A lappaconitine derivative with analgesic activity and its preparation method and application

Abstract

The present invention provides a lappaconitine derivative with analgesic activity, a preparation method and an application thereof. The structure of the lappaconitine derivative is shown in Formula I. The lappaconitine derivative provided by the present invention has high analgesic activity, good water solubility and low biological toxicity, can be used to prepare low-toxic analgesic drugs, and has broad application prospects.

Description

[0001] This application is a divisional application for the invention patent with application number 2021104192034 and application date April 19, 2021. Technical Field

[0002] The invention belongs to the pharmaceutical field, and specifically relates to a lappaconitine derivative with analgesic activity and a preparation method and application thereof. Background Art

[0003] Lappaconitine (LA), also known as aconitine and labaconitine, is an alkaloid extracted and separated from the root of Aconitum rapae, a plant of the Ranunculaceae family. It belongs to the C18 diterpenoids. Its main dosage form for clinical application is lappaconitine hydrobromide. Studies have shown that lappaconitine has analgesic, anti-inflammatory, detumescent, and antipyretic effects.

[0004] Due to its anti-inflammatory properties, lappaconitine is particularly effective in inflammatory analgesia, and has gained certain clinical experience in treating pain caused by rheumatic or rheumatoid arthritis. Yue Jianhua reported that lappaconitine can significantly improve symptoms such as frequent urination, urgency and pain after urinary tract infection treatment, and analyzed its mechanism to be that it can eliminate the chronic inflammatory response of the bladder caused by urinary tract infection.

[0005] The Drug Administration Bureau of the Ministry of Health has listed lappaconitine as an analgesic for mild and moderate pain in the three-step analgesic therapy for cancer patients. It is mainly used in the treatment of cancer pain in clinical practice. The analgesic mechanism of lappaconitine includes general mechanism and central mechanism. The former may be the analgesic mechanism of general antipyretic analgesics, while the latter is a special mechanism. The clinical application of lappaconitine is mainly concentrated in conventional pain treatment, especially the treatment of cancer pain. It has only been applied to surgical analgesia and postoperative pain treatment in recent years.

[0006] As a commonly used analgesic in clinical practice, lappaconitine has the advantages of high analgesic efficacy, non-dependence and non-addiction compared with traditional analgesics. However, it has a narrow safety range and high toxicity. During use, it can cause patients to experience side effects such as chills, fever, allergic reactions, ototoxicity, arrhythmias and anaphylactic shock.

[0007] Therefore, the development of new compounds with low toxicity and high analgesic activity is of great significance for the clinical application of analgesics. Summary of the invention

[0008] The purpose of the present invention is to provide a lappaconitine derivative with low toxicity and high analgesic activity, and a preparation method and pharmaceutical use thereof.

[0009] The present invention provides a compound represented by formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

[0010]

[0011] Among them, R a , R b , R c , R d , R e Each independently selected from hydroxyl, C 1～6 Alkyl, C 1～6 Alkoxy, COOR u ,OCOR u ; R u Selected from hydrogen, C 1～6 Alkyl, 5-6 membered aryl, 5-6 membered heteroaryl;

[0012] p is an integer selected from 0 to 4;

[0013] R v Each independently selected from hydrogen, hydroxyl, C 1～6 Alkyl, C 1～6 Alkoxy, halogen, COOR w ,OCOR w ; R w Selected from hydrogen, C 1～6 alkyl;

[0014] R0 is selected from COR f 、SO2R g , SOR g , C 1～6 alkyl;

[0015] R f Selected from C 2～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, MR1, one or more R x The following groups substituted: 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic, condensed cycloalkyl, heterocondensed cycloalkyl, bicyclic alkyl, heterobicyclic; the R x is selected from hydrogen, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, hydroxyl, carboxyl, phenyl, the substituent is selected from halogen, C 1～6 Alkyl, C 1～6 Alkoxy;

[0016] M is selected from O or NH; R1 is selected from C 1～6 Alkyl, C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl;

[0017] R g Selected from C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, L1R h ; L1 is selected from none, C 1～4 Alkylene; R h Selected from one or more R y The following groups substituted: 5-6 membered aryl, 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic, condensed cycloalkyl, heterocondensed cycloalkyl, bicyclic alkyl, heterobicyclic; the R y is selected from hydrogen, substituted or unsubstituted C 1～6 Alkyl, substituted or unsubstituted C 1～6 Alkoxy, C 2～6 Alkenyl, C 2～6 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, hydroxyl, carboxyl, phenyl, the substituent is selected from halogen, C 1～6 Alkyl, C 1～6 Alkoxy;

[0018] R3, R4, R5, and R6 are each independently selected from hydrogen, C 1～6 alkyl.

[0019] Furthermore, the structure of the compound is shown in Formula II:

[0020]

[0021] Among them, R0 is selected from COR f 、SO2R g ;

[0022] R f Selected from C 2～6 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, MR1, one or more R x The following groups substituted: 5-6 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic, condensed cycloalkyl, heterocondensed cycloalkyl, bicyclic alkyl, heterobicyclic; the R x is selected from hydrogen, halogenated or unsubstituted C 1～4 Alkyl, halogenated or unsubstituted C 1～4Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, phenyl;

[0023] M is selected from O or NH; R1 is selected from C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, 5- to 6-membered aryl, 5- to 6-membered heteroaryl;

[0024] R g Selected from C 1～6 Alkyl, C 2～3 Alkenyl, C 2～3 Alkynyl, L1R h ; L1 is selected from none, C 1～2 Alkylene; R h Selected from one or more R y The following groups substituted: 5-6 membered aryl, 5-6 membered heteroaryl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic, condensed cycloalkyl, heterocondensed cycloalkyl, bicyclic alkyl, heterobicyclic; the R y is selected from hydrogen, halogenated or unsubstituted C 1～4 Alkyl, halogenated or unsubstituted C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, phenyl;

[0025] R3, R4, R5, and R6 are each independently selected from hydrogen, C 1～4 alkyl.

[0026] Furthermore, the structure of the compound is shown in Formula III:

[0027]

[0028] wherein M is selected from O or NH;

[0029] R1 is selected from C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, 5- to 6-membered aryl, and 5- to 6-membered heteroaryl.

[0030] Furthermore, the structure of the compound is shown in Formula IV:

[0031]

[0032]

[0033] Wherein, m is selected from an integer of 0 to 3;

[0034] R2 is independently selected from hydrogen, halogen or unsubstituted C 1～4 Alkyl, halogenated or unsubstituted C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, phenyl; wherein R3, R4, R5, R6 are each independently selected from hydrogen, C 1～4 alkyl;

[0035] Ring A is selected from 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered saturated cycloalkyl, and 3- to 6-membered saturated heterocyclic group.

[0036] Furthermore, the structure of the compound is shown in Formula V:

[0037]

[0038] Wherein, L1 is selected from none, C 1～2 Alkylene;

[0039] n is an integer selected from 0 to 3;

[0040] R7 are each independently selected from hydrogen, halogenated or unsubstituted C 1～4 Alkyl, halogenated or unsubstituted C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR3R4, COOR5, SO2R6, halogen, cyano, nitro, phenyl; wherein R3, R4, R5, R6 are each independently selected from hydrogen, C 1～4 alkyl;

[0041] Ring B is selected from 5- to 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered saturated cycloalkyl, 3- to 6-membered saturated heterocyclic group, condensed cycloalkyl, heterocondensed cycloalkyl, bicyclic alkyl, and heterobicyclic group.

[0042] Furthermore, the structure of the compound is selected from:

[0043]

[0044]

[0045]

[0046]

[0047]

[0048] The present invention also provides an analgesic drug, which is a preparation prepared with the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its solvate, or its prodrug, or its metabolite, or its pharmaceutically acceptable salt as an active ingredient and pharmaceutically acceptable excipients.

[0049] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its solvate, or its prodrug, or its metabolite, or its pharmaceutically acceptable salt in the preparation of analgesic drugs.

[0050] Furthermore, the analgesic drug is a low-toxic analgesic drug.

[0051] Furthermore, the median lethal dose of the low-toxic analgesic drug is higher than the median lethal dose of lappaconitine.

[0052] Experimental results show that the lappaconitine derivatives provided by the present invention have high analgesic activity, good water solubility and low biological toxicity, can be used to prepare low-toxic analgesic drugs, and have broad application prospects.

[0053] The preparation method of the lappaconitine derivative of the invention is simple, the conditions are mild, and it is suitable for large-scale production.

[0054] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0055] In the compound represented by formula I of the present invention, R g Selected from L1R h When L1 is selected from None, it means R g For R h .

[0056] In the compound represented by formula I of the present invention, the dotted line indicates that the chemical bond is located behind the plane of the paper.

[0057] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. 1～6 The alkyl group refers to a straight chain or branched chain alkyl group containing 1 to 6 carbon atoms.

[0058] The term "substituted" herein refers to the replacement of one, two or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two or more substitutions on the isotopic or ectopic atoms in the molecule.

[0059] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups may be substituted or unsubstituted.

[0060] "Heteroaryl" refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0061] A "deuterated compound" is a compound in which one or more hydrogen atoms are replaced by deuterium.

[0062] "Bicycloalkyl" refers to a polycyclic cycloalkyl group in which two rings are connected by a single bond. For example:

[0063] "Heterocyclic group" refers to a polycyclic group in which two rings are connected by a single bond and at least one of the two rings contains a heterocyclic ring. For example:

[0064] "Fused cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms. For example:

[0065] "Heterofused ring group" refers to a polycyclic group, in which two rings share two adjacent carbon atoms, and the two rings contain at least one heterocyclic ring. For example:

[0066] Halogen refers to fluorine, chlorine, bromine or iodine.

[0067] "Pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0068] "Salt" refers to acidic and / or basic salts formed by a compound or its stereoisomers with inorganic and / or organic acids and / or bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. They can also be obtained by mixing the compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0069] The pharmaceutically acceptable salts of the present invention may be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compounds.

[0070] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0071] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0072] The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

[0073] The target compound of the present invention was synthesized by referring to the following route:

[0074]

[0075] The raw material N-deacetyl lappaconitine can be obtained by purchasing commercially available products, or can be prepared by the following route:

[0076]

[0077] Example 1. Preparation of Compound 1 from Lappaconitine and benzenesulfonyl chloride:

[0078] Weigh 110 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop 200 μl of dry pyridine under Ar gas protection, add benzenesulfonyl chloride (98 mg) under ice bath, react at 20°C, and monitor the reaction progress by thin layer chromatography. After 14 hours, the reaction is complete, spin dry the reaction solution, separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0079]

[0080] Molecular formula C 36 H 46 N2O9S, slightly yellow solid (129 mg), yield 93.2%.

[0081] 1 H-NMR (400MHz, CDCl3) δ: 10.51 (s, 1H), 7.79 (t, J = 8.6Hz, 3H), 7.63 (d, J = 8.2Hz, 1H), 7.50 (s, 1H), 7.41 (t ,J=7.8Hz,3H),6.99(t,J=7.6Hz,1H),3.53(d,J=11.3Hz,2H),3.43(d,J=4.7Hz,1H),3.40(s,3H),3.31(s ,3H),3.29(s,3H),3.16(dd,J=10.2,7.0Hz,1H),2.98(s,1H),2.67–2.45(m,5H),2.43–2.34(m,3H),2.32 –2.26(m,2H),2.14–1.95(m,4H),1.68(t,J=15.0Hz,1H),1.41(s,1H),1.28(s,1H),1.12(t,J=7.2Hz,3H).

[0082] MS (ESI) m / z: [(M+H) + ,683.3052].

[0083] Example 2. Preparation of Compound 2 from Lappaconitine and 2-methoxybenzenesulfonyl chloride:

[0084] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 2-methoxybenzenesulfonyl chloride (137 mg) under ice bath, react at 5 ° C, and monitor the progress of the reaction by thin layer chromatography. The reaction is complete in 29.5 hours, and a large amount of solid is precipitated. The reaction liquid is filtered, and the filter cake is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0085]

[0086] Molecular formula C 37 H 48 N2O 10 S, white foamy solid (116 mg), yield 73.6%.

[0087] 1H-NMR (400MHz, CDCl3) δ: 11.11 (s, 1H), 8.00 (d, J = 7.8Hz, 1H), 7.83 (d, J = 9.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.46 (t, J=8.8Hz,1H),7.32(t,J=8.6Hz,1H),7.00(t,J=7.6Hz,1H),6.90(t,J=8.8Hz,2H),3.85(s,3H),3.58(d,J=11.4Hz,1H ),3.53(s,1H),3.41(s,3H),3.32(s,3H),3.31(s,3H),3.19(dd,J=10.2,7.2Hz,1H),3.01(s,1H),2.70–2.36(m,10H ),2.18–1.92(m,5H),1.86(t,J=11.8Hz,1H),1.54(dd,J=15.0,8.2Hz,1H),1.36–1.24(m,1H),1.12(t,J=7.1Hz,3H).

[0088] 13 C-NMR(100MHz, CDCl3)δ:166.9,156.7,141.0,135.1,134.3,131.5,131.3,126.6,122.0,120.1,117.4,115.9,112.0,90.2,84.8, 84.2,82.9,78.6,75.7,61.7,58.0,56.6,56.2,56.0,55.7,51.0,49.9,49.1,48.4,47.6,44.9,36.3,31.9,26.9,26.3,24.2,13.6.

[0089] MS (ESI) m / z: [(M+H) + ,713.3173].

