A galanthamine intermediate compound

Abstract

The present application belongs to the field of medicine and chemical industry, and particularly relates to a galanthamine intermediate compound. The present application obtains a new intermediate compound III through a bromination reaction with compound II as a raw material; the present application simultaneously provides a new method for synthesizing galanthamine by using the intermediate, and the new intermediate compound III is ring-closed to obtain compound IV under the action of an oxidizing agent, and then is subjected to debromination, methylation and reduction to obtain galanthamine. Compared with the prior art, the method solves the problem of poor regioselectivity in the subsequent oxidation and ring-closing step, and in the next step of the oxidation and ring-closing reaction, there is no main impurity, so that the reaction yield is higher, the post-treatment process is simplified, the cost is reduced, and the method is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and particularly relates to a galanthamine intermediate compound. BACKGROUND

[0002] Galanthamine, chemical name 11-methyl-3-methoxy-4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro[3a, 3, 2ef][2]azepin-6-ol, molecular formula: C 17 H 21 NO3; molecular weight: 323.81; CAS registration number: 357-70-0, structural formula as follows:

[0003]

[0004] Pharmacological studies have proved that galanthamine is a strong acetylcholinesterase (AChE) inhibitor, and also has good regulation effect on neuronal nicotinic receptors, and is widely used in the treatment of Alzheimer's disease (AD) and myasthenia gravis and other diseases. At present, the drug has been marketed in many countries and regions such as the United Kingdom, Ireland, the United States, China and so on.

[0005] Natural galanthamine is mainly derived from plants of Amaryllidaceae such as Lycoris radiata, Zephyranthes candida, Snowflake and the like, and its content is only about one ten-thousandth. Due to limited resources and complex extraction process, many researchers have devoted themselves to the total synthesis of galanthamine. From the chemical structure of galanthamine, it is analyzed that the difficulty of synthesis of galanthamine mainly lies in that it contains a similar dibenzofuran tricyclic skeleton and a seven-membered nitrogen heterocyclic ring, and there are three chiral centers of 4a, 6, 8a. In 1962, Barton et al. first reported the synthesis route of galanthamine in J Chem Soc, 1962: 806-817. The route takes p-hydroxybenzaldehyde as a starting material, and the product is obtained through 10-step chemical reactions. The yield of the key intermediate 4 is only 1.4%, and the total yield is only 0.032%:

[0006]

[0007] In order to further improve the yield of the cyclization, based on the work of Barton et al., Kametani reported (J Chem Soc D, 1969, 8(8): 425-426) that the yield of the cyclization is improved to 40% by taking bromo-diphenol compound 7 as a key intermediate and taking potassium ferricyanide as an oxidizing agent:

[0008]

[0009] Although the presence of bromine atom can effectively prevent the side reaction of phenol para condensation, this reaction route is long, the operation is complex, the product purity and yield are not high, and it is not suitable for industrial production.

[0010] In the previous route, there is a problem of regioselectivity in the oxidative ring closure step, the yield is low due to the generation of by-products, and the purification is difficult, which is not conducive to mass production. SUMMARY

[0011] In order to solve the problems of poor regioselectivity, low yield and difficult purification in the oxidative ring closure step in the preparation method of galanthamine, the present application provides a galanthamine intermediate III, and provides a preparation method of the compound; and a new method for synthesizing galanthamine by using the compound, the method has the advantages of short reaction route, simple operation, mild reaction, economy, environmental protection and high yield, and is suitable for industrial production.

[0012] The present application is realized by the following technical solutions:

[0013] The first aspect of the present application provides a galanthamine intermediate compound, which has the structure shown in formula III:

[0014]

[0015] The second aspect of the present application provides a preparation method of the galanthamine intermediate compound III, which specifically comprises the following steps: adding compound II into an organic solvent A, slowly adding a bromination reagent under cooling, stirring until the bromination reaction is completed, then adding a base and methanol, and stirring overnight to obtain the intermediate compound III, and the synthesis route is as follows:

[0016]

[0017] Preferably, the bromination reagent is selected from one of liquid bromine, N-bromosuccinimide, pyridine tribromide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, and 1,3,5-tribromo-1,3,5-thiazane-2,4,6-trione, and N-bromosuccinimide is particularly preferred.

[0018] Preferably, the molar ratio of the compound II, the bromination reagent and the base is 1.0:1.0-1.5:0.1-0.2, and 1.0:1.05:0.15 is particularly preferred.

