Galantamine analog, and preparation method therefor and use thereof

Abstract

The present invention relates to a galantamine analog having a cholinesterase inhibitory activity, and a preparation method therefor and the use thereof. The galantamine analog has a general structural formula as shown in formula (IA), (IB) or (IC). In formula (IA), R1 is selected from hydrogen, o-fluoro, m-fluoro, p-fluoro, 2,4-difluoro, m-trifluoromethyl, p-methyl, 3,5-dimethoxy, p-chloro, p-nitro, p-cyano or p-trifluoromethoxy. In 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 formula (IC), R3 is selected from hydrogen, o-fluoro, m-fluoro, p-fluoro, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy or p-methoxy. The galantamine analog of the present invention has a cholinesterase inhibitory activity superior to that of galantamine, and is expected to be used for treating diseases associated with cholinergic dysfunction.

Description

Galanthamine analogs, methods of making and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims the benefit of Chinese application number 2024112833560, filed on September 12, 2024. The application number 2024112833560 is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a galanthamine analog with cholinesterase inhibitory activity, and a preparation method and application thereof. BACKGROUND

[0004] Alzheimer's disease (AD) is a destructive and progressive neurodegenerative disease commonly suffered by the elderly, and is characterized by overall dementia such as learning and memory impairment, executive function decline, and behavior change, and is called "a devastating disease" by the FDA. The pathogenesis of AD is characterized by depletion of the neurotransmitter acetylcholine (ACh).

[0005] Galanthamine is the most widely distributed and important alkaloid in the Amaryllidaceae family, and was approved by the FDA in 2001 as an AChEI. It has a dual mechanism of action on the cholinergic system: it can reversibly inhibit acetylcholinesterase (AChE), and it can allosterically modulate acetylcholine receptors to enhance the transmission of nicotinic neurotransmitters and promote the release of more ACh.

[0006] Although galanthamine exhibits low toxicity, the present inventors found that the inhibition rate of galanthamine on cholinesterase and its IC 50 There is still room for improvement, and therefore, from the perspective of medicinal chemistry, the core structure of galanthamine is suitable as an ideal lead part for designing high-efficiency and low-toxicity anti-AD compounds, and providing AChEIs with more excellent performance is a technical problem to be solved by the present application. SUMMARY

[0007] In view of the problems in the prior art, the present inventors designed and synthesized a series of novel galanthamine analogs, and found that some of the compounds have better inhibitory activity on AChE and butyrylcholinesterase (BuChE) than galanthamine, and their IC 50 values are less than the IC 50 value of galanthamine. Therefore, the galanthamine analogs provided by the present application are expected to be developed as new drugs for treating diseases related to cholinergic dysfunction, such as Alzheimer's disease treatment drugs.

[0008] Specifically, the present application is realized through the following technical solutions:

[0009] In the first aspect, the present application provides a galanthamine analogue, which is a compound shown in formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt thereof:

[0010] In the formula (IA), R1 is selected from one of hydrogen, ortho-fluoro, meta-fluoro, para-fluoro, 2,4-difluoro, meta-trifluoromethyl, para-methyl, 3,5-dimethoxy, para-chloro, para-nitro, para-cyano, para-trifluoromethoxy;

[0011] In the formula (IB), R2 is selected from one of phenyl, ortho-fluorophenyl, meta-fluorophenyl, para-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, ortho-methylphenyl, para-methylphenyl, para-methoxyphenyl, indole, para-cyanophenyl, para-trifluoromethylphenyl, para-trifluoromethoxyphenyl, para-nitrophenyl, naphthalene ring;

[0012] In the formula (IC), R3 is selected from one of hydrogen, ortho-fluoro, meta-fluoro, para-fluoro, meta-chloro, para-chloro, para-methyl, ortho-methoxy, meta-methoxy, para-methoxy.

[0013] As an optional mode, in the above-mentioned galanthamine analogue, the structure of the galanthamine analogue is shown in the following formula:

[0014] In the formula (IA), R1 is selected from one of hydrogen, ortho-fluoro, meta-fluoro, para-fluoro, 2,4-difluoro, meta-trifluoromethyl, para-methyl, 3,5-dimethoxy, para-chloro, para-nitro, para-cyano, para-trifluoromethoxy; R2 is selected from one of phenyl, ortho-fluorophenyl, meta-fluorophenyl, para-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, ortho-methylphenyl, para-methylphenyl, para-methoxyphenyl, indole, para-cyanophenyl, para-trifluoromethylphenyl, para-trifluoromethoxyphenyl, para-nitrophenyl, naphthalene ring; R3 is selected from one of hydrogen, ortho-fluoro, meta-fluoro, para-fluoro, meta-chloro, para-chloro, para-methyl, ortho-methoxy, meta-methoxy, para-methoxy.

[0015] As an optional mode, in the above-mentioned galanthamine analogue, the structure of the galanthamine analogue is shown in the following formula:

[0016] In the second aspect, the present application provides a preparation method of the galanthamine analogue shown in the above-mentioned first aspect, which is a compound shown in formula (IA), and the preparation method comprises the following steps:

[0017] (1) dissolving 4-tert-butoxycarbonylaminopiperidine in an organic solvent, and slowly adding benzyl bromide (II) containing R substituent group a), under the action of basic catalyst triethylamine, reaction at room temperature to obtain intermediate 1 with structural formula of formula (III a ) and R group 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, p-trifluoromethoxy;

[0018] (2) Dissolve intermediate 1 in anhydrous DCM, add trifluoroacetic acid, and stir at room temperature to react to obtain intermediate 2 with structural formula of formula (IV a );

[0019] (3) Dissolve galanthamine and di(p-nitrophenyl) carbonate in anhydrous DCM, slowly drop triethylamine after stirring for 10-15 min, and react at room temperature to obtain intermediate 3 with structural formula of formula (V a );

[0020] (4) Dissolve intermediate 2 in step (2) and intermediate 3 in step (3) in anhydrous DCM, under the action of basic catalyst DMAP, react at room temperature to obtain galanthamine analogues shown in formula (IA);

[0021] Structural formula in the above steps is as follows:

[0022] Alternatively, the present application provides a preparation method of galanthamine analogues shown in the first aspect, which is a compound shown in formula (IB), and the preparation method comprises the following steps:

[0023] (1) Dissolve galanthamine and di(p-nitrophenyl) carbonate in anhydrous DCM, slowly drop triethylamine after stirring for 10-15 min, and react at room temperature to obtain intermediate 1 with structural formula of formula (II b );

[0024] (2) Dissolve intermediate 1 and primary amine (III b ) containing R substituent group in anhydrous DCM, under the action of basic catalyst DMAP, react at room temperature to obtain galanthamine analogues shown in formula (IB), and 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, naphthalene ring;

[0025] Structural formula in the above steps is as follows:

[0026] Alternatively, the present invention provides a method for preparing a galantamine analogue as described in the first aspect above, wherein the galantamine analogue is a compound represented by formula (IC), and the preparation method comprises the following steps:

[0027] (1) Galantamine was dissolved in anhydrous DCM. Under ice bath conditions, the mixture was stirred for 20–40 min, and then 5-bromo-2-chloromethylenepyridine was slowly added. The reaction was carried out under the action of an alkaline catalyst to obtain the structure of formula (II). c Intermediate 1 of )

[0028] (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing R-substituted groups c Dissolved in an organic solvent, under nitrogen protection and with the aid of a catalyst, the mixture is heated to 75–95 °C to carry out a coupling reaction to obtain a galantamine analog (IC), wherein the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy.

[0029] The structural formula in the above steps is shown below:

[0030] Alternatively, in the method for preparing the compound represented by the galantamine analog (IA), the organic solvent in step (1) is anhydrous ethanol.

[0031] Alternatively, in the preparation method of the compound represented by the galantamine analog (IC), the alkaline catalyst in step (1) is DIPEA, the organic solvent is a mixed solution of 1,4-dioxane and water with a volume ratio of 4:1, and the catalyst is K2CO3, CsF and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride.