[0090] Example 3. Preparation of Compound 3 from Lappaconitine and 2-pyridinesulfonic acid:

[0091] Weigh 351 mg of 2-pyridinesulfonic acid and suspend it in 5 ml of dry dichloromethane. Add 447 mg of triethylamine under ice bath. After stirring for 15 min, 2-pyridinesulfonic acid is completely dissolved. Then add 624 mg of trifluoromethanesulfonic anhydride and react under ice bath for 2 h. Then weigh 600 mg of N-deacetyl lappaconitine and add it to the reaction solution. React under ice bath. Detect the reaction progress by thin layer chromatography. The reaction is complete after 1.5 h. The reaction solution is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0092]

[0093] Molecular formula C 35 H 45 N3O9S, yellow foamy solid (537 mg), yield 71.1%.

[0094] 1 H-NMR (400MHz, CDCl3) δ: 10.94 (s, 1H), 8.63 (s, 1H), 8.03 (d, J = 7.8Hz, 1H), 7.87 (t, J = 7.4Hz, 1H), 7.79 (dd, J = 2 0.7,8.0Hz,2H),7.48–7.37(m,2H),7.00(t,J=7.4Hz,1H),3.60(d,J=11.3Hz,2H),3.45(s,1H),3.41(s,3H),3.3 2(s,3H),3.30(s,3H),3.22–3.15(m,1H),3.00(s,1H),2.72–2.63(m,2H),2.50(dd,J=13.2,6.6Hz,3H),2.37(dt ,J=18.0,6.4Hz,4H),2.20–1.94(m,6H),1.53(dd,J=14.6,8.0Hz,1H),1.36–1.23(m,1H),1.12(t,J=7.1Hz,3H).

[0095] 13 C-NMR (100MHz, CDCl3) δ:167.0,156.9,150.1,140.3,138.1,134.2,131.3,127.0,123.0,122.7,119.3,117.3,90.2,85.1,8 4.2,82.9,78.7,75.7,61.6,58.0,56.6,56.2,55.3,51.0,49.9,49.1,48.6,47.6,44.9,36.3,31.8,26.9,26.3,24.2,13.6.

[0096] MS (ESI) m / z: [(M+H) + ,684.3010].

[0097] Example 4. Preparation of Compound 4 from Lappaconitine and Methyl Chloroformate:

[0098] Weigh 100 mg of N-deacetyl lappaconitine in a 5 ml round-bottom flask, add 2 ml of dry toluene to dissolve, drip triethylamine (112 mg) under Ar gas protection, add methyl chloroformate (52 mg) under ice bath, react at 30 ° C, and detect the progress of the reaction by thin layer chromatography. After 0.5 h, the reaction is halfway done, and methyl chloroformate (800 mg) is added. After the reaction is continued for 0.5 h, the reaction is complete, and the reaction liquid is dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0099]

[0100] Molecular formula C 32 H 44 N2O9, slightly yellow foamy solid (100 mg), yield 90.3%.

[0101] 1 H-NMR (400MHz, CDCl3) δ: 10.54 (s, 1H), 8.39 (d, J = 8.4Hz, 1H), 7.91 (d, J = 9.5Hz, 1H), 7.49 (t, J = 8.0Hz, 1H), 6.98 (t, J = 8.0Hz, 1H),3.77(s,3H),3.61(d,J=11.4Hz,1H),3.54(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.29(s,3H),3.18(dd, J=10.2,7.0Hz,1H),3.00(s,1H),2.72–2.65(m,2H),2.61–2.46(m,4H),2.44–2.35(m,3H),2.31–2.22(m,2H),2.15(d,J=8.0Hz ,1H),2.12–2.06(m,1H),2.01(dd,J=14.8,7.4Hz,2H),1.83–1.68(m,1H),1.59(dd,J=15.2,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0102] 13 C-NMR(100MHz, CDCl3)δ:167.4,154.2,141.9,134.5,131.3,121.6,118.8,115.6,90.3,84.6,84.3,83.0,78.7, 75.8,61.7,58.1,56.7,56.3,55.6,52.4,51.1,50.0,49.2,48.8,47.7,45.0,36.4,31.9,26.9,26.4,24.3,13.7.

[0103] MS (ESI) m / z: [(M+H) + ,601.3140].

[0104] Example 5. Preparation of Compound 5 from Lappaconitine and 4-dimethylaminobenzoyl chloride:

[0105] Weigh 300 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, dissolve 300 mg of 4-dimethylaminobenzoyl chloride solid in 5 ml of dry dichloromethane, slowly drop the acyl chloride solution into the substrate solution under ice bath, react at 20°C, detect the progress of the reaction by thin layer chromatography, and the reaction is complete after 18 hours. Add saturated sodium carbonate aqueous solution to the reaction solution, adjust the pH value of the reaction solution to 10, extract the reaction solution with dichloromethane, dry the dichloromethane layer with anhydrous sodium sulfate, filter out the sodium sulfate solid, spin dry the dichloromethane to obtain the crude product, separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0106]

[0107] Molecular formula C 39 H 51 N3O8, light yellow foamy solid (323 mg), yield 84.8%.

[0108] 1H-NMR (400MHz, CDCl3) δ: 11.86 (s, 1H), 8.90 (d, J = 8.0Hz, 1H), 7.99-7.91 (m, 2H), 7.95 (d, J = 9.0Hz, 1H), 7.53 (t, J = 8.6Hz, 1H), 7.02 (t, J = 7.8 Hz,1H),6.76(d,J=9.0Hz,1H),5.30(s,1H),4.12(q,J=7.2Hz,1H),3.62(d,J=11.4Hz,1H),3.56(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3. 32(s,3H),3.30(s,3H),3.21(dd,J=10.4,7.0Hz,1H),3.06(s,6H),3.0 2(s,1H),2.74–2.65(m,2H),2.64–2.47(m,4H),2.46–2.35(m,3H),2.27 (s,1H),2.17(d,J=8.1Hz,2H),2.12(dd,J=12.4,4.4Hz,1H),2.04(s,1H),1.65(d,J=8.4Hz,1H),1.26(t,J=7.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0109] 13 C-NMR (100MHz, CDCl3) δ: 167.9, 166.0, 152.8, 142.7, 134.5, 131.2, 129.2×2, 121.9, 121.8, 120.5, 116.0, 111.3×2, 90.3, 84.5, 84 .4,83.1,78.7,75.8,61.7,58.1,56.7,56.3,55.7,51.1,49.9,49.2,48.7,47.7,45.0,40.2×2,36.5,31.9,27.0,26.4,24.3,13.7.

[0110] MS (ESI) m / z: [(M+H) + ,690.3864].

[0111] Example 6. Preparation of Compound 6 from Lappaconitine and 2-fluorobenzenesulfonyl chloride:

[0112] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 2-fluorobenzenesulfonyl chloride (129 mg) under ice bath, react at 5 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is complete in 20 hours, and a large amount of solid is precipitated. The reaction liquid is filtered, and the filter cake is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0113]

[0114] Molecular formula C 36 H 45 FN2O9S, yellow-white foamy solid (125 mg), yield %.

[0115] 1 H-NMR (400MHz, CDCl3)δ:7.95(td,J=7.6,1.8Hz,1H),.83(dd,J=8.0,1.8Hz,1H),7.57(d,J=8.4Hz,1H),7.54–7.49(m,1H),7.40 –7.33(m,1H),7.23(t,J=7.8Hz,1H),7.11(t,J=9.2Hz,1H),6.98(t,J=7.6Hz,1H),5.30(s,1H),3.62(d,J=11.6Hz,1H),3.56(s,1 H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.32(s,3H),3.30(s,3H),3.19(dd,J=10.4,7.0Hz,1H),3.01(s,1H),2.73–2.64(m,2H), 2.59–2.47(m,4H),2.44–2.31(m,4H),2.18–1.96(m,5H),1.80–1.70(m,1H),1.53(dd,J=15.2,8.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0116] 13 C-NMR(100MHz, CDCl3)δ:167.0,139.9,135.6,134.2,131.5,131.0,124.4,122.9,118.2,117.3,90.2,85.2,84.2,83.0,78.7 ,77.5,77.2,76.8,75.7,61.6,58.0,56.6,56.2,55.4,51.1,49.9,49.1,48.7,47.7,44.9,36.3,31.8,26.9,26.2,24.2,13.6.

[0117] MS (ESI) m / z: [(M+H) + ,701.2905].

[0118] Example 7. Preparation of Compound 7 from Lappaconitine and 3-fluorobenzenesulfonyl chloride:

[0119] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 3-fluorobenzenesulfonyl chloride (129 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 16 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0120]

[0121] Molecular formula C 36 H 45 N2O9S, yellow-white foamy solid (114 mg), yield 73.5%.

[0122] 1 H-NMR (400MHz, CDCl3) δ: 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51 (dt, J = 8.2, 2.2 Hz, 1H), 7. 46–7.35(m,2H),7.19(td,J=8.4,2.6Hz,1H),7.02(t,J=7.6Hz,1H),3.53(d,J=11.4Hz,2H),3.42(d,J=5.0Hz,1H),3.39(s,3H),3. 30(s,3H),3.28(s,3H),3.15(dd,J=10.2,7.0Hz,1H),2.98(s,1H),2.63(dd,J=15.2,7.6Hz,1H),2.59–2.53(m,2H),2.52–2.44(m, 2H),2.44–2.33(m,4H),2.30(d,J=7.2Hz,1H),2.14–1.92(m,5H),1.67(m,1H),1.45(dd,J=15.2,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0123] 13C-NMR (100MHz, CDCl3) δ: 167.1, 163.5, 141.4, 140.0, 134.4, 131.5, 130.9, 123.6, 123.1, 120.4, 120.0, 117.7, 114.8, 90.2, 85. 3,84.1,83.0,78.6,75.7,61.6,58.0,56.6,56.2,55.4,51.0,49.9,49.0,48.6,47.6,44.9,36.3,31.8,26.9,26.3,24.2,13.6.

[0124] MS (ESI) m / z: [(M+H) + ,701.2905].

[0125] Example 8. Preparation of Compound 8 from Lappaconitine and 1-naphthalenesulfonyl chloride:

[0126] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 1-naphthalenesulfonyl chloride (150 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 19 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0127]

[0128] Molecular formula C 40 H 48 N2O9S, yellow-white foamy solid (108 mg), yield 66.7%.

[0129] 1H-NMR (400MHz, CDCl3) δ: 11.19 (s, 1H), 8.68 (d, J = 8.6Hz, 1H), 8.32 (dd, J = 7.4, 1.4Hz, 1H), 8.00 (d, J = 8.2Hz, 1H), 7.87 (dd, J = 8.2, 1.4Hz, 1H), 7 .70(dd,J=8.0,1.8Hz,1H),7.64(ddd,J=8.5,6.9,1.4Hz,1H),7.56(td,J=8.4,1.2Hz,2H),7.48(t,J=7.8Hz,1H),7.32(ddd,J=8.6,7.4,1.8Hz, 1H),6.91–6.85(m,1H),3.54(d,J=11.6Hz,2H),3.43(d,J=4.0Hz,1H),3 .40(s,3H),3.31(s,3H),3.30(s,3H),3.15(dd,J=10.2,7.2Hz,1H),2.9 8(s,1H),2.62–2.47(m,5H),2.37(m,3H),2.26(d,J=7.4Hz,2H),2.10–1 .92(m,5H),1.65–1.55(m,1H),1.44–1.37(m,1H),1.14(t,J=7.2Hz,3H).

[0130] 13 C-NMR (100MHz, CDCl3) δ:167.2,140.6,134.8,134.3,134.3,134.3,131.4,130.4,129.1,128.4,128.1,127.0,124.6,124.0,122.5,118.2,11 6.4,90.2,85.0,84.2,83.0,78.7,75.7,61.6,58.1,56.7,56.3,55.4, 51.1,50.0,49.1,48.7,47.6,45.0,36.4,31.7,26.9,26.3,24.2,13.7.

[0131] MS (ESI) m / z: [(M+H) + ,733.3260].

[0132] Example 9. Preparation of Compound 9 from Lappaconitine and Benzylsulfonyl chloride:

[0133] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add benzylsulfonyl chloride (126.5 mg) under ice bath, react at 20 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 4 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0134]

[0135] Molecular formula C 37 H 48 N2O9S, milky white foamy solid (86 mg), yield 55.8%.

[0136] 1 H-NMR (400MHz, CDCl3) δ: 10.42 (s, 1H), 7.90 (dd, J=8.0, 1.6Hz, 1H), 7.67 (dd, J=8.4, 1.2Hz, 1H), 7.46 (ddd, J=8.6, 7.4, 1.8Hz, 1H), 7.27 (m, 2H ),7.26–7.23(m,1H),7.13(dt,J=6.6,1.6Hz,2H),7.04(ddd,J=8.2,7.4,1.2Hz,1H),4.38(s,2H),3.55(s,1H),3.47(d,J=11.6Hz,1H),3.44(d d,J=4.9,1.0Hz,1H),3.41(s,3H),3.31(s,3H),3.28(s,3H),3.16(dd,J=10.2,7.0Hz,1H),2.99(s,1H),2.69(dd,J=15.2,7.4Hz,1H),2.60–2. 46(m,4H),2.45–2.35(m,3H),2.30(t,J=3.6Hz,2H),2.16(d,J=8.0Hz,2 H),2.11–1.95(m,3H),1.67(m,1H),1.53(m,1H),1.10(t,J=7.2Hz,3H).

[0137] 13C-NMR (100MHz, CDCl3)δ:166.9,141.4,134.7,131.8,130.7×2,129.0,128.8×2,128.4,122.6,117.5,116.0,90.3,85.1,84.2 ,83.0,78.7,75.8,61.7,58.1,56.7,56.3,55.4,51.1,49.9,49.1,48.8,47.7,45.0,36.4,31.9,30.3,26.9,26.3,24.3,13.7.

