A method for synthesizing polycyclic tetrahydroisoquinoline compounds and derivatives by a tandem cyclization strategy

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing polycyclic tetrahydroisoquinoline compounds and derivatives by a tandem cyclization strategy. The method comprises the following steps: (1) obtaining an o-alkynyl aryl aldehyde (ketone) compound with a primary amine at the end of the alkyne side chain by a Sonogashira coupling reaction and a tert-butyloxy carbonyl protection group; (2) obtaining isoquinoline salt by deprotection and tandem cyclization of the compound; (3) obtaining a series of polycyclic tetrahydroisoquinoline compounds and derivatives by further reduction of the isoquinoline salt without separation; the application is also applicable to rapid synthesis of berberine, tetrahydroberberine and numerous berberine derivatives; and the application has the advantages of easy-to-obtain raw materials, simple steps, simple operation, high ring formation efficiency, strong functional group tolerance and good reaction selectivity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing polycyclic tetrahydroisoquinoline compounds using a tandem cyclization strategy. Background Technology

[0002] Isoquinoline alkaloids constitute the largest family of alkaloids in nature, widely distributed in the metabolites of plants, animals, and microorganisms from terrestrial to deep-sea environments. They are structurally based on isoquinoline and tetrahydroisoquinoline (THIQ), with most possessing complex polycyclic molecular structures and abundant stereocenters and diverse functional group modifications. Many isoquinoline and tetrahydroisoquinoline alkaloids exhibit remarkable physiological and pharmacological activities, including antibacterial, antiviral, and anticancer effects. The clinical application of these alkaloids has long been booming. For example, berberine, an isoquinoline alkaloid derived from plants, has been widely used to treat gastroenteritis since ancient times; recent studies have shown it to be a promising candidate drug for the prevention and treatment of COVID-19 and SARS. Quinoccardin, a typical tetrahydroisoquinoline alkaloid, was first isolated from Streptomyces, and its citrate (KW2152) exhibits excellent antitumor activity and has entered clinical trials in Japan. Trabectin (ET743) is another well-known marine bis(tetrahydroisoquinoline) alkaloid from the Caribbean sea squirt and has been approved for the treatment of advanced soft tissue sarcoma.

[0003] The synthesis of isoquinolines and tetrahydroisoquinoline alkaloids has always been a research hotspot in the field of organic chemistry. For complex polycyclic tetrahydroisoquinoline alkaloids, the construction of the polycyclic structure is paramount and crucial. In the past, the most widely used methods were stepwise cyclization methods based on the Pictet-Spengler and Bischler-Napieralski reactions. However, these methods all suffer from one or more of the following problems:

[0004] (1) The ring is formed step by step, resulting in low efficiency.

[0005] (2) The electron cloud density of the aromatic ring of the reactant is very high, making it difficult to obtain the tetrahydroisoquinoline structure with electron-deficient group-substituted aromatic ring.

[0006] (3) When there are multiple cyclization sites on the aromatic ring, the position selectivity of the reaction is poor.

[0007] (4) Only tetrahydroisoquinoline can be obtained directly; isoquinoline salt structures cannot be obtained directly through this type of reaction.

[0008] Therefore, developing a method that has high cyclization efficiency, strong functional group tolerance, good reaction selectivity, and can simultaneously obtain polycyclic isoquinoline salts and tetrahydroisoquinoline compounds would be of great significance. Summary of the Invention

[0009] The purpose of this invention is to provide a rapid and efficient method for synthesizing polycyclic tetrahydroisoquinoline compounds and their derivatives, which features readily available raw materials, simple steps, easy operation, high cyclization efficiency, strong functional group tolerance, and excellent reaction selectivity.

[0010] This invention addresses the aforementioned technical problems in the prior art, and the technical solution is as follows: A method for synthesizing polyfused cyclic tetrahydroisoquinoline compounds and their derivatives using a tandem cyclization strategy, with the following reaction route:

[0011]

[0012] In Formula I, X is bromine, iodine, or trifluoromethanesulfonate; Ar is an aromatic ring or an aromatic heterocycle; and R... 1 It is composed of hydrogen, alkyl, or cycloalkyl groups connected to Ar substituents;

[0013] In Formula II, G represents alkyl, cycloalkyl, aryl, heteroaryl, ether, cyclic ether, thioether, cyclic thioether, tertiary amine, or cyclic tertiary amine; Boc represents tert-butyloxycarbonyl.

[0014] In Equation II, m and n are integers greater than or equal to 0.

[0015] Preferably, Ar in Formula I is selected from any one of benzene ring, naphthalene ring, thiophene, substituted thiophene, indole, substituted indole, pyridine, substituted pyridine, furan, and substituted furan.

[0016] Preferably, Ar in Formula I has a substituent, wherein the substituent is a 1,3-dioxopentane composed of alkyl, alkoxy, halogen, cyano, phenolic hydroxyl, trifluoromethoxy, ester, trifluoromethyl, nitro, or a substituent at an adjacent position, i.e. One or more of them.

[0017] Preferably, in Formula II, m = 0, 1, 2, and n = 0, 1, 2.

[0018] Preferably, the method specifically includes the following steps:

[0019] (1) The o-haloarene formaldehyde or o-haloarene ketone shown in Formula I and the terminal alkyne of the primary amine protected by the tert-butyloxycarbonyl group shown in Formula II are coupled via the Sonogashira reaction to obtain the o-alkynylarene formaldehyde or o-alkynyl ketone compound of the alkyne side chain protected by the tert-butyloxycarbonyl group shown in Formula III.

[0020] (2) The compound shown in Formula III undergoes deprotection and tandem cyclization reaction to obtain the isoquinoline salt compound shown in Formula IV;

[0021] (3) The compound shown in Formula IV was reduced to obtain the polycyclic tetrahydroisoquinoline compound shown in Formula V.

[0022] Preferably, in step (1), the catalyst used for the Sonogashira coupling reaction of Formula I and Formula II is any one or a combination of several of tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or cuprous iodide; the solvent is triethylamine and N,N-dimethylformamide; and the additive is tetrabutylammonium iodide.

[0023] Preferably, the Sonogashira coupling reaction conditions of Formula I and Formula II in step (1) are as follows: under nitrogen protection, Formula I, Formula II, tetrakis(triphenylphosphine)palladium, and cuprous iodide are reacted at 65°C for 4 hours in deoxytriethylamine and N,N-dimethylformamide. More preferably, the reaction further includes the following separation and purification steps: adding a saturated ammonium chloride solution, extracting with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying the residue by silica gel column chromatography.

[0024] Preferably, the Sonogashira coupling reaction conditions of Formula I and Formula II in step (1) can also be as follows: under nitrogen protection, Formula I is stirred at 80°C for 20 minutes with bis(triphenylphosphine)palladium dichloride, cuprous iodide and tetrabutylammonium iodide in deoxytriethylamine and N,N-dimethylformamide, then Formula II is added, and the reaction is continued at 80°C for 2 hours. More preferably, the reaction also includes the following separation and purification steps: adding a saturated ammonium chloride solution, then extracting with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, and purifying the residue by silica gel column chromatography.

[0025] Preferably, in step (2), the deprotection of formula III is performed using dichloromethane and trifluoroacetic acid. The solvent used for the tandem cyclization reaction is 1,2-dichloroethane and trifluoroacetic acid.

