WO2023221022A1

WO2023221022A1 - Method for preparing galanthamine, derivative thereof and intermediate thereof

Info

Publication number: WO2023221022A1
Application number: PCT/CN2022/093756
Authority: WO
Inventors: 怀特洛伦佐·瓦伦蒂诺; 班威尔马丁·格哈特; 蓝平; 何玉涛; 胡南
Original assignee: 暨南大学
Priority date: 2022-05-19
Filing date: 2022-05-19
Publication date: 2023-11-23
Also published as: CN117751125A

Abstract

Disclosed in the present invention are intermediate I and intermediate II which have structural formulas as represented by formula (I) and formula (II), respectively, and can be used for preparing galantamine, and a preparation method therefor, and a method for the asymmetric total synthesis of galantamine and a derivative thereof with a short synthetic route and a high yield. According to the present invention, the intermediates required for the preparation of galantamine and the derivative thereof, i.e., the intermediates as represented by formula (I) and formula (II), are synthesized in sequence by means of using the simple, cheap and readily available compound 2, tert-butyl vinylcarbamate and 3-hydroxy-2-iodo-4-methoxybenzaldehyde as starting materials, and performing multiple reactions, such as a Suzuki cross-coupling reaction and a Mitsunobu reaction, and galantamine and the derivative thereof are then prepared by means of using the intermediates. The methods provided in the present invention for preparing galantamine, the derivative thereof and the intermediate thereof have a short synthesis route and a high yield, and large-scale production is easily achieved.

Description

Preparation methods of galantamine, its derivatives and intermediates

Technical field

The invention belongs to the technical field of organic chemistry, and specifically relates to preparation methods of galantamine, its derivatives and intermediates.

Background technique

Galantamine is a biologically active tetracyclic alkaloid isolated from Amaryllidaceae plants such as Amaryllis, narcissus, snowdrops, etc. It is a pharmacologically reversible Cholinesterase inhibitors play an important role in the treatment of Alzheimer's disease, myasthenia gravis, angle-closure glaucoma, sequelae of polio and other diseases.

The traditional method of producing galantamine is to separate and extract it from Lycoris Lycoris. Due to limited resources, the plant has many components, complex structure and low content of galantamine. The extraction and purification process is complicated and the production cost is high, resulting in galantamine. The price of Min has remained high. Many total synthesis routes of galantamine have been published, but most of them synthesize racemic galantamine. There are few synthetic methods for the asymmetric synthesis of galantamine, and most of them have synthetic routes to varying degrees. Problems such as long process, cumbersome steps, and low yield. Some synthesis methods also have problems such as expensive raw materials, resulting in high production costs of galantamine and making it unsuitable for industrialization.

There is still a lack of a preparation method for synthesizing galantamine with fewer synthesis steps and high yield in the prior art.

Contents of the invention

The object of the present invention is to provide a preparation method of galantamine to solve at least one of the above technical problems.

According to a first aspect of the present invention, there is provided intermediate I (i.e., compound 6) for preparing galantamine with a structural formula such as formula (I):

According to the second aspect of this aspect, a method for preparing intermediate I shown in formula (I) is provided, which is characterized in that it includes the following steps:

With tert-butyl vinyl carbamate and compound 2

Synthesis of compound 4 via Suzuki cross-coupling reaction

Compound 4 and 3-hydroxy-2-iodo-4-methoxybenzaldehyde were reacted with Mitsunobu to synthesize intermediate I.

In some embodiments, Compound 2 can be obtained through commercial routes, or can be synthesized through the following synthetic route:

In some embodiments, the synthesis method of compound 4 includes the following steps:

Dissolve tert-butyl vinyl carbamate (i.e. compound 3) in the first solvent, add borane at room temperature (25-35°C) and react until the solution becomes clear and transparent to obtain solution I; wherein, tert-butyl vinyl carbamate is obtained. The molar ratio of butyl ester to borane is 1:1-1:2;

Dissolve compound 2, palladium reagent and triphenylarsenic in the second solvent, and then add alkali solution to obtain solution II; wherein, based on the amount of the substance, the amount of palladium reagent added is 5-25% of compound 2, The addition amount of triphenylarsenic is 9-50% of compound 2;

Add solution I to solution II and react under nitrogen protection for 0.5-1 hour. After separation and purification, compound 4 is obtained.