[0138] MS (ESI) m / z: [(M+H) + ,697.3236].

[0139] Example 10. Preparation of Compound 10 from Lappaconitine and 5-dimethylamino-1-naphthoyl chloride:

[0140] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 5-dimethylamino-1-naphthalenesulfonyl chloride (150 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 19 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0141]

[0142] Molecular formula C 42 H 53 N3O9S, yellow-white foamy solid (160 mg), yield 66.7%.

[0143] 1H-NMR (400MHz, CDCl3) δ: 8.49 (dd, J=8.6, 1.2Hz, 1H), 8.34 (d, J=7.6Hz, 2H), 7.73 (dd, J=8.0, 1.6Hz, 1H), 7.54 (dd, J=8.8, 7.6H z,2H),7.47(dd,J=8.6,7.4Hz,1H),7.31(ddd,J=8.8,7.4,1.6Hz,1H),7.13(d,J=7.6Hz,1H),6.87(t,J=7.8Hz,1H),3.59(d,J= 11.4Hz,1H),3.43(d,J=5.0Hz,1H),3.40(s,3H),3.31(s,3H),3.30(s,3H),3.16(dd,J=10.4,7.0Hz,1H),2.99(s,1H),2.83(s, 6H),2.66–2.47(m,6H),2.45–2.34(m,4H),2.28(d,J=7.4Hz,1H),2.21–1.93(m,6H),1.49–1.43(m,1H),1.15(t,J=7.2Hz,3H).

[0144] 13 C-NMR (100MHz, CDCl3) δ: 167.2, 151.9, 140.7, 134.4, 134.2, 131.4, 131. 0,130.4,129.9,129.6,128.5,123.0,122.2,119.0,117.8,116.2,115.3 ,90.2,84.9,84.2,83.0,78.6,75.7,61.6,58.0,56.7,56.2,55.4,51.0, 49.9,49.1,48.7,47.6,45.5×2,44.9,36.3,31.7,26.9,26.3,24.2,13.7.

[0145] MS (ESI) m / z: [(M+H) + ,776.3541].

[0146] Example 11. Preparation of Compound 11 from Lappaconitine and (4-nitrophenyl)methanesulfonyl chloride:

[0147] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar protection, add (4-nitrophenyl) methanesulfonyl chloride (156 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 2 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0148]

[0149] Molecular formula C 37 H 47 N3O 11 S, white foamy solid (77 mg), yield 47.0%.

[0150] 1 H-NMR (400MHz, CDCl3) δ: 10.52 (s, 1H), 8.13 (d, J = 8.8Hz, 2H), 7.94 (dd, J = 8.0, 1.6Hz, 1H), 7.75 (d, J = 8.4Hz, 1H), 7.51 (ddd, J = 8.6, 7.3 ,1.7Hz,1H),7.33(d,J=8.6Hz,2H),7.10(t,J=7.6Hz,1H),4.46(s,2H),3.54(s,1H),3.47–3.42(m,2H),3.40(s,3H),3.30(s,3H),3.27 (s,3H),3.15(dd,J=10.2,7.0Hz,1H),2.98(s,1H),2.69(dd,J=15.2,7.4Hz,1H),2.59–2.48(m,2H),2.48–2.40(m,3H),2.40–2.34(m,2 H),2.34–2.28(m,2H),2.14(d,J=7.8Hz,2H),2.08–1.93(m,3H),1.72–1.62(m,1H),1.50(dd,J=15.0,8.2Hz,1H),1.07(t,J=7.2Hz,3H).

[0151] 13 C-NMR (100MHz, CDCl3)δ:167.0,148.2,140.8,135.7×2,135.0,132.1,131.7,123.9×2,123.2,117.5,116.1,90.2,85.6,84.0 ,83.0,78.7,75.7,61.6,58.0,57.1,56.7,56.3,55.3,51.1,49.9,49.0,48.6,47.7,45.0,36.4,31.9,26.8,26.3,24.3,13.6.

[0152] MS (ESI) m / z: [(M+H) + ,742.3052].

[0153] Example 12. Preparation of Compound 12 from Lappaconitine and 8-quinolinesulfonyl chloride:

[0154] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 8-quinolinesulfonyl chloride (151 mg) under ice bath, react at 5 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is complete in 18 hours, and a large amount of solid is precipitated. The reaction liquid is filtered, and the filter cake is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0155]

[0156] Molecular formula C 39 H 47 N3O9S, yellow-white foamy solid (122 mg), yield 75.3%.

[0157] 1 H-NMR (400MHz, CDCl3) δ: 11.57 (s, 1H), 9.03 (d, J = 2.6Hz, 1H), 8.53 (d, J = 7.4Hz, 1H), 8.14 (d, J = 6.8Hz, 1H), 7.97 (d, J = 8.2Hz, 1H), 7.78 ( d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.57(t,J=7.8Hz,1H),7.46(dd,J=8.4,4.2Hz,1H),7.31–7.25(m,1H),6.83(t,J=7.6Hz,1H),5.30 (s,1H),3.62(d,J=11.4Hz,1H),3.54(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.32(s,6H),3.22–3.15(m,1H),3.01(s,1H),2.64–2.57 (m,4H),2.55–2.48(m,2H),2.43–2.38(m,4H),2.14–1.97(m,5H),1.83–1.74(m,1H),1.46(dd,J=15.2,8.4Hz,1H),1.16(t,J=7.2Hz,3H).

[0158] 13C-NMR (100MHz, CDCl3)δ:166.3,151.3,143.6,140.8,136.4,135.8,134.0,134.0,132.4,131.4,128.8,125.2,122.2,121.9,117.4,116.4 ,90.2,84.5,84.2,83.0,78.6,75.7,61.6,58.0,56.6,56.2,55.6,51 .0,49.9,49.1,48.4,47.6,44.9,36.3,31.8,26.9,26.3,24.1,13.7.

[0159] MS (ESI) m / z: [(M+H) + ,734.3103].

[0160] Example 13. Preparation of Compound 13 from Lappaconitine and 3-methoxybenzenesulfonyl chloride:

[0161] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 3-methoxybenzenesulfonyl chloride (137 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 1.5 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0162]

[0163] Molecular formula C 37 H 48 N2O 10 S, white foamy solid (100 mg), yield 63.7%.

[0164] 1H-NMR(400MHz, CDCl3)δ:10.61(s,1H),7.79(dd,J=8.0,1.6Hz,1H),7.63(dd,J=8.4,1.2Hz,1H),7.45–7.35(m,2H),7.33–7.2 6(m,2H),7.04–6.98(m,2H),3.76(s,3H),3.56–3.51(m,2H),3.43(d,J=4.4Hz,1H),3.40(s,3H),3.30(s,3H),3.28(s,3H),3.1 6(dd,J=10.2,7.0Hz,1H),2.98(s,1H),2.63(dd,J=15.2,7.4Hz,1H),2.59–2.53(m,2H),2.52–2.45(m,2H),2.42(s,1H),2.40– 2.35(m,2H),2.29(d,J=6.8Hz,2H),2.14–1.93(m,5H),1,70–1.62(m,1H),1.46(dd,J=15.0,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0165] 13 C-NMR (100MHz, CDCl3) δ:167.1,159.8,140.6,140.4,134.3,131.4,130.1,123.3,119.9,119.6,119.4,117.6,111.7,90.2,85.1, 84.2,83.0,78.7,75.7,61.6,58.0,56.7,56.3,55.7,55.4,51.0,49.9,49.1,48.7,47.6,45.0,36.4,31.8,26.9,26.3,24.2,13.7.

[0166] MS (ESI) m / z: [(M+H) + ,713.3121].

[0167] Example 14. Preparation of Compound 14 from Lappaconitine and isopropyl chloroformate:

[0168] Weigh 100 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry tetrahydrofuran to dissolve, and add isopropyl chloroformate (520 mg) under Ar gas protection in an ice bath. React at 60°C, and monitor the reaction progress by thin layer chromatography. After 1.5 hours, the reaction is complete, and the reaction liquid is dried by spin drying. Column chromatography is used for separation and purification to obtain the target compound. Its structure and characterization are as follows:

[0169]

[0170] Molecular formula C 34 H 48 N2O9, yellow foam solid (100 mg), yield 86.2%.

[0171] 1 H-NMR (400MHz, CDCl3) δ: 10.39 (s, 1H), 8.42 (d, J = 8.6Hz, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.47 (t, J = 7.2Hz, 1H), 6.96 (t, J = 7 .6Hz,1H),5.04–4.97(m,1H),3.60(d,J=11.4Hz,1H),3.55(s,1H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.31(s,3H),3.2 9(s,3H),3.18(dd,J=10.2,7.0Hz,2H),3.00(s,1H),2.69(m,2H),2.60–2.46(m,4H),2.44–2.34(m,3H),2.29(s,1H),2. 18–1.98(m,4H),1.79(t,J=12.0Hz,1H),1.59(dd,J=15.0,8.2Hz,1H),1.31(s,3H),1.29(s,3H),1.11(t,J=7.2Hz,3H).

[0172] MS (ESI) m / z: [(M+H) + ,629.3496].

[0173] Example 15. Preparation of Compound 15 from Lappaconitine and p-toluenesulfonyl chloride:

[0174] Weigh 100 mg of N-deacetyl lappaconitine in a 5 ml round-bottom flask, add 1 ml of dry pyridine to dissolve, add p-toluenesulfonyl chloride (105 mg) under Ar gas protection, react at 50 ° C, and monitor the reaction progress by thin layer chromatography. After 6.5 hours, the reaction is complete, and the reaction liquid is dried by spin drying, and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0175]

[0176] Molecular formula C 37 H 48 N2O9S, solid (69 mg), yield 53.7%. 1H-NMR (400MHz, CDCl3) δ: 10.44 (s, 1H), 7.78 (d, J = 8.0Hz, 1H), 7.69 (d, J = 8.3Hz, 2H), 7.61 (d, J = 8.0Hz, 1H), 7.40 (t ,J=8.6Hz,1H),7.20(d,J=8.2Hz,2H),6.98(t,J=8.2Hz,1H),3.55(d,J=11.6Hz,2H),3.43(d,J=4.6Hz,1H),3.40(s ,3H),3.31(s,3H),3.29(s,3H),3.16(dd,J=10.2,7.2Hz,1H),2.99(s,1H),2.69–2.53(m,3H),2.53–2.45(m,2H),2 .15–1.93(m,5H),1.52–1.40(m,2H),1.38–1.23(m,4H),2.36(s,3H),1.68(t,J=15.8Hz,1H),1.12(t,J=7.2Hz,3H).

[0177] MS (ESI) m / z: [(M+H) + ,697.3204].

[0178] Example 16. Preparation of Compound 16 from Lappaconitine and 2-butenoyl chloride:

[0179] Weigh 100 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop 200 μl of dry pyridine under Ar gas protection, add 2-butenoyl chloride (58 mg) under ice bath, react at 20°C, monitor the reaction progress by thin layer chromatography, the reaction is complete after 5 min, spin dry the reaction solution, separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0180]

[0181] Molecular formula C 34 H 46 N2O8, slightly yellow solid (105 mg), yield %. 1H-NMR (400MHz, CDCl3) δ: 11.15 (s, 1H), 8.76 (d, J = 8.2Hz, 1H), 7.93 (d, J = 9.4Hz, 1H), 7.50 (t, J = 8.6Hz, 1H), 7.00 (m, 2H), 6.02 (d,J=16.8Hz,1H),3.58(d,J=11.6Hz,1H),3.56(s,1H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.31(s,3H),3.29(s,3H),3.18(dd . 01(dd,J=14.8,7.4Hz,2H),1.92(dd,J=7.0,1.4Hz,3H),1.81(t,J=13.0Hz,2H),1.59(d,J=23.4Hz,1H),1.12(t,J=7.2Hz,3H).

[0182] MS (ESI) m / z: [(M+H) + ,611.3354].

[0183] Example 17. Preparation of Compound 17 from Lappaconitine and methanesulfonyl chloride:

[0184] Weigh 100 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 3 ml of dry tetrahydrofuran to dissolve, drop 75 mg of triethylamine under Ar gas protection, add methanesulfonyl chloride (98 mg) under ice bath, react at 20°C, monitor the reaction progress with thin layer chromatography, the reaction is complete after 0.5 h, spin dry the reaction solution, separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0185]

[0186] Molecular formula C 31 H 44 N2O9S, solid (105 mg), yield 91.8%.

[0187] 1H-NMR (400MHz, CDCl3) δ: 10.51 (s, 1H), 7.93 (d, J = 9.6Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.50 (t, J = 8.8Hz, 1H), 7.06 (t, J =8.2Hz,1H),3.58(d,J=11.4Hz,1H),3.54(s,1H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.30(s,3H),3.28(s,3H),3.17 (dd,J=10.4,7.0Hz,1H),3.05(s,3H),3.00(s,1H),2.73–2.61(m,2H),2.59–2.44(m,4H),2.37(dd,J=7.4,5.0Hz,3H) ,2.30(s,1H),2.17–1.93(m,4H),1.82–1.72(m,1H),1.56(dd,J=15.2,8.4Hz,1H),1.41(s,1H),1.11(t,J=7.2Hz,3H).

[0188] MS (ESI) m / z: [(M+H) + ,621.2888].

[0189] Example 18. Preparation of Compound 18 from Lappaconitine and methylcarbamoyl chloride:

[0190] Weigh 150 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 5 ml of dichloromethane to dissolve, add 112 mg of triethylamine under Ar gas protection, add 200 mg of methylaminoformyl chloride under ice bath, react at 70 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is basically complete in 6 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0191]

[0192] Molecular formula C 32 H 45 N3O8, light yellow foamy solid (60 mg), yield 36.2%.