[0032] In a third aspect, the present invention provides the use of the galantamine analogue described in the first aspect above in the preparation of cholinesterase inhibitors.

[0033] In a fourth aspect, the present invention provides the use of the galantamine analogue described in the first aspect above in the preparation of a medicament for treating cholinergic dysfunction-related diseases.

[0034] Alternatively, the cholinergic dysfunction-related disease is Alzheimer's disease.

[0035] The beneficial effects of this invention are as follows: the galantamine analogue provided by this invention has a better inhibition rate against AChE and BuChE than galantamine, and its IC50 is higher. 50 The value is less than the IC50 value of galantamine. 50 This value holds promise for development into a new drug for treating diseases related to cholinergic dysfunction. DETAILED DESCRIPTION

[0036] The schemes of the present application will be explained below in conjunction with examples. Those skilled in the art will understand that the examples below are only for illustration of the present application and should not be regarded as limiting the scope of the present application. If no specific technique or condition is specified in the examples, the technique or condition described in the literature in the art or according to the product manual is used. If no manufacturer of the reagent or instrument is specified, it is a conventional product that can be obtained commercially.

[0037] The instruments and equipment used in the following examples: The following examples can be performed according to the conventional techniques if no parameter is specifically mentioned. The nuclear magnetic spectrum is measured by using AVANCE III HD 600MHz nuclear magnetic resonance instrument of Bruker BioSpin Co., Ltd., Switzerland, with deuterated chloroform or deuterated DMSO as solvent; the IC 50 The multifunctional enzyme reader of Thermo Fisher Co., USA is used for measuring the IC

[0038] Example 1

[0039] The preparation of a galanthamine analogue compound of formula (IA) and the preparation of intermediates thereof in this example are as follows:

[0040] (1) Synthesis of intermediate 1-1: Galanthamine (0.6 g, 2.1 mmol) and bis(p-nitrophenyl) carbonate (0.95 g, 3.13 mmol) are dissolved in anhydrous DCM, and triethylamine (0.21 g, 2.1 mmol) is slowly added dropwise after stirring for 10-15 min. After reaction at room temperature for 6 h, the solvent is removed, and column chromatography is performed to separate to obtain 0.92 g of an oily liquid, i.e. intermediate 1-1, with a yield of 97%.

[0041] (2) Synthesis of intermediate 1-2-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) is dissolved in 5 mL of anhydrous ethanol, and benzyl bromide (0.43 g, 2.5 mmol) is slowly added. After reaction at room temperature for 12 h under the action of triethylamine (0.48 g, 4.74 mmol), the solvent is removed, and column chromatography is performed to separate to obtain 0.71 g of an oily liquid, i.e. intermediate 1-2-1, with a yield of 98%.

[0042] (3) Synthesis of intermediate 1-2-2: Intermediate 1-2-1 (0.71 g, 2.45 mmol) is dissolved in anhydrous DCM, and trifluoroacetic acid (0.84 g, 7.34 mmol) is added. After reaction at room temperature for 4 h, the solvent is removed, and the pH is adjusted to weak alkalinity with a saturated sodium bicarbonate solution. After extraction with ethyl acetate, the upper liquid is removed, and the solvent is removed to obtain 0.32 g of an oily liquid, i.e. intermediate 1-2-2, with a yield of 69%.

[0043] (4) Synthesis of intermediate 1-3-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 4-fluorobenzyl bromide (0.47 g, 2.5 mmol) was added slowly, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate the product, yielding 0.67 g of an oily liquid, i.e., intermediate 1-3-1, in a yield of 87%.

[0044] (5) Synthesis of intermediate 1-3-2: Intermediate 1-3-1 (0.67 g, 2.2 mmol) was dissolved in absolute DCM, and trifluoroacetic acid (0.75 g, 6.6 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity using a saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, and the upper liquid was removed. The solvent was removed to yield 0.39 g of an oily liquid, i.e., intermediate 1-3-2, in a yield of 85%.

[0045] (6) Synthesis of intermediate 1-4-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 2-fluorobenzyl bromide (0.47 g, 2.5 mmol) was added slowly, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate the product, yielding 0.69 g of an oily liquid, i.e., intermediate 1-4-1, in a yield of 90%.

[0046] (7) Synthesis of intermediate 1-4-2: Intermediate 1-4-1 (0.69 g, 2.2 mmol) was dissolved in absolute DCM, and trifluoroacetic acid (0.75 g, 6.6 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity using a saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, and the upper liquid was removed. The solvent was removed to yield 0.25 g of an oily liquid, i.e., intermediate 1-4-2, in a yield of 55%.

[0047] (8) Synthesis of intermediate 1-5-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 3-fluorobenzyl bromide (0.47 g, 2.5 mmol) was added slowly, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate the product, yielding 0.72 g of an oily liquid, i.e., intermediate 1-5-1, in a yield of 94%.

[0048] (9) Synthesis of intermediate 1-5-2: Intermediate 1-5-1 (0.72 g, 2.34 mmol) was dissolved in dry 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 alkaline with saturated sodium bicarbonate solution. The upper liquid was extracted with ethyl acetate, and the solvent was removed to obtain 0.35 g of an oily liquid, which was intermediate 1-5-2, with a yield of 72%.

[0049] (10) Synthesis of intermediate 1-6-1: 4-tert-Butylcarbonylamino piperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of dry ethanol, and 3-trifluoromethylbenzyl bromide (0.60 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to obtain 0.86 g of an oily liquid, which was intermediate 1-6-1, with a yield of 96%.

[0050] (11) Synthesis of intermediate 1-6-2: Intermediate 1-6-1 (0.86 g, 2.4 mmol) was dissolved in dry DCM, and trifluoroacetic acid (0.82 g, 7.2 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution. The upper liquid was extracted with ethyl acetate, and the solvent was removed to obtain 0.47 g of an oily liquid, which was intermediate 1-6-2, with a yield of 76%.

[0051] (12) Synthesis of intermediate 1-7-1: 4-tert-Butylcarbonylamino piperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of dry ethanol, and 4-methylbenzyl bromide (0.46 g, 2.5 mmol) was slowly added. The reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to obtain 0.70 g of an oily liquid, which was intermediate 1-7-1, with a yield of 92%.

[0052] (13) Synthesis of intermediate 1-7-2: Intermediate 1-7-1 (0.7 g, 2.3 mmol) was dissolved in dry DCM, and trifluoroacetic acid (0.79 g, 6.9 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution. The upper liquid was extracted with ethyl acetate, and the solvent was removed to obtain 0.36 g of an oily liquid, which was intermediate 1-7-2, with a yield of 77%.

[0053] (14) Synthesis of intermediate 1-8-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 3,5-dimethoxybenzyl bromide (0.58 g, 2.5 mmol) was slowly added, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate 0.86 g of an oily liquid, which was the intermediate 1-8-1, with a yield of 98%.

[0054] (15) Synthesis of intermediate 1-8-2: Intermediate 1-8-1 (0.86 g, 2.46 mmol) was dissolved in absolute DCM, and trifluoroacetic acid (0.84 g, 7.38 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity using a saturated sodium bicarbonate solution. Ethyl acetate was added to extract the upper liquid, and the solvent was removed to obtain 0.49 g of an oily liquid, which was the intermediate 1-8-2, with a yield of 80%.

[0055] (16) Synthesis of intermediate 1-9-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 2,4-difluorobenzyl bromide (0.52 g, 2.5 mmol) was slowly added, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate 0.78 g of an oily liquid, which was the intermediate 1-9-1, with a yield of 96%.