In some embodiments, the first solvent may be selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

In some embodiments, the borane can be selected from the group consisting of 9-borane bicyclo[3.3.1]nonane dimer, diisopinepinyl chloroborane, diethylmethoxyborane, dimethylborane, At least one catecholborane.

In some embodiments, the palladium reagent serves as a catalyst and can be selected from 1,1-bis(diphenylphosphine)ferrocene-palladium(II) dichloride dichloromethane complex, palladium acetate, tetrakis(triphenyl) At least one of common palladium reagents such as dichlorobis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, etc.

In some embodiments, the second solvent may be selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

In some embodiments, the base can be selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; the concentration of the alkali solution can be 2-5 mol/L, and the added volume is 0.2-5 mol/L of the volume of solution II. 0.5 times.

In some embodiments, the preparation method of compound 6 includes the following steps:

Mix compound 4 with 3-hydroxy-2-iodo-4-methoxybenzaldehyde (i.e. compound 5) and the third solvent at -20°C under nitrogen protection, then add tributylphosphine and azo compounds, and React at -20°C for 0.5-1.5 hours, then raise the temperature to room temperature and continue the reaction for 12-18 hours. After the reaction is completed, compound 6 is obtained by separation and purification;

Alternatively, compound 4 is mixed with 3-hydroxy-2-iodo-4-methoxybenzaldehyde (i.e. compound 5) and a third solvent at -20°C under nitrogen protection, and then triphenylphosphine and an azo compound are added , react at -20°C for 0.5-1.5 hours, then raise the temperature to room temperature and continue the reaction for 12-18 hours. After the reaction is completed, compound 6 is obtained by separation and purification;

Among them, the molar ratio of compound 4 to 3-hydroxy-2-iodo-4-methoxybenzaldehyde is 1:1-1:2.5; based on the amount of substance, the amount of tributylphosphine or triphenylphosphine added It is 1-1.5 times that of 3-hydroxy-2-iodo-4-methoxybenzaldehyde, and the molar ratio of tributylphosphine or triphenylphosphine to azo compound is 1:1.

In some embodiments, the third solvent may be selected from at least one of tetrahydrofuran, benzene, toluene, and acetonitrile.

In some embodiments, the azo compound may be selected from at least one of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.

According to a third aspect of the present invention, there is provided intermediate II (i.e., compound 7) for preparing galantamine having a structure shown in formula (II):

According to the fourth aspect of this aspect, a method for preparing intermediate II shown in formula (II) is provided, including the following steps:

Add intermediate I, catalyst, catalyst ligand, and base to the fourth solvent, and heat and reflux for 2-4 hours under nitrogen protection. After the reaction is completed, the intermediate II is obtained by separation and purification;

Among them, based on the amount of substances, the added amount of the catalyst is 5-15% of the intermediate I, the added amount of the catalyst ligand is 10-25% of the intermediate I; the added amount of the base is 200-200% of the intermediate I. 500%.

In some embodiments, the fourth solvent may be selected from at least one of acetonitrile, benzene, toluene, dimethylformamide, and 1,4-dioxane.

In some embodiments, the catalyst can be selected from palladium reagents; specifically, it can be selected from 1,1-bis(diphenylphosphine)ferrocene-palladium(II) dichloride dichloromethane complex, palladium acetate, tetrakis At least one of common palladium reagents such as (triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride, and palladium trifluoroacetate.

In some embodiments, the catalyst ligand can be selected from organic phosphine ligands; specifically, it can be selected from tris(o-toluene)phosphine, 1,2-bis(phenylphosphine)ethane, 1,1'-bis(diphenyl) At least one of common organic phosphine ligands such as (phosphine)ferrocene, 1,3-bis(diphenylphosphine)propane, 1,1-bis(diphenylphosphine)methane, etc.