[0193] 1H-NMR (400MHz, CDCl3) δ: 10.36 (s, 1H), 8.48 (d, J = 8.4Hz, 1H), 7.87 (dd, J = 8.0, 1.6Hz, 1H), 7.45 (t, J = 7.0Hz, 1H), 6.90 (t, J = 7.6Hz ,1H),3.60(s,1H),3.54(d,J=11.4Hz,1H),3.47(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.29(s,3H),3.17(dd,J= 10.2,7.0Hz,1H),3.00(s,1H),2.88(d,J=4.8Hz,3H),2.67(dd,J=15.2,7.6Hz,1H),2.60–2.46(m,5H),2.44–2.34(m,3H),2.32(s, 1H)2.32(s,1H),2.16(d,J=8.2Hz,1H),2.09–1.97(m,3H),1.85–1.75(m,1H),1.58(dd,J=15.2,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0194] MS (ESI) m / z: [(M+H) + ,600.3363].

[0195] Example 19. Preparation of Compound 19 from Lappaconitine and 4-trifluoromethylbenzoyl chloride:

[0196] Weigh 80 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop 200 μl of dry pyridine under Ar gas protection, add 4-trifluoromethylbenzenesulfonyl chloride (143 mg) under ice bath, react at 20°C, monitor the reaction progress by thin layer chromatography, and the reaction is complete after 2 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0197]

[0198] Molecular formula C 37 H 45 F3N2O9S, yellow oil (90 mg), yield 85.7%.

[0199] 1H-NMR (400MHz, CDCl3) δ: 7.93 (d, J = 8.2Hz, 2H), 7.81 (d, J = 6.6Hz, 1H), 7.66 (dd, J = 17.4, 8.2Hz, 3H), 7.45 (t, J = 8.6Hz, 1H), 7.05 (t, J =7.4Hz,1H),5.29(s,1H),3.51(d,J=11.4Hz,2H),3.43(d,J=4.7Hz,1H),3.40(s,3H),3.30(s,3H),3.29(s,3H),3.16(dd,J=10.2,7. 2Hz,1H),2.98(s,1H),2.91(q,J=7.4Hz,2H),2.64(dd,J=15.2,7.4Hz,1H),2.58–2.44(m,4H),2.44–2.34(m,3H),2.14–1.95(m,5H)2 .31(d,J=7.2Hz,1H),1.66(t,J=13.6Hz,1H),1.46(dd,J=15.1,8.3Hz,1H),1.42(s,1H),1.36(t,J=7.2Hz,3H),1.11(t,J=7.2Hz,3H).

[0200] MS (ESI) m / z: [(M+H) + ,751.2958].

[0201] Example 20. Preparation of Compound 20 from Lappaconitine and 4-methoxybenzenesulfonyl chloride:

[0202] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 4-methoxybenzenesulfonyl chloride (137 mg) under ice bath, react at 20 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 12 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0203]

[0204] Molecular formula C 37 H 48 N2O 10 S, milky white foamy solid (150 mg), yield 93.8%.

[0205] 1H-NMR(400MHz, CDCl3)δ:10.54(s,1H),7.79(dd,J=8.0,1.4Hz,1H),7.73(d,J=9.0Hz,2H),7.62(d,J=8.2Hz,1H),7.44–7.38(m,1H ),6.99(t,J=7.4Hz,1H),6.87(d,J=9.0Hz,2H),3.81(s,3H),3.53(t,J=5.8Hz,2H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.31(s,3H ),3.29(s,3H),3.17(dd,J=10.2,7.0Hz,1H),2.99(s,1H),2.67–2.60(m,1H),2.61–2.54(m,2H),2.54–2.45(m,2H),2.45–2.34(m, 3H), 2.31(d,J=7.4Hz,1H),2.26(s,1H),2.20–1.91(m,5H),1.75–1.66(m,1H),1.47(dd,J=14.6,6.4Hz,1H),1.12(t,J=7.2Hz,3H).

[0206] MS (ESI) m / z: [(M+H) + ,713.3121].

[0207] Example 21. Preparation of Compound 21 from Lappaconitine and Ethyl Chloroformate:

[0208] Weigh 100 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drip triethylamine (112 mg) under Ar gas protection, add ethyl chloroformate (60 mg) under ice bath, react at 70°C, monitor the reaction progress by thin layer chromatography, and the reaction is complete after 1 hour. The reaction liquid is dried by spin drying, and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0209]

[0210] Molecular formula C 33 H 46 N2O9, yellow-white foamy solid (102 mg), yield 90.3%.

[0211] 1H-NMR (400MHz, CDCl3) δ: 10.47 (s, 1H), 8.41 (d, J = 8.5Hz, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.48 (t, J = 7.8Hz, 1H), 6.97 (t,J=7.6Hz,1H),4.22(q,J=7.2Hz,2H),3.61(d,J=11.4Hz,1H),3.54(s,1H),3.44(d,J=4.7Hz,1H),3.41(s,3H), 3.31(s,3H),3.29(s,3H),3.18(dd,J=10.2,7.2Hz,1H),3.00(s,1H),2.73–2.64(m,2H),2.61–2.46(m,5H),2.40( dd,J=15.4,8.2Hz,4H),2.20–1.91(m,6H),1.84–1.73(m,2H),1.60(dd,J=15.2,8.2Hz,1H),1.12(t,J=7.2Hz,3H)

[0212] MS (ESI) m / z: [(M+H) + ,615.3331].

[0213] Example 22. Preparation of Compound 22 from Lappaconitine and 4-phenylbenzenesulfonyl chloride:

[0214] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 4-phenylbenzenesulfonyl chloride (168 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 21 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0215]

[0216] Molecular formula C 42 H 50 N2O9S, yellow-white foamy solid (108 mg), yield 64.3%.

[0217] 1H-NMR (400MHz, CDCl3) δ: 10.66 (s, 1H), 7.86 (d, J = 8.6Hz, 2H), 7.80 (dd, J = 8.0, 1.6Hz, 1H), 7.67 (dd, J = 8.4, 1.2Hz, 1H), 7.62 (d, J = 8.6Hz, 2H), 7. 57–7.53(m,2H),7.44(tdd,J=7.4,3.0,1.6Hz,3H),7.39(d,J=7.2Hz,1H),7.02(ddd,J=8.4,7.4,1.2Hz,1H),3.54(d,J=11.4Hz,1H),3.52(s,1H) ,3.42(dd,J=4.8,1.2Hz,1H),3.40(s,3H),3.30(s,3H),3.28(s,3H),3.14(dd,J=10.3,7.0Hz,1H),2.96(s,1H),2.63(dd,J=15.2,7.6Hz,1H),2. 59–2.32(m,8H),2.30(d,J=7.2Hz,1H),2.10–1.91(m,5H),1.67(tdd,J= 12.2,5.4,2.8,1H),1.46(dd,J=15.4,8.5Hz,1H),1.10(t,J=7.2Hz,3H).

[0218] 13 C-NMR (100MHz, CDCl3) δ: 167.1, 145.9, 140.5, 139.2, 138.1, 134.4, 131.5, 129.2×2, 128.6, 127.8×2, 127.7×2, 127.4×2, 123.3, 120.0, 117. 5,90.2,85.1,84.2,83.0,78.7,75.7,61.6,58.1,56.7,56.3,55.4,5 1.1,49.9,49.1,48.6,47.6,45.0,36.3,31.8,26.8,26.3,24.2,13.6.

[0219] MS (ESI) m / z: [(M+H) + ,759.3285].

[0220] Example 23. Preparation of Compound 23 from Lappaconitine and 4-fluorobenzenesulfonyl chloride:

[0221] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (105 mg) under Ar gas protection, add 4-fluorobenzenesulfonyl chloride (129 mg) under ice bath, react at 20 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 2 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0222]

[0223] Molecular formula C 36 H 45 FN2O9S, light yellow foamy solid (135 mg), yield 87.1%.

[0224] 1 H-NMR (400MHz, CDCl3) δ: 10.35 (s, 1H), 7.81 (m, 3H), 7.62 (d, J = 7.8Hz, 1H), 7.43 (t, J = 8.6Hz, 1H), 7.08 (t, J = 8.6Hz, 2 H),7.02(t,J=8.2Hz,1H),3.53(s,1H),3.50(s,1H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.31(s,3H),3.29(s,3H),3. 17(dd,J=10.2,7.2Hz,1H),2.99(s,1H),2.63(dd,J=15.2,7.4Hz,1H),2.59–2.45(m,4H),2.44–2.35(m,3H),2.32(d, J=7.2Hz,1H),2.27(s,1H),2.15–1.92(m,5H),1.76–1.66(m,1H),1.46(dd,J=15.2,8.2Hz,1H),1.12(t,J=7.2Hz,3H).

[0225] MS (ESI) m / z: [(M+H) + ,701.2905].

[0226] Example 24. Preparation of Compound 24 from Lappaconitine and Allyl Chloroformate:

[0227] Weigh 105 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 5 ml of dry toluene to dissolve, drip triethylamine (112 mg) under Ar gas protection, add allyl chloroformate (67 mg) under ice bath, react at 80 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is complete in 2.5 hours, and the reaction liquid is dried by spin drying, and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0228]

[0229] Molecular formula C 34 H 46 N2O9, white foamy solid (115 mg), yield 95.0%.

[0230] 1 H-NMR (400MHz, CDCl3) δ: 10.57 (s, 1H), 8.40 (d, J = 8.4Hz, 1H), 7.91 (dd, J = 8.0, 1.4Hz, 1H), 7.49 (t, J = 7.2Hz, 1H), 6.98 (t, J = 7.4Hz, 1H ),6.07–5.90(m,1H),5.37(dd,J=17.2,1.4Hz,1H),5.25(d,J=10.4Hz,1H),4.66(d,J=5.8Hz,2H),3.61(d,J=11.4Hz,1H),3.54(s,1H) ,3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,4H),3.29(s,3H),3.18(dd,J=10.2,7.0Hz,1H),3.00(s,1H),2.73–2.65(m,2H),2.60–2. 46(m,4H),2.44–2.33(m,3H),2.27(s,1H),2.19–1.91(m,5H),1.83–1.73(m,1H),1.60(dd,J=15.2,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0231] MS (ESI) m / z: [(M+H) + ,627.3347].

[0232] Example 25. Preparation of Compound 25 from Lappaconitine and 4-chlorobenzenesulfonyl chloride:

[0233] Weigh 150 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dichloromethane to dissolve, add 112 mg of triethylamine under Ar gas protection, add 4-chlorobenzenesulfonyl chloride (116 mg) under ice bath, react at 20 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is basically complete in 3 hours, and the reaction liquid is dried by spin drying, and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0234]

[0235] Molecular formula C 36 H 45 ClN2O9S, light yellow foamy solid (166 mg), yield 83.8%.

[0236] 1 H-NMR (400MHz, CDCl3)δ:10.36(s,1H),7.80(dd,J=8.0,1.4Hz,1H),7.72(d,J=8.8Hz,2H),7.62(d,J=8.0Hz,1H),7.46–7.41(m,1H) ,7.38(d,J=8.8Hz,2H),7.04(t,J=7.6Hz,1H),3.53(d,J=3.8Hz,1H),3.49(s,1H),3.43(d,J=4.8Hz,2H),3.40(s,3H),3.31(s,3H),3 .29(s,3H),3.17(dd,J=10.2,7.2Hz,1H),2.99(s,1H),2.64(dd,J=15.2,7.4Hz,1H),2.59–2.45(m,4H),2.43–2.35(m,3H),2.32(d, J=7.2Hz,1H),2.26(s,1H),2.15–1.92(m,5H),1.71(ddd,J=15.4,9.2,3.8,1H),1.46(dd,J=15.0,8.2Hz,1H),1.12(t,J=7.2Hz,3H).

[0237] MS (ESI) m / z: [(M+H) + ,717.2727].

[0238] Example 26. Preparation of Compound 26 from Lappaconitine and 4-bromobenzenesulfonyl chloride:

[0239] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dichloromethane to dissolve, add 112 mg of triethylamine under Ar gas protection, add 4-bromobenzenesulfonyl chloride (141 mg) under ice bath, react at 60 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is basically complete in 4 hours. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0240]

[0241] Molecular formula C 36 H 45 BrN2O9S, light yellow foamy solid (65 mg), yield 38.7%.

[0242] 1H-NMR(400MHz, CDCl3)δ:7.81(dd,J=8.0,1.4Hz,1H),7.64(t,J=9.6Hz,3H),7.55(d,J=8.7Hz,2H),7.48–7.40(m,1H), 7.04(t,J=8.2Hz,1H),3.53(d,J=2.8Hz,1H),3.50(s,1H),3.43(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H) ,3.17(dd,J=10.2,7.0Hz,1H),2.99(s,1H),2.64(dd,J=15.2,7.4Hz,1H),2.59–2.46(m,4H),2.43–2.35(m,3H),2.32(d ,J=7.2Hz,1H),2.26(s,1H),2.16–1.96(m,5H),1.75–1.65(m,1H),1.46(dd,J=15.0,8.3Hz,1H),1.12(t,J=7.2Hz,3H).

[0243] MS (ESI) m / z: [(M+H) + ,763.2000].

[0244] Example 27. Preparation of Compound 27 from Lappaconitine and Ethylsulfonyl Chloride:

[0245] Weigh 100 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 5 ml of dichloromethane to dissolve, add 112 mg of triethylamine under Ar gas protection, add ethylsulfonyl chloride (71 mg) under ice bath, react at 20 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is basically complete in 5 minutes. The reaction liquid is spin-dried and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0246]

[0247] Molecular formula C 32 H 46 N2O9S, light yellow foamy solid (77 mg), yield 65.8%.