[0056] (17) Synthesis of intermediate 1-9-2: Intermediate 1-9-1 (0.78 g, 2.39 mmol) was dissolved in absolute DCM, and trifluoroacetic acid (0.82 g, 7.17 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, and the pH was adjusted to weak alkalinity using a saturated sodium bicarbonate solution. Ethyl acetate was added to extract the upper liquid, and the solvent was removed to obtain 0.38 g of an oily liquid, which was the intermediate 1-9-2, with a yield of 70%.

[0057] (18) Synthesis of intermediate 1-10-1 : 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of absolute ethanol, 4-chlorobenzyl bromide (0.51 g, 2.5 mmol) was slowly added, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was performed to isolate 0.76 g of an oily liquid, which was the intermediate 1-10-1, with a yield of 94%.

[0058] (19) Synthesis of intermediate 1-10-2: Intermediate 1-10-1 (0.76 g, 2.35 mmol) was dissolved in dry 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, the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution, and the reaction was extracted with ethyl acetate. The upper liquid was taken, the solvent was removed, and 0.18 g of an oily liquid was obtained, which was intermediate 1-10-2, with a yield of 34%.

[0059] (20) Synthesis of intermediate 1-11-1: 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of dry ethanol, 4-nitrobenzyl bromide (0.54 g, 2.5 mmol) was slowly added, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was used for separation, and 0.81 g of an oily liquid was obtained, which was intermediate 1-11-1, with a yield of 97%.

[0060] (21) Synthesis of intermediate 1-11-2: Intermediate 1-11-1 (0.81 g, 2.42 mmol) was dissolved in dry 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, the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution, and the reaction was extracted with ethyl acetate. The upper liquid was taken, the solvent was removed, and 0.41 g of an oily liquid was obtained, which was intermediate 1-11-2, with a yield of 72%.

[0061] (22) Synthesis of intermediate 1-12-1: 4-tert-Butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of dry ethanol, 4-cyanobenzyl bromide (0.49 g, 2.5 mmol) was slowly added, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was used for separation, and 0.75 g of an oily liquid was obtained, which was intermediate 1-12-1, with a yield of 95%.

[0062] (23) Synthesis of intermediate 1-12-2: Intermediate 1-12-1 (0.75 g, 2.38 mmol) was dissolved in dry 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, the pH was adjusted to weak alkaline with saturated sodium bicarbonate solution, and the reaction was extracted with ethyl acetate. The upper liquid was taken, the solvent was removed, and 0.24 g of an oily liquid was obtained, which was intermediate 1-12-2, with a yield of 47%.

[0063] (24) Synthesis of intermediate 1-13-1: 4-tert-butoxycarbonylaminopiperidine (0.5 g, 2.5 mmol) was dissolved in 5 mL of anhydrous ethanol, 4-trifluoromethoxybenzyl bromide (0.64 g, 2.5 mmol) was added slowly, and the reaction was carried out at room temperature for 12 h in the presence of triethylamine (0.48 g, 4.74 mmol). The solvent was removed, and column chromatography was used to isolate 0.89 g of an oily liquid, which was intermediate 1-13-1, with a yield of 95%.

[0064] (25) Synthesis of intermediate 1-13-2: Intermediate 1-13-1 (0.89 g, 2.38 mmol) was dissolved in anhydrous DCM, and trifluoroacetic acid (0.81 g, 7.14 mmol) was added. The reaction was carried out at room temperature for 4 h. The solvent was removed, the pH was adjusted to weak alkalinity with a saturated sodium bicarbonate solution, and extraction was carried out with ethyl acetate. The upper liquid was removed, and the solvent was removed to obtain 0.47 g of an oily liquid, which was intermediate 1-13-2, with a yield of 72%.

[0065] (26) Synthesis of galantamine analogue 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. The reaction was carried out at room temperature for 5 h. The solvent was removed, and column chromatography was used to isolate 233 mg of an oily liquid, which was galantamine analogue A1, with a yield of 33%. The nuclear magnetic resonance data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.33 - 7.20 (m, 5H), 7.15 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.79 - 5.76 (m, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.42 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.41 (s, 2H), 3.35 (s, 1H), 3.27 (dt, J = 8.0, 4.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.90 (d, J = 14.3 Hz, 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, 3.7 Hz, 1H), 2.02 - 1.98 (m, 1H), 1.95 - 1.91 (m, 1H), 1.68 (dd, J = 26.1, 12.8 Hz, 2H), 1.51 - 1.47 (m, 1H), 1.40 (ddd, J = 28.6, 11.8, 3.6 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 155.84, 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.

[0066] (27) Synthesis of Galantamine analogue A2: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-3-2 (0.28 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 168 mg of an oily liquid, which was Galantamine analogue A2, with a yield of 24%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.30 (dd, J = 8.4, 5.7 Hz, 2H), 7.12 (t, J = 8.8 Hz, 3H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.78 (d, J = 4.7 Hz, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.43 (d, J = 3.2 Hz, 1H), 4.08 (d, J = 14.9 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.40 (s, 2H), 3.33 (s, 1H), 3.26 (s, 1H), 3.19 (t, J = 13.7 Hz, 1H), 2.93 - 2.87 (m, 1H), 2.75 - 2.67 (m, 2H), 2.38 (dd, J = 16.5, 3.2 Hz, 1H), 2.24 (s, 3H), 2.19 (ddd, J = 16.8, 6.5, 3.3 Hz, 1H), 1.99 (d, J = 3.6 Hz, 1H), 1.93 (d, J = 11.2 Hz, 1H), 1.68 (dd, J = 26.1, 12.5 Hz, 2H), 1.52 - 1.47 (m, 1H), 1.39 (ddd, J = 28.5, 11.8, 3.5 Hz, 2H); 13 C NMR (151 MHz, DMSO-d6) δ 162.46, 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.

[0067] (28) Synthesis of Galantamine analogue A3: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-4-2 (0.28 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 399 mg of an oily liquid, which was Galantamine analogue A3, with a yield of 58%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.67 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.80 - 5.76 (m, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.42 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.51 (s, 2H), 3.43 (s, 1H), 3.31 - 3.25 (m, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.90 (d, J = 16.1 Hz, 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, 3.0 Hz, 1H), 2.03 - 1.98 (m, 1H), 1.97 (s, 1H), 1.69 (dd, J = 25.5, 12.2 Hz, 2H), 1.51 - 1.46 (m, 1H), 1.41 (ddd, J = 28.9, 11.8, 3.6 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 162.01, 160.39, 155.84, 146.54, 143.70, 133.24, 131.91, 128.75, 124.60, 121.37, 115.64, 111.79, 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.

[0068] (29) Synthesis of Galantamine analogue A4: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-5-2 (0.28 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 456 mg of an oily liquid, which was Galantamine analogue A4, with a yield of 66%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.35 (td, J = 7.9, 6.1 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.13 - 7.03 (m, 3H), 6.70 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.78 (dd, J = 10.4, 4.6 Hz, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.43 (s, 1H), 4.11 (d, J = 14.9 Hz, 1H), 3.72 (s, 3H), 3.61 (d, J = 4.4 Hz, 1H), 3.59 (s, 1H), 3.44 (s, 2H), 3.20 (td, J = 31.9, 28.8, 15.3 Hz, 2H), 2.93 (d, J = 14.2 Hz, 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, 3.6 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.95 (s, 1H), 1.69 (dd, J = 26.5, 12.5 Hz, 2H), 1.54 - 1.49 (m, 1H), 1.41 (dtd, J = 27.7, 15.5, 13.8, 10.2 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 163.50, 161.89, 155.84, 146.54, 143.70, 142.30, 132.84, 130.53, 125.08, 123.88, 121.59, 115.59, 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.