In some embodiments, the base may be selected from at least one of triethylamine, cesium carbonate, potassium carbonate, and sodium carbonate.

According to the fifth aspect of the present invention, a preparation method of galantamine is provided, comprising the following steps:

(1) Mix intermediate II, the first part of selenium dioxide, the first part of quartz sand, 1,4-dioxane, and the first part of pyridine, and heat and reflux for 10-15 hours under nitrogen protection; then add The second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine continue to react for 18-30 hours. After the reaction is completed, the intermediate product I is obtained through separation and purification; among which, intermediate II, the first portion of selenium dioxide, The molar ratio of the second part of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of intermediate II, the first part of pyridine, and the second part of pyridine is 1:6:6-1:10:10 ; Adding selenium dioxide, quartz sand and pyridine in batches is conducive to complete reaction, thereby increasing the reaction yield;

(2) Mix the intermediate product I and the fifth solvent, add trifluoroacetic acid and react under nitrogen protection at 25-35°C for 2-4 hours, then add formaldehyde aqueous solution for reaction, then add sodium cyanoborohydride and continue at 25-35°C. React for 12-18 hours at 35°C. After the reaction is completed, galantamine is obtained through separation and purification; wherein, the mass-to-volume ratio of the intermediate product I to the fifth solvent is (2-6) mg/mL; the fifth solvent The volume ratio to trifluoroacetic acid is 10:1; the molar ratio of intermediate product I to formaldehyde is 1:1-1:200; the molar ratio of intermediate product I to sodium cyanoborohydride is 1:5-1:20.

In some embodiments, the fifth solvent may be selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

According to a sixth aspect of the present invention, a preparation method of desmethylgalantamine is provided, comprising the following steps:

Mix the intermediate product I and the sixth solvent, add trifluoroacetic acid and react under nitrogen protection at 25-35°C for 2-4 hours, then add sodium cyanoborohydride and continue the reaction at 25-35°C for 12-18 hours. After separation and purification, desmethylgalantamine is obtained; wherein, the mass volume ratio of the intermediate product I to the sixth solvent is (2-6) mg/mL; the volume ratio of the sixth solvent to trifluoroacetic acid is 10: 1; the molar ratio of intermediate product I to sodium cyanoborohydride is 1:5-1:20;

In some embodiments, the sixth solvent may be selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.

The present invention uses simple, cheap and easily available commercial compounds as starting materials, and provides an asymmetric synthesis method of galantamine and its derivatives with fewer synthesis steps and high yield. The synthesis method of galantamine provided by the invention has low production cost, short synthesis route, and is easy to realize large-scale production.

Description of the drawings

Figure 1 is a synthesis route diagram of galantamine, desmethylgalantamine and their intermediates of the present invention.

Detailed ways

The present invention will be described in further detail below in conjunction with the embodiments. The examples are for explanation only and do not limit the invention in any way. Unless otherwise specified, the raw materials and reagents used in the examples are conventional products that are commercially available; the experimental methods without specifying specific conditions in the examples are conventional methods and conditions well known in the art.

Example 1: Synthesis of Compound 4

Add vinyl carbamate tert-butyl ester (i.e. compound 3, 1917 mg, 13.39 mmol) into the first round-bottomed flask, dissolve it in 20 ml of degassed dry tetrahydrofuran, and add it dropwise to the solution at room temperature all at once. 9-Boron bicyclo[3.3.1]nonane dimer [recrystallized from hot solution of 1,2-dimethoxyethane] (1635 mg, 13.39 mmol), after 0.5 hours of reaction, the solution became clear and transparent .