[0248] 1H-NMR (400MHz, CDCl3) δ: 10.36 (s, 1H), 7.93 (dd, J=8.0, 1.6Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.54–7.44 (m, 1H), 7.05 (t, J=7. 6Hz,1H),3.59(d,J=11.4Hz,1H),3.53(s,1H),3.44(d,J=4.8Hz,2H),3.41(s,3H),3.31(s,3H),3.29(s,3H),3.21–3.12(m,3 H),3.00(s,1H),2.73–2.62(m,2H),2.60–2.46(m,4H),2.45–2.34(m,3H),2.27(s,1H),2.15(d,J=8.0Hz,1H),2.09–2.07(m ,1H),2.04–1.95(m,2H),1.78(t,J=12.0Hz,1H),1.57(dd,J=15.0,8.4Hz,1H),1.34(t,J=7.4Hz,3H),1.11(t,J=7.2Hz,3H).

[0249] MS (ESI) m / z: [(M+H) + ,635.3107].

[0250] Example 28. Preparation of Compound 28 from Lappaconitine and Phenyl Chloroformate:

[0251] Weigh 115 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 5 ml of dry toluene to dissolve, add phenyl chloroformate (87 mg) under Ar gas protection and ice bath, react at 40 ° C, and monitor the reaction progress by thin layer chromatography. The reaction is complete in 0.5 h, and a large amount of solid is precipitated. The solid is washed with methanol and separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0252]

[0253] Molecular formula C 37 H 46 N2O9, light yellow solid (53 mg), yield 37.9%.

[0254] 1H-NMR (400MHz, CDCl3) δ: 10.94 (s, 1H), 8.42 (d, J = 8.4Hz, 1H), 7.96 (d, J = 8.0Hz, 1H), 7.51 (t, J = 7.4Hz, 1H), 7.39 (t, J = 8 .0Hz,2H),7.21(t,J=7.0Hz,3H),7.04(t,J=7.6Hz,1H),3.64(d,J=11.4Hz,1H),3.55(s,1H),3.45(d,J=4.6Hz,1H),3.4 1(s,3H),3.32(s,3H),3.30(s,3H),3.20(dd,J=10.2,7.2Hz,1H),3.02(s,1H),2.76–2.68(m,2H),2.61–2.47(m,4H),2. 45–2.36(m,3H),2.28(s,1H),2.19–1.94(m,5H),1.88–1.77(m,1H),1.62(dd,J=15.2,8.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0255] MS (ESI) m / z: [(M+H) + ,663.3340].

[0256] Example 29. Preparation of Compound 29 from Lappaconitine and 2-thenoyl chloride:

[0257] Weigh 120 mg of N-deacetyl lappaconitine into a 5 ml round-bottom flask, add 2 ml of dry dichloromethane to dissolve, drop pyridine (107 μl) under Ar gas protection, add 2-thiophenecarbonyl chloride (121 mg) under ice bath, react at 5 ° C, monitor the reaction progress by thin layer chromatography, and the reaction is complete in 1.5 hours. Separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0258]

[0259] Molecular formula C 34 H 44 N2O9S2, yellow-white foamy solid (80 mg), yield 52.6%.

[0260] 1H-NMR(400MHz, CDCl3)δ:7.82(dd,J=8.0,1.6Hz,1H),7.71(dd,J=8.4,1.2Hz,1H),7.54(dd,J=3.8,1.4Hz,1H),7.51– 7.43(m,2H),7.05(td,J=7.6,1.2Hz,1H),6.98(dd,J=5.0,3.8Hz,1H),3.54(d,J=11.6Hz,2H),3.43(d,J=5.0Hz,1H), 3.40(s,3H),3.31(s,3H),3.29(s,3H),3.16(dd,J=10.2,7.2Hz,1H),2.98(s,1H),2.68–2.55(m,3H),2.53–2.35(m,6 H),2.32(d,J=7.4Hz,1H),2.16–1.94(m,5H),1.76–1.65(m,1H),1.47(dd,J=15.0,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0261] 13 C-NMR (100MHz, CDCl3) δ:167.1,140.2,140.1,134.4,132.8,132.5,131.4,127.3,123.6,120.1,117.7,90.2,85.1,84.1 ,83.0,78.6,75.7,61.6,58.1,56.7,56.3,55.5,51.1,49.9,49.2,48.4,47.6,45.0,36.4,31.7,26.7,26.3,24.2,13.6.

[0262] MS (ESI) m / z: [(M+H) + ,689.2659].

[0263] Example 30. Preparation of Compound 30 from Lappaconitine and 4-diethylaminobenzoic acid:

[0264] Weigh 172 mg of 4-diethylaminobenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 375 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 4-diethylaminobenzoyl chloride, weigh 102 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 14 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0265]

[0266] Molecular formula C 41 H 55 N3O8, light yellow foamy solid (96 mg), yield 71.2%.

[0267] 1 H-NMR (400MHz, CDCl3) δ: 11.81 (s, 1H), 8.89 (dd, J=8.6, 1.2Hz, 1H), 7.95 (dd, J=8.0, 1.8Hz, 1H), 7.91 (d, J=9.0Hz, 2H), 7.52 (ddd, J=8.8, 7.2, 1.8 Hz,1H),7.01(t,J=7.0Hz,1H),6.72(d,J=9.0Hz,2H),3.62(d,J=11.4Hz, 1H),3.56(s,1H),3.46(d,J=3.6Hz,1H),3.44(d,J=7.0Hz,3H),3.41(s,3H ),3.32(s,3H),3.30(s,3H),3.21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2 .74–2.65(m,2H),2.61–2.48(m,4H),2.47–2.36(m,3H),2.32(d,J=12.8H z,1H),2.26(s,1H),2.20–2.09(m,3H),2.06–1.94(m,2H),1.85(t,J=13. 8Hz,1H),1.67–1.62(m,1H),1.22(t,J=7.0Hz,6H),1.14(t,J=7.2Hz,3H).

[0268] MS (ESI) m / z: [(M+H)+ ,718.4086].

[0269] Example 31. Preparation of Compound 31 from Lappaconitine and 4-ethoxybenzoyl chloride:

[0270] Weigh 99 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 102 mg of 4-ethoxybenzoyl chloride into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. After 2 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0271]

[0272] Molecular formula C 39 H 50 N2O9, light yellow foamy solid (90 mg), yield 70.9%.

[0273] 1 H-NMR (400MHz, CDCl3) δ: 11.94 (s, 1H), 8.87 (d, J = 8.4Hz, 1H), 8.10–7.89 (m, 3H), 7.55 (ddd, J = 8.8, 7.4, 1.8Hz, 1H), 7.05 (t, J = 7.4Hz, 1H), 7.00(d,J=8.8Hz,2H),4.11(q,J=7.0Hz,2H),3.60(d,J=11.4Hz,1H),3.56(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.32(s,3H),3.30(s, 3H),3.21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.70(dd,J=15.0,8.2Hz,2H),2.60–2.48(m,4H),2.45(d,J=7.6Hz,1H),2.40–2.36(m,2H), 2.28(s,1H),2.20–2.07(m,3H),2.06–1.96(m,2H),1.86(t,J=12.6Hz,1H),1.65–1.59(m,1H),1.45(t,J=7.0Hz,3H),1.13(t,J=7.2Hz,3H).

[0274] MS (ESI) m / z: [(M+H) +,691.3702].

[0275] Example 32. Preparation of Compound 32 from Lappaconitine and 4-methoxybenzoic acid:

[0276] Weigh 120 mg of 4-methoxybenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 129 mg of oxalyl chloride in an ice bath, react at room temperature for 3 hours to obtain 4-methoxybenzoyl chloride, weigh 69 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly drop the obtained acid chloride into the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 17 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0277]

[0278] Molecular formula C 38 H 48 N2O9, light yellow foamy solid (33 mg), yield 38.4%.

[0279] 1 H-NMR (400MHz, CDCl3) δ: 11.95 (s, 1H), 8.87 (d, J = 8.4Hz, 1H), 8.08–7.90 (m, 3H), 7.61–7.49 (m, 1H), 7.10–6.99 (m, 3H ),3.88(s,3H),3.60(d,J=11.6Hz,1H),3.57(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3. 21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.70(dd,J=15.8,8.4Hz,2H),2.61–2.48(m,4H),2.45(d,J=7.8Hz,1H),2.42 –2.35(m,2H),2.28(s,1H),2.19–1.95(m,5H),1.91–1.81(m,1H),1.62(dd,J=15.0,8.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0280] MS (ESI) m / z: [(M+H) +,677.3514].

[0281] Example 33. Preparation of Compound 33 from Lappaconitine and Cyclopentanecarboxylic Acid:

[0282] Weigh 116 mg of cyclopentanecarboxylic acid in a 25 ml dry round-bottom flask, add 5 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 375 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain cyclopentanecarboxylic acid chloride, weigh 107 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 15 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain the crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0283]

[0284] Molecular formula C 36 H 50 N2O8, light yellow foamy solid (81 mg), yield 64.3%.

[0285] 1 H-NMR(400MHz, CDCl3)δ:11.10(s,1H),8.71(dd,J=8.6,1.2Hz,1H),7.92(dd,J=8.2,1.8Hz,1H),7.49(ddd,J=8.8,7.4,1.8Hz,1H),7 .01(ddd,J=8.2,7.4,1.2Hz,1H),3.58(d,J=11.4Hz,1H),3.55(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H), 3.19(dd,J=10.4,7.0Hz,1H),3.01(s,1H),2.78(p,J=8.2Hz,1H),2.73–2.62(m,2H),2.61–2.47(m,4H),2.40(dt,J=14.4,7.2Hz,3H) ,2.26(s,1H),2.19–2.07(m,3H),2.05–1.94(m,4H),1.93–1.85(m,2H),1.82–1.75(m,2H),1.68–1.55(m,5H),1.13(t,J=7.2Hz,3H).

[0286] MS (ESI) m / z: [(M+H) + ,639.2407].

[0287] Example 34. Preparation of Compound 34 from Lappaconitine and Heptanoyl Chloride:

[0288] Weigh 98 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 77 mg of heptanoyl chloride into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. After 18 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0289]

[0290] Molecular formula C 40 H 54 N2O8, light yellow foamy solid (90 mg), yield 76.3%.

[0291] 1 H-NMR (400MHz, CDCl3) δ: 11.05 (s, 1H), 8.69 (d, J = 8.6Hz, 1H), 7.91 (dd, J = 8.0, 1.6Hz, 1H), 7.49 (t, J = 8.0Hz, 1H), 7.01 (t, J = 7.8 Hz,1H),3.58(d,J=11.6Hz,2H),3.44(d,J=5.0Hz,1H),3.40(s,3H),3.31(s,3H),3.29(s,3H),3.19(dd,J=10.4,7.0Hz,1H),3.00 (s,1H),2.73–2.61(m,2H),2.61–2.46(m,4H),2.44–2.35(m,5H),2.30(s,1H),2.18–1.92(m,5H),1.86–1.78(m,1H),1.73(p,J=7 .6Hz,2H),1.59(dd,J=15.2,8.2Hz,1H),1.24(d,J=6.8Hz,6H),1.12(t,J=7.2Hz,3H),0.89(t,J=7.2Hz,3H).MS(ESI)m / z:[(M+H) + ,654.3979].

[0292] Example 35. Preparation of Compound 35 from Lappaconitine and n-propoxybenzoic acid:

[0293] Weigh 181 mg of 4-n-propoxybenzoic acid in a 25 ml dry round-bottom flask, add 5 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 381 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 4-n-propoxybenzoyl chloride, weigh 89 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly drop the obtained acid chloride into the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 15 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0294]

[0295] Molecular formula C 40 H 52 N2O9, light yellow foamy solid (50 mg), yield 43.5%.

[0296] 1 H-NMR (400MHz, CDCl3) δ: 11.94 (s, 1H), 8.87 (d, J = 8.4Hz, 1H), 7.98 (dd, J = 8.2, 5.8Hz, 3H), 7.55 (t, J = 8.2Hz, 1H), 7.06 (t, J = 7.6Hz, 1H), 7. 01(d,J=8.8Hz,2H),4.00(t,J=6.6Hz,2H),3.61(d,J=11.4Hz,1H),3.56(s,1H),3.45(d,J=5.0Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H ),3.21(dd,J=10.2,7.2Hz,1H),3.02(s,1H),2.73–2.64(m,2H),2.60–2.48(m,4H),2.45(d,J=7.0Hz,1H),2.38(t,J=6.6Hz,2H),2.27(s,1 H),2.20–2.07(m,3H),2.06–1.97(m,2H),1.84(q,J=7.0Hz,2H),1.62(dd,J=15.2,8.4Hz,2H),1.13(t,J=7.2Hz,3H),1.06(t,J=7.4Hz,3H).

[0297] MS (ESI) m / z: [(M+H) +,705.3805].

[0298] Example 36. Preparation of Compound 36 from Lappaconitine and methyl 4-chloroformylbenzoate:

[0299] Weigh 216 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drop 600 μl of dry pyridine under Ar gas protection, add 238.3 mg of methyl 4-chloroformylbenzoate under ice bath, react at 20°C, and detect the progress of the reaction by thin layer chromatography. After 19 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0300]

[0301] Molecular formula C 39 H 48 N2O 10 , light yellow foamy solid (200 mg), yield 71.3%.