[0069] (30) Synthesis of Galantamine analogue A5: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-6-2 (0.34 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and the product was isolated by column chromatography, obtaining 389 mg of an oily liquid, which is Galantamine analogue A5, with a yield of 51%. NMR data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.67 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.82 - 5.76 (m, 1H), 5.08 (d, J = 5.4 Hz, 1H), 4.43 (s, 1H), 4.08 (d, J = 14.9 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.52 (s, 2H), 3.33 (s, 1H), 3.30 - 3.24 (m, 1H), 3.19 (t, J = 13.8 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 2.78 - 2.68 (m, 2H), 2.38 (dd, J = 16.4, 2.9 Hz, 1H), 2.24 (s, 3H), 2.22 - 2.17 (m, 1H), 2.01 (d, J = 11.3 Hz, 1H), 1.97 (s, 1H), 1.69 (dd, J = 26.0, 12.6 Hz, 2H), 1.52 - 1.47 (m, 1H), 1.42 (ddd, J = 28.9, 11.7, 3.6 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 155.85, 146.52, 144.28, 143.60, 132.84, 129.72, 128.08, 125.50, 123.79, 121.48, 111.88, 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.

[0070] (31) Synthesis of Galantamine analogue A6: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-7-2 (0.27 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 227 mg of an oily liquid, which was Galantamine analogue A6, with a yield of 33%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.16 - 7.08 (m, 5H), 6.68 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.79 - 5.74 (m, 1H), 5.06 (t, J = 5.3 Hz, 1H), 4.42 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.55 (d, J = 15.2 Hz, 1H), 3.36 (s, 3H), 3.25 (dt, J = 8.0, 4.1 Hz, 1H), 3.17 (d, J = 13.5 Hz, 1H), 2.90 (d, J = 14.2 Hz, 1H), 2.72 (t, J = 13.8 Hz, 2H), 2.37 (ddd, J = 15.3, 3.2, 1.6 Hz, 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, 6.1 Hz, 1H), 1.90 (d, J = 11.3 Hz, 1H), 1.67 (dd, J = 26.1, 12.7 Hz, 2H), 1.52 - 1.46 (m, 1H), 1.43 - 1.30 (m, 2H); 13 C NMR (151 MHz, DMSO) δ 155.84, 146.52, 143.60, 136.28, 136.01, 132.84, 130.03, 129.18, 123.80, 121.48, 111.89, 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.

[0071] (32) Synthesis of Galantamine analogue A7: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-8-2 (0.33 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 221 mg of an oily liquid, which was Galantamine analogue A7, with a yield of 30%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.14 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.43 (s, 2H), 6.36 (t, J = 2.3 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.79 - 5.76 (m, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.43 (d, J = 3.3 Hz, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 6H), 3.56 (d, J = 15.2 Hz, 1H), 3.34 (s, 3H), 3.28 - 3.24 (m, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.90 (d, J = 14.2 Hz, 1H), 2.74 (t, J = 14.0 Hz, 2H), 2.38 (ddt, J = 16.4, 2.9, 1.4 Hz, 1H), 2.23 (s, 3H), 2.19 (ddd, J = 16.3, 6.2, 3.3 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.92 (d, J = 11.2 Hz, 1H), 1.68 (dd, J = 26.4, 12.4 Hz, 2H), 1.51 - 1.46 (m, 1H), 1.39 (ddd, J = 24.4, 12.2, 8.6 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 160.79, 155.85, 146.53, 143.60, 141.65, 132.84, 124.72, 121.96, 112.35, 106.91, 98.99, 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.

[0072] (33) Synthesis of Galantamine analogue A8: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-9-2 (0.3 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and the product was isolated by column chromatography, obtaining 461 mg of an oily liquid, which is Galantamine analogue A8, with a yield of 64%. NMR data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.41 (td, J = 8.5, 6.7 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (td, J = 8.4, 2.6 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.79 - 5.76 (m, 1H), 5.08 - 5.05 (m, 1H), 4.42 (s, 1H), 4.07 (d, J = 14.9 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.44 (s, 2H), 3.32 - 3.21 (m, 2H), 3.21 - 3.15 (m, 1H), 2.90 (d, J = 14.3 Hz, 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, 12.5 Hz, 2H), 1.52 - 1.47 (m, 1H), 1.43 - 1.30 (m, 2H); 13 C NMR (151 MHz, DMSO) δ 162.59, 161.99, 161.05, 160.27, 155.83, 146.52, 143.61, 132.83, 123.80, 121.49, 111.89, 104.02, 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.

[0073] (34) Synthesis of Galantamine analogue A9: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-10-2 (0.31 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 469 mg of an oily liquid, which was Galantamine analogue A9, with a yield of 66%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 6.69 (dd, J = 8.2, 3.9 Hz, 1H), 6.56 (dd, J = 8.1, 5.3 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.81 - 5.76 (m, 1H), 5.09 - 5.05 (m, 1H), 4.42 (d, J = 3.4 Hz, 1H), 4.08 (dd, J = 15.1, 3.7 Hz, 1H), 3.72 (s, 3H), 3.56 (dd, J = 15.0, 2.4 Hz, 1H), 3.40 (s, 2H), 3.34 (s, 1H), 3.30 - 3.23 (m, 1H), 3.18 (t, J = 13.6 Hz, 1H), 2.90 (d, J = 14.0 Hz, 1H), 2.75 - 2.68 (m, 2H), 2.38 (ddd, J = 15.3, 3.2, 1.6 Hz, 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, 3.1 Hz, 1H), 1.39 (ddd, J = 28.8, 11.8, 3.5 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 155.84, 146.52, 143.61, 138.23, 132.83, 131.78, 130.92, 128.57, 123.81, 121.49, 111.88, 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.

[0074] (35) Synthesis of Galantamine analogue A10: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-11-2 (0.31 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 532 mg of an oily liquid, which was Galantamine analogue A10, with a yield of 73%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 8.19 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.80 - 5.76 (m, 1H), 5.07 (t, J = 5.5 Hz, 1H), 4.43 (s, 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 9.2 Hz, 3H), 3.29 (dd, J = 7.6, 3.9 Hz, 2H), 3.19 (t, J = 13.8 Hz, 1H), 2.91 (d, J = 14.2 Hz, 1H), 2.78 - 2.68 (m, 2H), 2.38 (ddd, J = 15.3, 3.2, 1.6 Hz, 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, 12.5 Hz, 2H), 1.52 - 1.48 (m, 1H), 1.43 (ddd, J = 28.6, 11.9, 3.5 Hz, 2H); 13 C NMR (151 MHz, DMSO) δ 155.85, 147.67, 146.97, 146.52, 143.61, 132.83, 130.34, 130.04, 123.83, 121.49, 111.89, 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.

[0075] (36) Synthesis of Galantamine analogue A11: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-12-2 (0.31 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 127 mg of an oily liquid, which was Galantamine analogue A11, with a yield of 18%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.77 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 10.4 Hz, 1H), 5.78 (d, J = 4.9 Hz, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.42 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.51 (s, 2H), 3.31 - 3.25 (m, 2H), 3.18 (t, J = 13.6 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 2.75 - 2.65 (m, 2H), 2.40 - 2.33 (m, 1H), 2.23 (s, 3H), 2.22 - 2.16 (m, 1H), 2.00 (d, J = 13.8 Hz, 1H), 1.97 (t, J = 6.2 Hz, 1H), 1.69 (dd, J = 26.1, 12.5 Hz, 2H), 1.52 - 1.47 (m, 1H), 1.45 - 1.36 (m, 2H); 13 C NMR (151 MHz, DMSO) δ 155.85, 146.52, 145.40, 143.60, 132.84, 132.61, 129.89, 123.79, 121.49, 119.41, 111.88, 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.