[0026] Preferably, the catalyst used in the tandem cyclization reaction is a metal salt. More preferably, the catalyst is a monovalent silver salt such as silver nitrate, silver trifluoromethanesulfonate, or silver trifluoroacetate, or a trivalent gold salt such as gold chloride or gold acetate, or a monovalent gold salt such as (triphenylphosphine) gold chloride, or palladium acetate. Preferably, the reaction conditions for the deprotection and tandem cyclization reaction of formula III in step (2) are as follows: a dichloromethane solution of formula III is added to trifluoroacetic acid at 0°C, reacted at 25°C for 3 hours, and then evaporated to dryness; silver nitrate is added, and the mixture is refluxed in 1,2-dichloroethane under nitrogen protection for 3 hours, and then evaporated to dryness to obtain formula IV.

[0027] Preferably, the reaction conditions for the deprotection and tandem cyclization reaction of Formula III in step (2) can also be as follows: add trifluoroacetic acid to the dichloromethane solution of Formula III at 0°C, react at 25°C for 3 hours, and evaporate to dryness; add silver nitrate, reflux in 1,2-dichloroethane and trifluoroacetic acid under nitrogen protection for 5 hours, and evaporate to dryness to obtain Formula IV.

[0028] Preferably, in step (3), the reduction reaction of formula IV uses NaBH4 with methanol, NaBH3CN with methanol, or NaBH(OAc)3 with 1,2-dichloroethane, preferably NaBH4 with methanol.

[0029] Preferably, the reduction reaction conditions for formula IV in step (3) are as follows: NaBH4 is added to the methanol solution of formula IV at 0°C, and the reaction is allowed to proceed naturally at room temperature. More preferably, the following separation and purification steps are also included: water is added for quenching, the mixture is evaporated to dryness, and the residue is purified by silica gel column chromatography.

[0030] This invention also provides a novel polycyclic tetrahydroisoquinoline compound with the following structural formula:

[0031]

[0032] in:

[0033] Ar is an aromatic ring or an aromatic heterocyclic ring, R 1 It is composed of hydrogen, alkyl, or cycloalkyl groups connected to Ar substituents;

[0034] G is an alkyl, cycloalkyl, aryl, heteroaryl, ether, cyclic ether, thioether, cyclic thioether, tertiary amine, or cyclic tertiary amine;

[0035] m and n are integers greater than or equal to 0.

[0036] Preferably, in the structural formula, Ar is selected from any one of benzene ring, substituted benzene ring, naphthalene ring, substituted naphthalene ring, thiophene, substituted thiophene, indole, substituted indole, pyridine, substituted pyridine, furan, and substituted furan.

[0037] Preferably, in the structural formula, when Ar has a substituent, the substituent is a 1,3-dioxopentane composed of alkyl, alkoxy, halogen, cyano, phenolic hydroxyl, trifluoromethoxy, ester, trifluoromethyl, nitro, or a substituent at an adjacent position, i.e. One or more of them.

[0038] Preferably, in the structural formula, m = 0, 1, 2, and n = 0, 1, 2.

[0039] Preferably, the structural formula of the polycyclic tetrahydroisoquinoline compound is as follows:

[0040]

[0041] Compared with existing technologies, the advantages of this invention are as follows: This invention provides a rapid and efficient method for synthesizing polyfused cyclic tetrahydroisoquinoline compounds using a tandem cyclization strategy. The method uses o-haloaryl formaldehyde or o-haloaryl ketone and terminal alkynes with tert-butoxycarbonyl-protected primary amines as raw materials, and prepares a tandem reaction precursor via Sonogashira coupling. Then, through a series of non-separation operations such as deprotection, tandem intramolecular cyclization, and reduction, a series of polyfused cyclic isoquinoline salts and tetrahydroisoquinoline compounds can be obtained, and this method has been successfully applied to the synthesis of berberine, tetrahydroberberine, and numerous berberine derivatives. This invention has the advantages of readily available raw materials, simple steps, convenient operation, high cyclization efficiency, strong functional group tolerance, and excellent reaction selectivity, providing a new and important route for synthesizing structurally complex polyfused cyclic isoquinoline salts and tetrahydroisoquinoline compounds. Attached image description:

[0042] Figure 1 It is the general formula for the synthesis route 1.

[0043] Figure 2 It is the general formula for the synthesis route, Formula 2.

[0044] Figure 3 It is the general formula for the synthesis route, 3. Detailed implementation method:

[0045] In this invention: halogens are fluorine, chlorine, bromine, or iodine. Tert-butyloxycarbonyl is represented by Boc. Trifluoromethanesulfonic acid is represented by Tf. Triethylamine is represented by TEA. N,N-dimethylformamide is represented by DMF. Tetrabutylammonium iodide is represented by TBAI. 1,2-Dichloroethane is represented by DCE. Trifluoroacetic acid is represented by TFA. Dichloromethane is represented by DCM. "Substitution" refers to the replacement of hydrogen atoms in a molecule with other different atoms or molecules.

[0046] The raw materials used in this invention, o-haloaryl formaldehyde or o-haloaryl ketone as shown in Formula I and terminal alkyne with Boc-protected primary amine as shown in Formula II, were purchased from reagent companies or synthesized by ourselves according to existing literature.

[0047] Example 1:

[0048] 1. Synthesis steps: Formula I Formula II (0.02 eq.) and CuI (0.02 eq.) were added under nitrogen protection with a deoxygenated TEA:DMF ratio of 3:1. The system was stirred at 65 °C for 4 hours. A saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain o-alkynyl carboxaldehydes or o-alkynyl ketones with Boc-protected primary amines at the end of the alkyne side chain, which are compounds of formula III. The compound (0.2 mmol) was dissolved in 4 mL of dichloromethane. 0.4 mL of trifluoroacetic acid was added at 0 °C, and the reaction was carried out at 25 °C for 3 hours, followed by rotary evaporation to dryness. Silver nitrate (0.1 eq.) was added, and the mixture was refluxed in 4 mL of 1,2-dichloroethane under nitrogen protection for 3 hours, followed by rotary evaporation to dryness. 4 mL of methanol was added, and NaBH4 (4.0 eq.) was added at 0 °C. The reaction was then carried out at 25 °C for 1 hour. 0.1 mL of water was added, and the mixture was rotary evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the final product. The general synthetic route is as follows: Figure 1 As shown.

[0049] 2. Experimental Results:

[0050] The yield is calculated as (product mass / product molecular weight) / (starter mass / starter molecular weight) × 100%, and the same applies below. The yield is 75%. 1 H NMR (400MHz, CDCl3): δ6.54(s,1H),6.50(s,1H),3.82(s,3H),3.82(s,3H),3.77(d,J=14.8Hz,1H),3.33(d,J=14.7Hz,1H),3.10–3.05( m,1H),2.72–2.61(m,2H),2.26–2.19(m,1H),2.12(td,J=11.2,4.5Hz,1H),1.86–1.76(m,2H),1.73–1.62(m,2H),1.42–1.20(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ147.7,147.3,126.1,125.9,110.9,109.0,58.4,58.1,56.2,56.1,56.0,36.5,33.6,25.9,24.4ppm.HRMS(ESI):calc'd for C 15 H 22 NO2 + [M+H] + :248.1645,found:248.1650.

[0051] Example 2:

[0052] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0053] 2. Experimental Results:

[0054] The yield was 77%.1 H NMR (400MHz, CDCl3): δ6.60 (s, 1H), 6.55 (s, 1H), 4.04 (d, J = 14.2Hz, 1H), 3.84 (s, 3H),3.83(s,3H),3.39(d,J=14.2Hz,1H),3.26(td,J=8.7,2.6Hz,1H),2.89(dd,J =15.6,3.9Hz,1H),2.65(dd,J=15.5,10.6Hz,1H),2.37(s,1H),2.33–2.27(m,1H) ,2.12–2.04(m,1H),1.98–1.88(m,1H),1.86–1.76(m,1H),1.60–1.50(m,1H)ppm. 13 C NMR (101MHz, CDCl3): δ147.7,147.4,126.6,126.3,111.7,109.6,60.9,56.0,56.0,55.1,54.6,35.2,30.8,21.7ppm.HRMS(ESI):calc'd for C 14 H 20 NO2 + [M+H] + :234.1489,found:234.1489.