[0019] Preferably, the temperature for adding the bromination reagent is 0-20℃, and the temperature is particularly preferably 0-5℃.

[0020] Preferably, the organic solvent A is selected from one of dichloromethane, trichloromethane, methyl chloroform, 1,2-dichloroethane, and particularly preferably dichloromethane.

[0021] Preferably, the added base is selected from one of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, and particularly preferably sodium hydroxide.

[0022] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required, and the operation is as follows: the reaction is raised to room temperature, saturated aqueous sodium bicarbonate solution is added, the organic phase is collected, the organic phase is dried with anhydrous sodium sulfate, the filtrate is collected after filtration, and the intermediate compound III is obtained after concentration under reduced pressure.

[0023] The third aspect of the present application provides a use of the compound III for preparing galanthamine.

[0024] The use of the compound III for preparing galanthamine includes the following steps: ring closure of the compound III under the action of an oxidizing agent to obtain the compound IV, and then debromination, methylation and reduction to obtain galanthamine, and the synthesis route is as follows:

[0025]

[0026] Preferably, the above steps are further described in detail in the following parts:

[0027] Preparation of the compound IV:

[0028] The preparation method of the compound IV includes the following steps: the compound III is added to the organic solvent B, stirring to dissolve the solid, adding an oxidizing agent at low temperature, and continuing to stir under temperature control until the reaction is completed to obtain the intermediate compound IV.

[0029] Preferably, the oxidizing agent is selected from one of di(trifluoroacetic acid)iodobenzene, hydroxyl toluenesulfonyl iodobenzene, iodobenzene diacetic acid, and 2-iodoxybenzoic acid, and particularly preferably di(trifluoroacetic acid)iodobenzene.

[0030] Preferably, the temperature for adding the oxidizing agent is -10℃ to 20℃, and particularly preferably 0℃ to 5℃.

[0031] Preferably, the organic solvent B is selected from one of dichloromethane, trichloromethane, acetonitrile, ethyl acetate, and toluene, and particularly preferably dichloromethane.

[0032] Preferably, the molar ratio of the compound III to the oxidizing agent is 1:1.0 to 2.0, and particularly preferably 1:1.2.

[0033] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required. The operation is as follows: the reaction solution is raised to room temperature, saturated sodium bicarbonate aqueous solution is added to the reaction solution, the obtained mixture is extracted with an organic solvent, the extract is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product, which is recrystallized with ethanol to obtain the intermediate compound IV; the organic extraction solvent is one of dichloromethane, trichloromethane, and ethyl acetate.

[0034] Preparation of compound V

[0035] The preparation method of compound V includes the following steps: compound IV, Lewis acid, and zinc powder are dissolved in organic solvent C, heated to reflux, cooled after the reaction is completed, and the intermediate compound V is obtained.

[0036] Preferably, the Lewis acid can be selected from one of zinc chloride, calcium chloride, and magnesium chloride, and zinc chloride is particularly preferred.

[0037] Preferably, the molar ratio of compound IV, Lewis acid, and zinc powder is 1.0:1.0-2.0:1.5-10.0, and 1:1.5:5.0 is particularly preferred.

[0038] Preferably, the organic solvent C is selected from an aqueous solution of methanol, ethanol, and isopropanol, and the volume fraction of the alcohol is preferably 30%-70%, and an aqueous solution of 50% ethanol is particularly preferred.

[0039] In a preferred embodiment, after the reaction is completed, a post-treatment operation is required. The operation is as follows: the reaction solution is filtered to remove unreacted zinc powder, the filtrate is extracted with an organic solvent, the organic layer is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the intermediate compound V, and the organic extraction solvent is one or a combination of dichloromethane, trichloromethane, and ethyl acetate.

[0040] Preparation of compound I:

[0041] The preparation method of compound I includes the following steps: compound V is added to dehydrated tetrahydrofuran, stirred to dissolve the solid, sodium hydroxide and iodomethane are added at 0°C, then gradually raised to room temperature and stirred to react, after the reaction is detected to be completed, lithium tri-sec-butylborohydride is added to the reaction solution to continue the reaction until the reaction is completed to obtain galanthamine.

[0042] Preferably, the molar ratio of the reaction compound V, iodomethane, and base is 1:1.2:1.2.

[0043] In a preferred embodiment, the molar ratio of the reaction compound V and lithium tri-sec-butylborohydride is 1:2.0.

[0044] In a preferred embodiment, after the reaction is completed, a post-treatment operation is needed: water and ethyl acetate are added to the reaction solution, the organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated, and vacuum dried to obtain the galanthamine.