In a second round bottom flask, compound 2 (2000 mg, 8.93 mmol), 1,1-bis(diphenylphosphine)ferrocene-palladium(II) dichloride dichloromethane complex ( 367 mg, 0.45 mmol), triphenylarsenic (273 mg, 0.89 mmol) were dissolved in 40 ml of degassed dry tetrahydrofuran, and then a degassed sodium hydroxide solution (3 mol per liter, 12 ml).

Add the solution in the first round-bottom flask to the second round-bottom flask at room temperature, and then stir for 0.5 hours under nitrogen protection. Once the thin layer chromatography monitors that compound 2 has been consumed, dilute the light orange reaction mixture with ethyl acetate (20 ml), then add saturated brine (60 ml), and then add aqueous hydrogen peroxide solution (9.8 mol/ml). liter, 1.2 ml). Extract the aqueous solution with ethyl acetate (3×60 ml), combine the extracted organic phases, dry (anhydrous sodium sulfate), concentrate under reduced pressure, and purify by silica gel column chromatography (gradient elution, ethyl acetate:petroleum ether=1 :5-1:3), 1980 mg of colorless oily compound 4 (R _f =0.25, petroleum ether: ethyl acetate =1:3) was obtained, with a yield of 92%.

¹ H-NMR (500MHz, CDCl ₃ ) δ5.55 (dd, J＝4.2, 3.1Hz, 1H), 4.05 (dd, J＝5.2, 3.9Hz, 1H), 3.49–3.39 (m, 1H), 3.10 (ddd,J＝13.7,12.5,6.1Hz,1H),2.84–2.45(broad s,1H),2.30–2.23(m,1H),2.22–2.16(m,1H),2.03–1.97(m,1H ),1.97–1.88(m,1H),1.75–1.70(m,2H),1.68–1.58(m,1H),1.57–1.48(m,1H),1.41(s,9H)[signal due to Boc- NH group proton not observed];

¹³ C-NMR (126MHz, CDCl ₃ ) δ 156.6, 136.0, 127.9, 79.3, 67.5, 39.7, 36.6, 32.6, 28.4, 25.7, 17.9.

IR ν _max 3337,2929,1683,1520,1364,1277,1250,1167,1050,985cm ^-1 .

HRMS(ESI,+ve)[M+Na]calculated for C ₁₃ H ₂₃ NO ₃ Na 264.1576, found 264.1570.

Example 2: Synthesis of Compound 6 (Intermediate I)

Under a nitrogen atmosphere, compound 4 (230 mg, 0.95 mmol) and 3-hydroxy-2-iodo-4-methoxybenzaldehyde (i.e., compound 5, 531 mg, 1.91 mg) were added successively to a -20°C round-bottomed flask. mmol), 5 ml of dry, degassed tetrahydrofuran solution. Then, tributylphosphine (0.91 ml, 1.91 mmol) and tetramethylazodicarbonamide (327 mg, 1.91 mmol) were added to the reaction solution. Finally, the reaction solution was stirred at this temperature for one hour, then the temperature was raised to normal temperature and stirring was continued for 16 hours. After the reaction is completed, add 15 ml of ethyl acetate to dilute, and then filter with silica gel. The resulting solution was concentrated under reduced pressure, then 15 ml of methylene chloride was added, and 15 ml of 3 mol per liter sodium hydroxide solution was added for extraction three times. The organic layers were then combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and further purified by column chromatography to obtain 330 mg of a foamy white compound with a yield of 70%.

¹ H-NMR (500MHz, CDCl ₃ ) δ10.03 (s, 1H), 7.66 (d, J = 8.6Hz, 1H), 6.95 (d, J = 8.6Hz, 1H), 5.77 (t, J = 3.4 Hz,1H),5.01(d,J＝4.3Hz,1H),4.69(s,1H),3.93(s,3H),3.32(q,J＝6.1Hz,2H),2.58(q,J＝6.6 ,6.2Hz,1H),2.35–1.72(m,6H),1.60–1.49(m,1H),1.41(s,9H).