[0055] Example 3:

[0056] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0057] 2. Experimental Results:

[0058] The yield was 64%. 1 H NMR (400MHz, CDCl3): δ6.57(s,1H),6.51(s,1H),4.10–3.94(m,2H),3.82(s,3H),3.81(s,3H),3.22(ddd,J=13 .9,7.5,2.7Hz,1H),3.09–2.98(m,3H),2.71(dd,J=15.6,3.1Hz,1H),1.97–1.80(m,5H),1.72–1.56(m,3H)ppm. 13C NMR (101MHz, CDCl3): δ148.4,147.9,125.6,123.5,111.2,109.1,61.7,57.1,56.1,56.0,55.2,35.4,32.1,27.8,25.1,25.0ppm.HRMS(ESI):calc'd for C 16 H 24 NO2 + [M+H] + :262.1802,found:262.1802.

[0059] Example 4:

[0060] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0061] 2. Experimental Results:

[0062] The yield was 77%. 1 H NMR (400MHz, CDCl3): δ7.32–7.22(m,4H),6.72(s,1H),6.62(s,1H),4.33(d,J=11.2Hz,1H),4.12(d,J=13.9Hz ,1H),3.88(s,3H),3.86–3.83(m,4H),3.77–3.71(m,2H),3.26(dd,J=14.9,3.4Hz,1H),2.98–2.89(m,1H)ppm. 13 C NMR (101MHz, CDCl3): δ147.6,147.4,143.2,140.1,127.4,127.1,126.9,126.1,122 .5,121.2,112.3,109.8,64.4,58.1,56.0,56.0,54.1,33.6ppm.HRMS(ESI):calc'd forC 18 H 20 NO2 + [M+H] + :282.1489,found:282.1490.

[0063] Example 5:

[0064] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0065] 2. Experimental Results:

[0066] Yield: 60%. 1 H NMR (400MHz, CDCl3): δ7.17–7.10(m,2H),7.08–7.06(m,1H),7.03–7.00(m,1H),4.05(d,J=15 .3Hz,1H),3.58(d,J=15.3Hz,1H),3.24(ddd,J=11.9,4.4,2.5Hz,1H),2.93(dd,J=17.0,10.8H z,1H),2.82(dd,J=17.0,4.4Hz,1H),2.55(t,J=11.4Hz,1H),2.33(td,J=11.5,3.1Hz,1H),1. 96–1.75(m,4H),1.57(tdd,J=13.4,10.3,3.2Hz,1H),1.44(ddt,J=15.9,12.1,3.3Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ133.0,132.1,128.3,126.9,126.2,126.1,58.6,57.4,55.7,35.5,32.4,25.0,23.5ppm.HRMS(ESI):calc'd for C 13 H 18 N + [M+H] + :188.1434,found:188.1430.

[0067] Example 6:

[0068] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0069] 2. Experimental Results:

[0070] The yield was 68%. 1H NMR (400MHz, CDCl3): δ7.07–7.03(m,2H),6.93(d,J=8.1Hz,1H),3.83(d,J=15.3Hz,1H),3.33(d,J=15.3Hz,1H),3.10–3.05(m,1H),2.77–2. 65(m,2H),2.26–2.19(m,1H),2.12(td,J=11.4,3.8Hz,1H),1.89–1.82(m,1H),1.81–1.77(m,1H),1.76–1.65(m,2H),1.41–1.28(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ135.9,132.7,131.8,127.9,127.4,125.9,58.1,57.8,56.2,36.6,33.5,25.8,24.2ppm.HRMS(ESI):calc'd for C 13 H 17 ClN + [M+H] + :222.1044,found:222.1046.

[0071] Example 7:

[0072] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0073] 2. Experimental Results:

[0074] Yield: 39%. 1 H NMR (400MHz, CDCl3): δ6.96 (dd, J=8.4, 5.7Hz, 1H), 6.82–6.73 (m, 2H), 3.84 (d, J=14.9Hz, 1H), 3.33 (d, J=14.9Hz, 1H), 3.09 (dt, J=11.8, 3.1Hz, 1H), 2.80–2.67(m,2H),2.27–2.19(m,1H),2.13(td,J=11.4,4.0Hz,1H),1.87– 1.83(m,1H),1.81–1.77(m,1H),1.76–1.65(m,2H),1.38–1.32(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ

[0075] 161.4(d,J=243.5Hz),136.0(d,J=7.3Hz),129.9,127.5(d,J=8.1Hz),114.4(d,J=20.5H z),112.9(d,J=21.5Hz),58.1,57.8,56.2,36.9,33.6,25.9,24.3ppm.HRMS(ESI):calc'd for C 13 H 17 FN + [M+H] + :206.1340,found:206.1340.

[0076] Example 8:

[0077] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0078] 2. Experimental Results:

[0079] Yield: 39%. 1 H NMR (400MHz, CDCl3): δ7.39–7.35(m,2H),7.10(d,J=7.8Hz,1H),3.92(d,J=16.3Hz,1H),3.41(d,J=16.2Hz,1H),3.10(dt,J=12.1,4.1Hz,1H),2. 83–2.69(m,2H),2.31–2.24(m,1H),2.15(td,J=11.7,3.4Hz,1H),1.90–1 .85(m,1H),1.83–1.78(m,1H),1.77–1.62(m,2H),1.38–1.31(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ139.8,135.5,132.0,129.3,126.9,119.2,110.2,58.1,57.9,56.1,36.3,33.4,25.8,24.1ppm.HRMS(ESI):calc'd for C 14 H 17 N2 + [M+H] + :213.1386,found:213.1387.

[0080] Example 9:

[0081] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0082] 2. Experimental Results:

[0083] The yield was 57%. 1 H NMR (400MHz, CDCl3): δ6.54(s,1H),6.50(s,1H),3.89(dd,J=11.1,1.8Hz,2H),3.81(s,6H),3.79–3.72(m,2H),3.38(d ,J=14.6Hz,1H),3.35–3.29(m,1H),2.87(dt,J=11.7,2.0Hz,1H),2.55–2.49(m,3H),2.45(td,J=11.6,3.5Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ147.8,147.4,125.5,124.6,111.2,109.1,72.0,67.3,57.1,56.9,56.0,56.0,54.3,30.2ppm.HRMS(ESI):calc'd for C 14 H 20 NO3 + [M+H] + :250.1438,found:250.1429.

[0084] Example 10:

[0085] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is (The synthetic method is referenced in Chem. Eur. J., 2008, 14, 6173–6183), Formula III is...

[0086] 2. Experimental Results:

[0087] The yield was 71%. 1H NMR (400MHz, CDCl3): δ6.53(s,1H),6.50(s,1H),3.82(s,3H),3.81(s,3H),3.71(d,J=15.0Hz,1H),3.52(d,J=14.9Hz,1H),3 .26(ddd,J=11.4,4.0,2.5Hz,1H),2.94(ddd,J=14.4,11.7,2.6Hz,1H),2.77–2.65(m,5H),2.57(tt,J=11.4,2.5Hz,2H)ppm. 13 C NMR (101MHz, CDCl3): δ147.9,147.5,125.5,125.1,110.9,108.9,58.3,58.1,56.1,56.1,56.0,34.8,34.1,28.1ppm.HRMS(ESI):calc'd forC 14 H 20 NO2S + [M+H] + :266.1209,found:266.1208.

