19–7.11(m,4H),7.04(d,J=7.2Hz,1H),6.94(d,J=2.2Hz,1H),6.39(s,1H),3.59–3.37(m,2H),3.15(t,J=6.7Hz,2H),2.84(t,J=6.4Hz,2H),2.37(s,3H). 13 C NMR(100MHz,CDCl3)δ143.79,135.76,135.06,132.92,132.03,130.24,129.91,129.24,128.75,128.33,128.16,127.36,126.86,119.19,77.36,47.63,23.16,21.71.HRMS(ESI-TOF)Calcd.forC 23 H 21 BrN2O2S[M+H] + :469.0580;found:469.0581.

[0099] 6e:white solid,(27.6mg,49%yield), 1 H NMR(400MHz,CDCl3)δ8.14(s,1H),7.60–7.55(m,1H),7.53(d,J=7.9Hz,2H),7.23(s,1H),7.14(d,J=8.2Hz,4H),7.04(t,J=4.3Hz,1H),6.90(d,J=8.0Hz,1H),6.38(s,1H),3.53(s,2H),3.20(t,J=6.7Hz,2H),2.93–2.76(m,2H),2.36(s,3H). 13 C NMR(100MHz,CDCl3)δ143.95,135.56,134.94,134.23,133.46,132.93,129.25,128.82,128.25,128.00,127.54,127.16,126.96,123.29,122.05,77.36,47.77,47.38,22.96,21.71.HRMS(ESI-TOF)Calcd.for C24 H 21 F3N2O2S[M+H] + :459.1349;found:459.1355.

[0100] 6h:white solid,(29.1mg,72%yield), 1 H NMR(400MHz,CDCl3)δ7.69(d,J=8.2Hz,1H),7.56(dd,J=6.7,2.2Hz,1H),7.50(d,J=8.1Hz,2H),7.11(d,J=7.8Hz,4H),7.07(d,J=7.9Hz,1H),7.05–7.00(m,1H),6.86(d,J=7.5Hz,1H),6.32(s,1H),3.35(s,2H),3.23(s,2H),2.73(s,2H),2.35(s,3H),1.95(s,3H). 13 C NMR(100MHz,CDCl3)δ143.29,136.12,135.12,134.96,133.54,133.22,128.89,128.72,128.32,127.59,127.38,126.97,126.69,126.34,124.49,47.86,45.59,22.62,21.67,18.37.HRMS(ESI-TOF)Calcd.forC 24 H 24 N2O2S[M+H] + :405.1631;found:405.1641.

[0101] 6u:yellow solid,(30.5mg,76%yield), 1 H NMR(400MHz,CDCl3)δ7.58(d,J=8.0Hz,2H),7.50(d,J=7.9Hz,2H),7.10(t,J=9.3Hz,5H),7.02(d,J=7.1Hz,1H),6.51(d,J=8.3Hz,1H),6.34(s,1H),3.65(s,3H),3.46(d,J=20.8Hz,2H),3.28(s,2H),2.86(s,2H),2.34(s,3H). 13C NMR(100MHz,CDCl3)δ155.82,143.32,136.13,135.29,134.06,133.53,129.01,128.81,128.29,127.51,126.75,126.67,126.62,118.33,118.17,106.74,71.50,55.31,47.96,42.40,22.20,21.69.HRMS(ESI-TOF)Calcd.for C 24 H 24 N2O3S[M+H] + :421.1580;found:421.1588.

[0102] 6v:white solid,(24.3mg,58%yield), 1 H NMR(400MHz,CDCl3)δ7.74–7.69(m,1H),7.59(d,J=7.9Hz,2H),7.21(d,J=8.0Hz,2H),7.14–7.10(m,2H),7.07(t,J=8.0Hz,1H),7.02–6.97(m,1H),6.76(d,J=8.3Hz,1H),6.53(d,J=7.5Hz,1H),6.26–6.05(m,1H),3.74(s,3H),3.41(s,2H),2.90(s,2H),2.76(t,J=6.2Hz,2H),2.41(s,3H). 13 C NMR(100MHz,CDCl3)δ156.45,143.28,137.47,135.71,133.90,129.11,129.02,128.25,128.19,127.73,127.50,126.49,118.97,111.14,55.98,49.83,47.44,25.52,21.69.HRMS(ESI-TOF)Calcd.for C 24 H 24 N2O3S[M+H] + :421.1580;found:421.1589.