[0076] (37) Synthesis of Galantamine analogue A12: Intermediate 1-1 (0.6 g, 1.33 mmol) and Intermediate 1-13-2 (0.36 g, 1.33 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.24 g, 2.1 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 267 mg of an oily liquid, which was Galantamine analogue A12, with a yield of 34%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.40 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.21 (d, J = 10.4 Hz, 1H), 5.85 - 5.71 (m, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.43 (s, 1H), 4.10 (d, J = 14.6 Hz, 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 = 14.1 Hz, 1H), 2.76 - 2.69 (m, 2H), 2.38 (dd, J = 16.5, 3.0 Hz, 1H), 2.26 (s, 3H), 2.20 (ddd, J = 16.7, 6.6, 3.5 Hz, 1H), 2.01 (dt, J = 13.2, 3.9 Hz, 1H), 1.97 (s, 1H), 1.69 (dd, J = 26.2, 12.6 Hz, 2H), 1.51 (dd, J = 13.4, 3.5 Hz, 1H), 1.39 (dtd, J = 28.0, 12.1, 3.5 Hz, 2H); 13 C NMR (151 MHz, DMSO-d6) δ 155.84, 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.

[0077] The structure of the above step is as follows:

[0078] The preparation of a galanthamine analogue compound of formula (IB) and the preparation of intermediates thereof in this embodiment are as follows:

[0079] (1) Synthesis of intermediate 2-1: Dissolve galanthamine (0.6 g, 2.1 mmol) and bis (p-nitrophenyl) carbonate (0.95 g, 3.13 mmol) in anhydrous DCM, slowly drop triethylamine (0.21 g, 2.1 mmol) after stirring for 10-15 min, and react at room temperature for 6 h. Remove the solvent, separate by column chromatography, and obtain 0.92 g of an oily liquid, i.e. the intermediate 2-1, with a yield of 97%.

[0080] (2) Synthesis of Galantamine analogue B1 : Intermediate 2-1 (0.5 g, 1.1 mmol) and benzylamine (0.098 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 248 mg of an oily liquid, which was Galantamine analogue B1, with a yield of 64%. NMR data are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 7.71 (t, J = 6.2 Hz, 1 H), 7.32 - 7.29 (m, 2H), 7.26 - 7.20 (m, 3H), 6.69 (d, J = 8.1 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1 H), 6.24 (d, J = 10.4 Hz, 1 H), 5.79 (dd, J = 10.4, 4.6 Hz, 1 H), 5.10 (t, J = 5.5 Hz, 1 H), 4.44 (t, J = 3.3 Hz, 1 H), 4.16 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.0 Hz, 1 H), 3.72 (s, 3H), 3.56 (d, J = 15.1 Hz, 1 H), 3.19 (t, J = 13.6 Hz, 1 H), 2.90 (d, J = 14.2 Hz, 1 H), 2.44 - 2.38 (m, 1 H), 2.24 (s, 3H), 2.22 - 2.16 (m, 1 H), 2.05 - 1.96 (m, 1 H), 1.53 - 1.46 (m, 1 H); 13 C NMR (151 MHz, DMSO-d6) δ 156.84, 146.62, 143.65, 140.41, 132.84, 130.04, 128.68, 127.52, 127.15, 123.67, 121.46, 112.06, 85.97, 63.42, 59.88, 56.02, 53.44, 47.82, 44.22, 41.56, 33.80, 28.17.

[0081] (3) Synthesis of Galantamine analogue B2: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 213 mg of an oily liquid, which was Galantamine analogue B2, with a yield of 53%. NMR data are as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.73 (t, J = 6.1 Hz, 1H), 7.39 - 7.26 (m, 2H), 7.22 - 7.09 (m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.7 Hz, 1H), 5.12 - 5.09 (m, 1H), 4.44 (d, J = 3.2 Hz, 1H), 4.22 (d, J = 6.1 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.19 (t, J = 13.5 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.24 (s, 3H), 2.20 (ddd, J = 16.4, 6.3, 3.4 Hz, 1H), 2.00 (td, J = 13.5, 3.0 Hz, 1H), 1.50 (dd, J = 13.7, 3.0 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ 172.54, 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.

[0082] (4) Synthesis of Galantamine analogue B3: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3- fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4- dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 197 mg of an oily liquid, which was Galantamine analogue B3, with a yield of 49%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.76 (t, J = 6.2 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.07 - 7.02 (m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.6 Hz, 1H), 5.12 - 5.09 (m, 1H), 4.44 (s, 1H), 4.18 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.19 (t, J = 13.5 Hz, 1H), 2.90 (d, J = 14.1 Hz, 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 (151 MHz, DMSO) δ 163.47, 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.

[0083] (5) Synthesis of Galantamine analogue B4: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-fluorobenzylamine (0.12 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 237 mg of an oily liquid, which was Galantamine analogue B4, with a yield of 59%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.73 (t, J = 6.2 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.6 Hz, 1H), 5.12 - 5.08 (m, 1H), 4.44 (d, J = 3.3 Hz, 1H), 4.15 (d, J = 6.3 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 15.2 Hz, 1H), 3.19 (t, J = 13.5 Hz, 1H), 2.91 (d, J = 14.8 Hz, 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 (151 MHz, DMSO) δ 162.41, 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.

[0084] (6) Synthesis of Galantamine analogue B5: Intermediate 2-1 (0.5 g, 1.1 mmol) and 3,5-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 156 mg of an oily liquid, which was Galantamine analogue B5, with a yield of 37%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.79 (t, J = 6.2 Hz, 1H), 7.08 (ddd, J = 9.4, 6.9, 2.4 Hz, 1H), 6.97 - 6.94 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.25 (d, J = 10.3 Hz, 1H), 5.80 (dd, J = 10.3, 4.7 Hz, 1H), 5.12 - 5.08 (m, 1H), 4.45 (t, 1H), 4.19 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.20 (t, J = 13.6 Hz, 1H), 2.90 (d, J = 14.3 Hz, 1H), 2.46 - 2.41 (m, 1H), 2.24 (s, 3H), 2.22 - 2.16 (m, 1H), 2.00 (td, J = 13.4, 3.0 Hz, 1H), 1.52 - 1.47 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 163.66, 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.

[0085] (7) Synthesis of Galantamine analogue B6: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 216 mg of an oily liquid, which was Galantamine analogue B6, with a yield of 54%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.63 (t, J = 6.1 Hz, 1H), 7.23 - 7.11 (m, 4H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.7 Hz, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.44 (s, 1H), 4.16 - 4.13 (m, 2H), 4.08 (d, J = 15.0 Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 15.1 Hz, 1H), 3.20 (t, J = 13.6 Hz, 1H), 2.91 (d, J = 14.2 Hz, 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, 3.1 Hz, 1H), 1.53 - 1.47 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 156.76, 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.

[0086] (8) Synthesis of Galantamine analogue B7: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methoxybenzylamine (0.13 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 192 mg of an oily liquid, which was Galantamine analogue B7, with a yield of 46%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.64 (t, J = 6.2 Hz, 1H), 7.17 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.23 (d, J = 10.4 Hz, 1H), 5.78 (dd, J = 10.4, 4.8 Hz, 1H), 5.11 - 5.08 (m, 1H), 4.43 (s, 1H), 4.09 (d, J = 6.5 Hz, 2H), 4.08 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.57 (d, J = 15.1 Hz, 1H), 3.19 (t, J = 13.5 Hz, 1H), 2.91 (d, J = 14.3 Hz, 1H), 2.44 - 2.38 (m, 1H), 2.24 (s, 3H), 2.19 (ddd, J = 16.3, 6.3, 3.4 Hz, 1H), 2.00 (td, J = 13.5, 3.1 Hz, 1H), 1.50 (dd, J = 13.9, 3.3 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ 158.61, 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.

[0087] (9) Synthesis of Galantamine analogue B8: Intermediate 2-1 (0.5 g, 1.1 mmol) and 5-(aminomethyl)indole (0.13 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 127 mg of an oily liquid, which was Galantamine analogue B8, with a yield of 30%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.64 (t, J = 6.2 Hz, 1H), 7.40 (s, 1H), 7.33 - 7.29 (m, 2H), 7.01 (dd, J = 8.4, 1.7 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.37 (t, J = 2.5 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H), 5.78 (ddd, J = 10.4, 4.8, 1.1 Hz, 1H), 5.14 - 5.08 (m, 1H), 4.44 (d, J = 3.3 Hz, 1H), 4.22 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 15.2 Hz, 1H), 3.19 (t, J = 13.5 Hz, 1H), 2.91 (d, J = 14.0 Hz, 1H), 2.41 (ddd, J = 16.7, 3.1, 1.6 Hz, 1H), 2.24 (s, 3H), 2.23 - 2.17 (m, 1H), 2.00 (ddt, J = 15.9, 11.7, 3.6 Hz, 1H), 1.50 (d, J = 13.6 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ 156.75, 146.62, 143.66, 135.45, 132.85, 130.69, 130.41, 127.94, 125.92, 123.81, 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.

[0088] (10) Synthesis of Galantamine analogue B9: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-cyanobenzylamine (0.12 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 98 mg of an oily liquid, which was Galantamine analogue B9, with a yield of 24%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.83 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 6.70 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.26 (s, 1H), 5.79 (dd, J = 10.4, 4.7 Hz, 1H), 5.13 - 5.07 (m, 1H), 4.44 (s, 1H), 4.24 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.2 Hz, 1H), 3.19 (t, J = 13.6 Hz, 1H), 2.90 (d, J = 14.3 Hz, 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 (151 MHz, DMSO) δ 156.88, 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.

[0089] (11) Synthesis of Galantamine analogue B10: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethylbenzylamine (0.16 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 67 mg of an oily liquid, which was Galantamine analogue B10, with a yield of 16%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.83 (t, J = 6.2 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.6 Hz, 1H), 5.10 (t, J = 5.4 Hz, 1H), 4.45 (d, J = 3.3 Hz, 1H), 4.25 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 15.2 Hz, 1H), 3.20 (t, J = 13.6 Hz, 1H), 2.91 (d, J = 14.1 Hz, 1H), 2.43 (dd, J = 16.5, 2.9 Hz, 1H), 2.24 (s, 3H), 2.20 (ddd, J = 16.6, 6.4, 3.5 Hz, 1H), 2.00 (td, J = 13.5, 3.1 Hz, 1H), 1.52 - 1.47 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 156.88, 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.

[0090] (12) Synthesis of Galantamine analogue B11: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-trifluoromethoxybenzylamine (0.23 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 167 mg of an oily liquid, which was Galantamine analogue B11, with a yield of 36%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.77 (t, J = 6.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 10.4 Hz, 1H), 5.79 (dd, J = 10.4, 4.7 Hz, 1H), 5.10 (t, J = 5.5 Hz, 1H), 4.45 (t, J = 3.3 Hz, 1H), 4.19 (d, J = 6.2 Hz, 2H), 4.09 (d, J = 15.0 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 15.1 Hz, 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-d6) δ 156.83, 147.59, 146.61, 143.66, 139.96, 132.82, 130.61, 129.99, 129.33, 123.59, 121.37, 112.02, 85.95, 63.54, 59.85, 55.98, 53.43, 47.81, 43.52, 33.77, 28.11.

[0091] (13) Synthesis of Galantamine analogue B12: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-nitrobenzylamine (0.14 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 298 mg of an oily liquid, which was Galantamine analogue B12, with a yield of 70%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 8.19 (d, J = 8.6 Hz, 2H), 7.89 (t, J = 6.2 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.80 (dd, J = 10.4, 4.7 Hz, 1H), 5.11 (t, J = 5.5 Hz, 1H), 4.45 (d, J = 3.3 Hz, 1H), 4.30 (d, J = 6.2 Hz, 2H), 4.09 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 15.2 Hz, 1H), 3.20 (t, J = 13.4 Hz, 1H), 2.91 (d, J = 14.3 Hz, 1H), 2.46 - 2.39 (m, 1H), 2.24 (s, 3H), 2.20 (ddd, J = 16.8, 6.4, 3.6 Hz, 1H), 2.00 (ddd, J = 16.5, 11.2, 2.9 Hz, 1H), 1.54 - 1.46 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 156.89, 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.

[0092] (14) Synthesis of Galantamine analogue B13: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2-(aminomethyl)naphthalene (0.14 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 320 mg of an oily liquid, which was Galantamine analogue B13, with a yield of 74%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.87 (t, J = 7.6 Hz, 3H), 7.81 (t, J = 6.2 Hz, 1H), 7.74 (s, 1H), 7.51 - 7.41 (m, 3H), 6.70 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.25 (d, J = 10.4 Hz, 1H), 5.80 (dd, J = 10.4, 4.6 Hz, 1H), 5.13 (t, J = 5.3 Hz, 1H), 4.45 (d, J = 3.3 Hz, 1H), 4.34 (d, J = 6.2 Hz, 2H), 4.09 (d, J = 15.2 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 14.9 Hz, 1H), 3.20 (t, J = 13.5 Hz, 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, 3.0 Hz, 1H), 1.53 - 1.48 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 156.90, 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.

[0093] (15) Synthesis of Galantamine analogue B14: Intermediate 2-1 (0.5 g, 1.1 mmol) and 2,4-difluorobenzylamine (0.13 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 167 mg of an oily liquid, which was Galantamine analogue B14, with a yield of 40%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.73 (t, J = 6.0 Hz, 1H), 7.37 (td, J = 8.6, 6.6 Hz, 1H), 7.18 (td, J = 9.9, 2.6 Hz, 1H), 7.05 (td, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 10.3 Hz, 1H), 5.78 (dd, J = 10.4, 4.7 Hz, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.44 (s, 1H), 4.17 (d, J = 6.0 Hz, 2H), 4.09 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.57 (d, J = 15.1 Hz, 1H), 3.20 (t, J = 13.5 Hz, 1H), 2.91 (d, J = 14.2 Hz, 1H), 2.41 (dd, J = 16.2, 2.8 Hz, 1H), 2.25 (s, 3H), 2.21 (d, J = 3.0 Hz, 1H), 2.00 (tt, J = 11.9, 3.4 Hz, 1H), 1.53 - 1.48 (m, 1H); 13 C NMR (151 MHz, DMSO) δ 162.63, 161.01, 156.72, 146.60, 143.67, 132.81, 131.03, 123.56, 121.50, 112.02, 104.02, 85.92, 63.60, 59.84, 55.99, 53.43, 47.80, 37.52, 33.74, 28.10.

[0094] (16) Synthesis of Galantamine analogue B15: Intermediate 2-1 (0.5 g, 1.1 mmol) and 4-methylbenzylamine (0.11 g, 0.92 mmol) were dissolved in dry DCM, basic catalyst 4-dimethylaminopyridine (0.017 g, 0.14 mmol) was added, after 5 h of reaction at room temperature, the solvent was removed and column chromatography was used to isolate 170 mg of an oily liquid, which was Galantamine analogue B15, with a yield of 43%. NMR data as follows: 1H NMR (600 MHz, DMSO-d6) δ 7.66 (t, J = 6.2 Hz, 1H), 7.15 - 7.09 (m, 4H), 6.69 (d, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.23 (d, J = 10.3 Hz, 1H), 5.78 (dd, J = 10.3, 4.7 Hz, 1H), 5.11 - 5.08 (m, 1H), 4.43 (s, 1H), 4.11 (d, J = 6.2 Hz, 2H), 4.08 (d, J = 15.1 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.1 Hz, 1H), 3.19 (t, J = 13.4 Hz, 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, 3.4 Hz, 1H), 1.99 (td, J = 13.4, 3.0 Hz, 1H), 1.49 (dd, J = 13.8, 3.2 Hz, 1H); 13 C NMR (151 MHz, DMSO) δ 156.79, 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.

[0095] The structure of the above step is as follows:

[0096] The preparation of a galanthamine analogue compound of formula (IC) and the preparation of intermediates thereof in this embodiment are as follows:

[0097] (1) Synthesis of intermediate 3-1: Galanthamine (0.5 g, 1.7 mmol) was stirred in anhydrous DCM for 20-40 min, 5-bromo-2-chloromethylpyridine (0.36 g, 1.7 mmol) and basic 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. After removing the solvent, column chromatography was performed to separate and obtain 0.69 g of white solid, i.e. intermediate 3-1, with a yield of 89%.

[0098] (2) Synthesis of Galantamine analogue Cl: 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 165 mg of an oily liquid, which was Galantamine analogue Cl, with a yield of 34%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 7.9, 2.3 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.34 - 7.29 (m, 4H), 7.24 - 7.20 (m, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 5.93 - 5.89 (m, 1H), 5.15 (s, 1H), 4.89 (t, J = 15.0 Hz, 2H), 4.67 - 4.61 (m, 2H), 4.53 (s, 1H), 4.09 (t, J = 4.1 Hz, 1H), 4.06 (s, 2H), 3.77 (s, 3H), 3.63 (d, J = 13.3 Hz, 1H), 2.81 (s, 3H), 2.27 (s, 1H), 2.20 (t, J = 16.3 Hz, 1H), 2.06 (ddd, J = 15.3, 5.5, 4.0 Hz, 1H), 1.87 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 150.70, 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.

[0099] (3) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 223 mg of an oily liquid, which was Galantamine analogue C2, with a yield of 46%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.67 (d, J = 2.3 Hz, 1H), 7.79 (dd, J = 8.0, 2.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.40 (td, J = 7.7, 1.8 Hz, 1H), 7.32 (tdd, J = 7.5, 5.3, 1.8 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.88 (d, J = 8.2 Hz, 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 = 3.9 Hz, 3H), 3.63 (d, J = 18.8 Hz, 1H), 2.80 (s, 3H), 2.25 - 2.15 (m, 1H), 2.07 (td, J = 11.2, 5.9 Hz, 1H), 2.03 - 1.96 (m, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 163.58, 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.

[0100] (4) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 184 mg of an oily liquid, which was Galantamine analogue C3, with a yield of 38%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.70 (d, J = 2.3 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.36 (td, J = 8.0, 6.3 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.05 (td, J = 9.1, 2.7 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 5.91 (dd, J = 9.8, 4.5 Hz, 1H), 5.15 (d, J = 13.4 Hz, 1H), 4.89 (t, J = 15.5 Hz, 2H), 4.64 (t, J = 3.5 Hz, 2H), 4.54 - 4.51 (m, 1H), 4.10 (s, 1H), 4.08 (s, 2H), 3.77 (s, 3H), 3.64 (d, J = 11.2 Hz, 1H), 2.81 (s, 3H), 2.27 (d, J = 9.4 Hz, 1H), 2.22 (d, J = 15.7 Hz, 1H), 2.06 (ddd, J = 15.3, 5.5, 4.0 Hz, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 163.57, 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.

[0101] (5) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 187 mg of an oily liquid, which was Galantamine analogue C4, with a yield of 38%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 7.9, 2.3 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.19 - 7.12 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 5.91 (d, J = 10.2 Hz, 1H), 5.13 (s, 1H), 4.92 - 4.83 (m, 2H), 4.65 (q, J = 4.2 Hz, 2H), 4.53 (s, 1H), 4.10 (td, J = 5.3, 2.8 Hz, 1H), 4.06 (s, 2H), 3.77 (s, 3H), 3.64 (d, J = 15.0 Hz, 1H), 2.80 (s, 3H), 2.28 (s, 1H), 2.22 (d, J = 15.7 Hz, 1H), 2.06 (ddd, J = 15.3, 5.6, 4.1 Hz, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 162.21, 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, 128.71, 125.38, 124.32, 115.91, 115.77, 112.63, 86.96, 71.46, 65.88, 60.65, 59.99, 56.12, 55.40, 49.06, 46.44, 43.61, 37.26, 32.41, 31.75.

[0102] (6) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 67 mg of an oily liquid, which was Galantamine analogue C5, with a yield of 13%. NMR data are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 7.9, 2.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.17 (s, 1H), 5.92 (s, 1H), 5.12 (s, 1H), 4.85 (t, J = 12.8 Hz, 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 = 20.4 Hz, 1H), 2.80 (s, 3H), 2.22 (d, J = 15.6 Hz, 1H), 2.11 - 2.03 (m, 1H), 2.03 - 1.95 (m, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 150.70, 147.40, 139.49, 138.21, 138.03, 131.59, 131.17, 129.06, 128.72, 124.31, 112.64, 86.96, 70.25, 63.25, 59.99, 56.09, 46.44, 43.62, 37.39, 31.74.

[0103] (7) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 106 mg of an oily liquid, which was Galantamine analogue C6, with a yield of 21%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.71 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 7.9, 2.3 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 1.9 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.29 (dd, J = 7.8, 1.9 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.19 (s, 1H), 5.91 (dd, J = 10.5, 4.8 Hz, 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 = 9.5 Hz, 1H), 2.25 - 2.17 (m, 1H), 2.06 (ddd, J = 15.3, 5.6, 4.1 Hz, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 150.71, 147.52, 146.92, 145.91, 143.03, 138.07, 133.68, 131.00, 129.09, 128.76, 128.04, 126.91, 124.32, 112.64, 86.97, 71.39, 65.86, 59.99, 56.10, 55.41, 46.45, 43.64, 37.63, 32.43.

[0104] (8) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 267 mg of an oily liquid, which was Galantamine analogue C7, with a yield of 55%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 7.9, 2.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.76 (s, 1H), 6.18 (s, 1H), 5.94 - 5.91 (m, 1H), 5.13 (d, J = 9.9 Hz, 1H), 4.87 (t, J = 16.2 Hz, 2H), 4.64 (t, J = 3.9 Hz, 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, 4.0 Hz, 1H), 2.01 (s, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 150.65, 147.19, 145.91, 138.85, 137.93, 137.33, 135.89, 129.69, 129.16, 128.66, 125.38, 124.31, 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.

[0105] (9) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 222 mg of an oily liquid, which was Galantamine analogue C8, with a yield of 45%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 7.9, 2.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.24 - 7.19 (m, 2H), 6.88 (dd, J = 9.0, 2.6 Hz, 3H), 6.76 (s, 1H), 6.18 (s, 1H), 5.92 (d, J = 10.0 Hz, 1H), 5.14 (s, 1H), 4.88 (q, J = 12.7 Hz, 2H), 4.64 (t, J = 3.8 Hz, 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 = 15.8 Hz, 1H), 2.12 - 1.95 (m, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 158.32, 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.

[0106] (10) Synthesis of Galantamine analogue 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, heated at 75-95 °C for 3 h, the solvent was removed, and column chromatography was used to isolate 216 mg of an oily liquid, which was Galantamine analogue C9, with a yield of 43%. NMR data as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 7.9, 2.3 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.9 Hz, 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 = 23.1 Hz, 1H), 4.89 (q, J = 12.3 Hz, 2H), 4.64 (t, J = 3.8 Hz, 2H), 4.53 (s, 1H), 4.09 (q, J = 4.4 Hz, 1H), 4.02 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.63 (q, J = 9.8, 8.5 Hz, 1H), 2.80 (s, 3H), 2.27 (s, 1H), 2.20 (t, J = 16.3 Hz, 1H), 2.09 - 2.04 (m, 1H), 1.87 (s, 1H); 13 C NMR (151 MHz, DMSO) δ 159.95, 150.68, 147.28, 146.92, 145.92, 141.92, 138.51, 137.99, 130.20, 128.67, 125.38, 124.30, 121.46, 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.