[0088] Example 11:

[0089] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is (The synthesis method is referenced in J.Org.Chem.2016,81,8696–8709), Formula III is...

[0090] 2. Experimental Results:

[0091] Yield: 54%. [α] D 23 =120.7(c=0.535g / 100ml, MeOH). 1H NMR(400MHz,CDCl3):δ7.45–7.40(m,2H),7.38–7.29(m,3H),6.58(s,1H),6.36(s,1H),4.01(ddd,J=11.4,3.2,1.3Hz,1H),3.83(s,3H),3.82(ddd,J=11.3,3.6,1.3Hz,1H),3.74(s,3H),3.63(d,J=14.7Hz,1H),3.56(t,J=10.9Hz,1H),3.52(dd,J=11.3,10.1Hz,1H),3.41(dd,J=10.5,3.5Hz,1H),3.14(d,J=14.8Hz,1H),2.77(dddd,J=10.1,7.8,6.8,3.4Hz,1H),2.62(d,J=7.3Hz,2H)ppm. 13 C NMR(101MHz,CDCl3):δ147.7,147.5,139.1,128.8,128.3,128.0,126.2,124.7,111.2,109.3,73.8,72.4,68.5,56.8,56.1,56.0,54.6,30.8ppm.HRMS(ESI):calc’dfor C 20 H 24 NO3 + [M+H] + :326.1751,found:326.1753.

[0092] [α] D 22 =74.5(c=0.333g / 100ml,MeOH). 1 H NMR(400MHz,CDCl3):δ7.32–7.27(m,5H),6.64(s,1H),6.29(s,1H),4.05–4.01(m,1H),3.88–3.87(m,4H),3.85–3.81(m,2H),3.80–3.77(m,1H),3.75(s,3H),3.54–3.47(m,2H),3.44–3.40(m,1H),3.36–

[0093] 3.32(m,1H),2.47(dd,J=16.4,4.8Hz,1H)ppm. 13C NMR (101MHz, CDCl3): δ147.7,147.5,139.2,128.6,128.6,128.0,125.5,124.7,11 1.8,109.5,73.5,71.0,58.6,56.0,56.0,52.7,51.7,24.6ppm.HRMS(ESI):calc'd for C 20 H 24 NO3 + [M+H] + :326.1751,found:326.1749.

[0094] Example 12:

[0095] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is

[0096] (The synthesis method is referenced from Org. Synth., 1977, 57, 53.), Formula III is...

[0097] 2. Experimental Results:

[0098] Yield: 62%. 1 H NMR (400MHz, CDCl3): δ6.96 (d, J=8.3Hz, 1H), 6.68 (dd, J=8.3, 2.7Hz, 1H), 6.65 (d, J=2.6Hz, 1H ),4.01(d,J=14.0Hz,1H),3.76(s,3H),3.62(d,J=14.0Hz,1H),3.12(t,J=9.4Hz,1H),2.94–2. 88(m,2H),2.72–2.64(m,2H),2.50–2.42(m,1H),2.06–1.99(m,1H),1.72(dt,J=12.7,3.8Hz,1 H),1.66–1.55(m,3H),1.54–1.48(m,1H),1.40–1.29(m,2H),1.18(tt,J=12.5,3.3Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ158.3,136.6,127.7,126.8,113.9,111.9,64.7,55.8,55.5,55.3,40.4,35.7,30.6,25.9,24.5,23.6,20.9ppm.HRMS(ESI):calc'd for C17 H 24 NO + [M+H] + :258.1852,found:258.1860.

[0099] Example 13:

[0100] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is (The synthesis method is based on international patent WO2021227439—An aryl glucosyl derivative, international application number PCT / CN2020 / 131248, formula III is...)

[0101] 2. Experimental Results:

[0102] The yield was 83%. 1 H NMR (400MHz, CDCl3): δ6.34(s,1H),3.83(s,3H),3.82(s,3H),3.79(s,3H),3. 77(d,J=14.9Hz,1H),3.35(d,J=14.8Hz,1H),2.98(ddt,J=11.1,8.6,2.6Hz,2H ),2.84(dq,J=11.2,2.5Hz,1H),2.76(dd,J=15.9,2.9Hz,1H),2.48–2.36(m,3H ), 2.33 (s, 3H), 2.28 (dd, J = 11.5, 2.4Hz, 1H), 1.97 (dd, J = 11.2, 9.3Hz, 1H) ppm. 13 C NMR (101MHz, CDCl3): δ151.9,151.1,140.6,129.5,119.4,105.0,62.0,61.0,60.5,57.3,56.6,56.1,55.2,54.6,46.1,27.8ppm.HRMS(ESI):calc'd for C 16 H 25 N2O3 + [M+H] + :293.1860,found:293.1860.

[0103] Example 14:

[0104] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... (The synthesis method is based on Angew. Chem. Int. Ed., 2022, 61, e202111783.), Formula II is... Formula III is

[0105] 2. Experimental Results:

[0106] Yield: 58%. 1 H NMR (400MHz, CDCl3): δ6.36 (s, 1H), 4.05 (d, J = 15.2Hz, 1H), 3.77 (s, 3H), 3.6 9(s,3H),3.23(d,J=15.2Hz,1H),3.06(dt,J=11.5,2.6Hz,1H),2.96(dt,J=1 1.2,2.6Hz,1H),2.89(dq,J=11.3,2.6Hz,1H),2.67(d,J=7.4Hz,2H),2.56–2 .49(m,2H),2.37–2.31(m,4H),2.10(s,3H),1.98(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ157.2,155.5,131.7,119.5,117.1,105.8,61.7,60.3,56.4,55.7,55.2,54.7,52.4,46.1,33.6,8.9ppm.HRMS(ESI):calc'd for C 16 H 25 N2O2 + [M+H] + :277.1911,found:277.1912.

[0107] Example 15:

[0108] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0109] 2. Experimental Results:

[0110] The yield was 53%. 1H NMR (500MHz, Methanol-d4): δ6.65(s,1H),6.51(s,1H),3.81(s,3H),3.78(d,J=14.7Hz,1H),3.35–3.34(m,1H),3.03(ddt,J=11.4,9. 0,2.5Hz,2H),2.93(dq,J=11.6,2.5Hz,1H),2.74–2.67(m,1H),2.61–2.50(m,2H),2.46(td,J=11.9,2.8Hz,1H),2.39–2.33(m,4H)ppm. 13 C NMR (101MHz, CDCl3:Methanol-d4≈1:1): δ146.3,144.0,124.7,122.7,111.9,110.5,60.2,56.2,55.9,55.0,53.8,53.2,44.7,31.8ppm.HRMS(ESI):calc'dfor C 14 H21N2O2 + [M+H] + :249.1598,found:249.1599.

[0111] Example 16:

[0112] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is Formula III is

[0113] 2. Experimental Results:

[0114] Yield: 50%. 1H NMR (400MHz, CDCl3): δ6.93(d,J=8.4Hz,1H),6.68(dd,J=8.4,2.7Hz,1H),6.60(d,J=2.6Hz,1H),3 .83(d,J=14.6Hz,1H),3.76(s,3H),3.36(d,J=14.5Hz,1H),3.00(dt,J=11.3,2.6Hz,1H),2.93(dt ,J=11.2,2.6Hz,1H),2.84(dq,J=11.1,2.5Hz,1H),2.74–2.63(m,2H),2.55–2.48(m,1H),2.46(td ,J=11.5,2.9Hz,1H),2.33(s,3H),2.28(td,J=11.5,2.8Hz,1H),1.94(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ158.2,134.3,127.2,126.3,113.0,112.2,61.9,56.9,56.7,55.4,55.2,54.7,46.2,33.6ppm.HRMS(ESI):calc'd for C 14 H 21 N2O + [M+H] + :233.1648,found:233.1652.