[0302] 1 H-NMR (400MHz, CDCl3) δ: 12.15 (s, 1H), 8.87 (dd, J = 8.6, 1.4Hz, 1H), 8.19 (dd, J = 8.4, 1.8Hz, 2H), 8.08 (d, J = 8.6Hz, 2H), 7.98 (d, J = 8. 0Hz,1H),7.61–7.53(m,1H),7.10(t,J=7.8Hz,1H),3.95(s,3H),3.59(d,J=11.6Hz,1H),3.56(s,1H),3.44(d,J=4.8Hz,1H),3.40(s,3 H),3.31(s,3H),3.30(s,3H),3.20(dd,J=10.3,7.0Hz,1H),3.01(s,1H),2.74–2.63(m,2H),2.60–2.48(m,4H),2.44(d,J=8.0Hz,1H) ,2.38(dd,J=7.8,5.0Hz,2H),2.29(s,1H),2.20–1.95(m,5H),1.91–1.81(m,1H),1.60(dd,J=15.2,8.4Hz,1H),1.13(t,J=7.2Hz,3H).

[0303] MS (ESI) m / z: [(M+H) + ,705.1904].

[0304] Example 37. Preparation of Compound 37 from Lappaconitine and Cyclohexanecarbonyl Chloride:

[0305] Weigh 107 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 88 mg of cyclohexanecarbonyl chloride into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. After 18 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0306]

[0307] Molecular formula C 37 H 52 N2O8, light yellow foamy solid (60 mg), yield 46.0%.

[0308] 1 H-NMR (400MHz, CDCl3) δ: 11.06 (s, 1H), 8.71 (dd, J=8.5, 1.1Hz, 1H), 7.92 (dd, J=8.0, 1.8Hz, 1H), 7.48 (ddd, J=8.8, 7.4, 1.8Hz, 1H), 7.0 1(ddd,J=8.2,7.4,1.2Hz,1H),3.58(d,J=11.6Hz,1H),3.55(s,1H),3.44(d,J=4.4Hz,1H),3.41(s,3H),3.32(s,3H),3.30(s,3H),3.20 (dd,J=10.4,7.0Hz,1H),3.01(s,1H),2.73–2.60(m,2H),2.60–2.47(m,4H),2.43(d,J=8.0Hz,1H),2.38(t,J=6.6Hz,1H),2.31–2.25(m ,2H),2.18–2.07(m,3H),2.03–1.96(m,3H),1.87–1.80(m,3H),1.73–1.48(m,6H),1.32(dd,J=23.8,11.4Hz,3H),1.13(t,J=7.2Hz,3H).

[0309] MS (ESI) m / z: [(M+H) + ,654.3873].

[0310] Example 38. Preparation of Compound 38 from Lappaconitine and 3-tetrahydrofurancarboxylic acid:

[0311] Weigh 116 mg of 3-tetrahydrofurancarboxylic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 375 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 3-tetrahydrofurancarboxylic acid chloride, weigh 87 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly drop the obtained acid chloride into the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 14 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0312]

[0313] Molecular formula C 35 H 48 N2O9, light yellow foamy solid (99 mg), yield 96.1%.

[0314] 1 H-NMR (400MHz, CDCl3) δ: 11.23 (d, J = 5.2Hz, 1H), 8.67 (d, J = 8.4Hz, 1H), 7.93 (dd, J = 8.0, 1.8Hz, 1H), 7.50 (t, J = 8.8Hz, 1H) ,7.09–7.00(m,1H),4.10(t,J=8.4Hz,1H),4.03–3.95(m,2H),3.88(q,J=7.6Hz,1H),3.60–3.54(m,2H),3.44(d,J=4.8Hz, 1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.22–3.11(m,2H),3.01(s,1H),2.73–2.62(m,2H),2.59–2.47(m,4H),2.45–2 .35(m,3H),2.32–2.23(m,3H),2.18–1.94(m,5H),1.87–1.77(m,1H),1.59(dd,J=15.2,8.4Hz,1H),1.12(t,J=7.2Hz,3H).

[0315] MS (ESI) m / z: [(M+H) + ,641.3510].

[0316] Example 39. Preparation of Compound 39 from Lappaconitine and Cyclopropanecarbonyl Chloride:

[0317] Weigh 198 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 600 μl of dry pyridine under Ar gas protection, add 115 mg of cyclopropanecarbonyl chloride under ice bath, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 19 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0318]

[0319] Molecular formula C 34 H 46 N2O8, light yellow foamy solid (184 mg), yield 82.6%.

[0320] 1 H-NMR (400MHz, CDCl3) δ: 11.31 (s, 1H), 8.67 (dd, J=8.6, 1.2Hz, 1H), 7.93 (dd, J=8.0, 1.6Hz, 1H), 7.47 (ddd, J=8.8, 7.4, 1.8Hz ,1H),7.00(t,J=7.8Hz,1H),3.59(d,J=11.4Hz,1H),3.54(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H) ,3.19(dd,J=10.3,7.0Hz,1H),3.01(s,1H),2.74–2.64(m,2H),2.62–2.46(m,5H),2.43–2.35(m,3H),2.27(s,1H),2.18–1.96 (m,5H),1.87–1.77(m,1H),1.67–1.56(m,1H),1.13(t,J=7.2Hz,3H),1.08(dd,J=4.4,3.0Hz,2H),0.86(dd,J=7.8,3.2Hz,2H).

[0321] MS (ESI) m / z: [(M+H) + ,611.3364].

[0322] Example 40. Preparation of Compound 40 from Lappaconitine and 4-chlorobenzoyl chloride:

[0323] Weigh 210 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 600 μl of dry pyridine under Ar gas protection, add 200 mg of 4-chlorobenzoyl chloride under ice bath, react at 20°C, and detect the progress of the reaction by thin layer chromatography. After 18 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0324]

[0325] Molecular formula C 37 H 45 N2O8, light yellow foamy solid (240 mg), yield 91.0%.

[0326] 1 H-NMR (400MHz, CDCl3) δ: 12.05 (s, 1H), 8.84 (d, J = 8.8Hz, 1H), 7.99–7.93 (m, 3H), 7.55 (t, J = 8.0Hz, 1H), 7. 49(d,J=8.6Hz,2H),7.08(d,J=7.4Hz,1H),3.57(d,J=10.8Hz,2H),3.43(d,J=4.8Hz,1H),3.40(s,3H),3.3 0(s,3H),3.29(s,3H),3.19(dd,J=10.4,7.2Hz,1H),3.01(s,1H),2.73–2.61(m,2H),2.58–2.43(m,5H),2. 41–2.30(m,3H),2.18–1.96(m,5H),1.91–1.82(m,1H),1.60(dd,J=15.2,8.2Hz,1H),1.12(t,J=7.2Hz,3H).

[0327] MS (ESI) m / z: [(M+H) + ,681.1469].

[0328] Example 41. Preparation of Compound 41 from Lappaconitine and 4-chlorobenzoyl chloride:

[0329] Weigh 156 mg of 5-chloropyrazine-2-carboxylic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 300 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 5-chloropyrazine-2-acyl chloride, weigh 88 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly drop the obtained acyl chloride into the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 17 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0330]

[0331] Molecular formula C 35 H 43 ClN4O8, light yellow foamy solid (84 mg), yield 75.7%.

[0332] 1 H-NMR (400MHz, CDCl3) δ: 12.75 (s, 1H), 9.25 (d, J = 1.4Hz, 1H), 8.86 (dd, J = 8.6, 1.2Hz, 1H), 8.76 (d, J = 1.4Hz, 1H), 8.00 (dd ,J=8.0,1.8Hz,1H),7.58(t,J=8.8Hz,1H),7.14(t,J=8.4Hz,1H),3.63(d,J=10.8Hz,1H),3.54(s,1H),3.45(d,J=4.8Hz,1 H),3.41(s,3H),3.32(s,3H),3.31(s,3H),3.21(dd,J=10.2,6.8Hz,1H),3.02(s,1H),2.69(dd,J=14.8,7.8Hz,2H),2.61– 2.35(m,8H),2.26(s,1H),2.18–2.08(m,3H),2.02(dd,J=15.0,7.6Hz,2H),1.86(t,J=13.0Hz,1H),1.14(t,J=7.2Hz,3H).

[0333] 13 C-NMR (100MHz,CDCl3)δ: None

[0334] MS (ESI) m / z: [(M+H) + ,683.2892].

[0335] Example 42. Preparation of Compound 42 from Lappaconitine and 2-methylvaleric acid:

[0336] Weigh 130 mg of 2-methylvaleric acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 129 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 2-methylvaleryl chloride, weigh 101 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly drop the obtained acid chloride into the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 17 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0337]

[0338] Molecular formula C 36 H 52 N2O8, light yellow foamy solid (41 mg), yield 35.6%.

[0339] 1 H-NMR (400MHz, CDCl3) δ: 11.09 (s, 1H), 8.71 (d, J = 8.6Hz, 1H), 7.92 (dd, J = 8.0, 1.8Hz, 1H), 7.49 (t, J = 8.0Hz, 1H), 7.02 (t, J = 7.6 Hz,1H),3.59(d,J=11.6Hz,1H),3.55(s,1H),3.44(d,J=5.0Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.19(dd,J=10.4,7.0 Hz,1H),3.01(s,1H),2.72–2.63(m,2H),2.60–2.47(m,4H),2.45–2.34(m,4H),2.27(s,1H),2.19–1.96(m,5H),1.88–1.69(m,3H) ,1.60(dd,J=15.3,8.2Hz,1H),1.42–1.36(m,3H),1.24(s,2H),1.12(t,J=7.2Hz,3H),0.93(t,J=7.2Hz,3H).MS(ESI)m / z:[(M+H) + ,641.3828].

[0340] Example 43. Preparation of Compound 43 from Lappaconitine and 4-iodobenzoic acid:

[0341] Weigh 320 mg of 4-iodobenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 491 mg of oxalyl chloride in an ice bath, react at room temperature for 3 hours to obtain 4-iodobenzoyl chloride, weigh 210 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly add the obtained 4-iodobenzoyl chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 14 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0342]

[0343] Molecular formula C 37 H 45 IN2O8, pale yellow foamy solid (270 mg), yield 90.3%.

[0344] 1 H-NMR (400MHz, CDCl3) δ: 12.06 (s, 1H), 8.83 (t, J = 8.0Hz, 1H), 7.96 (t, J = 6.6Hz, 1H), 7.87 (t, J = 6.8Hz, 2H), 7.73 (dd, J=8.2,5.6Hz,2H),7.55(q,J=7.0Hz,1H),7.07(t,J=7.6Hz,1H),3.72–3.66(m,2H),3.56(dd,J=11.4,5.2Hz,1H),3.4 0(s,3H),3.31(s,3H),3.29(s,3H),3.23–3.15(m,1H),3.00(d,J=5.4Hz,1H),2.74–2.60(m,2H),2.59–2.40(m,5H),2 .37(dd,J=7.8,4.8Hz,2H),2.19–1.94(m,6H),1.90–1.80(m,1H),1.59(dt,J=14.6,7.0Hz,1H),1.12(t,J=7.2Hz,3H).

[0345] MS (ESI) m / z: [(M+H) + ,773.2341].

[0346] Example 44. Preparation of Compound 44 from Lappaconitine and 4-n-butylbenzoic acid:

[0347] Weigh 178 mg of 4-n-butylbenzoic acid in a 25 ml dry round-bottom flask, add 5 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 300 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 4-n-butylbenzoyl chloride, weigh 106 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 15 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0348]

[0349] Molecular formula C 41 H 54 N2O8, light yellow foamy solid (81 mg), yield 59.1%.

[0350] 1 H-NMR(400MHz, CDCl3)δ:11.99(s,1H),8.89(d,J=8.6Hz,1H),8.05–7.87(m,3H),7.56(ddd,J=8.8,7.4,1.8Hz,1H),7.33(d,J=8.0 Hz,2H),7.11–7.02(m,1H),3.61(d,J=11.4Hz,1H),3.56(s,1H),3.45(d,J=5.0Hz,1H),3.41(s,3H),3.32(s,3H),3.30(s,3H),3.2 1(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.71–2.66(m,3H),2.59–2.48(m,4H),2.46–2.35(m,3H),2.27(s,1H),2.20–2.09(m,3H),2 .07–1.95(m,2H),1.90–1.81(m,1H),1.69–1.58(m,3H),1.38(dq,J=15.0,7.2Hz,3H),1.13(t,J=7.2Hz,3H),0.94(t,J=7.4Hz,3H).

[0351] MS (ESI) m / z: [(M+H)+ ,703.2626].

[0352] Example 45. Preparation of Compound 45 from Lappaconitine and 5-chloro-2-acylthiophene chloride:

[0353] Weigh 99 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 88 mg of 5-chloro-2-acyl chloride thiophene into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. The reaction is complete after 1.5 hours. Add saturated sodium carbonate aqueous solution to the reaction solution, adjust the pH value of the reaction solution to 10, extract the reaction solution with dichloromethane, dry the dichloromethane layer with anhydrous sodium sulfate, filter out the sodium sulfate solid, spin dry the dichloromethane to obtain the crude product, separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0354]

[0355] Molecular formula C 35 H 43 ClN2O8S, pale yellow foamy solid (90 mg), yield 80.8%.

[0356] 1 H-NMR(400MHz, CDCl3)δ:12.02(s,1H),8.73(dd,J=8.6,1.2Hz,1H),7.97(dd,J=8.0,1.6Hz,1H),7.57–7.51(m,2H),7.10–7.0 4(m,1H),6.98(d,J=4.2Hz,1H),3.59(d,J=11.4Hz,1H),3.56(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.32(s,3H),3.31(s ,3H),3.21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.74–2.63(m,2H),2.61–2.48(m,4H),2.45(d,J=8.0Hz,1H),2.42–2.36(m,2 H),2.27(s,1H),2.20–2.07(m,3H),2.06–1.96(m,2H),1.92–1.82(m,1H),1.60(dd,J=15.0,8.0Hz,1H),1.13(t,J=7.2Hz,3H).

