Galanthamine analogue as well as preparation method and application thereof

Abstract

The invention relates to a galanthamine analogue capable of inhibiting cholinesterase activity and a preparation method and application of the galanthamine analogue, the structural general formula of the galanthamine analogue is shown as a formula (IA), a formula (IB) or a formula (IC), in the formula (IA), R1 is selected from hydrogen, o-fluorine, m-fluorine, p-fluorine, 2, 4-difluorine, m-trifluoromethyl, p-methyl, 3, 5-dimethoxy, p-chlorine, p-nitro, p-cyano or p-trifluoromethoxy, and R2 is selected from hydrogen, o-fluorine, m-fluorine, p-fluorine, 2, 4-difluoro, m-trifluoromethyl, p-methyl, 3, 5-dimethoxy, p-chlorine, p-nitro, p-cyano or p-trifluoromethoxy; in the formula (IB), R2 is selected from phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2, 4-difluorophenyl, 3, 5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl or naphthalene ring; in the formula (IC), R3 is selected from hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxyl, m-methoxyl or p-methoxyl. The inhibition activity of the galanthamine analogue on cholinesterase is superior to that of galanthamine, and the galanthamine analogue is expected to be used for treating cholinergic function disorder related diseases; # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a galanthamine analogue capable of inhibiting cholinesterase activity, and a preparation method and application thereof. Background Art

[0002] Alzheimer's disease (AD) is a destructive and progressive neurodegenerative disease common in the elderly. It is clinically characterized by comprehensive dementia such as learning and memory impairment, decreased executive ability, and behavioral changes. The FDA calls it "a devastating disease." The pathogenesis of AD is characterized by the depletion of the neurotransmitter acetylcholine (ACh).

[0003] Galanthamine is the most widely distributed and important alkaloid in the Amaryllidaceae family and was approved by the FDA as an AChEI in 2001. It has a dual mechanism of action on the cholinergic system: it can reversibly inhibit acetylcholinesterase (AChE) and allosterically regulate acetylcholine receptors to enhance the transmission of nicotinic neurotransmitters and promote the release of more ACh.

[0004] Although galantamine exhibits low toxicity, the inventors found that the inhibition rate of galantamine on cholinesterase and its IC 50 There is still room for improvement. In view of this, from the perspective of medicinal chemistry, the core structure of galantamine is suitable as an ideal lead part for designing high-efficiency and low-toxicity anti-AD compounds. Providing AChEI with better performance is the technical problem that the present invention needs to solve. Summary of the invention

[0005] In view of the problems existing in the prior art, the inventors designed and synthesized a series of novel galantamine analogs, and found that some of the compounds have better inhibitory activity against AChE and butyrylcholinesterase (BuChE) than galantamine, and their IC 50 The value is less than the IC of galantamine 50 Therefore, the galanthamine analogs provided by the present invention are expected to be developed as new drugs for treating diseases related to cholinergic dysfunction, such as drugs for treating Alzheimer's disease.

[0006] Specifically, the present invention is realized through the following technical solutions:

[0007] In the first aspect, the present invention provides a galanthamine analog, wherein the galanthamine analog is a compound represented by formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt thereof:

[0008]

[0009] In the formula (IA), R 1One selected from the group consisting of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorine, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chlorine, p-nitro, p-cyano, and p-trifluoromethoxy;

[0010] In the formula (IB), R 2 One selected from phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring;

[0011] In the formula (IC), R 3 One selected from the group consisting of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxy, m-methoxy and p-methoxy.

[0012] As an optional manner, in the above-mentioned galanthamine analog, the structure of the galanthamine analog is shown in the following formula:

[0013]

[0014] Among them, R 1 is selected from the group consisting of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorine, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chlorine, p-nitro, p-cyano, and p-trifluoromethoxy; R 2 is selected from the group consisting of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring; R 3 One selected from the group consisting of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxy, m-methoxy and p-methoxy.

[0015] As an optional mode, in the above-mentioned galanthamine analog, the structure of the galanthamine analog is as follows:

[0016]

[0017]

[0018] In a second aspect, the present invention provides a method for preparing the galanthamine analogue described in the first aspect, wherein the galanthamine analogue is a compound represented by formula (IA), and the preparation method comprises the following steps:

[0019] (1) Dissolve 4-tert-butyloxycarbonylaminopiperidine in an organic solvent and slowly add benzyl bromide (Ⅱ) containing an R-substituted group. a), under the action of alkaline catalyst triethylamine, react at room temperature to obtain a compound having a structural formula (III a ) of the intermediate 1; the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorine, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chlorine, p-nitro, p-cyano, and p-trifluoromethoxy;

[0020] (2) The intermediate 1 was dissolved in anhydrous DCM, trifluoroacetic acid was added, and the reaction was stirred at room temperature to obtain a solution having a structural formula (IV a ) of intermediate 2;

[0021] (3) Dissolve galanthamine and di(p-nitrobenzene) carbonate in anhydrous DCM, stir for 10 to 15 minutes, then slowly dropwise add triethylamine, and react at room temperature to obtain a compound of formula (V) a ) of intermediate 3;

[0022] (4) dissolving the intermediate 2 described in step (2) and the intermediate 3 described in step (3) in anhydrous DCM, and reacting at room temperature under the action of an alkaline catalyst DMAP to obtain a galanthamine analog compound represented by formula (IA);

[0023] The structural formula in the above steps is as follows:

[0024]

[0025] Alternatively, the present invention provides a method for preparing the galanthamine analogue described in the first aspect above, wherein the galanthamine analogue is a compound represented by formula (IB), and the preparation method comprises the following steps:

[0026] (1) Dissolve galanthamine and di(p-nitrobenzene) carbonate in anhydrous DCM, stir for 10 to 15 minutes, then slowly add triethylamine dropwise, and react at room temperature to obtain a compound of formula (II b ) of intermediate 1;

[0027] (2) Intermediate 1 and a primary amine containing an R-substituted group (III b ) is dissolved in anhydrous DCM, and reacted at room temperature under the action of an alkaline catalyst DMAP to obtain a galanthamine analogue compound represented by formula (IB), wherein the R group is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring;

[0028] The structural formula in the above steps is as follows:

[0029]

[0030] Alternatively, the present invention provides a method for preparing the galanthamine analogue described in the first aspect above, wherein the galanthamine analogue is a compound represented by formula (IC), and the preparation method comprises the following steps:

[0031] (1) Dissolve galanthamine in anhydrous DCM, stir for 20 to 40 minutes in an ice bath, then slowly add 5-bromo-2-chloromethylenepyridine, and react under the action of an alkaline catalyst to obtain a compound of formula (II c ) of intermediate 1;

[0032] (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing an R-substituted group c ) is dissolved in an organic solvent, and heated at 75-95° C. under nitrogen protection and in the presence of a catalyst to perform a coupling reaction to obtain a galanthamine analog (IC), wherein the R group is selected from one of hydrogen, o-fluoro, m-fluoro, p-fluoro, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy;

[0033] The structural formula in the above steps is as follows:

[0034]

[0035] As an optional manner, in the method for preparing the compound represented by the galanthamine analogue formula (IA), the organic solvent in step (1) is anhydrous ethanol.

[0036] As an optional manner, in the method for preparing the compound represented by the galanthamine analogue formula (IC), the alkaline catalyst in step (1) is DIPEA, the organic solvent is a mixed solution of 1,4-dioxane and water, the mixed volume ratio of which is 4:1, and the catalyst is K 2 CO 3 , CsF and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0037] In a third aspect, the present invention provides use of the galanthamine analogue described in the first aspect in the preparation of a cholinesterase inhibitor.

[0038] In a fourth aspect, the present invention provides use of the galanthamine analogue described in the first aspect in the preparation of a drug for treating diseases related to cholinergic dysfunction.

[0039] As an alternative, the cholinergic dysfunction-related disease is Alzheimer's disease.

[0040] The beneficial effects of the present invention are: the inhibition rate of the galanthamine analogues provided by the present invention on AChE and BuChE is better than that of galanthamine, and its IC 50The value is less than the IC of galantamine 50 It has the potential to be developed into a new drug for the treatment of diseases related to cholinergic dysfunction. DETAILED DESCRIPTION

[0041] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0042] Instruments and equipment used in the following examples: The following examples can be carried out with reference to conventional techniques for parameters not specifically noted. The nuclear magnetic resonance spectra were measured using an AVANCE III HD 600 MHz nuclear magnetic resonance spectrometer from Bruker BioSpin Co., Ltd., Switzerland, with deuterated chloroform or deuterated DMSO as solvent; Compound IC 50 The values ​​were determined using the multifunctional microplate reader from Thermo Fisher, USA.

[0043] Example 1

[0044] The preparation of a galanthamine analog compound of formula (IA) and its intermediates in this embodiment, the specific synthesis steps are as follows:

[0045] (1) Synthesis of intermediate 1-1: Galantamine (0.6 g, 2.1 mmol) and di(p-nitrobenzene) carbonate (0.95 g, 3.13 mmol) were dissolved in anhydrous DCM. After stirring for 10 to 15 min, triethylamine (0.21 g, 2.1 mmol) was slowly added dropwise. After reacting at room temperature for 6 h, the solvent was removed and separated by column chromatography to obtain 0.92 g of an oily liquid, namely intermediate 1-1, with a yield of 97%.

[0046] (2) Synthesis of intermediate 1-2-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, and benzyl bromide (0.43 g, 2.5 mmol) was slowly added. In the presence of triethylamine (0.48 g, 4.74 mmol), the mixture was reacted at room temperature for 12 h, and then the solvent was removed and separated by column chromatography to obtain 0.71 g of an oily liquid, namely intermediate 1-2-1, with a yield of 98%.

[0047] (3) Synthesis of intermediate 1-2-2: The intermediate 1-2-1 (0.71 g, 2.45 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.84 g, 7.34 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.32 g of an oily liquid, namely, intermediate 1-2-2, with a yield of 69%.

[0048] (4) Synthesis of intermediate 1-3-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.67 g of an oily liquid, namely intermediate 1-3-1, with a yield of 87%.

[0049] (5) Synthesis of intermediate 1-3-2: The intermediate 1-3-1 (0.67 g, 2.2 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.75 g, 6.6 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.39 g of an oily liquid, namely, intermediate 1-3-2, with a yield of 85%.

[0050] (6) Synthesis of intermediate 1-4-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 2-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.69 g of an oily liquid, namely intermediate 1-4-1, with a yield of 90%.

[0051] (7) Synthesis of intermediate 1-4-2: The intermediate 1-4-1 (0.69 g, 2.2 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.75 g, 6.6 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.25 g of an oily liquid, namely, intermediate 1-4-2, with a yield of 55%.

[0052] (8) Synthesis of intermediate 1-5-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 3-fluorobenzyl bromide (0.47 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.72 g of an oily liquid, namely intermediate 1-5-1, with a yield of 94%.

[0053] (9) Synthesis of intermediate 1-5-2: The intermediate 1-5-1 (0.72 g, 2.34 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.8 g, 7.02 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.35 g of an oily liquid, namely, intermediate 1-5-2, with a yield of 72%.

[0054] (10) Synthesis of intermediate 1-6-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 3-trifluoromethylbenzyl bromide (0.60 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.86 g of an oily liquid, namely intermediate 1-6-1, with a yield of 96%.

[0055] (11) Synthesis of intermediate 1-6-2: The intermediate 1-6-1 (0.86 g, 2.4 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.82 g, 7.2 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.47 g of an oily liquid, namely, intermediate 1-6-2, with a yield of 76%.

[0056] (12) Synthesis of intermediate 1-7-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-methylbenzyl bromide (0.46 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.70 g of an oily liquid, namely intermediate 1-7-1, with a yield of 92%.

[0057] (13) Synthesis of intermediate 1-7-2: The intermediate 1-7-1 (0.7 g, 2.3 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.79 g, 6.9 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.36 g of an oily liquid, namely, intermediate 1-7-2, with a yield of 77%.

[0058] (14) Synthesis of intermediate 1-8-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 3,5-dimethoxybenzyl bromide (0.58 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.86 g of an oily liquid, namely intermediate 1-8-1, with a yield of 98%.

[0059] (15) Synthesis of intermediate 1-8-2: Intermediate 1-8-1 (0.86 g, 2.46 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.84 g, 7.38 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.49 g of an oily liquid, namely, intermediate 1-8-2, with a yield of 80%.

[0060] (16) Synthesis of intermediate 1-9-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 2,4-difluorobenzyl bromide (0.52 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.78 g of an oily liquid, namely intermediate 1-9-1, with a yield of 96%.

[0061] (17) Synthesis of intermediate 1-9-2: Intermediate 1-9-1 (0.78 g, 2.39 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.82 g, 7.17 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.38 g of an oily liquid, namely, intermediate 1-9-2, with a yield of 70%.

[0062] (18) Synthesis of intermediate 1-10-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-chlorobenzyl bromide (0.51 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.76 g of an oily liquid, namely intermediate 1-10-1, with a yield of 94%.

[0063] (19) Synthesis of intermediate 1-10-2: The intermediate 1-10-1 (0.76 g, 2.35 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.8 g, 7.04 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.18 g of an oily liquid, namely, intermediate 1-10-2, with a yield of 34%.

[0064] (20) Synthesis of intermediate 1-11-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-nitrobenzyl bromide (0.54 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.81 g of an oily liquid, namely intermediate 1-11-1, with a yield of 97%.

[0065] (21) Synthesis of intermediate 1-11-2: The intermediate 1-11-1 (0.81 g, 2.42 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.83 g, 7.26 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.41 g of an oily liquid, namely, intermediate 1-11-2, with a yield of 72%.

[0066] (22) Synthesis of intermediate 1-12-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-cyanobenzyl bromide (0.49 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.75 g of an oily liquid, namely intermediate 1-12-1, with a yield of 95%.

[0067] (23) Synthesis of intermediate 1-12-2: The intermediate 1-12-1 (0.75 g, 2.38 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.81 g, 7.14 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.24 g of an oily liquid, namely, intermediate 1-12-2, with a yield of 47%.

[0068] (24) Synthesis of intermediate 1-13-1: 4-tert-Butyloxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-trifluoromethylbenzyl bromide (0.64 g, 2.5 mmol) was slowly added, and the mixture was reacted at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed and separated by column chromatography to obtain 0.89 g of an oily liquid, namely intermediate 1-13-1, with a yield of 95%.

[0069] (25) Synthesis of intermediate 1-13-2: Intermediate 1-13-1 (0.89 g, 2.38 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (0.81 g, 7.14 mmol) was added, and the reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the upper layer of liquid was taken and the solvent was removed to obtain 0.47 g of an oily liquid, namely intermediate 1-13-2, with a yield of 72%.

[0070] (26) Synthesis of galanthamine analog A1: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-2-2 (0.25 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 233 mg of an oily liquid, namely galanthamine analog A1, with a yield of 33%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.33–7.20(m,5H),7.15(d,J=7.8Hz,1H),6.69(d,J=8.2Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4Hz,1H),5.79–5.76(m,1H),5.0 7(t,J=5.4Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.41(s,2H),3.35(s,1H),3.27(dt,J=8.0, 4.2Hz,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=14.3Hz,1H),2.77–2.69(m,2H),2.41–2.34(m,1H),2.23(s,3H),2.19(ddd,J=16.5,6.6,3 .7Hz,1H),2.02–1.98(m,1H),1.95–1.91(m,1H),1.68(dd,J=26.1,12.8Hz,2H),1.51–1.47(m,1H),1.40(ddd,J=28.6,11.8,3.6Hz,2H); 13 C NMR (151MHz, DMSO) δ155.84,146.53,143.62,139.11,132.84,129.18,128.59,127.29,123.81,121.49 ,111.89,85.99,63.05,62.61,59.88,55.91,53.45,52.63,48.56,47.80,41.55,33.79,32.22,28.22.

[0071] (27) Synthesis of galanthamine analog A2: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-3-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 168 mg of an oily liquid, namely galanthamine analog A2, with a yield of 24%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.30(dd,J=8.4,5.7Hz,2H),7.12(t,J=8.8Hz,3H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.2Hz,1H),6.20(d,J=10.4Hz,1H),5.78(d,J=4.7Hz, 1H),5.07(t,J=5.3Hz,1H),4.43(d,J=3.2Hz,1H),4.08(d,J=14.9Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.40(s,2H),3.33(s,1H),3.26 (s,1H),3.19(t,J=13.7Hz,1H),2.93–2.87(m,1H),2.75–2.67(m,2H),2.38(dd,J=16.5,3.2Hz,1H),2.24(s,3H),2.19(ddd,J=16.8,6.5,3.3 Hz,1H),1.99(d,J=3.6Hz,1H),1.93(d,J=11.2Hz,1H),1.68(dd,J=26.1,12.5Hz,2H),1.52–1.47(m,1H),1.39(ddd,J=28.5,11.8,3.5Hz,2H); 13 CNMR (151MHz, DMSO-d 6 )δ162.46,160.85,155.84,146.52,143.62,135.26,132.84,130.95,129.92,123.81,121.50,115 .36,111.89,85.98,63.05,61.64,55.38,53.44,52.47,48.53,47.80,41.55,33.77,32.20,28.21.

[0072] (28) Synthesis of galanthamine analog A3: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-4-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 399 mg of an oily liquid, namely galanthamine analog A3, with a yield of 58%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.67(d,J=8.0Hz,2H),7.50(d,J=7.9Hz,2H),7.17(d,J=7.7Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4Hz,1H) ,5.80–5.76(m,1H),5.07(t,J=5.3Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.51(s,2H),3.43(s, 1H),3.31–3.25(m,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=16.1Hz,1H),2.78–2.67(m,2H),2.41–2.34(m,1H),2.23(s,3H),2.19(ddd,J=15 .6,5.8,3.0Hz,1H),2.03–1.98(m,1H),1.97(s,1H),1.69(dd,J=25.5,12.2Hz,2H),1.51–1.46(m,1H),1.41(ddd,J=28.9,11.8,3.6Hz,2H); 13 C NMR (151MHz, DMSO) δ162.01,160.39,155.84,146.54,143.70,133.24,131.91,128.75,124.60,121.37,115.64,1 11.79,87.20,85.98,63.05,60.35,59.87,55.96,55.38,55.03,53.55,48.07,47.79,41.56,34.11,32.17,31.50.

[0073] (29) Synthesis of galanthamine analog A4: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-5-2 (0.28 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 456 mg of an oily liquid, namely galanthamine analog A4, with a yield of 66%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.35(td,J=7.9,6.1Hz,1H),7.16(d,J=7.8Hz,1H),7.13–7.03(m,3H),6.70(d,J=8.2Hz,1H),6.57(d,J=8.1Hz,1H),6.21(d,J=10.4Hz,1H), 5.78(dd,J=10.4,4.6Hz,1H),5.07(t,J=5.3Hz,1H),4.43(s,1H),4.11(d,J=14.9Hz,1H),3.72(s,3H),3.61(d,J=4.4Hz,1H),3.59(s,1H),3.4 4(s,2H),3.20(td,J=31.9,28.8,15.3Hz,2H),2.93(d,J=14.2Hz,1H), 2.79–2.68(m,2H),2.40–2.35(m,1H),2.26(s,3H),2.20(ddd,J=16.6,6 .7,3.6Hz,1H),2.04–1.97(m,1H),1.95(s,1H),1.69(dd,J=26.5,12.5Hz,2H),1.54–1.49(m,1H),1.41(dtd,J=27.7,15.5,13.8,10.2Hz,2H); 13 CNMR(151MHz,DMSO)δ163.50,161.89,155.84,146.54,143.70,142.30,132.84,130.53,125.08,123.88,121.59,115.5 9,114.15,111.93,85.97,63.04,61.81,59.79,55.92,55.39,53.45,52.54,48.46,47.75,41.59,33.72,32.23,28.20.

[0074] (30) Synthesis of galanthamine analog A5: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-6-2 (0.34 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 389 mg of an oily liquid, namely galanthamine analog A5, with a yield of 51%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.67(d,J=7.9Hz,2H),7.51(d,J=7.9Hz,2H),7.17(d,J=7.7Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.21(d,J=10.4Hz,1H) ,5.82–5.76(m,1H),5.08(d,J=5.4Hz,1H),4.43(s,1H),4.08(d,J=14.9Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.52(s,2H),3.33(s, 1H),3.30–3.24(m,1H),3.19(t,J=13.8Hz,1H),2.90(d,J=14.3Hz,1H),2.78–2.68(m,2H),2.38(dd,J=16.4,2.9Hz,1H),2.24(s,3H),2.22 –2.17(m,1H),2.01(d,J=11.3Hz,1H),1.97(s,1H),1.69(dd,J=26.0,12.6Hz,2H),1.52–1.47(m,1H),1.42(ddd,J=28.9,11.7,3.6Hz,2H); 13 CNMR(151MHz,DMSO)δ155.85,146.52,144.28,143.60,132.84,129.72,128.08,125.50,123.79,121.48,1 11.88,85.98,63.06,61.86,59.88,55.91,55.38,53.44,52.59,48.45,47.81,41.55,33.79,32.21,28.21.

[0075] (31) Synthesis of galanthamine analog A6: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-7-2 (0.27 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 227 mg of an oily liquid, namely galanthamine analog A6, with a yield of 33%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.16–7.08(m,5H),6.68(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4Hz,1H),5.79–5.74(m,1H),5.06(t,J=5.3Hz,1H),4.4 2(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.55(d,J=15.2Hz,1H),3.36(s,3H),3.25(dt,J=8.0,4.1Hz,1H),3.17(d,J=13.5Hz,1H),2 .90(d,J=14.2Hz,1H),2.72(t,J=13.8Hz,2H),2.37(ddd,J=15.3,3.2,1.6Hz,1H),2.27(s,3H),2.23(s,3H),2.19(ddd,J=16.1,6.2,3.1 Hz,1H),1.99(td,J=12.4,11.0,6.1Hz,1H),1.90(d,J=11.3Hz,1H),1.67(dd,J=26.1,12.7Hz,2H),1.52–1.46(m,1H),1.43–1.30(m,2H); 13 C NMR (151MHz, DMSO) δ155.84,146.52,143.60,136.28,136.01,132.84,130.03,129.18,123.80,121.48,111.8 9,85.98,63.05,62.35,59.88,55.91,55.39,53.44,52.53,48.58,47.81,41.54,33.78,32.22,28.21,21.16.

[0076] (32) Synthesis of galanthamine analog A7: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-8-2 (0.33 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 221 mg of an oily liquid, namely galanthamine analog A7, with a yield of 30%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.14(d,J=7.8Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6. 43(s,2H),6.36(t,J=2.3Hz,1H),6.20(d,J=10.4Hz,1H),5.79–5.76(m,1H ),5.07(t,J=5.4Hz,1H),4.43(d,J=3.3Hz,1H),4.07(d,J=15.0Hz,1H),3 .72(s,3H),3.71(s,6H),3.56(d,J=15.2Hz,1H),3.34(s,3H),3.28–3.24( m,1H),3.18(t,J=13.7Hz,1H),2.90(d,J=14.2Hz,1H),2.74(t,J=14.0Hz ,2H),2.38(ddt,J=16.4,2.9,1.4Hz,1H),2.23(s,3H),2.19(ddd,J=16.3, 6.2,3.3Hz,1H),2.02–1.95(m,1H),1.92(d,J=11.2Hz,1H),1.68(dd,J=2 6.4,12.4Hz,2H),1.51–1.46(m,1H),1.39(ddd,J=24.4,12.2,8.6Hz,2H); 13 C NMR (151MHz, DMSO) δ160.79,155.85,146.53,143.60,141.65,132.84,124.72,121.96,112.35,106.91,9 8.99,85.98,63.06,62.65,59.88,55.92,55.52,53.44,52.62,48.56,47.81,41.54,33.78,32.22,28.21.

[0077] (33) Synthesis of galanthamine analog A8: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-9-2 (0.3 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 461 mg of an oily liquid, namely galanthamine analog A8, with a yield of 64%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.41(td,J=8.5,6.7Hz,1H),7.21–7.12(m,2H),7.05(td,J=8.4,2.6Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.2Hz,1H),6.2 0(d,J=10.4Hz,1H),5.79–5.76(m,1H),5.08–5.05(m,1H),4.42(s,1H),4.07(d,J=14.9Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1 H),3.44(s,2H),3.32–3.21(m,2H),3.21–3.15(m,1H),2.90(d,J=14.3Hz,1H),2.76–2.69(m,2H),2.40–2.34(m,1H),2.23(s,3H ),2.20–2.16(m,1H),2.02–1.99(m,1H),1.99–1.95(m,1H),1.68(dd,J=26.2,12.5Hz,2H),1.52–1.47(m,1H),1.43–1.30(m,2H); 13 C NMR (151MHz, DMSO) δ162.59,161.99,161.05,160.27,155.83,146.52,143.61,132.83,123.80,121.49,111.89,1 04.02,85.98,63.59,63.05,59.87,55.91,55.39,54.53,53.44,52.29,48.37,47.80,41.55,33.77,32.19,28.21.

[0078] (34) Synthesis of galanthamine analog A9: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-10-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 469 mg of an oily liquid, namely galanthamine analog A9, with a yield of 66%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.36(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),7.15(d,J=7.8Hz,1H),6.69 (dd,J=8.2,3.9Hz,1H),6.56(dd,J=8.1,5.3Hz,1H),6.20(d,J=10.4Hz,1H) ,5.81–5.76(m,1H),5.09–5.05(m,1H),4.42(d,J=3.4Hz,1H),4.08(dd,J=1 5.1,3.7Hz,1H),3.72(s,3H),3.56(dd,J=15.0,2.4Hz,1H),3.40(s,2H),3. 34(s,1H),3.30–3.23(m,1H),3.18(t,J=13.6Hz,1H),2.90(d,J=14.0Hz,1H ),2.75–2.68(m,2H),2.38(ddd,J=15.3,3.2,1.6Hz,1H),2.23(s,3H),2.22 –2.16(m,1H),2.03–1.96(m,1H),1.96–1.90(m,1H),1.68(dd,J=26.0,12.5 Hz, 2H), 1.49 (dd, J=13.8, 3.1Hz, 1H), 1.39 (ddd, J=28.8, 11.8, 3.5Hz, 2H); 13 C NMR (151MHz, DMSO) δ155.84,146.52,143.61,138.23,132.83,131.78,130.92,128.57,123.81,121.49,111.8 8,85.98,63.06,61.65,60.35,59.88,55.91,55.39,53.45,52.49,48.50,47.80,41.56,33.79,32.21,28.21.

[0079] (35) Synthesis of galanthamine analog A10: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-11-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 532 mg of an oily liquid, namely galanthamine analog A10, with a yield of 73%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ8.19(d,J=8.6Hz,2H),7.57(d,J=8.7Hz,2H),7.18(d,J=7.8Hz,1H),6.70(d,J=8.1Hz,1H),6.57(d,J=8.1Hz,1H),6.21(d,J=10.4Hz, 1H),5.80–5.76(m,1H),5.07(t,J=5.5Hz,1H),4.43(s,1H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=9.2Hz,3H),3.29(dd,J=7.6, 3.9Hz,2H),3.19(t,J=13.8Hz,1H),2.91(d,J=14.2Hz,1H),2.78–2.68(m,2H),2.38(ddd,J=15.3,3.2,1.6Hz,1H),2.24(s,3H),2.22–2. 17(m,1H),2.06–2.01(m,1H),2.00–1.94(m,1H),1.70(dd,J=25.9,12.5Hz,2H),1.52–1.48(m,1H),1.43(ddd,J=28.6,11.9,3.5Hz,2H); 13 C NMR (151MHz, DMSO) δ155.85,147.67,146.97,146.52,143.61,132.83,130.34,130.04,123.83,121.49,11 1.89,85.98,63.07,61.59,59.87,55.91,55.39,53.44,52.63,48.38,47.80,41.56,33.78,32.20,28.21.

[0080] (36) Synthesis of galanthamine analog A11: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-12-2 (0.31 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 127 mg of an oily liquid, namely galanthamine analog A11, with a yield of 18%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.77(d,J=8.1Hz,2H),7.48(d,J=8.0Hz,2H),7.17(d,J=7.8Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.20(d,J=10.4 Hz,1H),5.78(d,J=4.9Hz,1H),5.07(t,J=5.3Hz,1H),4.42(s,1H),4.07(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.5 1(s,2H),3.31–3.25(m,2H),3.18(t,J=13.6Hz,1H),2.90(d,J=14.3Hz,1H),2.75–2.65(m,2H),2.40–2.33(m,1H),2.23(s,3H),2.2 2–2.16(m,1H),2.00(d,J=13.8Hz,1H),1.97(t,J=6.2Hz,1H),1.69(dd,J=26.1,12.5Hz,2H),1.52–1.47(m,1H),1.45–1.36(m,2H); 13 C NMR (151MHz, DMSO) δ155.85,146.52,145.40,143.60,132.84,132.61,129.89,123.79,121.49,119.41,111.8 8,110.06,85.12,63.07,61.89,59.88,55.91,55.39,53.44,52.63,48.40,47.81,41.55,33.78,32.20,28.21.

[0081] (37) Synthesis of galanthamine analog A12: Intermediate 1-1 (0.6 g, 1.33 mmol) and intermediate 1-13-2 (0.36 g, 1.33 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 267 mg of an oily liquid, namely galanthamine analog A12, with a yield of 34%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.40(d,J=8.3Hz,2H),7.29(d,J=8.1Hz,2H),7.16(d,J=7.8Hz,1H),6.70(d,J=8.2Hz,1H),6.57(d,J=8.0Hz,1H),6.21(d,J=10.4Hz,1 H),5.85–5.71(m,1H),5.07(t,J=5.4Hz,1H),4.43(s,1H),4.10(d,J=14.6Hz,1H),3.72(s,3H),3.61–3.56(m,1H),3.45(s,2H),3.30–3. 15(m,3H),2.93(d,J=14.1Hz,1H),2.76–2.69(m,2H),2.38(dd,J=16.5,3.0Hz,1H),2.26(s,3H),2.20(ddd,J=16.7,6.6,3.5Hz,1H),2.0 1(dt,J=13.2,3.9Hz,1H),1.97(s,1H),1.69(dd,J=26.2,12.6Hz,2H),1.51(dd,J=13.4,3.5Hz,1H),1.39(dtd,J=28.0,12.1,3.5Hz,2H); 13 C NMR (151 MHz, DMSO-d 6 )δ155.84,147.66,146.53,143.68,138.71,132.84,130.83,123.86,121.57,121.42,121.27,119.73 ,111.92,85.97,63.05,61.55,59.80,55.91,53.44,52.52,48.47,47.76,41.57,33.73,32.18,28.19.

[0082] The structural formula in the above steps is as follows:

[0083]

[0084]

[0085] The preparation of a galanthamine analog compound of formula (IB) and its intermediates in this embodiment, the specific synthesis steps are as follows:

[0086] (1) Synthesis of intermediate 2-1: Galantamine (0.6 g, 2.1 mmol) and di(p-nitrobenzene) carbonate (0.95 g, 3.13 mmol) were dissolved in anhydrous DCM. After stirring for 10 to 15 min, triethylamine (0.21 g, 2.1 mmol) was slowly added dropwise. After reacting at room temperature for 6 h, the solvent was removed and separated by column chromatography to obtain 0.92 g of an oily liquid, namely intermediate 2-1, with a yield of 97%.

[0087] (2) Synthesis of galanthamine analog B1: Intermediate 2-1 (0.5 g, 1.1 mmol) and benzylamine (0.098 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 248 mg of an oily liquid, namely galanthamine analog B1, with a yield of 64%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6 )δ7.71(t,J=6.2Hz,1H),7.32–7.29(m,2H),7.26–7.20(m,3H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H ),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.10(t,J=5.5Hz,1H),4.44(t,J=3.3Hz,1H),4.16( d,J=6.2Hz,2H),4.08(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.1Hz,1H),3.19(t,J=13.6Hz,1H),2.90( d,J=14.2Hz,1H),2.44–2.38(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.05–1.96(m,1H),1.53–1.46(m,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ156.84,146.62,143.65,140.41,132.84,130.04,128.68,127.52,127.15,123.67,1 21.46,112.06,85.97,63.42,59.88,56.02,53.44,47.82,44.22,41.56,33.80,28.17.

[0088] (3) Synthesis of galanthamine analog B2: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 213 mg of an oily liquid, namely galanthamine analog B2, with a yield of 53%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6 )δ7.73(t,J=6.1Hz,1H),7.39–7.26(m,2H),7.22–7.09(m,2H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.24(d ,J=10.4Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.12–5.09(m,1H),4.44(d,J=3.2Hz,1H),4.22(d,J=6.1Hz,2H),4.08 (d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.90(d,J=14.3Hz,1H),2.45–2.38( m,1H),2.24(s,3H),2.20(ddd,J=16.4,6.3,3.4Hz,1H),2.00(td,J=13.5,3.0Hz,1H),1.50(dd,J=13.7,3.0Hz,1H); 13 C NMR (151MHz, DMSO) δ172.54,161.11,159.49,156.78,146.62,143.65,132.82,130.62,130.05,129.74,129.26,126.87,124 .76,123.58,121.47,115.37,112.04,85.95,63.58,59.87,56.00,55.38,53.43,53.31,47.83,37.90,37.87,33.79,28.13.

[0089] (4) Synthesis of galanthamine analog B3: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 197 mg of an oily liquid, namely galanthamine analog B3, with a yield of 49%. The NMR data are as follows:1 HNMR (600 MHz, DMSO-d 6 )δ7.76(t,J=6.2Hz,1H),7.38–7.32(m,1H),7.10(d,J=7.7Hz,1H),7.07–7.02(m,2H),6.69(d,J=8.1Hz,1H), 6.56(d,J=8.1Hz,1H),6.25(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.12–5.09(m,1H),4.44(s,1H),4 .18(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.9 0(d,J=14.1Hz,1H),2.46–2.37(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.03–1.97(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ163.47,161.86,156.84,146.62,143.64,143.45,132.82,130.63,130.11,123.57, 121.45,114.21,113.99,112.05,85.95,63.56,59.89,55.95,55.38,53.43,47.83,43.75,33.80,28.13.

[0090] (5) Synthesis of galanthamine analog B4: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 237 mg of an oily liquid, namely galanthamine analog B4, with a yield of 59%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6)δ7.73(t,J=6.2Hz,1H),7.31–7.26(m,2H),7.13(t,J=8.8Hz,2H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz ,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.12–5.08(m,1H),4.44(d,J=3.3Hz,1H),4.15( d,J=6.3Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.91( d,J=14.8Hz,1H),2.44–2.39(m,1H),2.24(s,3H),2.22–2.17(m,1H),2.05–1.95(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ162.41,160.80,156.80,146.61,143.66,136.59,132.82,130.56,129.99,129.55,123 .63,121.47,115.46,112.01,85.96,63.47,59.86,55.98,55.38,53.43,47.82,43.54,41.55,33.79,28.14.

[0091] (6) Synthesis of galanthamine analog B5: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3,5-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 156 mg of an oily liquid, namely galanthamine analog B5, with a yield of 37%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.79(t,J=6.2Hz,1H),7.08(ddd,J=9.4,6.9,2.4Hz,1H),6.97–6.94(m,2H),6.70(d,J=8.1Hz,1H),6.56(d, J=8.1Hz,1H),6.25(d,J=10.3Hz,1H),5.80(dd,J=10.3,4.7Hz,1H),5.12–5.08(m,1H),4.45(t,1H),4.19(d,J= 6.2Hz,2H),4.08(d,J=15.0Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.20(t,J=13.6Hz,1H),2.90(d,J=14 .3Hz,1H),2.46–2.41(m,1H),2.24(s,3H),2.22–2.16(m,1H),2.00(td,J=13.4,3.0Hz,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ163.66,161.95,156.83,146.63,145.31,143.65,132.80,130.72,130.08,123.49, 121.46,112.06,110.32,102.53,85.94,63.70,59.87,56.00,55.38,53.42,47.83,43.56,33.78,28.08.

[0092] (7) Synthesis of galanthamine analog B6: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 216 mg of an oily liquid, namely galanthamine analog B6, with a yield of 54%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.63(t,J=6.1Hz,1H),7.23–7.11(m,4H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.24(d,J=10.4 Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.10(t,J=5.5Hz,1H),4.44(s,1H),4.16–4.13(m,2H),4.08(d,J=1 5.0Hz,1H),3.71(s,3H),3.57(d,J=15.1Hz,1H),3.20(t,J=13.6Hz,1H),2.91(d,J=14.2Hz,1H),2.45–2. 39(m,1H),2.26(s,3H),2.24(s,3H),2.22–2.16(m,1H),2.00(td,J=13.4,3.1Hz,1H),1.53–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.76,146.63,143.66,137.99,135.73,132.84,130.26,127.67,127.13,126.15, 123.72,121.48,112.05,85.98,63.42,59.87,56.01,55.39,53.45,47.81,42.10,33.81,28.19,19.08.

[0093] (8) Synthesis of galanthamine analog B7: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methoxybenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 192 mg of an oily liquid, namely galanthamine analog B7, with a yield of 46%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.64(t,J=6.2Hz,1H),7.17(d,J=8.3Hz,2H),6.86(d,J=8.6Hz,2H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6. 23(d,J=10.4Hz,1H),5.78(dd,J=10.4,4.8Hz,1H),5.11–5.08(m,1H),4.43(s,1H),4.09(d,J=6.5Hz,2H),4.08(d,J=1 5.0Hz,1H),3.72(s,3H),3.71(s,3H),3.57(d,J=15.1Hz,1H),3.19(t,J=13.5Hz,1H),2.91(d,J=14.3Hz,1H),2.44–2. 38(m,1H),2.24(s,3H),2.19(ddd,J=16.3,6.3,3.4Hz,1H),2.00(td,J=13.5,3.1Hz,1H),1.50(dd,J=13.9,3.3Hz,1H); 13 C NMR (151MHz, DMSO) δ158.61,156.75,146.61,143.65,132.40,128.90,123.71,121. 47,114.07,112.03,85.97,63.34,59.86,55.48,53.44,47.81,43.68,33.79,28.19.

[0094] (9) Synthesis of galanthamine analog B8: Intermediate 2-1 (0.5 g, 1.1 mmol) and 5-(aminomethyl)indole (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 127 mg of an oily liquid, namely galanthamine analog B8, with a yield of 30%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ11.01(s,1H),7.64(t,J=6.2Hz,1H),7.40(s,1H),7.33–7.29(m,2H),7.01(dd,J=8.4,1.7Hz,1H),6.69(d,J=8.1Hz,1H),6.56(d,J =8.1Hz,1H),6.37(t,J=2.5Hz,1H),6.22(d,J=10.4Hz,1H),5.78(ddd,J=10.4,4.8,1.1Hz,1H),5.14–5.08(m,1H),4.44(d,J=3.3Hz, 1H),4.22(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H),3.71(s,3H),3.57(d,J=15.2Hz,1H),3.19(t,J=13.5Hz,1H),2.91(d,J=14.0Hz,1 H),2.41(ddd,J=16.7,3.1,1.6Hz,1H),2.24(s,3H),2.23–2.17(m,1H),2.00(ddt,J=15.9,11.7,3.6Hz,1H),1.50(d,J=13.6Hz,1H); 13 C NMR (151MHz, DMSO) δ156.75,146.62,143.66,135.45,132.85,130.69,130.41,127.94,125.92,123.8 1,121.42,119.10,112.04,111.58,101.36,85.99,63.23,59.86,53.44,47.37,44.84,33.79,28.24.

[0095] (10) Synthesis of galanthamine analog B9: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-cyanobenzylamine (0.12 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 98 mg of an oily liquid, namely galanthamine analog B9, with a yield of 24%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.83(t,J=6.2Hz,1H),7.78(d,J=8.0Hz,2H),7.44(d,J=7.9Hz,2H),6.70(d,J=8.1Hz,1H),6.57(d,J =8.1Hz,1H),6.26(s,1H),5.79(dd,J=10.4,4.7Hz,1H),5.13–5.07(m,1H),4.44(s,1H),4.24(d,J=6.2 Hz,2H),4.08(d,J=15.1Hz,1H),3.72(s,3H),3.56(d,J=15.2Hz,1H),3.19(t,J=13.6Hz,1H),2.90(d,J =14.3Hz,1H),2.44–2.37(m,1H),2.24(s,3H),2.22–2.17(m,1H),2.03–1.96(m,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.88,146.61,146.30,143.64,132.72,130.70,130.10,128.34,123.50,121. 46,119.39,112.02,109.98,85.93,63.66,59.87,56.00,55.39,53.42,47.83,43.45,33.77,28.09.

[0096] (11) Synthesis of galanthamine analog B10: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethylbenzylamine (0.16 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 67 mg of an oily liquid, namely galanthamine analog B10, with a yield of 16%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.83(t,J=6.2Hz,1H),7.68(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),6.70(d,J=8.2Hz,1H),6.57(d,J=8.2Hz,1H),6. 25(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.6Hz,1H),5.10(t,J=5.4Hz,1H),4.45(d,J=3.3Hz,1H),4.25(d,J=6.2Hz,2H) ,4.08(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.20(t,J=13.6Hz,1H),2.91(d,J=14.1Hz,1H),2.43(dd ,J=16.5,2.9Hz,1H),2.24(s,3H),2.20(ddd,J=16.6,6.4,3.5Hz,1H),2.00(td,J=13.5,3.1Hz,1H),1.52–1.47(m,1H); 13 C NMR (151MHz, DMSO) δ156.88,146.61,145.30,143.65,132.81,130.66,130.06,128.17,125.57, 123.54,121.47,112.01,85.95,63.61,59.87,55.98,55.38,53.43,47.83,43.87,33.78,28.10.

[0097] (12) Synthesis of galanthamine analog B11: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethoxybenzylamine (0.23 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 167 mg of an oily liquid, namely galanthamine analog B11, with a yield of 36%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.77(t,J=6.2Hz,1H),7.37(d,J=8.3Hz,2H),7.31(d,J=8.3Hz,2H),6.70(d,J=8.2Hz,1H),6.57(d,J=8. 2Hz,1H),6.24(d,J=10.4Hz,1H),5.79(dd,J=10.4,4.7Hz,1H),5.10(t,J=5.5Hz,1H),4.45(t,J=3.3Hz,1H ),4.19(d,J=6.2Hz,2H),4.09(d,J=15.0Hz,1H),3.72(s,3H),3.57(d,J=15.1Hz,1H),3.25–3.16(m,1H),2 .95–2.88(m,1H),2.46–2.39(m,1H),2.24(s,3H),2.23–2.16(m,1H),2.04–1.97(m,1H),1.53–1.48(m,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ156.83,147.59,146.61,143.66,139.96,132.82,130.61,129.99,129.33,123.5 9,121.37,112.02,85.95,63.54,59.85,55.98,53.43,47.81,43.52,33.77,28.11.

[0098] (13) Synthesis of galanthamine analog B12: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-nitrobenzylamine (0.14 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 298 mg of an oily liquid, namely galanthamine analog B12, with a yield of 70%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ8.19(d,J=8.6Hz,2H),7.89(t,J=6.2Hz,1H),7.52(d,J=8.3Hz,2H),6.71(d,J=8.2Hz,1H),6.57(d,J=8.2Hz,1H),6 .25(d,J=10.4Hz,1H),5.80(dd,J=10.4,4.7Hz,1H),5.11(t,J=5.5Hz,1H),4.45(d,J=3.3Hz,1H),4.30(d,J=6.2Hz,2H ),4.09(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.2Hz,1H),3.20(t,J=13.4Hz,1H),2.91(d,J=14.3Hz,1H),2.46– 2.39(m,1H),2.24(s,3H),2.20(ddd,J=16.8,6.4,3.6Hz,1H),2.00(ddd,J=16.5,11.2,2.9Hz,1H),1.54–1.46(m,1H); 13 CNMR(151MHz,DMSO)δ156.89,148.48,146.90,146.61,143.67,132.80,130.70,129.97,128.53,123.95 ,123.50,121.50,112.00,85.94,63.71,59.85,55.99,55.38,53.42,52.98,47.82,43.82,33.76,28.06.

[0099] (14) Synthesis of galanthamine analog B13: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-(aminomethyl)naphthalene (0.14 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 320 mg of an oily liquid, namely galanthamine analog B13, with a yield of 74%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.87(t,J=7.6Hz,3H),7.81(t,J=6.2Hz,1H),7.74(s,1H),7.51–7.41(m,3H),6.70(d,J=8.1Hz,1H),6.57(d,J=8 .1Hz,1H),6.25(d,J=10.4Hz,1H),5.80(dd,J=10.4,4.6Hz,1H),5.13(t,J=5.3Hz,1H),4.45(d,J=3.3Hz,1H),4.34 (d,J=6.2Hz,2H),4.09(d,J=15.2Hz,1H),3.72(s,3H),3.57(d,J=14.9Hz,1H),3.20(t,J=13.5Hz,1H),2.96–2.85( m,1H),2.47–2.40(m,1H),2.24(s,3H),2.22–2.18(m,1H),2.00(ddd,J=15.5,10.0,3.0Hz,1H),1.53–1.48(m,1H); 13 C NMR (151MHz, DMSO) δ156.90,146.64,143.66,137.99,133.34,132.84,132.55,130.59,130.03,128.32,128.03,126.59, 126.29,126.06,125.61,123.66,121.47,112.04,85.98,63.49,59.87,56.02,55.39,53.44,47.83,44.45,33.79,28.16.

[0100] (15) Synthesis of galanthamine analog B14: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2,4-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 167 mg of an oily liquid, namely galanthamine analog B14, with a yield of 40%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.73(t,J=6.0Hz,1H),7.37(td,J=8.6,6.6Hz,1H),7.18(td,J=9.9,2.6Hz,1H),7.05(td,J=8.6,2.6Hz,1H),6.70(d,J=8 .1Hz,1H),6.57(d,J=8.1Hz,1H),6.24(d,J=10.3Hz,1H),5.78(dd,J=10.4,4.7Hz,1H),5.09(t,J=5.4Hz,1H),4.44(s,1H), 4.17(d,J=6.0Hz,2H),4.09(d,J=15.1Hz,1H),3.72(s,3H),3.57(d,J=15.1Hz,1H),3.20(t,J=13.5Hz,1H),2.91(d,J=14.2 Hz,1H),2.41(dd,J=16.2,2.8Hz,1H),2.25(s,3H),2.21(d,J=3.0Hz,1H),2.00(tt,J=11.9,3.4Hz,1H),1.53–1.48(m,1H); 13 C NMR (151MHz, DMSO) δ162.63,161.01,156.72,146.60,143.67,132.81,131.03,123.56,1 21.50,112.02,104.02,85.92,63.60,59.84,55.99,53.43,47.80,37.52,33.74,28.10.

[0101] (16) Synthesis of galanthamine analog B15: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in anhydrous DCM, and a basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added. After reacting at room temperature for 5 h, the solvent was removed and separated by column chromatography to obtain 170 mg of an oily liquid, namely galanthamine analog B15, with a yield of 43%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ7.66(t,J=6.2Hz,1H),7.15–7.09(m,4H),6.69(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),6.23(d,J=10.3Hz,1 H),5.78(dd,J=10.3,4.7Hz,1H),5.11–5.08(m,1H),4.43(s,1H),4.11(d,J=6.2Hz,2H),4.08(d,J=15.1Hz,1H) ,3.72(s,3H),3.56(d,J=15.1Hz,1H),3.19(t,J=13.4Hz,1H),2.93–2.86(m,1H),2.44–2.37(m,1H),2.26(s,3H ),2.24(s,3H),2.19(ddd,J=16.4,6.3,3.4Hz,1H),1.99(td,J=13.4,3.0Hz,1H),1.49(dd,J=13.8,3.2Hz,1H); 13 C NMR (151MHz, DMSO) δ156.79,146.62,143.63,137.39,136.15,132.84,130.10,129.22,127.56, 123.68,121.44,112.04,85.97,63.37,59.89,56.01,53.44,47.83,43.98,33.81,28.19,21.14.

[0102] The structural formula in the above steps is as follows:

[0103]

[0104]

[0105] The preparation of a galanthamine analog compound of formula (IC) and its intermediates in this embodiment, the specific synthesis steps are as follows:

[0106] (1) Synthesis of intermediate 3-1: Galantamine (0.5 g, 1.7 mmol) was stirred in anhydrous DCM for 20 to 40 min. 5-bromo-2-chloromethylenepyridine (0.36 g, 1.7 mmol) and alkaline catalyst N,N-diisopropylethylamine (0.33 g, 2.55 mmol) were slowly added under ice bath. The ice bath was removed and the reaction was carried out at room temperature for 12 h. The solvent was removed and separated by column chromatography to obtain 0.69 g of a white solid, namely intermediate 3-1, with a yield of 89%.

[0107] (2) Synthesis of galanthamine analog C1: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), benzylboronic acid pinacol ester (0.28 g, 1.3 mmol), K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 165 mg of an oily liquid, namely, galanthamine analog C1, with a yield of 34%. The NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.68(d,J=2.2Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.68(d,J=8.0Hz,1H),7.34–7.29( m,4H),7.24–7.20(m,1H),6.87(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.93–5.89(m,1H),5.15(s,1H),4.89 (t,J=15.0Hz,2H),4.67–4.61(m,2H),4.53(s,1H),4.09(t,J=4.1Hz,1H),4.06(s,2H),3.77(s,3H),3.63(d,J= 13.3Hz,1H),2.81(s,3H),2.27(s,1H),2.20(t,J=16.3Hz,1H),2.06(ddd,J=15.3,5.5,4.0Hz,1H),1.87(s,1H); 13 C NMR (151MHz, DMSO) δ150.70,147.31,146.91,145.91,140.41,138.59,138.01,133.26,131.05,129.27,129.14,128 .69,126.87,125.41,124.31,112.64,86.97,71.38,65.86,59.99,56.10,55.41,46.45,43.61,38.21,32.43,31.75.

[0108] (3) Synthesis of galanthamine analog C2: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 2-fluorobenzylboronic acid pinacol ester (0.31 g, 1.3 mmol), K2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 223 mg of an oily liquid, namely, galanthamine analog C2, with a yield of 46%. The NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.67(d,J=2.3Hz,1H),7.79(dd,J=8.0,2.3Hz,1H),7.66(d,J=8.0Hz,1H),7.40(td,J=7.7 ,1.8Hz,1H),7.32(tdd,J=7.5,5.3,1.8Hz,1H),7.23–7.16(m,2H),6.88(d,J=8.2Hz,1H),6.75(s,1H),6.17(s,1H), 5.92(s,1H),5.13(s,1H),4.89–4.82(m,2H),4.68–4.62(m,2H),4.53(s,1H),4.10(s,3H),3.78(d,J=3.9Hz,3H),3. 63(d,J=18.8Hz,1H),2.80(s,3H),2.25–2.15(m,1H),2.07(td,J=11.2,5.9Hz,1H),2.03–1.96(m,1H),1.88(s,1H); 13 CNMR (151MHz, DMSO-d 6 )δ163.58,161.96,150.72,147.47,146.67,143.34,138.08,133.28,131.08,129.76,128.73,127.54,124.32,116 .10,113.78,112.64,112.04,86.97,71.46,65.89,60.63,60.00,56.10,55.40,46.45,43.63,37.75,32.43,31.85.

[0109] (4) Synthesis of galanthamine analog C3: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 3-fluorobenzylboronic acid pinacol ester (0.28 g, 1.3 mmol), K 2 CO 3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 184 mg of an oily liquid, namely, galanthamine analog C3, with a yield of 38%. The NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ8.70(d,J=2.3Hz,1H),7.88–7.81(m,1H),7.68(d,J=8.0Hz,1H),7.36(td,J=8.0,6.3Hz,1H),7.20–7 .14(m,2H),7.05(td,J=9.1,2.7Hz,1H),6.88(d,J=8.1Hz,1H),6.76(s,1H),6.18(s,1H),5.91(dd,J=9.8,4.5Hz,1H),5.15(d, J=13.4Hz,1H),4.89(t,J=15.5Hz,2H),4.64(t,J=3.5Hz,2H),4.54–4.51(m,1H),4.10(s,1H),4.08(s,2H),3.77(s,3H),3.64( d,J=11.2Hz,1H),2.81(s,3H),2.27(d,J=9.4Hz,1H),2.22(d,J=15.7Hz,1H),2.06(ddd,J=15.3,5.5,4.0Hz,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ163.57,161.96,150.72,147.49,146.92,145.92,143.30,138.07,133.26,131.08,129.76,128.74,127.54,125 .43,124.32,118.61,115.96,113.77,112.63,86.97,71.39,65.87,60.61,59.99,56.09,55.41,46.45,43.63,37.75,32.44,31.74.

[0110] (5) Synthesis of galanthamine analog C4: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 4-fluorobenzylboronic acid pinacol ester (0.28 g, 1.3 mmol), K 2 CO 3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 187 mg of an oily liquid, namely, galanthamine analog C4, with a yield of 38%. The NMR data are as follows: 1 HNMR(600MHz,DMSO-d6)δ8.68(d,J=2.3Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.67(d,J=7.9Hz,1H),7.37–7.32(m, 2H),7.19–7.12(m,2H),6.88(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.91(d,J=10.2Hz,1H),5.13(s,1H),4.92 –4.83(m,2H),4.65(q,J=4.2Hz,2H),4.53(s,1H),4.10(td,J=5.3,2.8Hz,1H),4.06(s,2H),3.77(s,3H),3.64(d, J=15.0Hz,1H),2.80(s,3H),2.28(s,1H),2.22(d,J=15.7Hz,1H),2.06(ddd,J=15.3,5.6,4.1Hz,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ162.21,160.61,151.41,150.67,148.23,147.34,146.92,145.92,140.75,138.51,137.97,136.61,133.25,131.09,12 8.71,125.38,124.32,115.91,115.77,112.63,86.96,71.46,65.88,6 0.65,59.99,56.12,55.40,49.06,46.44,43.61,37.26,32.41,31.75.

[0111] (6) Synthesis of galanthamine analog C5: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 4-chlorobenzylboronic acid pinacol ester (0.33 g, 1.3 mmol), K 2 CO 3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 67 mg of an oily liquid, namely, galanthamine analog C5, with a yield of 13%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6 )δ8.68(d,J=2.3Hz,1H),7.83(dd,J=7.9,2.3Hz,1H),7.65(d,J=7.9Hz,1H),7.38(d,J=8.5Hz,2H),7.3 3(d,J=8.5Hz,2H),6.88(d,J=8.2Hz,1H),6.75(s,1H),6.17(s,1H),5.92(s,1H),5.12(s,1H),4.85(t, J=12.8Hz,2H),4.67–4.62(m,2H),4.53(s,1H),4.11–4.08(m,1H),4.06(s,2H),3.77(s,3H),3.63(d,J =20.4Hz,1H),2.80(s,3H),2.22(d,J=15.6Hz,1H),2.11–2.03(m,1H),2.03–1.95(m,1H),1.88(s,1H); 13 C NMR(151MHz,DMSO)δ150.70,147.40,139.49,138.21,138.03,131.59,131.17,129.06,1 28.72,124.31,112.64,86.96,70.25,63.25,59.99,56.09,46.44,43.62,37.39,31.74.

[0112] (7) Synthesis of galanthamine analog C6: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 3-chlorobenzylboronic acid pinacol ester (0.33 g, 1.3 mmol), K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 106 mg of an oily liquid, namely, galanthamine analog C6, with a yield of 21%. The NMR data are as follows: 1 HNMR (600 MHz, DMSO-d 6 )δ8.71(d,J=2.3Hz,1H),7.87(dd,J=7.9,2.3Hz,1H),7.70(d,J=7.9Hz,1H),7.42(t,J=1.9Hz,1H),7.35(d,J=7.5 Hz,1H),7.29(dd,J=7.8,1.9Hz,2H),6.87(d,J=8.0Hz,1H),6.77(s,1H),6.19(s,1H),5.91(dd,J=10.5,4.8Hz,1H) ,5.17(s,1H),4.96–4.84(m,2H),4.71–4.60(m,2H),4.52(s,1H),4.14(s,1H),4.07(s,2H),3.77(s,3H),3.66–3. 63(m,1H),2.81(s,3H),2.27(d,J=9.5Hz,1H),2.25–2.17(m,1H),2.06(ddd,J=15.3,5.6,4.1Hz,1H),1.88(s,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ150.71,147.52,146.92,145.91,143.03,138.07,133.68,131.00,129.09,128.76,128.04,1 26.91,124.32,112.64,86.97,71.39,65.86,59.99,56.10,55.41,46.45,43.64,37.63,32.43.

[0113] (8) Synthesis of galanthamine analog C7: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 4-methylbenzylboronic acid pinacol ester (0.3 g, 1.3 mmol), K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 267 mg of an oily liquid, namely, galanthamine analog C7, with a yield of 55%. The NMR data are as follows: 1 HNMR (600MHz, DMSO-d6) δ8.66(d,J=2.2Hz,1H),7.81(dd,J=7.9,2.3Hz,1H),7.66(d,J=8.0Hz,1H),7.18(d,J=8. 0Hz,2H),7.12(d,J=7.8Hz,2H),6.88(d,J=8.2Hz,1H),6.76(s,1H),6.18(s,1H),5.94–5.91(m,1H),5.13(d,J=9 .9Hz,1H),4.87(t,J=16.2Hz,2H),4.64(t,J=3.9Hz,2H),4.53(s,1H),4.09(s,1H),4.00(s,2H),3.77(s,3H),3. 62(s,1H),2.80(s,3H),2.26(s,3H),2.21(s,1H),2.06(ddd,J=15.4,5.5,4.0Hz,1H),2.01(s,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ150.65,147.19,145.91,138.85,137.93,137.33,135.89,129.69,129.16,128.66,125.38,124.3 1,118.61,112.64,93.33,86.96,71.45,70.25,65.88,63.26,60.00,56.09,46.45,43.61,37.83,31.74,22.56,21.07.

[0114] (9) Synthesis of galanthamine analog C8: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 4-methoxybenzylboronic acid pinacol ester (0.32 g, 1.3 mmol), K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 222 mg of an oily liquid, namely, galanthamine analog C8, with a yield of 45%. The NMR data are as follows: 1HNMR(600MHz,DMSO-d6)δ8.66(d,J=2.3Hz,1H),7.80(dd,J=7.9,2.3Hz,1H),7.66(d,J=7.9Hz,1H),7.24–7. 19(m,2H),6.88(dd,J=9.0,2.6Hz,3H),6.76(s,1H),6.18(s,1H),5.92(d,J=10.0Hz,1H),5.14(s,1H),4.88 (q,J=12.7Hz,2H),4.64(t,J=3.8Hz,2H),4.53(s,1H),4.11–4.08(m,1H),3.99(s,2H),3.77(s,3H),3.72(s ,3H),3.65–3.58(m,1H),2.80(s,3H),2.27(s,1H),2.22(d,J=15.8Hz,1H),2.12–1.95(m,1H),1.88(s,1H); 13 C NMR (151MHz, DMSO) δ158.32,150.61,147.16,146.92,145.92,140.75,139.07,137.87,133.25,132.29,130.30, 128.65,125.39,124.31,114.54,112.64,86.96,71.45,65.87,60.62,59.99,55.52,55.40,46.45,37.36,32.42.

[0115] (10) Synthesis of galanthamine analog C9: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 3-methoxybenzylboronic acid pinacol ester (0.32 g, 1.3 mmol), K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 216 mg of an oily liquid, namely, galanthamine analog C9, with a yield of 43%. The NMR data are as follows: 1H NMR (600MHz, DMSO-d6) δ8.68(d,J=2.2Hz,1H),7.84(dd,J=7.9,2.3Hz,1H),7.67(d,J=8.0Hz,1H),7.23(t,J=7.9Hz ,1H),6.90–6.84(m,3H),6.82–6.77(m,1H),6.76(s,1H),6.17(s,1H),5.93–5.90(m,1H),5.13(d,J=23.1Hz,1H),4 .89(q,J=12.3Hz,2H),4.64(t,J=3.8Hz,2H),4.53(s,1H),4.09(q,J=4.4Hz,1H),4.02(s,2H),3.77(s,3H),3.73(s ,3H),3.63(q,J=9.8,8.5Hz,1H),2.80(s,3H),2.27(s,1H),2.20(t,J=16.3Hz,1H),2.09–2.04(m,1H),1.87(s,1H); 13 C NMR (151MHz, DMSO) δ159.95,150.68,147.28,146.92,145.92,141.92,138.51,137.99,130.20,128.67,125.38,124.30,12 1.46,115.13,112.64,112.11,93.33,86.96,71.44,65.87,63.25,59.99,56.09,55.47,46.45,43.63,38.22,32.42,31.74.

[0116] (11) Synthesis of galanthamine analog C10: 4 mL of 1,4-dioxane and 1 mL of water were mixed and added to a mixture containing intermediate 3-1 (0.46 g, 1.0 mmol), 2-methoxybenzylboronic acid pinacol ester (0.28 g, 1.3 mmol), and K 2 CO 3 (0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.11 g, 0.15 mmol) were added in N 2 Under protective conditions, the reaction was heated at 75-95°C for 3 hours, the solvent was removed, and column chromatography was performed to obtain 98 mg of an oily liquid, namely, galanthamine analog C10, with a yield of 20%. The NMR data are as follows: 1 H NMR (600 MHz, DMSO-d 6)δ8.68(d,J=2.3Hz,1H),7.84(dd,J=7.9,2.3Hz,1H),7.67(d,J=8.0Hz,1H),7.23(t,J=7.9Hz,1H),6.94–6.84(m,3H ),6.79(dd,J=8.2,2.6Hz,1H),6.76(s,1H),6.17(s,1H),5.91(d,J=10.2Hz,1H),5.14(d,J=14.3Hz,1H),4.87(t,J=1 4.8Hz,2H),4.64(s,2H),4.52(s,1H),4.09(q,J=4.4,3.9Hz,1H),4.02(s,2H),3.77(s,3H),3.73(s,3H),3.63(q,J= 10.5,8.9Hz,1H),2.80(s,3H),2.27(s,1H),2.22(d,J=15.6Hz,1H),2.06(ddd,J=15.3,5.5,3.9Hz,1H),1.88(s,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ159.95,150.68,147.28,141.92,138.51,137.99,130.20,128.67,121.46,115.13, 112.11,86.97,71.44,65.87,63.26,59.99,56.10,55.47,46.45,43.62,38.22,32.42.

[0117] The structural formula in the above steps is as follows:

[0118]

[0119] Example 2

[0120] Cholinesterase inhibition test of galantamine analogs A1~A12, B1~B15, C1~C10:

[0121] Experimental materials and instruments: human serum acetylcholinesterase, human serum butyrylcholinesterase, acetylcholinesterase activity assay kit, DTNB, BTCl, Tris HCl were purchased from Sigma Aldrich, positive compounds galantamine, donepezil, rivastigmine were purchased from MedChemExpress, multifunctional microplate reader was purchased from Thermo Fisher, USA, and microplate constant temperature oscillator was purchased from Haimen Qilin Bell Instrument Manufacturing Co., Ltd.

[0122] Experimental method (acetylcholinesterase): The test compounds (A1-A12, B1-B15, C1-C10) and positive control drugs (galantamine, rivastigmine, donepezil) were dissolved in DMSO and diluted with the buffer solution from the assay kit to a final concentration of 10 μM for initial screening. The compound solution (50 μL) was combined with the AChE solution (2.005 U / mL, 50 μL) and incubated at 37°C in the dark for 10 min. After that, the working reagent (100 μL) was added, and the absorbance at a wavelength of 405 nm was recorded using a multifunctional microplate reader, and then the data was processed.

[0123] Experimental method (butyrylcholinesterase): Compound solution (10 μL), BuChE solution (2.040 U / mL, 50 μL) and DTNB solution (1.5 mM, 160 μL) were mixed and incubated at 37°C in the dark for 10 min. Then, BTCl solution (15 mM, 30 μL) was added, and the absorbance at 405 nm was recorded using a multifunctional microplate reader, and then data processing was performed.

[0124]

[0125] OD represents the absorbance OD value.

[0126] The final DMSO in this experiment did not exceed 1%, which would lead to enzyme inactivation. After three repeated experiments with 10 μM compounds, IC 50 According to the initial screening results, five to seven compound concentrations were selected to determine their inhibition rates, and the negative logarithm of the compound molar concentration was linearly regressed with the enzyme activity to obtain the molar concentration at 50% inhibition, which was the IC of the compound. 50 The specific results are shown in Table 1 and Table 2.

[0127] Table 1

[0128]

[0129] Table 2

[0130]

[0131]

[0132] As can be seen from Table 1 and Table 2, the comprehensive performance of the galanthamine analogs provided by the present invention is superior to that of the existing known substance galanthamine, and is expected to be developed as a new drug for treating cholinergic dysfunction.

[0133] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A galantamine analogue, characterized in that The galanthamine analog is a compound represented by formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt thereof: In the formula (IA), R1 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorine, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chlorine, p-nitro, p-cyano, and p-trifluoromethoxy; In the formula (IB), R2 is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring; In the formula (IC), R3 is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chlorine, p-chlorine, p-methyl, o-methoxy, m-methoxy and p-methoxy.

2. The galanthamine analogue according to claim 1, characterized in that The structure of the galanthamine analog is shown below: Among them, R1 is selected from one of hydrogen, o-fluoro, m-fluoro, p-fluoro, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano, and p-trifluoromethoxy; R2 is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring; R3 is selected from one of hydrogen, o-fluoro, m-fluoro, p-fluoro, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

3. The galanthamine analogue according to claim 1, characterized in that The structure of the galanthamine analog is shown below:

4. A method for preparing a galanthamine analogue as claimed in claim 1, characterized in that: The galanthamine analog is a compound represented by formula (IA), and the preparation method comprises the following steps: (1) Dissolve 4-tert-butyloxycarbonylaminopiperidine in an organic solvent and slowly add benzyl bromide (Ⅱ) containing an R-substituted group. a ), under the action of alkaline catalyst triethylamine, react at room temperature to obtain a compound having a structural formula (III a ) of the intermediate 1, wherein the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, 2,4-difluorine, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chlorine, p-nitro, p-cyano, and p-trifluoromethoxy; (2) The intermediate 1 was dissolved in anhydrous DCM, trifluoroacetic acid was added, and the reaction was stirred at room temperature to obtain a solution having a structural formula (IV a ) of intermediate 2; (3) Dissolve galanthamine and di(p-nitrobenzene) carbonate in anhydrous DCM, stir for 10 to 15 minutes, then slowly dropwise add triethylamine, and react at room temperature to obtain a compound of formula (V) a ) of intermediate 3; (4) dissolving the intermediate 2 described in step (2) and the intermediate 3 described in step (3) in anhydrous DCM, and reacting at room temperature under the action of a basic catalyst DMAP to obtain a galanthamine analog compound represented by formula (IA); The structural formula in the above steps is as follows:

5. A method for preparing a galanthamine analogue as claimed in claim 1, characterized in that: The galanthamine analog is a compound represented by formula (IB), and the preparation method comprises the following steps: (1) Dissolve galanthamine and di(p-nitrobenzene) carbonate in anhydrous DCM, stir for 10 to 15 minutes, then slowly add triethylamine dropwise, and react at room temperature to obtain a compound of formula (II b ) of intermediate 1; (2) Intermediate 1 and a primary amine containing an R-substituted group (III b ) is dissolved in anhydrous DCM, and reacted at room temperature under the action of an alkaline catalyst DMAP to obtain a galanthamine analogue compound represented by formula (IB), wherein the R group is selected from one of phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, o-methylphenyl, p-methylphenyl, p-methoxyphenyl, indole, p-cyanophenyl, p-trifluoromethylphenyl, p-trifluoromethoxyphenyl, p-nitrophenyl, and naphthalene ring; The structural formula in the above steps is as follows:

6. A method for preparing a galanthamine analogue as claimed in claim 1, characterized in that: The galanthamine analog is a compound represented by formula (IC), and the preparation method comprises the following steps: (1) Dissolve galanthamine in anhydrous DCM, stir for 20 to 40 minutes in an ice bath, then slowly add 5-bromo-2-chloromethylenepyridine, and react under the action of an alkaline catalyst to obtain a compound of formula (II c ) of intermediate 1; (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing an R-substituted group c ) is dissolved in an organic solvent, and heated at 75-95° C. under nitrogen protection and in the presence of a catalyst to perform a coupling reaction to obtain a galanthamine analog (IC), wherein the R group is selected from one of hydrogen, o-fluoro, m-fluoro, p-fluoro, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy; The structural formula in the above steps is as follows:

7. The preparation method according to claim 4, characterized in that: The organic solvent in step (1) is anhydrous ethanol.

8. The preparation method according to claim 6, characterized in that: In step (1), the alkaline catalyst is DIPEA, the organic solvent is a mixed solution of 1,4-dioxane and water, the mixed volume ratio of which is 4:1, and the catalyst is K2CO3, CsF and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

9. Use of the galanthamine analogue according to any one of claims 1 to 3 in the preparation of a cholinesterase inhibitor.

10. Use of the galanthamine analogue according to any one of claims 1 to 3 in the preparation of a medicament for treating diseases related to cholinergic dysfunction.

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