[0115] Example 17:

[0116] 1. Synthesis steps: Formula I (1.0 eq.), Pd(PPh3)2Cl2 (0.05 eq.), CuI (0.05 eq.), and TBAI (1.0 eq.) were added under nitrogen protection with a deoxidizing agent TEA:DMF ratio of 2:1. The system was stirred at 80 °C for 20 minutes. Formula II was then added. (1.2 eq.), continue the reaction at 80 °C for 2 hours. Add saturated ammonium chloride solution, then extract with ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify the residue by silica gel column chromatography to obtain the corresponding o-alkynyl carboxaldehyde or o-alkynyl ketone compound of formula III, with Boc-protected primary amine side chain terminal. The compound (0.2 mmol) was dissolved in 4 mL of dichloromethane. 0.4 mL of trifluoroacetic acid was added at 0 °C, and the reaction was carried out at 25 °C for 3 hours, followed by rotary evaporation to dryness. Silver nitrate (0.1 eq.) was added, and the mixture was refluxed under nitrogen protection in a mixed solvent of 4 mL of 1,2-dichloroethane and 0.4 mL of trifluoroacetic acid for 6 hours, followed by rotary evaporation to dryness. 4 mL of methanol was added, and NaBH4 (4.0 eq.) was added at 0 °C. The reaction was then transferred to 25 °C for 1 hour. 0.1 mL of water was added, and the mixture was rotary evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the final product. The general synthetic route is as follows: Figure 2 As shown.

[0117] 2. Experimental Results:

[0118] Yield: 60%. 1 H NMR (400MHz, CDCl3): δ6.50(s,1H),6.46(s,1H),3.77(s,3H),3.77–3.73(m,4H),3. 35–3.29(m,1H),2.94(dt,J=11.3,2.6Hz,1H),2.87(dt,J=11.2,2.6Hz,1H),2.79(d q,J=11.1,2.5Hz,1H),2.61–2.52(m,2H),2.49–2.42(m,1H),2.40(td,J=11.5,3.0H z,1H),2.27(s,3H),2.23(dd,J=11.4,2.8Hz,1H),1.90(dd,J=11.2,9.6Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ147.6,147.3,125.7,124.9,111.0,109.0,61.7,56.9,56.7,55.9,55.9,55.1,54.5,46.0,32.8ppm.HRMS(ESI):calc'd forC 15 H 23 N2O2 + [M+H] + :263.1754,found:263.1757.

[0119] Example 18:

[0120] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0121] 2. Experimental Results:

[0122] The yield was 53%. 1 H NMR (400MHz, CDCl3): δ7.15–7.08(m,2H),7.07–7.05(m,1H),7.03–6.99(m,1H),3.89(d,J =15.0Hz,1H),3.44(d,J=15.0Hz,1H),3.01(dt,J=11.3,2.6Hz,1H),2.93(dt,J=11.2,2.6H z,1H),2.84(dq,J=11.2,2.6Hz,1H),2.77–2.65(m,2H),2.57–2.50(m,1H),2.46(td,J=11. 5,2.9Hz,1H),2.32(s,3H),2.29(td,J=11.5,2.8Hz,1H),1.94(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ134.0,133.2,128.4,126.4,126.2,125.8,61.9,57.4,56.8,55.2,54.7,46.2,33.4ppm.HRMS(ESI):calc'd for C 13 H 19 N2 + [M+H] + :203.1543,found:203.1543.

[0123] Example 19:

[0124] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0125] 2. Experimental Results:

[0126] The yield was 57%. 1H NMR (400MHz, CDCl3): δ7.10(t,J=7.9Hz,1H),6.67(dd,J=15.3,7.9Hz,2H),4.09(d,J =16.0Hz,1H),3.80(s,3H),3.16(d,J=16.0Hz,1H),3.05(dt,J=11.4,2.6Hz,1H),2.9 3(dt,J=11.2,2.6Hz,1H),2.85(dq,J=11.1,2.5Hz,1H),2.72–2.64(m,2H),2.54–2.4 7(m,2H),2.33(s,3H),2.29(td,J=11.5,2.8Hz,1H),1.92(dd,J=11.2,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ155.8,134.6,126.7,123.0,120.6,107.1,61.9,56.1,55.4,55.4,54.9,52.3,46.3,33.6ppm.HRMS(ESI):calc'd for C 14 H 21 N2O + [M+H] + :233.1648,found:233.1650.

[0127] Example 20:

[0128] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0129] 2. Experimental Results:

[0130] Yield: 58%. 1H NMR (400MHz, CDCl3): δ6.97 (d, J=8.4Hz, 1H), 6.70 (dd, J=8.4, 2.7Hz, 1H), 6.55 (d, J=2.6Hz, 1H), 3.85 (d,J=15.1Hz,1H),3.75(s,3H),3.41(d,J=15.1Hz,1H),3.00(dt,J=11.3,2.6Hz,1H),2.91(dt,J=11.2 ,2.6Hz,1H),2.84(dq,J=11.1,2.5Hz,1H),2.70–2.57(m,2H),2.51(dtd,J=10.0,4.9,3.1Hz,1H),2.4 5(td,J=11.5,2.9Hz,1H),2.32(s,3H),2.27(td,J=11.5,2.7Hz,1H),1.94(dd,J=11.3,9.6Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ157.8,135.0,129.3,125.3,112.8,110.9,61.9,57.6,57.0,55.4,55.2,54.7,46.2,32.6ppm.HRMS(ESI):calc'd for C 14 H 21 N2O + [M+H] + :233.1648,found:233.1649.

[0131] Example 21:

[0132] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0133] 2. Experimental Results:

[0134] The yield was 56%. 1H NMR (400MHz, CDCl3): δ7.09(t,J=7.9Hz,1H),6.68–6.64(m,2H),3.85(d,J=15.1Hz,1 H),3.81(s,3H),3.41(d,J=15.0Hz,1H),3.01(dt,J=11.3,2.6Hz,1H),2.97(dt,J=11 .3,2.7Hz,1H),2.85(dq,J=11.0,2.5Hz,1H),2.80(dd,J=16.8,3.7Hz,1H),2.52–2.3 7(m,3H),2.33(s,3H),2.30(td,J=11.5,2.7Hz,1H),1.98(dd,J=11.3,9.7Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ157.0,135.3,126.4,122.1,118.4,107.6,62.0,57.3,56.7,55.4,55.3,54.7,46.2,28.0ppm.HRMS(ESI):calc'd forC 14 H 21 N2O + [M+H] + :233.1648,found:233.1651.

[0135] Example 22:

[0136] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0137] 2. Experimental Results:

[0138] Yield: 58%. 1H NMR (400MHz, CDCl3): δ7.04(d,J=8.4Hz,1H),6.98–6.93(m,2H),3.88(d,J=15.1Hz,1H ),3.39(d,J=15.1Hz,1H),3.00(dt,J=11.3,2.6Hz,1H),2.93(dt,J=11.3,2.6Hz,1H),2 .84(dq,J=11.2,2.5Hz,1H),2.78–2.65(m,2H),2.55–2.50(m,1H),2.46(td,J=11.5,3 .0Hz,1H),2.33(s,3H),2.28(td,J=11.4,2.7Hz,1H),1.92(dd,J=11.3,9.7Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ147.7(q,J=1.8Hz),135.2,132.9,127.5,120.7,120.6(q,J =256.6Hz),118.7,61.8,56.9,56.5,55.2,54.7,46.2,33.4ppm.HRMS(ESI):calc'd for C 14 H 18 F3N2O + [M+H] + :287.1366,found:287.1368.

[0139] Example 23:

[0140] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0141] 2. Experimental Results:

[0142] Yield: 54%. 1H NMR (400MHz, CDCl3): δ6.97(dd,J=8.4,5.7Hz,1H),6.83–6.75(m,2H),3.85(d,J=14.8H z,1H),3.36(d,J=14.4Hz,1H),3.00(dt,J=11.3,2.6Hz,1H),2.92(dt,J=11.2,2.5Hz,1H ),2.84(dq,J=11.2,2.5Hz,1H),2.75–2.63(m,2H),2.53–2.46(m,1H),2.45(td,J=11.6, 3.1Hz,1H),2.32(s,3H),2.28(td,J=11.6,2.9Hz,1H),1.92(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ161.5(d,J=243.7Hz), 135.3(d,J=7.6Hz), 129.7, 127.7(d,J=8.2Hz), 114.7( d,J=20.8Hz),113.1(d,J=21.5Hz),61.8,56.9,56.5,55.2,54.7,46.2,33.5ppm.HRMS(ESI):calc'd forC 13 H 18 FN2 + [M+H] + :221.1449,found:221.1452.

[0143] Example 24:

[0144] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0145] 2. Experimental Results:

[0146] Yield: 54%. 1H NMR (400MHz, CDCl3): δ7.78–7.76(m,2H),7.10–7.08(m,1H)),3.94(d,J=15.9Hz,1H),3. 89(s,3H),3.45(d,J=15.8Hz,1H),3.01(dt,J=11.3,2.6Hz,1H),2.94(dt,J=11.3,2.6Hz, 1H),2.85(dq,J=11.2,2.6Hz,1H),2.82–2.67(m,2H),2.57–2.50(m,1H),2.46(td,J=11.5 ,2.9Hz,1H),2.33(s,3H),2.28(td,J=11.5,2.8Hz,1H),1.94(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ167.3,139.4,133.6,129.8,128.4,127.0,126.3,61.8,57.4,56.7,55.2,54.7,52.2,46.2,33.2ppm.HRMS(ESI):calc'd for C 15 H 21 N2O2 + [M+H] + :261.1598,found:261.1595.

[0147] Example 25:

[0148] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0149] 2. Experimental Results:

[0150] The yield was 66%. 1H NMR (400MHz, CDCl3): δ7.37–7.33(m,2H),7.13(d,J=7.9Hz,1H),3.94(d,J=15.6Hz,1H ),3.45(d,J=15.6Hz,1H),3.02(dt,J=11.3,2.6Hz,1H),2.95(dt,J=11.2,2.7Hz,1H),2 .86(dq,J=11.2,2.5Hz,1H),2.81–2.68(m,2H),2.59–2.52(m,1H),2.48(td,J=11.5,2 .9Hz,1H),2.34(s,3H),2.29(td,J=11.5,2.8Hz,1H),1.95(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ138.1, 134.0, 128.8 (q, J = 32.2Hz), 126.7, 125.3 (q, J = 4.0Hz), 124.4 (q, J =272.1Hz),122.7(q,J=4.0Hz),61.7,57.2,56.5,55.2,54.6,46.2,33.3ppm.HRMS(ESI):calc'd for C 14 H 18 F3N2 + [M+H] + :271.1417,found:271.1420.

[0151] Example 26:

[0152] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0153] 2. Experimental Results:

[0154] Yield: 39%. 1H NMR (400MHz, CDCl3): δ7.98–7.96(m,2H),7.19–7.16(m,1H),3.98(d,J=16.3Hz,1H),3.47 (d,J=16.3Hz,1H),3.02(dt,J=11.3,2.6Hz,1H),2.96(dt,J=11.2,2.6Hz,1H),2.85(ddd,J =17.0,7.0,3.6Hz,2H),2.75(dd,J=16.5,10.8Hz,1H),2.59–2.52(m,1H),2.48(td,J=11. 5,3.0Hz,1H),2.33(s,3H),2.28(td,J=11.4,2.7Hz,1H),1.94(dd,J=11.3,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ146.7,141.7,135.1,127.2,123.6,121.0,61.6,57.2,56.3,55.1,54.6,46.2,33.3ppm.HRMS(ESI):calc'd for C 13 H 18 N3O2 +

[0155] [M+H] + :248.1394,found:248.1388.

[0156] Example 27:

[0157] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0158] 2. Experimental Results:

[0159] Yield: 43%. 1H NMR (400MHz, CDCl3): δ8.36 (dd, J=4.8, 1.6Hz, 1H), 7.38 (dd, J=7.8, 1.5Hz, 1H), 7.07 (dd, J=7.7, 4 .8Hz,1H),4.06(d,J=16.1Hz,1H),3.50(d,J=16.2Hz,1H),3.06(dt,J=11.4,2.6Hz,1H),2.96(dt,J =11.2,2.6Hz,1H),2.86(dq,J=11.3,2.6Hz,1H),2.72(d,J=7.3Hz,2H),2.61–2.56(m,1H),2.51(t d,J=11.6,3.0Hz,1H),2.34(s,3H),2.29(td,J=11.4,2.8Hz,1H),1.96(dd,J=11.2,9.7Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ

[0160] 154.1,147.2,136.1,129.4,121.8,61.6,59.6,56.3,55.1,54.6,46.2,32.6ppm.HRMS(ESI):calc'dfor C 12 H 18 N3 + [M+H] + :204.1495,found:204.1490.

[0161] Example 28:

[0162] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0163] 2. Experimental Results:

[0164] The yield was 52%. 1H NMR (400MHz, CDCl3): δ8.39(d,J=4.7Hz,1H),7.33(d,J=7.7Hz,1H),7.06(dd,J=7.7,4.8Hz,1H),3.88(d, J=15.1Hz,1H),3.45(d,J=15.1Hz,1H),3.03(dt,J=11.3,2.6Hz,1H),2.99(dt,J=11.5,2.7Hz,1H),2.93( dd,J=17.1,4.3Hz,1H),2.86(dq,J=11.5,2.7Hz,1H),2.80(dd,J=17.3,10.9Hz,1H),2.68–2.61(m,1H),2 .49(td,J=11.5,2.9Hz,1H),2.34(s,3H),2.29(td,J=11.5,2.8Hz,1H),1.98(dd,J=11.4,9.7Hz,1H)ppm. 13 CNMR(101MHz, CDCl3): δ153.9,148.0,133.9,129.4,121.2,61.8,57.0,56.6,55.2,54.5,46.2,36.4ppm.HRMS(ESI):calc'd for C 12 H 18 N3 + [M+H] + :204.1495,found:204.1500.

[0165] Example 29:

[0166] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0167] 2. Experimental Results:

[0168] Yield: 41%. 1H NMR (400MHz, CDCl3): δ7.80 (dd, J=8.0, 1.5Hz, 2H), 7.65 (d, J=8.4Hz, 1H), 7.49 (ddd, J=8.2, 6.8, 1.6H z,1H),7.43(ddd,J=8.2,6.8,1.3Hz,1H),7.19(d,J=8.4Hz,1H),4.51(d,J=15.5Hz,1H),3.69(d,J=15 .5Hz,1H),3.18(dt,J=11.4,2.7Hz,1H),3.02(dt,J=11.2,2.7Hz,1H),2.94(dq,J=11.1,2.5Hz,1H),2 .88–2.80(m,2H),2.71–2.62(m,2H),2.41–2.35(m,1H),2.38(s,3H),2.04(dd,J=11.2,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ132.1,130.6,130.4,128.7,128.4,127.1,126.7,126.3 ,125.1,122.1,61.8,56.2,55.3,54.9,54.6,46.2,34.3ppm.HRMS(ESI):calc'd forC 17 H 21 N2 + [M+H] + :253.1699,found:253.1699.

[0169] Example 30:

[0170] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is Formula III is

[0171] 2. Experimental Results:

[0172] Yield: 59%. 1H NMR (400MHz, CDCl3): δ7.73–7.70(m,2H),7.54(s,1H),7.50(s,1H),7.40–7.35(m ,2H),4.10(d,J=15.1Hz,1H),3.59(d,J=15.0Hz,1H),3.06(dt,J=11.2,2.6Hz,1H) ,2.99–2.93(m,2H),2.91–2.84(m,2H),2.63–2.56(m,1H),2.49(td,J=11.5,2.9Hz ,1H),2.34(s,3H),2.32(td,J=11.5,2.7Hz,1H),1.99(dd,J=11.2,9.8Hz,1H)ppm. 13 C NMR (101MHz, CDCl3): δ132.8,132.6,132.1,131.9,127.4,127.2,126.4,125.4 ,125.3,124.3,62.0,57.9,57.3,55.2,54.9,46.2,33.7ppm.HRMS(ESI):calc'd for C 17 H 21 N2 + [M+H] + :253.1699,found:253.1700.

[0173] Example 31:

[0174] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is (The synthetic method is described in ACS Med. Chem. Lett. 2020, 11, 1137–1144.), Formula III is...

[0175] 2. Experimental Results:

[0176] The yield was 53%. 1 H NMR (400MHz, CDCl3): δ6.56(s,1H),6.50(s,1H),3.83(s,3H),3.82–3.81(m,5H),3.41–3.30(m,3H),3.22(t,J=10.8Hz ,1H),3.00(t,J=11.6Hz,1H),2.90–2.75(m,4H),2.73(s,3H),2.56(d,J=13.7Hz,1H),1.95(dd,J=16.5,8.5Hz,1H)ppm.13 C NMR (101MHz, CDCl3): δ148.0,147.7,126.2,125.7,111.3,109.0,58.7,58.6,58.2,56.1,52.7,50.9,44.9,36.1,30.33,29.8ppm.HRMS(ESI):calc'd forC 16 H 25 N2O2 + [M+H] + :277.1911,found:277.1915.

[0177] Example 32:

[0178] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is (The synthesis method is based on international patent WO2021227439—An aryl glucosyl derivative, international application number PCT / CN2020 / 131248), Formula III is...

[0179] 2. Experimental Results:

[0180] The yield was 57%. 1 H NMR (400MHz, CDCl3): δ6.54(s,1H),6.49(s,1H),3.81(s,3H),3.80(s,3H),3.70(q,J=14.5Hz,2H),2.99(ddd,J=13.4,7.7,2.2Hz,1H),2.90( ddd,J=13.3,8.9,1.8Hz,1H),2.86–2.80(m,1H),2.72–2.64(m,3H),2. 60–2.52(m,2H),2.43–2.37(m,1H),2.40(s,3H),1.98–1.82(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ147.6,147.2,127.2,126.3,111.2,109.1,61.5,61.4,58.4,57.8,56.0,56.0,54.3,47.7,34.9,26.9ppm.HRMS(ESI):calc'd for C 16 H 25 N2O2 + [M+H] + :277.1911,found:277.1913.

[0181] Example 33:

[0182] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... (The synthesis method is based on Org. Biomol. Chem., 2012, 10, 512-515.), Formula II is... Formula III is

[0183]

[0184] 2. Experimental Results:

[0185] Yield: 54%. 1 H NMR (400MHz, CDCl3) δ7.10(td,J=7.4,0.9Hz,1H),7.02(d,J=7.4Hz,1H),6.89(d,J=7.5Hz ,1H),3.42(dd,J=10.7,6.4Hz,1H),3.17–3.13(m,1H),3.02(dt,J=11.4,2.6Hz,1H),2.99 –2.95(m,1H),2.94–2.81(m,3H),2.81–2.74(m,1H),2.57(dd,J=16.5,10.7Hz,1H),2.48– 2.35(m,3H),2.39(s,3H),2.12(dd,J=11.4,10.0Hz,1H),1.74(qd,J=11.2,8.5Hz,1H)ppm. 13 C NMR (101MHz, CDCl3) δ141.6,141.0,130.5,127.7,124.4,121.8,67.2,61.3,58.6,55.0,51.9,45.8,34.0,31.7,30.7ppm.HRMS(ESI):calc'd for C 15 H 21 N2 + [M+H] + :229.1699,found:229.1696.

[0186] 1H NMR (400MHz, CDCl3) δ7.12(td,J=7.4,0.9Hz,1H),7.06(d,J=7.3Hz,1H),6.94(d,J=7.4Hz,1 H),4.38(dd,J=10.9,6.2Hz,1H),3.48–3.41(m,1H),3.28(ddd,J=13.5,11.1,3.8Hz,1H),3. 18(dt,J=13.4,2.9Hz,1H),3.03(dd,J=17.0,6.4Hz,1H),2.89–2.80(m,2H),2.68–2.62(m,4 H),2.49(d,J=11.3Hz,1H),2.45–2.41(m,1H),2.39(s,3H),1.83(qd,J=11.0,8.3Hz,1H)ppm. 13 C NMR (101MHz, CDCl3) δ141.8,140.3,131.3,127.5,124.7,122.0,57.5,56.0,55.3,49.5,48.6,46.1,34.3,31.2,30.5ppm.HRMS(ESI):calc'd for C 15 H 21 N2 + [M+H] + :229.1699,found:229.1696.

[0187] Example 34: Synthesis of tetrahydroberberine (Canadine)

[0188] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is (Org. Lett., 2003, 5, 2323-2325), Equation III is

[0189] 2. Experimental Results:

[0190] Yield: 62%. 1H NMR (400MHz, CDCl3): δ6.86(d,J=8.4Hz,1H),6.79(d,J=8.4Hz,1H),6.73(s,1H),6.59(s,1H),5.92(s,2H),4.24(d,J=15.8Hz,1 H),3.85(s,6H),3.56–3.52(m,2H),3.25–3.16(m,2H),3.14–3.08(m,1H),2.82(dd,J=15.9,11.3Hz,1H),2.68–2.60(m,2H)ppm. 13 C NMR (400MHz, CDCl3): δ150.4,146.3,146.1,145.2,130.9,128.7,127.9,127.8,124.0,11 1.1,108.6,105.7,100.9,60.3,59.8,56.0,54.1,51.5,36.5,29.7ppm.HRMS(ESI):calc'd for C 20 H 22 NO4 + :340.1543,found:340.1548.

[0191] Example 35: Synthesis of tetrahydroberberine thiophene derivatives

[0192] 1. The synthesis steps are the same as in Example 1, and the general formula of the synthesis route is as follows: Figure 1 As shown. Wherein, Equation I is... Formula II is (Org. Lett., 2003, 5, 2323-2325), Equation III is

[0193] 2. Experimental Results:

[0194] (Bioorganic & Medicinal Chemistry, 2018, 26, 2017–2027) The yield is 45%. 1HNMR (400MHz, CDCl3): δ7.11 (dd, J=5.1, 0.9Hz, 1H), 6.78 (d, J=5.1Hz, 1H), 6.70 ( s,1H),6.59(s,1H),5.92(s,2H),4.00(dd,J=14.5,1.5Hz,1H),3.67(dd,J=10.8, 4.0Hz,1H),3.61(dt,J=14.5,2.4Hz,1H),3.33(ddd,J=15.9,4.1,1.9Hz,1H),3.1 5–3.06(m,2H),2.82(dddt,J=16.1,10.7,2.8,1.3Hz,1H),2.70–2.64(m,2H)ppm. 13 C NMR (101MHz, CDCl3): δ146.3,146.2,133.6,133.5,130.6,128.0,125.0 123.1,108.6,105.7,101.0,60.2,55.7,51.3,33.4,29.9ppm.HRMS(ESI):calc'd for C 16 H 16 NO2S + [M+H + ]:286.0896,found:286.0899.

[0195] Example 36: Synthesis of tetrahydroberberine indole derivatives

[0196] 1. The synthesis steps are the same as in Example 17, and the general formula of the synthesis route is as follows: Figure 2 As shown. Wherein, Equation I is... Formula II is (Org. Lett., 2003, 5, 2323-2325), Equation III is

[0197] 2. Experimental Results:

[0198] (J.Med.Chem.,2016,59,9489-9502) Yield 45%. 1H NMR (400MHz, DMSO-d6): δ10.75(s,1H),7.40(d,J=7.7Hz,1H),7.29(d,J=8.0Hz,1H),7.02(td,J=7. 0,1.3Hz,1H),6.99(s,1H),6.95(td,J=7.4,1.1Hz,1H),6.68(s,1H),5.96(dd,J=4.9,1.0Hz,2H),3. 99(d,J=14.9Hz,1H),3.67(d,J=15.0Hz,1H),3.60–3.57(m,1H),3.40–3.32(m,1H,overlapped),3. 14–3.09(m,1H),2.92(ddd,J=16.7,11.0,5.2Hz,1H),2.67–2.57(m,2H),2.44(t,J=13.0Hz,1H)ppm. 13 C NMR (101MHz, DMSO-d6): δ145.7,145.4,135.9,132.4,131.6,127.5,126.8,120.4,118.3,11 7.5,110.9,108.1,106.8,106.0,100.6,59.7,52.4,50.7,29.4,29.2ppm.HRMS(ESI):calc'd for C 20 H 19 N2O2 + [M+H + ]:319.1441,found:319.1436.

[0199] Example 37: Synthesis of Berberine Trifluoroacetate

[0200] 1. Synthesis steps: Formula I Formula II (Org. Lett., 2003, 5, 2323-2325), Pd(PPh3)4 (0.02 eq.) and CuI (0.02 eq.) were added under nitrogen protection with a deoxygenated TEA:DMF ratio of 3:1. The system was stirred at 65 °C for 4 hours. A saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain the corresponding o-alkynyl aromatic carboxaldehyde (ketone) compound of formula III, with a Boc-protected primary amine side chain at the end of the alkyne side chain. The compound (0.2 mmol) was dissolved in 4 mL of dichloromethane. 0.4 mL of trifluoroacetic acid was added at 0 °C, and the reaction was carried out at 25 °C for 3 hours, followed by rotary evaporation to dryness. Silver nitrate (0.1 eq.) was added, and the mixture was refluxed in 4 mL of 1,2-dichloroethane under nitrogen protection for 3 hours, followed by rotary evaporation to dryness. The residue was purified by silica gel column chromatography to obtain the final product. The general synthetic route is shown below. Figure 3 As shown.

[0201] 2. Experimental Results:

[0202] The yield was 67%. 1 H NMR (400MHz, Methanol-d4): δ9.77(s,1H),8.69(s,1H),8.11(d,J=9.1Hz,1H),7.99(d,J=9.1Hz,1H),7.65( s,1H),6.96(s,1H),6.10(s,2H),4.93(t,J=6.3Hz,2H),4.20(s,3H),4.11(s,3H),3.26(t,J=6.3Hz,2H)ppm. 13 CNMR (101MHz, Methanol-d4): δ152.2,152.0,149.9,146.4,145.8,139.7,135.2 131.9,128.1,124.5,123.3,121.9,121.5,109.4,106.5,103.7,62.6,57.6,57.2,28.2ppm.HRMS(ESI):calc'd for C 20 H 18 NO4 + :336.1230,found:336.1234.

[0203] It should be noted that the above embodiments are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Equivalent substitutions or alternatives made on the basis of the above shall all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing polycyclic tetrahydroisoquinoline compounds and their derivatives using a tandem cyclization strategy, characterized in that, The reaction route is as follows: ， Wherein, in formula I X is bromine, iodine, or trifluoromethanesulfonate; R 1 It is composed of hydrogen, alkyl, or cycloalkyl groups connected to Ar substituents; Ar is selected from any one of benzene ring, substituted benzene ring, naphthyl ring, substituted naphthyl ring, thiophene, substituted thiophene, indole, substituted indole, pyridine, substituted pyridine, furan, substituted furan; when Ar in Formula I has a substituent, the substituent is one or more of alkyl, alkoxy, halogen, cyano, phenolic hydroxyl, trifluoromethoxy, ester, trifluoromethyl, nitro or adjacent substituents forming a 1,3-dioxopentane. In Formula II, G is an alkyl, cycloalkyl, aryl, heteroaryl, ether, thioether, or tertiary amine; Boc represents tert-butyloxycarbonyl. In Equation II, m and n are integers greater than or equal to 0; The method specifically includes the following steps: Step (1): The compound shown in Formula I and the compound shown in Formula II undergo a Sonogashira coupling reaction to obtain the compound shown in Formula III. The Sonogashira coupling reaction conditions in step (1) are as follows: Under nitrogen protection, Formula I and Formula II, along with tetrakis(triphenylphosphine)palladium and cuprous iodide, were reacted in deoxytriethylamine and N,N-dimethylformamide at 65 °C for 4 hours. or Under nitrogen protection, Formula I was reacted with bis(triphenylphosphine)palladium dichloride, cuprous iodide and tetrabutylammonium iodide in deoxytriethylamine and N,N-dimethylformamide at 80 °C for 20 minutes, then Formula II was added and the reaction was continued at 80 °C for 2 hours. Step (2): The compound shown in Formula III undergoes deprotection and a tandem cyclization reaction to obtain the compound of Formula IV; The reaction conditions for the deprotection and tandem cyclization reaction of formula III in step (2) are as follows: The dichloromethane solution of Formula III was reacted with trifluoroacetic acid at 0 °C for 3 hours at 25 °C, and then evaporated to dryness. Silver nitrate was added, and the mixture was refluxed in 1,2-dichloroethane under nitrogen protection for 3 hours, and then evaporated to dryness to obtain Formula IV. or The dichloromethane solution of Formula III was added to trifluoroacetic acid at 0 °C and reacted at 25 °C for 3 hours, then evaporated to dryness; silver nitrate was added and the mixture was refluxed in 1,2-dichloroethane and trifluoroacetic acid under nitrogen protection for 5 hours, then evaporated to dryness to obtain Formula IV; Step (3): The compound shown in Formula IV is reduced to obtain the compound shown in Formula V.

2. The method as described in claim 1, characterized in that, In step (3), the reduction reaction of formula IV uses NaBH4 with methanol, NaBH3CN with methanol, or NaBH(OAc)3 with 1,2-dichloroethane.

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