[0357] MS (ESI) m / z: [(M+H) + ,687.2567].

[0358] Example 46. Preparation of Compound 46 from Lappaconitine and 3-ethylbenzoyl chloride:

[0359] Weigh 220 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drop 600 μl of dry pyridine under Ar gas protection, add 205 mg of 3-ethylbenzoyl chloride under ice bath, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 19 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0360]

[0361] Molecular formula C 39 H 50 N2O8, light yellow foamy solid (227 mg), yield 83.0%.

[0362] 1 H-NMR (400MHz, CDCl3) δ: 11.99 (s, 1H), 8.89 (dd, J=8.6, 1.2Hz, 1H), 7.96 (t, J=7.6Hz, 3H), 7.56 (ddd, J=8.8, 7.4, 1.8Hz, 1H), 7.3 5(d,J=8.0Hz,2H),7.06(t,J=7.0Hz,1H),3.61(d,J=11.6Hz,1H),3.56(s,1H),3.45(d,J=4.8Hz,1H),3.41(s,3H),3.32(s,3H),3. 30(s,3H),3.21(dd,J=10.4,6.9Hz,1H),3.02(s,1H),2.77–2.65(m,4H),2.61–2.48(m,4H),2.45(d,J=7.2Hz,1H),2.40–2.36(m,2 H),2.27(s,1H),2.19–1.97(m,5H),1.91–1.81(m,1H),1.62(dd,J=15.2,8.2Hz,1H),1.28(t,J=7.6Hz,3H),1.13(t,J=7.2Hz,3H).

[0363] MS (ESI) m / z: [(M+H) + ,675.3637].

[0364] Example 47. Preparation of Compound 47 from Lappaconitine and 3,3-dimethylbutyryl chloride:

[0365] Weigh 102 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 78 mg of 3,3-dimethylbutyryl chloride into the substrate solution, react at 20°C, and detect the progress of the reaction by thin layer chromatography. After 18 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0366]

[0367] Molecular formula C 36 H 52 N2O8, light yellow foamy solid (78 mg), yield 64.8%.

[0368] 1 H-NMR (400MHz, CDCl3) δ: 10.97 (s, 1H), 8.69 (dd, J=8.6, 1.2Hz, 1H), 7.91 (dd, J=8.0, 1.8Hz, 1H), 7.49 (ddd, J=8.8, 7.4, 1. 8Hz,1H),7.02(t,J=7.2Hz,1H),3.58(d,J=11.4Hz,1H),3.55(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30 (s,3H),3.19(dd,J=10.4,7.0Hz,1H),3.01(s,1H),2.71–2.61(m,2H),2.60–2.45(m,5H),2.44–2.35(m,3H),2.28(s,2H), 2.18–2.07(m,3H),2.05–1.96(m,2H),1.85–1.76(m,1H),1.59(dd,J=15.2,8.4Hz,1H),1.12(t,J=7.2Hz,3H),1.10(s,9H).

[0369] MS (ESI) m / z: [(M+H) + ,641.3213].

[0370] Example 48. Preparation of Compound 48 from Lappaconitine and 2-tetrahydrofurancarboxylic acid:

[0371] Weigh 116 mg of 2-tetrahydrofurancarboxylic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 375 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain 2-tetrahydrofurancarboxylic acid chloride, weigh 99 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 14 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0372]

[0373] Molecular formula C 35 H 48 N2O9, light yellow foamy solid (99 mg), yield 85.9%.

[0374] 1 H-NMR (400MHz, CDCl3) δ: 11.80 (d, J = 5.2Hz, 1H), 8.70 (d, J = 8.6Hz, 1H), 7.92 (d, J = 8.0Hz, 1H), 7.50 (t, J = 8.8Hz, 1H), 7.05 (ddd, J = 8.4, 7.4, 1.2Hz ,1H),4.52(dd,J=8.4,5.0Hz,1H),4.22–4.12(m,1H),4.01(q,J=7.4Hz,1 H),3.66(d,J=11.4Hz,1H),3.58(d,J=11.6Hz,1H),3.54(d,J=5.6Hz,1H) ,3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.19(dd, J=10.2,6.8Hz,1H),3.01(s,1H),2.76–2.64(m,2H),2.58–2.48(m,4H),2 .39–2.35(m,2H),2.31–2.25(m,2H),2.18–2.07(m,3H),2.05–1.88(m,5H ),1.80–1.72(m,1H),1.60(dd,J=15.2,8.4Hz,1H),1.12(t,J=7.2Hz,3H).

[0375] MS (ESI) m / z: [(M+H) +,641.3510].

[0376] Example 49. Preparation of Compound 49 from Lappaconitine and 4-isopropylbenzoic acid:

[0377] Weigh 120 mg of 4-isopropylbenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 129 mg of oxalyl chloride in an ice bath, react at room temperature for 3 hours to obtain 4-isopropylbenzoyl chloride, weigh 69 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 17 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0378]

[0379] Molecular formula C 40 H 52 N2O8, light yellow foamy solid (103 mg), yield 87.3%.

[0380] 1 H-NMR (400MHz, CDCl3) δ: 11.99 (s, 1H), 8.89 (d, J = 7.4Hz, 1H), 8.00–7.94 (m, 3H), 7.55 (ddd, J = 8.8, 7.4, 1.8Hz, 1H), 7.38 (d, J = 8.2Hz, 2H),7.10–7.02(m,1H),3.60(d,J=11.6Hz,1H),3.56(s,1H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.21(dd,J =10.4,7.0Hz,1H),3.02(s,1H),2.98(dd,J=14.0,7.0Hz,1H),2.74–2.64(m,2H),2.60–2.47(m,4H),2.45(d,J=7.6Hz,1H),2.42–2.35 (m,2H),2.30(s,1H),2.19–1.97(m,5H),1.91–1.81(m,1H),1.62(dd,J=15.2,8.4Hz,1H),1.29(d,J=7.0Hz,6H),1.13(t,J=7.2Hz,3H).

[0381] MS (ESI) m / z: [(M+H) + ,689.3871].

[0382] Example 50. Preparation of Compound 50 from Lappaconitine and tetrahydrofuran-4-carbonyl chloride:

[0383] Weigh 68 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 300 μl of dry pyridine under Ar gas protection, slowly drip 60 mg of tetrahydropyran-4-carbonyl chloride into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. After 18 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0384]

[0385] Molecular formula C 36 H 50 N2O9, light yellow foamy solid (32 mg), yield 39.1%.

[0386] 1 H-NMR (400MHz, CDCl3) δ: 11.20 (s, 1H), 8.69 (d, J = 8.5Hz, 1H), 7.93 (dd, J = 8.0, 1.6Hz, 1H), 7.50 (t, J = 7.6Hz, 1H), 7.03 (t,J=7.6Hz,1H),4.07(d,J=11.8Hz,2H),3.58–3.46(m,4H),3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3 H),3.20(dd,J=10.3,6.9Hz,1H),3.01(s,1H),2.69(dd,J=15.2,7.6Hz,1H),2.64–2.46(m,6H),2.46–2.35(m,3H),2.2 9(s,1H),2.19–1.96(m,5H),1.95–1.87(m,4H),1.91–1.81(m,1H),1.59(dd,J=15.2,8.2Hz,1H),1.12(t,J=7.2Hz,3H).

[0387] MS (ESI) m / z: [(M+H) + ,655.3666].

[0388] Example 51. Preparation of Compound 51 from Lappaconitine and 5-bromo-2-thiophenecarboxylic acid:

[0389] Weigh 246 mg of 5-bromo-2-thiophenecarboxylic acid into a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 389 mg of oxalyl chloride in an ice bath, react at room temperature for 3 h to obtain 5-bromo-2-thiophene acid chloride, weigh 168 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly add the obtained 5-bromo-2-thiophene acid chloride to the substrate solution, react at 35° C., and monitor the reaction progress by thin layer chromatography. After 17 h, the reaction is complete, add saturated sodium carbonate aqueous solution to the reaction solution, adjust the pH value of the reaction solution to 10, extract the reaction solution with dichloromethane, dry the dichloromethane layer with anhydrous sodium sulfate, filter out the sodium sulfate solid, spin-dry the dichloromethane to obtain the crude product, and separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0390]

[0391] Molecular formula C 35 H 43 BrN2O8S, light yellow foamy solid (223 mg), yield 98.7%.

[0392] 1 H-NMR (400MHz, CDCl3) δ: 12.01 (s, 1H), 8.73 (dd, J=8.5, 1.1Hz, 1H), 7.96 (dd, J=8.0, 1.6Hz, 1H), 7.54 (ddd, J=8.8, 7.4, 1.8Hz, 1H), 7. 49(d,J=4.0Hz,1H),7.12(d,J=4.0Hz,1H),7.07(ddd,J=8.2,7.3,1.2Hz,1H),3.59(d,J=11.4Hz,1H),3.56(s,1H),3.44(d,J=4.8Hz,1H ),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.74–2.63(m,2H),2.62–2.48(m,4H),2.45(d,J= 8.0Hz,1H),2.43–2.35(m,2H),2.27(s,1H),2.20–1.94(m,5H),1.92–1.82(m,1H),1.60(dd,J=15.2,8.4Hz,1H),1.13(t,J=7.2Hz,3H).

[0393] MS (ESI) m / z: [(M+H) + ,733.2078].

[0394] Example 52. Preparation of Compound 52 from Lappaconitine and 3-cyanobenzoyl chloride:

[0395] Weigh 247 mg of 3-cyanobenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 639 mg of oxalyl chloride in an ice bath, react at room temperature for 3 hours to obtain 3-cyanobenzoyl chloride, weigh 190 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly drop the obtained 3-cyanobenzoyl chloride into the substrate solution, react at 35 ° C, and detect the reaction progress by thin layer chromatography. After 17 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain the crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0396]

[0397] Molecular formula C 38 H 45 N3O8, light yellow foamy solid (201 mg), yield 83.5%.

[0398] 1H-NMR(400MHz, CDCl3)δ:12.18(s,1H),8.83(dd,J=8.6,1.2Hz,1H),8.31(s,1H),8.24(dd,J=8.0,1.6Hz,1H),8.00(d,J=6.4Hz,1H),7. 84(d,J=7.8Hz,1H),7.67(t,J=7.8Hz,1H),7.58(ddd,J=8.8,7.4,1.8Hz,1H),7.12(t,J=7.8Hz,1H),3.58(d,J=11.4Hz,1H),3.55(s,1H) ,3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.22(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.74–2.62(m,2H),2.60–2.4 2(m,5H),2.38(t,J=6.4Hz,2H),2.28(s,1H),2.22–1.95(m,5H),1.95–1.85(m,1H),1.60(dd,J=15.2,8.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0399] MS (ESI) m / z: [(M+H) + ,672.3356].

[0400] Example 53. Preparation of Compound 53 from Lappaconitine and 4-trifluoromethoxybenzoyl chloride:

[0401] Weigh 161 mg of 4-trifluoromethoxybenzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 129 mg of oxalyl chloride in an ice bath, react at room temperature for 3 hours to obtain 4-trifluoromethoxybenzoyl chloride, weigh 103 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly drop the obtained acid chloride into the substrate solution, react at 35 ° C, and detect the reaction progress by thin layer chromatography. After 17 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain the crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0402]

[0403] Molecular formula C 38 H 45F3N2O9, light yellow foamy solid (126 mg), yield 91.3%.

[0404] 1 H-NMR(400MHz, CDCl3)δ:12.09(s,1H),8.83(dd,J=8.6,1.2Hz,1H),8.06(d,J=8.8Hz,2H),7.97(dd,J=8.0,1.8Hz,1H),7.56( ddd,J=8.8,7.4,1.8Hz,1H),7.35(d,J=7.8Hz,2H),7.11–7.06(m,1H),3.62(s,1H),3.57(d,J=11.4Hz,1H),3.43(d,J=4.8Hz,1 H),3.40(s,3H),3.30(s,3H),3.29(s,3H),3.20(dd,J=10.4,7.0Hz,1H),3.01(s,1H),2.73–2.60(m,2H),2.59–2.42(m,4H),2. 41–2.35(m,2H),2.18–2.07(m,2H),2.05–1.92(m,3H),1.92–1.83(m,3H),1.59(dd,J=15.2,8.4Hz,1H),1.12(t,J=7.2Hz,3H).

[0405] MS (ESI) m / z: [(M+H) + ,731.3259].

[0406] Example 54. Preparation of Compound 54 from Lappaconitine and 4-(methylsulfonyl)benzoic acid:

[0407] Weigh 295 mg of 4-(methylsulfonyl)benzoic acid in a 25 ml dry round-bottom flask, add 10 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 561 mg of oxalyl chloride in an ice bath, react at room temperature for 3 h to obtain 4-(methylsulfonyl)benzoyl chloride, weigh 300 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 300 μl of dry pyridine under Ar gas protection, slowly add the obtained 4-(methylsulfonyl)benzoyl chloride to the substrate solution, react at 35° C., and monitor the reaction progress by thin layer chromatography. After 14 h, the reaction is complete, add saturated sodium carbonate aqueous solution to the reaction solution, adjust the pH value of the reaction solution to 10, extract the reaction solution with dichloromethane, dry the dichloromethane layer with anhydrous sodium sulfate, filter out the sodium sulfate solid, spin-dry the dichloromethane to obtain the crude product, and separate and purify by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0408]

[0409] Molecular formula C 38 H 48 N2O 10 S, light yellow foamy solid (216 mg), yield 80.9%.