¹³ C-NMR (126MHz, CDCl ₃ ) δ 195.62, 157.08, 155.97, 146.56, 133.98, 129.73, 129.29, 126.38, 111.70, 101.57, 78.80, 55.97, 39.24, 34.69, 28.39, 28. 38,28.20,25.43,18.63.

IR ν _max 3360,3188,2920,2849,1682,1572,1471,1271,1246,1170,1020cm ^-1 .

HRMS(ESI,+ve)[M+Na]calculated for C ₂₁ H ₂₈ INO ₅ 524.0910,found 524.0904.

Example 3: Synthesis of Compound 7 (Intermediate II)

To a dry, degassed 10 ml acetonitrile solution were added compound 6 (540 mg, 1.08 mmol), tris(dibenzylidene)acetone palladium (110 mg, 0.12 mmol), tris(o-toluene)phosphine ( 73 mg, 0.24 mmol), triethylamine (0.33 mL, 4.47 mmol). The reaction solution was heated and refluxed under nitrogen protection for 3 hours. After the reaction is completed, filter the reaction solution through diatomaceous earth, and wash the filter cake three times with ethyl acetate (dichloromethane can be used), 10 ml each time. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 325 mg of a white foam compound with a yield of 81%.

¹ H-NMR (300MHz, CDCl ₃ ) δ9.84 (s, 1H), 7.33 (d, J = 8.4Hz, 1H), 6.86 (d, J = 8.4Hz, 1H), 6.05 (dt, J = 9.8 ,1.3Hz,1H),5.83(ddd,J＝10.1,5.5,2.5Hz,1H),4.91(d,J＝4.2Hz,1H),4.50(s,1H),3.94(s,3H),3.10 (m,1H),2.98–2.84(m,1H),2.41–1.76(m,6H),1.39(s,9H).

¹³ C-NMR (75MHz, CDCl ₃ ) δ190.91,155.68,149.85,148.54,133.04,130.27,129.09,128.08,126.81,110.12,86.24,79.09,56.01,49.21,37.13,36.9 1,28.33,24.42,19.01.

IR ν _max 3359,3184,2920,2849,1687,1607,1570,1505,1409,1435,1365,1248,1284,1169,765,723cm ^-1 .

HRMS(ESI,+ve)[M+Na]calculated for C ₂₁ H ₂₇ NO ₅ Na 396.1787,found 396.1781.

Example 4: Synthesis of Compounds 8&9 (Intermediate Product I)

In a dry, nitrogen-protected round-bottomed flask, compound 7 (60 mg, 0.16 mmol), finely ground selenium dioxide (18 mg, 0.16 mmol), and oven-dried quartz sand (300 mg) were added in sequence. ), and 2 mL of dry 1,4-dioxane solution, dry pyridine (0.1 mL, 1.29 mmol). After the reaction solution was heated and refluxed for 12 hours, finely ground selenium dioxide (18 mg, 0.16 mmol), oven-dried quartz sand (300 mg), and dried pyridine (0.1 ml, 1.29 mmol) were added to the reaction. mmol) and continue the reaction for 24 hours. After the reaction is completed, the reaction solution is filtered through diatom, and the filter cake is washed three times with ethyl acetate, 2 ml each time. Combine the organic phases. Then wash with saturated sodium bicarbonate solution three times, 10 ml each time; further wash with saturated saline solution three times, 10 ml each time. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 9 mg of compound 7 and 36 mg of a mixture of compound 8 and compound 9, with a yield of 57% and a recovery yield of 67%. Compound 8 and compound 9 were obtained. The molar ratio of 9 is about 1:10.

The spectral data of compound 9 are as follows:

¹ H-NMR (300MHz, CDCl ₃ ) δ9.86 (s, 1H), 7.40 (d, J = 8.4Hz, 1H), 6.90 (d, J = 8.3Hz, 1H), 6.17 (d, J = 10.2 Hz,1H),5.95(dd,J＝10.2,4.5Hz,1H),4.94(t,J＝8.1,4.2Hz,1H),4.47(s,1H),4.22–4.16(m,1H),3.95 (d,J＝1.5Hz,4H),3.15–3.02(m,1H),2.95–2.78(m,1H),2.41(ddt,J＝16.0,11.1,5.3Hz,2H),2.17(dt,J ＝15.8,4.7Hz,1H),1.97(s,2H),1.40(s,11H).