[0103] 6w:yellow solid,(30.4mg,65%yield), 1H NMR(400MHz,CDCl3)δ7.89(d,J=8.5Hz,1H),7.67(s,1H),7.41(ddt,J=50.2,34.2,8.1Hz,8H),7.13(d,J=9.4Hz,4H),7.03(d,J=9.9Hz,2H),6.34(s,1H),3.50(s,2H),3.15(s,2H),2.88(d,J=21.3Hz,2H),2.35(s,3H). 13 C NMR(100MHz,CDCl3)δ143.55,140.17,138.35,135.97,135.16,133.62,132.90,130.39,129.13,128.88,128.69,128.24,127.71,127.49,127.34,127.00,126.92,126.78,125.68,125.33,72.21,47.82,47.78,23.39,21.71.HRMS(ESI-TOF)Calcd.for C 29 H 26 N2O2S[M+H] + :467.1788;found:467.1794.

[0104] 6x:white solid,(29.6mg,80%yield), 1 H NMR(400MHz,CDCl3)δ7.74(d,J=8.2Hz,1H),7.40–7.30(m,5H),7.23–7.19(m,1H),7.17–7.11(m,2H),7.06(dt,J=7.2,3.2Hz,2H),6.98(t,J=7.4Hz,1H),6.93(dd,J=7.7,1.6Hz,1H),6.49(s,1H),5.36–5.25(m,2H),3.98–3.84(m,2H),3.48(ddd,J=13.5,10.1,6.6Hz,1H),3.25(ddd,J=13.6,7.1,2.4Hz,1H),3.14(ddd,J=17.3,10.1,7.1Hz,1H),2.70(ddd,J=17.5,6.8,2.2Hz,1H). 13CNMR(100MHz, CDCl3)δ155.09,136.09,134.97,134.59,133.49,128.72,128.53,128.12,127.98,127.50,127.44 ,126.57,126.45,126.33,126.27,124.97,124.06,69.76,68.00,48.08,47.83,23.08.HRMS(ESI-TOF)Calcd.for C 24 H 22 N2O2[M+H] + :371.1754; found:371.1759.

[0105] 6y: white solid, (27.6mg, 61% yield), 1 H NMR (400MHz, CDCl3) δ7.82(d,J=8.2Hz,1H),7.57(d,J=6.9Hz,1H),7.45(s,4H),7.16(dt,J=18.5,6.2Hz,3H),7.0 2(d,J=7.2Hz,2H),6.79(d,J=7.7Hz,1H),6.31(s,1H),3.47(s,2H),3.15(t,J=6.7Hz,2H),2.84(t,J=6.7Hz,2H). 13 C NMR (100MHz, CDCl3) δ137.79,134.95,133.02,132.93,131.43,129.87,129.68,128.66,127.65, 126.93,126.86,126.77,126.62,126.01,72.25,47.58,47.16,22.77.HRMS(ESI-TOF)Calcd.for C 22 H 19 BrN2O2S[M+H] + :455.0423; found:455.0424.

[0106] The embodiments described above are only descriptions of the preferred modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations, modifications, and substitutions made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for synthesizing a polycyclic nitrogen heterocyclic compound, characterized in that: The method is carried out by the following reaction equation: R=Ts,Bz,Ms,COOBn,COOEt,Boc,Bs R 1 =H,Cl,Br,CF3,CH3,OMe,Ph R 2 =H,Ph。 2. The method according to claim 1, characterized in that: The method comprises the following steps: dissolving N-(o-chloromethyl)arylamide or its derivative, dihydro-β-carboline or 3,4-dihydroisoquinoline in a solvent, adding a base, and stirring at 0-40° C. for more than 3 hours to obtain the polycyclic nitrogen heterocyclic compound.

3. The method according to claim 1, characterized in that: The solvent is an organic solvent, which is any one of dichloromethane, toluene, ether, acetonitrile, tetrahydrofuran or chloroform.

4. The method according to claim 1, characterized in that: The base is any one of cesium carbonate, potassium bicarbonate, potassium carbonate and sodium bicarbonate.

5. The method according to claim 1, characterized in that: In terms of molar ratio, N-(o-chloromethyl)arylamide or its derivative: dihydro-β-carboline or 3,4-dihydroisoquinoline: base = (1-2): 1:

2.

6. A polycyclic nitrogen heterocyclic compound prepared by the method according to any one of claims 1 to 5.

7. The polycyclic nitrogen heterocyclic compound according to claim 6, characterized in that: The compound structural formula is:

8. The polycyclic nitrogen heterocyclic compound according to claim 7, characterized in that: The compound is any one of the following compounds:

9. The polycyclic nitrogen heterocyclic compound according to claim 6, characterized in that: The compound structural formula is:

10. The polycyclic nitrogen heterocyclic compound according to claim 9, characterized in that: The compound is any one of the following compounds:

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