[0410] 1 H-NMR (400MHz, CDCl3) δ: 12.22 (s, 1H), 8.83 (d, J = 8.6Hz, 1H), 8.19 (d, J = 7.8Hz, 2H), 8.09 (d, J = 8.6Hz, 2H), 7.98 (d, J = 8.0 Hz,1H),7.61–7.52(m,1H),7.11(t,J=7.8Hz,1H),3.55(d,J=12.0Hz,2H),3.42(d,J=4.8Hz,1H),3.39(s,3H),3.29(s,3H), 3.28(s,3H),3.19(dd,J=10.2,7.2Hz,1H),3.09(s,3H),3.00(s,1H),2.69(dd,J=15.2,7.6Hz,1H),2.64–2.43(m,6H),2.3 5(dd,J=14.7,10.0Hz,3H),2.17–1.96(m,5H),1.89(t,J=14.8Hz,1H),1.58(dd,J=15.2,8.4Hz,1H),1.11(t,J=7.2Hz,3H).

[0411] MS (ESI) m / z: [(M+H) + ,725.1605].

[0412] Example 55. Preparation of Compound 55 from Lappaconitine and 3-bromobenzoyl chloride:

[0413] Weigh 192 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drop 600 μl of dry pyridine under Ar gas protection, add 233 mg of 3-bromobenzoyl chloride under ice bath, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 19 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0414]

[0415] Molecular formula C 37 H 45BrN2O8, light yellow foamy solid (208 mg), yield 81.0%.

[0416] 1 H-NMR (400MHz, CDCl3) δ: 12.04 (s, 1H), 8.83 (dd, J = 8.5, 1.2Hz, 1H), 8.19 (t, J = 1.8Hz, 1H), 7.98 (dd, J = 8.0, 1.6Hz, 1H), 7.91 (d, J = 8.4Hz, 1H) ,7.68(d,J=8.0Hz,1H),7.57(ddd,J=8.8,7.4,1.8Hz,1H),7.41(t,J=8.0Hz,1H),7.10(t,J=7.2Hz,1H),3.61(d,J=11.4Hz,1H),3.56(s,1H), 3.44(d,J=4.8Hz,1H),3.41(s,3H),3.31(s,3H),3.30(s,3H),3.21(dd,J=10.4,7.0Hz,1H),3.02(s,1H),2.75–2.64(m,2H),2.60–2.48(m,4H ),2.46–2.35(m,3H),2.27(s,1H),2.20–1.96(m,5H),1.86(td,J=12.8,12.0,7.0Hz,1H),1.61(dd,J=15.2,8.2Hz,1H),1.13(t,J=7.2Hz,3H).

[0417] MS (ESI) m / z: [(M+H) + ,727.2495].

[0418] Example 56. Preparation of Compound 56 from Lappaconitine and 2-bromobenzoyl chloride:

[0419] Weigh 200 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drop 600 μl of dry pyridine under Ar gas protection, add 115 mg of 2-bromobenzoyl chloride under ice bath, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 19 hours, the reaction is complete, and saturated sodium bicarbonate aqueous solution is added to the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0420]

[0421] Molecular formula C 37 H 45BrN2O8, light yellow foamy solid (261 mg), yield 97.5%.

[0422] 1 H-NMR(400MHz, CDCl3)δ:11.43(s,1H),8.87(d,J=8.4Hz,1H),7.99(dd,J=8.2,1.8Hz,1H),7.68(d,J=7.8Hz,1H),7.63–7.57(m,2H) ,7.44(td,J=7.5,1.2Hz,1H),7.34(td,J=7.8,1.8Hz,1H),7.15–7.11(m,1H),3.53(d,J=11.4Hz,2H),3.45(d,J=5.0Hz,1H),3.43(s, 3H),3.33(s,3H),3.30(s,3H),3.19(dd,J=10.3,7.0Hz,1H),3.01(s,1H),2.70(dd,J=15.2,7.4Hz,1H),2.65–2.59(m,1H),2.58–2.4 6(m,4H),2.44–2.37(m,3H),2.29(s,1H),2.20–1.95(m,5H),1.88–1.78(m,1H),1.60(dd,J=15.2,8.2Hz,1H),1.11(t,J=7.2Hz,3H).

[0423] MS (ESI) m / z: [(M+H) + ,727.2495].

[0424] Example 57. Preparation of Compound 57 from Lappaconitine and 3-methoxybenzoic acid:

[0425] Weigh 140 mg of 3-methoxybenzoic acid in a 25 ml dry round-bottom flask, add 5 ml of dry dichloromethane to dissolve, add a few drops of dimethylformamide, add 345 mg of oxalyl chloride in an ice bath, react at room temperature for 2 hours to obtain cyclopentanecarbonyl chloride, weigh 105 mg of N-deacetyl lappaconitine in a 25 ml round-bottom flask, add 10 ml of dry dichloromethane to dissolve, drop 105 μl of dry pyridine under Ar gas protection, slowly add the obtained acid chloride to the substrate solution, react at 35 ° C, and detect the progress of the reaction by thin layer chromatography. After 13 hours, the reaction is complete, and a saturated sodium carbonate aqueous solution is added to the reaction solution, the pH value of the reaction solution is adjusted to 10, and the reaction solution is extracted with dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, the sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0426]

[0427] Molecular formula C 38 H 48 N2O9, light yellow foamy solid (81 mg), yield 91.6%.

[0428] 1 H-NMR (400MHz, CDCl3) δ: 12.06 (s, 1H), 8.90 (d, J = 8.4Hz, 1H), 8.00 (dd, J = 8.0, 1.8Hz, 1H), 7.64–7.55 (m, 3H), 7.46 (t, J = 8.0Hz, 1 H),7.17–7.07(m,2H),3.92(s,3H),3.63(d,J=11.4Hz,1H),3.58(s,1H),3.47(d,J=4.8Hz,1H),3.44(s,3H),3.34(s,3H),3.32(s, 3H),3.22(dd,J=10.3,6.9Hz,1H),3.04(s,1H),2.77–2.67(m,2H),2.63–2.49(m,4H),2.48–2.37(m,3H),2.30(s,1H),2.21–2.10 (m,3H),2.04(dd,J=14.8,7.2Hz,2H),1.91–1.82(m,1H),1.64(dd,J=15.1,8.2Hz,1H),1.15(t,J=7.2Hz,3H).MS(ESI)m / z:[(M+H) + ,676.6913].

[0429] Example 58. Preparation of Compound 58 from Lappaconitine and Benzoyl Chloride:

[0430] Weigh 207 mg of N-deacetyl lappaconitine into a 25 ml round-bottom flask, add 5 ml of dry dichloromethane to dissolve, drip 105 μl of dry pyridine under Ar gas protection, slowly drip 157 mg of benzoyl chloride into the substrate solution, react at 20 ° C, and detect the progress of the reaction by thin layer chromatography. After 17 hours, the reaction is complete, and saturated sodium carbonate aqueous solution is dripped into the reaction solution, and the pH value of the reaction solution is adjusted to 10. The reaction solution is extracted with dichloromethane, and the dichloromethane layer is dried with anhydrous sodium sulfate. The sodium sulfate solid is filtered off, and the dichloromethane is spin-dried to obtain a crude product, which is separated and purified by column chromatography to obtain the target compound. Its structure and characterization are as follows:

[0431]

[0432] Molecular formula C 37 H 46 N2O8, light yellow foamy solid (212 mg), yield 91.6%.

[0433] 1 H-NMR (400MHz, CDCl3) δ: 12.06 (s, 1H), 8.91 (d, J = 8.4Hz, 1H), 8.06 (d, J = 6.0Hz, 2H), 8.00 (dd, J = 8.2, 1.6Hz, 1H), 7.57 (dq, J = 13. 8,6.6Hz,4H),7.13–7.07(m,1H),3.62(d,J=11.6Hz,1H),3.59(s,1H),3.47(d,J=4.8Hz,1H),3.43(s,3H),3.34(s,3H),3.32(s,3H ),3.23(dd,J=10.4,7.0Hz,1H),3.04(s,1H),2.77–2.66(m,2H),2.64–2.50(m,4H),2.47(d,J=7.7Hz,1H),2.44–2.38(m,2H),2.3 2(s,1H),2.21–2.11(m,3H),2.04(dd,J=14.8,7.2Hz,2H),1.93–1.83(m,1H),1.64(dd,J=15.1,8.2Hz,1H),1.15(t,J=7.1Hz,3H).

[0434] MS (ESI) m / z: [(M+H) + ,646.7090].

[0435] The beneficial effects of the present invention are demonstrated by experimental examples below.

[0436] Experimental Example 1: Analgesic activity and toxicity test of the compounds of the present invention

[0437] 1. Experimental methods

[0438] Experimental animals: All were Kunming mice provided by Chengdu Dashuo Experimental Animal Co., Ltd., half male and half female, weighing between 22±2g. The mice were raised for 2-3 days before the experiment, with free access to water and feed to allow the mice to adapt to the new animal room environment. The mice were fasted for 12h before the experiment. There were 10 experimental animals in each group, ensuring that at least 6 available data were obtained for each group.

[0439] Samples to be tested: compounds prepared in the examples of the present invention, positive control lappaconitine. All samples to be tested were dissolved in 0.1M HCl at a 1:1 ratio, diluted with physiological saline to a specific test concentration, and used in animal experiments at a dose of 0.1 ml / 10 g body weight. The experiment was conducted in accordance with the relevant national regulations on the management of experimental animals. Except that the samples to be tested were replaced with physiological saline, the animals in the control group received the same treatment as the experimental group.

[0440] The analgesic activity was determined by the acetic acid writhing method: 10 mice were randomly selected, half male and half female, and placed in separate cages. Each mouse was subcutaneously injected with physiological saline or different test sample solutions, and 15 minutes later, 0.7% acetic acid solution was intraperitoneally injected. The number of writhing reactions of each mouse within 15 minutes was observed and recorded. The group injected with physiological saline subcutaneously was the blank group, and the group injected with the test sample was the experimental group. The analgesic activity was expressed as the percentage of the reduction in the number of writhing times compared with the blank group (analgesia rate).

[0441] The median effective dose (ED 50 ) Determination: The drug to be tested was dissolved in 0.1mol / L HCl solution at a 1:1 ratio of the amount of substance, diluted with physiological saline to the required concentration, and at least 5 different dose groups were set up according to the geometric progression. The experimental animals were Kunming mice. Before the experiment, the mice were placed in a quiet, dimly lit environment at a temperature of 20-25°C for 2-3 days to adapt, during which time the mice were free to take in food and water. Fasting but not water was allowed for 12 hours before the experiment. In the determination of each dose group, 10 mice, half male and half female, weighing 20±2g, were randomly selected, and 0.2mL / 20g of the drug to be tested was injected subcutaneously. 15min later, 0.2mL / 20g of 0.7% acetic acid solution was injected intraperitoneally. The number of writhing reactions in the mice within 15min was observed and recorded, and the inhibition rate of each dose group was calculated. The data obtained were entered into SPSS software (version 17.2), and the ED of the drug was calculated using the Probit regression method. 50 .

[0442] Toxicity test: The sample to be tested is set up in 5 concentration gradients from low to high. Ten mice are randomly selected from each group, half male and half female, and placed separately. Each mouse is subcutaneously injected with different concentrations of the sample to be tested, and the survival of the mice within 24 hours is observed. The concentration gradient is determined through several preliminary experiments. The median lethal dose (LD50) of the sample to be tested is calculated based on the mortality rate of each group of animals. 50 ):

[0443] Median lethal dose (LD 50 ) Determination: The drug to be tested was dissolved in 0.1mol / L HCl solution at a 1:1 ratio of the amount of substance, diluted with physiological saline to the required concentration, and at least 5 different dose groups were set up according to the geometric progression. The experimental animals were Kunming mice. Before the experiment, the mice were placed in a quiet, dimly lit environment at a temperature of 20-25°C for 2-3 days to adapt, during which time the mice were free to take in food and water. Fasting but not water was allowed for 12 hours before the experiment. In the determination of each group of doses, 10 Kunming mice, half male and half female, weighing 20±2g, were randomly selected and subcutaneously injected with 0.2mL / 20g of the drug to be tested, and the survival rate of the mice within 24 hours was observed and recorded. The obtained dose-inhibition rate data were entered into SPSS software (version 17.2), and the LD of the drug was calculated using the Probit regression method. 50 .

[0444] 2. Experimental results

[0445] Table 1 Analgesic activity test results of each compound

[0446]

[0447]

[0448] Table 2 ED of some compounds 50 and LD 50 Test Results

[0449]

[0450]

[0451] It can be seen from Table 1 that most of the compounds prepared in the examples of the present invention have good analgesic activity. It can be further seen from Table 2 that compared with the positive control lappaconitine, the analgesic activity of the compound 1 of the present invention is significantly improved; compared with the positive control lappaconitine, the biological toxicity of the compounds 2 to 5 and 32 of the present invention is significantly reduced.

[0452] The above experimental results show that the compounds of the present invention have good analgesic activity and low biological toxicity, and can be used to prepare low-toxic analgesic drugs.

[0453] In summary, the present invention provides a lappaconitine derivative shown in formula I having analgesic activity, and a preparation method and application thereof. Experimental results show that the lappaconitine derivative provided by the present invention has high analgesic activity, good water solubility and low biological toxicity, can be used to prepare low-toxic analgesic drugs, and has broad application prospects.

Claims

1. The following compound, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

2. An analgesic drug, characterized in that: The invention relates to a preparation comprising the compound as claimed in claim 1, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable auxiliary materials.

3. Use of the compound according to claim 1, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the preparation of analgesics.

4. Use of the following compounds, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in the preparation of analgesic drugs:

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