¹³ C-NMR (75MHz, CDCl ₃ ) δ191.09,155.67,150.24,147.74,131.77,131.40,129.65,128.99,126.88,110.47,85.52,79.26,62.32,56.10,49.55,36.9 0,32.11,28.35.

IR ν _max 3359,2921,2851,1687,1607,1506,1435,1366,1285,1169,1067,967,764cm ^-1 .

HRMS(ESI,+ve)[M+Na]calculated for C ₂₁ H ₂₇ HO ₆ Na 412.1736,found 412.1731.

Example 5: Synthesis of compound 1 (galantamine)

Add intermediate product I (33 mg, 0.08 mmol) and 7.5 ml of dichloromethane to a dry, nitrogen-protected round-bottomed flask, and then add 0.75 ml of trifluoroacetic acid (dichloromethane: Trifluoroacetic acid = 10:1, volume ratio). The reaction was monitored by thin layer chromatography and once compound 9 was complete, formaldehyde (10 mmol, 3.25 mL, 37% in water) was added to the reaction followed by sodium cyanoborohydride over 5 min. (27 mg, 0.42 mmol), and the resulting mixture continued to react at room temperature for 16 hours. After the reaction is completed, 10 ml of saturated sodium bicarbonate solution is added dropwise to the reaction solution. The mixture was extracted three times with ethyl acetate, 10 ml each time, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 13 mg of compound 1 with a yield of 53%.

¹ H-NMR (500MHz, CDCl ₃ ) δ6.67 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 6.05 (dd, J = 10.3, 1.5 Hz, 1H), 6.01(ddd,J＝10.2,4.7,1.2Hz,1H),4.62(q,J＝2.8,2.3Hz,1H),4.18–4.10(m,2H),3.84(s,3H),3.72(d, J＝15.2Hz,1H),3.31(t,J＝13.6Hz,1H),3.09(d,J＝14.6Hz,1H),2.69(ddt,J＝15.7,3.3,1.5Hz,1H),2.43( s,3H),2.09(td,J＝13.3,3.0Hz,1H),2.05–2.01(m,1H),1.99(dd,J＝5.0,2.5Hz,1H),1.61(d,J＝13.6Hz ,1H).

¹³ C-NMR (126MHz, CDCl ₃ ) δ 146.02, 144.46, 133.14, 127.98, 126.78, 122.41, 111.44, 88.87, 62.20, 56.08, 53.85, 48.30, 30.08, 29.85.

IR ν _max 3387,3024,2920,2850,1624,1507,1439,1282,1230,1202,1167,1067,1045,990,801,764,663cm ^-1 .

HRMS(ESI,+ve)[M+H]calculated for C ₁₇ H ₂₂ NO ₃ 288.1600, found 288.1594.

Example 6: Synthesis of compound 1’ (desmethylgalantamine)

Add intermediate product I (33 mg, 0.08 mmol) and 7.5 ml of dichloromethane to a dry, nitrogen-protected round-bottomed flask, and then add 0.75 ml of trifluoroacetic acid (dichloromethane: Trifluoroacetic acid = 10:1, volume ratio). The reaction was monitored by thin layer chromatography. Once the reaction of compound 9 was completed, sodium cyanoborohydride (27 mg, 0.42 mmol) was added to the reaction solution within 5 minutes, and the resulting mixture continued to react at room temperature for 16 hours. After the reaction is completed, 10 ml of saturated sodium bicarbonate solution is added dropwise to the reaction solution. The mixture was extracted three times with chloroform, 10 ml each time, the organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 13 mg of compound 1', with a yield of 56%.