[0107] (11) Synthesis of galantamine 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), K2CO3(0.28 g, 2.0 mmol), CsF (0.08 g, 0.5 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.11 g, 0.15 mmol) under N2protection, and heated at 75-95 °C for 3 h. The solvent was removed, and column chromatography was performed to isolate 98 mg of an oily liquid, which was galantamine analog C10, with a yield of 20%. The nuclear magnetic resonance data are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 8.68 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 7.9, 2.3 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.94 - 6.84 (m, 3H), 6.79 (dd, J = 8.2, 2.6 Hz, 1H), 6.76 (s, 1H), 6.17 (s, 1H), 5.91 (d, J = 10.2 Hz, 1H), 5.14 (d, J = 14.3 Hz, 1H), 4.87 (t, J = 14.8 Hz, 2H), 4.64 (s, 2H), 4.52 (s, 1H), 4.09 (q, J = 4.4, 3.9 Hz, 1H), 4.02 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.63 (q, J = 10.5, 8.9 Hz, 1H), 2.80 (s, 3H), 2.27 (s, 1H), 2.22 (d, J = 15.6 Hz, 1H), 2.06 (ddd, J = 15.3, 5.5, 3.9 Hz, 1H), 1.88 (s, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 159.95, 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.

[0108] The structural formula in the above step is as follows:

[0109] Example 2

[0110] Cholinesterase inhibition experiment of galantamine analogs A1-A12, B1-B15, C1-C10:

[0111] Experimental materials and instruments: Human serum acetylcholinesterase, human serum butyrylcholinesterase, acetylcholinesterase activity assay kit, DTNB, BTCI, Tris HCl were purchased from Sigma Aldrich company, positive compounds galantamine, donepezil, rivastigmine were purchased from MedChemExpress company, multifunctional enzyme label instrument was purchased from Thermo Fisher company of the United States, enzyme label plate constant temperature oscillator was purchased from Haimen Qislinbel Instrument Manufacturing Co., Ltd.

[0112] Experimental method (acetylcholinesterase): The test compound (A1-A12, B1-B15, C1-C10) and positive control drug (galantamine, rivastigmine, donepezil) were dissolved in DMSO, and diluted with buffer solution from the assay kit, the final concentration was 10 μM, and the primary screening was carried out. Compound solution (50 μL) and AChE solution (2.005 U / mL, 50 μL) were combined, and incubated at 37°C for 10 min in the dark. Then, working reagent (100 μL) was added, and the absorbance value at 405 nm was recorded using a multifunctional enzyme label instrument, and then data processing was carried out.

[0113] 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 for 10 min in the dark. Then, BTCI solution (15 mM, 30 μL) was added, and the absorbance value at 405 nm was recorded using a multifunctional enzyme label instrument, and then data processing was carried out.

[0114] Wherein OD represents the absorbance OD value.

[0115] In this experiment, the final DMSO does not exceed 1%, which will cause enzyme inactivation at this concentration. After three repeated experiments of 10 μM compound, the enzyme inhibition rate reaches more than 50%, and then IC 50 re-determination is carried out. According to the primary screening results, five to seven compound concentrations are selected to determine the inhibition rate, and the negative logarithm of the molar concentration of the compound is linearly regressed with the enzyme activity, and the molar concentration at 50% inhibition is obtained, which is the IC 50 value of the compound (using data processing software GraphPad Prism). The specific results are shown in Table 1 and Table 2.

[0116] Table 1

[0117] Table 2

[0118] As shown in Table 1 and Table 2, the comprehensive performance of the galanthamine analog provided by the application is superior to that of the known galanthamine, and the galanthamine analog is expected to be developed as a new drug for treating cholinergic functional disorder.

[0119] Obviously, various modifications and changes can be made to the present application by those skilled in the art without departing from the spirit and scope of the present application. Thus, it is intended that the present application cover the modifications and changes as long as they come within the scope of the claims of the present application and their equivalents.

Claims

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

2. The galantamine analogue of claim 1, wherein, The structure of the galantamine analog is shown below: In the formula (IA), R1 is selected from one of hydrogen, ortho-fluorine, meta-fluorine, para-fluorine, 2,4-difluorine, meta-trifluoromethyl, para-methyl, 3,5-dimethoxy, para-chlorine, para-nitro, para-cyano, para-trifluoromethoxy; R2 is selected from one of phenyl, ortho-fluorophenyl, meta-fluorophenyl, para-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, ortho-methylphenyl, para-methylphenyl, para-methoxyphenyl, indole, para-cyanophenyl, para-trifluoromethylphenyl, para-trifluoromethoxyphenyl, para-nitrophenyl, naphthalene ring; R3 is selected from one of hydrogen, ortho-fluorine, meta-fluorine, para-fluorine, meta-chlorine, para-chlorine, para-methyl, ortho-methoxy, meta-methoxy, para-methoxy.

3. The galantamine analogue of claim 1, wherein The structure of the galantamine analog is shown below:

4. A process for preparing a galantamine analogue according to claim 1, characterized by, The galantamine analogue is a compound shown in the formula (IA), and the preparation method comprises the following steps: (1) 4-t-butoxycarbonylaminopiperidine is dissolved in an organic solvent, and benzyl bromide (II a ) containing an R substituent is slowly added, and an intermediate 1 of structural formula (III a ) is obtained by reaction at room temperature in the presence of a basic catalyst triethylamine, wherein the R group is selected from one of hydrogen, ortho-fluoro, meta-fluoro, para-fluoro, 2,4-difluoro, meta-trifluoromethyl, para-methyl, 3,5-dimethoxy, para-chloro, para-nitro, para-cyano, para-trifluoromethoxy; (2) The intermediate 1 is dissolved in anhydrous DCM, trifluoroacetic acid is added, and the reaction is carried out by stirring at room temperature to obtain the intermediate 2 with the structural formula of formula (IV) a ). (3) Galanthamine and di(p-nitrophenyl) carbonate were dissolved in anhydrous DCM, and triethylamine was added dropwise slowly after stirring for 10-15 min. The reaction was carried out at room temperature to obtain intermediate 3 with the structural formula of formula (V) a ). (4) dissolving the intermediate 2 in step (2) and the intermediate 3 in step (3) in anhydrous DCM, reacting at room temperature under the action of a basic catalyst DMAP to obtain a galantamine analogue compound shown in the formula (IA); The structure formula in the above step is as follows:

5. A method of preparing a galantamine analogue according to claim 1, characterized by, The galantamine analogue is a compound shown in the formula (IB), and the preparation method comprises the following steps: (1) Galanthamine and di(p-nitrophenyl)carbonate were dissolved in anhydrous DCM, and triethylamine was added dropwise slowly after stirring for 10-15 min. The reaction was carried out at room temperature to obtain intermediate 1 with the structural formula of formula (II) b ). (2) Intermediate 1 and primary amine (III) containing R-substituted groups b Dissolved in anhydrous DCM, the compound was reacted at room temperature with the alkaline catalyst DMAP to give the galantamine analog of 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 naphthyl ring; The structure formula in the above step is as follows:

6. A method of preparing a galantamine analogue according to claim 1, characterized by, The galantamine analogue is a compound shown in the formula (IC), and the preparation method comprises the following steps: (1) Dissolve galanthamine in anhydrous DCM, slowly add 5-bromo-2- chloromethylenepicolin under the condition of ice-bath after stirring for 20-40 min, and react to obtain intermediate 1 with the structure of formula (II) under the action of basic catalyst. c ) (2) Intermediate 1 and benzylboronic acid pinacol ester (III) containing R-substituted groups c Dissolved in an organic solvent, under nitrogen protection and with the aid of a catalyst, the mixture is heated to 75–95 °C to carry out a coupling reaction to obtain a galantamine analog (IC), wherein the R group is selected from one of hydrogen, o-fluorine, m-fluorine, p-fluorine, m-chloro, p-chloro, p-methyl, o-methoxy, m-methoxy, and p-methoxy. The structure formula in the above step is as follows:

7. The production method according to claim 4, wherein The organic solvent in step (1) is anhydrous ethanol.

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

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

10. Use of the galantamine analogue according to any one of claims 1 to 3 in the preparation of a drug for treating a disease related to cholinergic functional disorder.

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