[0045] Compared with the prior art, the present application has the following technical effects:

[0046] 1. A new intermediate compound III of galanthamine is provided, which solves the problem of poor regioselectivity in the oxidation cyclization step.

[0047] 2. The new intermediate compound obtained has no major impurities in the next step of oxidation cyclization, so that the reaction yield is higher and the post-treatment is simpler.

[0048] In summary, the present application provides an improved synthesis method of a galanthamine intermediate, which solves the problem of poor regioselectivity by introducing a bromine atom, avoids the problem of column chromatography separation in post-treatment, reduces the cost, and is more suitable for industrial production. DETAILED DESCRIPTION

[0049] The present application will be further described by the following examples. It should be correctly understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so that simple improvements of the present application under the method of the present application are within the scope of the present application.

[0050] The structure of the compound obtained by the present application is confirmed as follows:

[0051]

[0052] High resolution mass spectrum of compound II: ESI-HRMS: m / z = 328.1158 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6): δ 7.28-7.16 (m, 4H), 6.98 (s, 1H), 6.80-6.86 (m, 2H), 5.98 (s, 2H), 3.66 (s, 2H), 2.65-2.68 (m, 4H), 2.33 (s, 3H), 2.25 (s, 3H); 13 C-NMR (100MHz, DMSO-d6): δ 170.1, 148.5, 147.3, 145.8, 138.9, 133.2, 129.6, 121.6, 121.5, 111.0, 107.6, 101.3, 65.6, 62.3, 44.5, 33.0, 20.5.

[0053]

[0054] High resolution mass spectrum of compound III: ESI-HRMS: m / z = 364.0517 [M+H] + ; NMR data: 1 H-NMR (400 MHz, CDC13): δ 9.05 (br, 1H), 7.34 (s, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.80 (s, 1H), 6.67 (d, J = 8.5 Hz, 2H), 6.17 (s, 2H), 3.56 (s, 2H), 2.72-2.64 (m, 4H), 2.26 (s, 3H); 13 C-NMR (100 MHz, CDC13) δ 155.8, 147.3, 146.8, 135.0, 133.1, 130.2, 129.5, 119.5, 117.1, 116.2, 115.8, 62.4, 61.7, 44.0, 33.5.

[0055]

[0056] High resolution mass spectrum of compound IV: ESI-HRMS: m / z = 350.0423 [M+H] + ; NMR data: 1 H-NMR (400 MHz, CDC13): δ 10.05 (br, 1H), 7.18-7.16 (m, 2H), 6.07 (d, J = 8.5 Hz, 2H), 4.25 (t, J = 7.9 Hz, 1H), 3.62 (dd, J = 8.0, 24.1 Hz, 2H), 3.42-3.11 (m, 2H), 3.39-3.28 (m, 2H), 2.17 (s, 3H), 1.72-1.55 (m, 2H); 13 C-NMR (100 MHz, CDC13) δ 198.7, 155.5, 146.8, 146.4, 135.7, 133.1, 127.8, 116.9, 116.8, 77.5, 61.5, 56.6, 47.5, 44.5, 40.3, 33.7.

[0057] Preparation of compound II

[0058] Into a three-necked flask was placed compound II (28.5 g, 0.10 mol), 100 mL of dichloromethane. The solution was stirred and cooled to 0-5 °C, and then N-bromosuccinimide (18.7 g, 0.105 mol) was added in portions. The mixture was stirred for 2 hours. Sodium hydroxide (0.6 g, 0.015 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. The reaction mixture was allowed to warm to room temperature slowly, and then 100 mL of saturated aqueous sodium bicarbonate solution was added. The aqueous phase was removed, and the organic phase was washed once with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate compound III as a white solid powder in 91.8% yield and 99.86% purity by HPLC.

[0059] Preparation of compound III

[0060] Example 1

[0061] Into a three-necked flask was placed compound II (28.5 g, 0.10 mol), 100 mL of dichloromethane. The solution was stirred and cooled to 0-5 °C, and then N-bromosuccinimide (18.7 g, 0.105 mol) was added in portions. The mixture was stirred for 2 hours. Sodium hydroxide (0.6 g, 0.015 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. The reaction mixture was allowed to warm to room temperature slowly, and then 100 mL of saturated aqueous sodium bicarbonate solution was added. The aqueous phase was removed, and the organic phase was washed once with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate compound III as a white solid powder in 91.8% yield and 99.86% purity by HPLC.

[0062] Example 2

[0063] Into a three-necked flask was placed compound II (28.5 g, 0.10 mol), 100 mL of dichloromethane. The solution was stirred and cooled to 0-5 °C, and then N-bromosuccinimide (18.7 g, 0.105 mol) was added in portions. The mixture was stirred for 2 hours. Sodium hydroxide (0.6 g, 0.015 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. The reaction mixture was allowed to warm to room temperature slowly, and then 100 mL of saturated aqueous sodium bicarbonate solution was added. The aqueous phase was removed, and the organic phase was washed once with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate compound III as a white solid powder in 91.8% yield and 99.86% purity by HPLC.

[0064] Example 3

[0065] Into a three-necked flask was added compound II (28.50 g, 0.10 mol), 100 mL of methylene chloride. After stirring and dissolving, the temperature was lowered to 10-15 °C, and pyridine tribromide (47.97 g, 0.15 mol) was added in portions. The mixture was stirred for 2 hours. Potassium carbonate (2.07 g, 0.015 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. After the reaction was completed, the temperature was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the aqueous phase was removed by liquid separation. The organic phase was washed once with saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate compound III as a white solid powder in a yield of 87.1% and a HPLC purity of 99.48%.

[0066] Example 4

[0067] Into a three-necked flask was added compound II (28.50 g, 0.10 mol), 100 mL of 1,2-dichloroethane. After stirring and dissolving, the temperature was lowered to -5-0 °C, and 1,3,5-tribromo-1,3,5-thiazinan-2,4,6-trione (65.84 g, 1.8 mol) was added in portions. The mixture was stirred for 2 hours. Potassium hydroxide (0.4 g, 0.015 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. After the reaction was completed, the temperature was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the aqueous phase was removed by liquid separation. The organic phase was washed once with saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate compound III as a white solid powder in a yield of 80.9% and a HPLC purity of 99.04%.

[0068] Example 5

[0069] Into a three-necked flask was added compound II (28.5 g, 0.10 mol), 100 mL of chloroform. After stirring and dissolving, the temperature was lowered to 15-20 °C, and N-bromosuccinimide (14.8 g, 0.105 mol) was added in portions. The mixture was stirred for 2 hours. Sodium carbonate (1.06 g, 0.01 mol) and 15 mL of methanol were added, and the mixture was stirred overnight. After the reaction was completed, the temperature was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the aqueous phase was removed by liquid separation. The organic phase was washed once with saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate compound III as a white solid powder in a yield of 81.2% and a HPLC purity of 99.13%.

[0070] Example 6

[0071] Into a three-necked flask was added compound II (28.5 g, 0.10 mol), 100 mL of methylene chloride. The mixture was stirred and dissolved, and then cooled to 0-5°C. 1,3-dibromo-5,5-dimethylhydantoin (30.02 g, 0.105 mol) was added in portions, and the mixture was stirred for 2 hours. Potassium hydroxide (1.12 g, 0.02 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was separated. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate compound III as a white solid powder in a yield of 86.7% and with a HPLC purity of 99.86%.

[0072] Example 7

[0073] Into a three-necked flask was added compound II (28.5 g, 0.10 mol), 100 mL of methylene chloride. The mixture was stirred and dissolved, and then cooled to 0-5°C. 1,3-dibromo-5,5-dimethylhydantoin (30.02 g, 0.105 mol) was added in portions, and the mixture was stirred for 2 hours. Potassium hydroxide (1.12 g, 0.02 mol) and 25 mL of methanol were added, and the mixture was stirred overnight. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was separated. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate compound III as a white solid powder in a yield of 86.7% and with a HPLC purity of 99.86%.

[0074] Preparation of compound IV

[0075] Example 8

[0076] Into a three-necked flask was added compound III (36.42 g, 0.10 mol), 100 mL of methylene chloride. The mixture was stirred and dissolved, and then cooled to 0-5°C. Di(trifluoroacetic acid)iodobenzene (51.60 g, 0.12 mol) was added in portions, and the mixture was stirred until the reaction was completed. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ethanol (100 mL) to obtain intermediate compound IV in a yield of 93.7% and with a HPLC purity of 99.91%.

[0077] Example 9

[0078] Into a three-necked flask was added compound III (36.42 g, 0.10 mol) and 100 mL of acetonitrile. The mixture was stirred and dissolved, and then cooled to 10-15°C. Iodobenzenedicarboxylic acid (64.42 g, 0.20 mol) was added in portions while maintaining the temperature. The stirring was continued until the reaction was completed. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The resulting mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol (100 mL) to obtain intermediate compound IV at a yield of 89.8% and a HPLC purity of 99.52%.

[0079] Example 10

[0080] Into a three-necked flask was added compound III (36.42 g, 0.10 mol) and 100 mL of acetonitrile. The mixture was stirred and dissolved, and then cooled to 10-15°C. Iodobenzenedicarboxylic acid (64.42 g, 0.20 mol) was added in portions while maintaining the temperature. The stirring was continued until the reaction was completed. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The resulting mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol (100 mL) to obtain intermediate compound IV at a yield of 89.8% and a HPLC purity of 99.52%.

[0081] Example 11

[0082] Into a three-necked flask was added compound III (36.42 g, 0.10 mol) and 100 mL of acetonitrile. The mixture was stirred and dissolved, and then cooled to 10-15°C. Iodobenzenedicarboxylic acid (64.42 g, 0.20 mol) was added in portions while maintaining the temperature. The stirring was continued until the reaction was completed. After the reaction was completed, the mixture was slowly returned to room temperature. 100 mL of saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The resulting mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol (100 mL) to obtain intermediate compound IV at a yield of 89.8% and a HPLC purity of 99.52%.

[0083] Preparation of compound V

[0084] Example 12

[0085] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), calcium chloride (11.10 g, 0.1 mol), and activated zinc powder (32.70 g, 0.5 mol) in 50% methanol (200 ml) and stirred uniformly. The reaction was carried out under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature. The unreacted zinc was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate compound V in 93.1% yield and 99.71% purity by HPLC.

[0086] Example 13

[0087] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), calcium chloride (11.10 g, 0.1 mol), and activated zinc powder (32.70 g, 0.5 mol) in 50% methanol (200 ml) and stirred uniformly. The reaction was carried out under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature. The unreacted zinc was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate compound V in 93.1% yield and 99.71% purity by HPLC.

[0088] Example 14

[0089] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), calcium chloride (11.10 g, 0.1 mol), and activated zinc powder (32.70 g, 0.5 mol) in 50% methanol (200 ml) and stirred uniformly. The reaction was carried out under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature. The unreacted zinc was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate compound V in 93.1% yield and 99.71% purity by HPLC.

[0090] Example 15

[0091] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), calcium chloride (11.10 g, 0.1 mol), and activated zinc powder (32.70 g, 0.5 mol) in 50% methanol (200 ml) and stirred uniformly. The reaction was carried out under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature. The unreacted zinc was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the intermediate compound V in 93.1% yield and 99.71% purity by HPLC.

[0092] Example 16

[0093] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), zinc chloride (20.44 g, 0.15 mol), activated zinc dust (9.81 g, 0.15 mol) and 50% isopropanol (200 ml). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature. The unreacted zinc dust was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the intermediate compound V in a yield of 94.4% and a HPLC purity of 99.66%.

[0094] Example 17

[0095] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), zinc chloride (20.44 g, 0.15 mol), activated zinc dust (6.54 g, 0.1 mol) and 50% methanol (200 ml). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature. The unreacted zinc dust was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the intermediate compound V in a yield of 88.9% and a HPLC purity of 99.02%.

[0096] Example 18

[0097] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), zinc chloride (20.44 g, 0.15 mol), activated zinc dust (65.39 g, 1 mol) and 50% ethanol (200 ml). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature. The unreacted zinc dust was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the intermediate compound V in a yield of 95.3% and a HPLC purity of 99.68%.

[0098] Example 19

[0099] A three-necked flask was charged with compound IV (35.12 g, 0.1 mol), zinc chloride (20.44 g, 0.15 mol), activated zinc dust (78.47 g, 1.2 mol) and 30% methanol (200 ml). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled to room temperature. The unreacted zinc dust was removed by filtration. The filtrate was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the intermediate compound V in a yield of 89.7% and a HPLC purity of 99.11%.

[0100] Preparation of galantamine

[0101] Example 20

[0102] Into a three-necked flask was added compound V (27.11 g, 0.1 mol), 100 mL of anhydrous tetrahydrofuran, stirred until dissolved, cooled to 0°C, added solid sodium hydroxide (2.8 g, 0.12 mol), stirred until the reaction was complete, iodomethane (17.03 g, 0.12 mol) was dissolved in 20 mL of anhydrous tetrahydrofuran, added dropwise to the reaction solution, the temperature was maintained at 0°C, stirred for 2.0 hours, gradually warmed to room temperature, TLC detected that the reaction was complete, slowly added lithium tri-sec-butylborohydride (38.02 g, 0.2 mol) at 0°C, maintained at 0°C and continued to react, after the reaction was complete, added purified water (100 mL) and ethyl acetate (100 mL), after vigorous shaking, the water phase was removed, the organic phase was dried with anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a white solid, vacuum dried at 40°C to obtain galanthamine, the yield was 90.6%, the HPLC purity was 99.95%.

[0103] Example 21

[0104] Into a three-necked flask was added compound V (27.11 g, 0.1 mol), 100 mL of anhydrous tetrahydrofuran, stirred until dissolved, cooled to -5°C, added potassium tert-butoxide (13.47 g, 0.12 mol), stirred until the reaction was complete, iodomethane (15.61 g, 0.11 mol) was dissolved in 20 mL of anhydrous tetrahydrofuran, added dropwise to the reaction solution, the temperature was maintained at -5°C, stirred for 2.0 hours, gradually warmed to room temperature, TLC detected that the reaction was complete, slowly added lithium tri-sec-butylborohydride (38.02 g, 0.2 mol) at -5°C, maintained at -5°C and continued to react, after the reaction was complete, added purified water (100 mL) and ethyl acetate (100 mL), after vigorous shaking, the water phase was removed, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a white solid, vacuum dried at 40°C to obtain galanthamine, the yield was 84.5%, the HPLC purity was 99.85%.

Claims

1. A galantamine intermediate compound, characterized by, The structure is shown as formula III: 。 2. A process for the preparation of the galantamine intermediate compound III according to claim 1, characterized by, The preparation method comprises the following steps: compound II is added into an organic solvent A, a brominating reagent is slowly added under cooling, stirring is continued until the reaction is completed, a base and methanol are continuously added, and then the intermediate compound III is obtained after overnight stirring, and the synthetic route is as follows: 。 3. The production method according to claim 2, characterized by, The reaction solvent A is selected from one of dichloromethane, chloroform, methyl chloroform, 1,2-dichloroethane; the brominating reagent is selected from one of liquid bromine, N-bromosuccinimide, pyridine tribromide, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, 1,3,5-tribromo-1,3,5-thiazane-2,4,6-trione; the temperature for adding the brominating reagent is 0-20 DEG C; and the base is selected from one of sodium hydroxide, potassium carbonate, sodium carbonate and potassium hydroxide.

4. The production method according to claim 2, characterized by, The molar ratio of the compound II, the brominating reagent and the base is 1.0:1.0-1.5:0.1-0.

2.

5. Use of a galanthamine intermediate compound according to claim 1 for the preparation of galanthamine, characterized in that, The method comprises the following steps: (1) compound III is added into an organic solvent B, an oxidizing agent is added under low temperature, and the temperature is controlled until the reaction is completed to obtain the intermediate IV; (2) compound IV, a Lewis acid and zinc powder are dissolved in an organic solvent C, heating is carried out until reflux, the temperature is lowered after the reaction is completed to obtain the intermediate compound V; (3) compound V is added into anhydrous tetrahydrofuran, sodium hydroxide and iodomethane are added under 0 DEG C, the temperature is gradually increased to room temperature for stirring reaction, after the reaction is completed, lithium tri-sec-butyl borohydride is added into the reaction solution for continuous reaction until the reaction is completed to obtain the compound galanthamine, and the synthetic route is as follows: 。 6. Use according to claim 5, characterized in that, The oxidizing agent in step (1) is selected from one of di(trifluoroacetic acid)iodobenzene, hydroxytoluene sulfonyl iodobenzene, iodobenzene diacetic acid and 2-iodoxybenzoic acid.

7. Use according to claim 5, characterized in that, The Lewis acid in step (2) is selected from one of zinc chloride, calcium chloride and magnesium chloride; and the molar ratio of compound IV, the Lewis acid and zinc powder is 1.0:1.0-2.0:1.5-10.

0.

8. Use according to claim 5, characterized in that, The organic solvent B in step (1) is selected from one of dichloromethane, chloroform, acetonitrile, ethyl acetate and toluene; and the organic solvent C in step (2) is selected from an aqueous solution of methanol, ethanol and isopropanol, and the volume fraction of the alcohol is 30-70%.

9. Use according to claim 5, characterized in that, The molar ratio of compound V, iodomethane, sodium hydroxide and lithium tri-sec-butyl borohydride in step (3) is 1:1.2:1.2:2.0.

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