¹ H-NMR (300MHz, CDCl ₃ ): 6.65 (1H, d, J = 8.0Hz), 6.63 (1H, d, J = 8.0Hz), 6.06 (1H, dd, J = 10.5, 1.5Hz,), 6.01(1H,ddd,J＝10.5,5.0,1.0Hz),4.61-4.64(1H,m,H1),4.13-4.17(1H,m),4.03(1H,d,J＝15.5Hz),3.96( 1H,d,J＝15.5Hz),3.84(3H,s,OCH3),3.36(1H,dt,J＝14.5,3.5Hz),3.23(1H,ddd,J＝14.5,12.5,2.0Hz),2.70 (1H,ddt,J＝15.5,3.0,1.5,1.5Hz),2.02(1H,ddd,J＝15.5,5.0,2.0Hz),1.86(1H,ddd,J＝13.5,4.0,2.0Hz),1.75 (1H,ddd,J＝13.5,12.5,3.5Hz).

¹³ C-NMR (75MHz, CDCl ₃ ): 146.2, 144.06, 133.11, 132.78, 127.67, 126.99, 120.73, 110.99, 88.57, 62, 55.91, 53.77, 48.7, 47, 40.13, 29.66.

What is described above are only some embodiments of the present invention. For those of ordinary skill in the art, several modifications and improvements can be made without departing from the creative concept of the present invention, and these all belong to the protection scope of the present invention.

Claims

Intermediate I for preparing galantamine is characterized in that the structural formula is as shown in formula (I):
The preparation method of intermediate I according to claim 1, characterized in that it includes the following steps:

With tert-butyl vinyl carbamate and compound 2
Synthesis of compound 4 via Suzuki cross-coupling reaction

Compound 4 and 3-hydroxy-2-iodo-4-methoxybenzaldehyde were reacted with Mitsunobu to synthesize intermediate I.
The preparation method of Intermediate I according to claim 2, characterized in that the preparation method of compound 4 includes the following steps:

Dissolve tert-butyl vinyl carbamate in the first solvent, add borane at room temperature and react until the solution becomes clear and transparent to obtain solution I; wherein, the molar ratio of tert-butyl vinyl carbamate to borane is 1 :1-1:2;

Dissolve compound 2, palladium reagent and triphenylarsenic in the second solvent, and then add alkali solution to obtain solution II; wherein, based on the amount of the substance, the amount of palladium reagent added is 5-25% of compound 2, The addition amount of triphenylarsenic is 9-50% of compound 2;

Add solution I to solution II and react under nitrogen protection for 0.5-1 hour. After separation and purification, compound 4 is obtained.
The preparation method of intermediate I according to claim 3, characterized in that the first solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, dimethyl At least one of the acyl sulfones;

The borane is selected from the group consisting of 9-borane bicyclo[3.3.1]nonane dimer, diisopinepinyl chloroborane, diethylmethoxyborane, dimethylborane, and catecholborane at least one of;

The palladium reagent is selected from the group consisting of 1,1-bis(diphenylphosphine)ferrocene-palladium(II) dichloride dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, dichloride At least one of palladium, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, and palladium trifluoroacetate;

The second solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide;

The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate;

The concentration of the alkali solution is 2-5 mol/L, and the added volume is 0.2-0.5 times the volume of solution II.
The preparation method of intermediate I according to any one of claims 2 to 4, characterized in that the step of synthesizing intermediate I through Mitsunobu reaction of compound 4 and 3-hydroxy-2-iodo-4-methoxybenzaldehyde include:

Mix compound 4 with 3-hydroxy-2-iodo-4-methoxybenzaldehyde and the third solvent at -20°C under nitrogen protection, then add tributylphosphine and azo compounds, or add triphenylphosphine and an azo compound, react at -20°C for 0.5-1.5 hours, then raise the temperature to room temperature and continue the reaction for 12-18 hours. After the reaction is completed, the intermediate I is obtained by separation and purification;

Among them, the molar ratio of compound 4 to 3-hydroxy-2-iodo-4-methoxybenzaldehyde is 1:1-1:2.5; tributylphosphine or triphenylphosphine and 3-hydroxy-2-iodo- The molar ratio of 4-methoxybenzaldehyde is 1:1-1.5:1, and the molar ratio of tributylphosphine or triphenylphosphine and azo compounds is 1:1;

The third solvent is selected from at least one of tetrahydrofuran, benzene, toluene, and acetonitrile;

The azo compound is selected from at least one selected from the group consisting of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.
Intermediate II for preparing galantamine is characterized in that the structural formula is as shown in formula (II):
The preparation method of intermediate II according to claim 6, characterized in that it includes the following steps:

Add intermediate I, catalyst, catalyst ligand, and base to the fourth solvent, and heat and reflux for 2-4 hours under nitrogen protection. After the reaction is completed, the intermediate II is obtained by separation and purification;

Among them, based on the amount of substances, the added amount of the catalyst is 5-15% of the intermediate I, the added amount of the catalyst ligand is 10-25% of the intermediate I; the added amount of the base is 200-200% of the intermediate I. 500%.
The preparation method of intermediate II according to claim 7, characterized in that the fourth solvent is selected from at least one of acetonitrile, benzene, toluene, dimethylformamide, and 1,4-dioxane. ; The catalyst is selected from a palladium reagent; the catalyst ligand is selected from an organic phosphine ligand; the base is selected from at least one of triethylamine, cesium carbonate, potassium carbonate, and sodium carbonate.
The preparation method of galantamine is characterized by comprising the following steps:

(1) Mix intermediate II, the first part of selenium dioxide, the first part of quartz sand, 1,4-dioxane, and the first part of pyridine, and heat and reflux for 10-15 hours under nitrogen protection; then add The second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine continue to react for 18-30 hours. After the reaction is completed, the intermediate product I is obtained through separation and purification; among which, intermediate II, the first portion of selenium dioxide, The molar ratio of the second part of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of intermediate II, the first part of pyridine, and the second part of pyridine is 1:6:6-1:10:10 ;

(2) Mix the intermediate product I and the fifth solvent, add trifluoroacetic acid and react under nitrogen protection at 25-35°C for 2-4 hours, then add formaldehyde aqueous solution for reaction, then add sodium cyanoborohydride and continue at 25-35°C. React for 12-18 hours at 35°C. After the reaction is completed, galantamine is obtained through separation and purification; wherein, the mass-to-volume ratio of the intermediate product I to the fifth solvent is (2-6) mg/mL; the fifth solvent The volume ratio to trifluoroacetic acid is 10:1; the molar ratio of intermediate product I to formaldehyde is 1:1-1:200; the molar ratio of intermediate product I to sodium cyanoborohydride is 1:5-1:20;

The fifth solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.
The preparation method of desmethylgalantamine is characterized by comprising the following steps:

(1) Mix intermediate II, the first part of selenium dioxide, the first part of quartz sand, 1,4-dioxane, and the first part of pyridine, and heat and reflux for 10-15 hours under nitrogen protection; then add The second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine continue to react for 18-30 hours. After the reaction is completed, the intermediate product I is obtained through separation and purification; among which, intermediate II, the first portion of selenium dioxide, The molar ratio of the second part of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of intermediate II, the first part of pyridine, and the second part of pyridine is 1:6:6-1:10:10 ;

(2) Mix the intermediate product I and the sixth solvent, add trifluoroacetic acid and react under nitrogen protection at 25-35°C for 2-4 hours, then add sodium cyanoborohydride and continue the reaction at 25-35°C for 12-18 hours, after the reaction is completed, desmethylgalantamine is obtained through separation and purification; wherein, the mass-volume ratio of the intermediate product I to the sixth solvent is (2-6) mg/mL; the sixth solvent and trifluoroacetic acid The volume ratio is 10:1; the molar ratio of intermediate product I to sodium cyanoborohydride is 1:5-1:20;

The sixth solvent is selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide.