Preparation method of galantamine, its derivatives and intermediates

Abstract

The present invention discloses intermediate I and intermediate II that can be used for preparing galanthamine, and its preparation method and a kind of asymmetric total synthesis method of galanthamine and derivatives thereof as shown in structural formula (I) and formula (II) respectively, and a kind of synthetic route is short, high yield galanthamine and its derivatives. The present invention uses simple, cheap and easily available compound 2, vinylcarbamic acid tert-butyl ester and 3 hydroxy 2 iodine 4 methoxybenzaldehyde as starting raw materials, and the intermediate required for preparing galanthamine and its derivatives, i.e. the intermediate shown in formula (I) and formula (II) is synthesized in sequence by multiple reactions such as Suzuki cross-coupling reaction and Mitsunobu reaction, and then galanthamine and its derivatives are prepared using these intermediates. The synthetic route of the preparation method of galanthamine, its derivatives and intermediates provided by the present invention is short, high yield, and it is easy to realize large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of galanthamine, its derivatives and intermediates. Background Art

[0002] Galanthamine is a biologically active tetracyclic alkaloid isolated from Amaryllis plants such as Lycoris radiata, Daffodil, and Snowdrop. Pharmacologically, it is a reversible cholinesterase inhibitor and plays an important role in the treatment of diseases such as Alzheimer's disease, myasthenia gravis, angle-closure glaucoma, and sequelae of polio.

[0003] The traditional method for producing galanthamine is to isolate and extract it from Lycoris radiata. Due to limited resources, the plant's numerous components, complex structure, and low galanthamine content, the extraction and purification processes are complex, and production costs are high, resulting in a persistently high price for galanthamine. Numerous total synthetic routes for galanthamine have been published, but most result in racemic galanthamine. Fewer methods exist for the asymmetric synthesis of galanthamine, and most suffer from varying degrees of lengthy synthetic routes, cumbersome steps, and low yields. Some synthetic methods also require expensive raw materials, resulting in high production costs and making them unsuitable for industrialization.

[0004] The prior art still lacks a preparation method for synthesizing galanthamine with fewer synthesis steps and higher yield. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing galanthamine to solve at least one of the above-mentioned technical problems.

[0006] According to a first aspect of the present invention, there is provided an intermediate I (i.e., compound 6) for preparing galanthamine having a structural formula as shown in formula (I):

[0007]

[0008] According to a second aspect of the present invention, a method for preparing the intermediate I represented by formula (I) is provided, characterized in that it comprises the following steps:

[0009] With vinyl carbamic acid tert-butyl ester and compound 2 Compound 4 was synthesized via Suzuki cross-coupling reaction

[0010] Compound 4 was reacted with 3-hydroxy-2-iodo-4-methoxybenzaldehyde to synthesize intermediate I.

[0011] In some embodiments, compound 2 can be obtained through commercial routes or synthesized through the following synthetic route:

[0012]

[0013] In some embodiments, the synthesis method of compound 4 comprises the following steps:

[0014] Dissolve tert-butyl vinylcarbamate (i.e., compound 3) in a first solvent, add borane at room temperature (25-35° C.) and react until the solution becomes clear and transparent to obtain solution I; wherein the molar ratio of tert-butyl vinylcarbamate to borane is 1:1-1:2;

[0015] Dissolving compound 2, a palladium reagent, and triphenylarsenic in a second solvent, and then adding an alkaline solution to obtain a solution II; wherein, based on the amount of substance, the amount of the palladium reagent added is 5-25% of compound 2, and the amount of triphenylarsenic added is 9-50% of compound 2;

[0016] Solution I was added to solution II, and the mixture was reacted for 0.5-1 hour under nitrogen protection. Compound 4 was obtained after separation and purification.

[0017] 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.

[0018] In some embodiments, the borane may be selected from at least one of 9-borabicyclo[3.3.1]nonane dimer, diisopinocampheylchloroborane, diethylmethoxyborane, dimethylborane, and catecholborane.

[0019] In some embodiments, the palladium reagent used as a catalyst can be selected from at least one of common palladium reagents such as 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II)dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, and palladium trifluoroacetate.

[0020] 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.

[0021] 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 alkaline solution can be 2-5 mol / L, and the added volume is 0.2-0.5 times the volume of Solution II.

[0022] In some embodiments, the preparation method of compound 6 comprises the following steps:

[0023] 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 tributylphosphine and an azo compound are added. The mixture is reacted at -20°C for 0.5-1.5 hours, and then the temperature is raised to room temperature and the reaction is continued for 12-18 hours. After the reaction is completed, the mixture is separated and purified to obtain compound 6;

[0024] 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. The mixture is reacted at -20°C for 0.5-1.5 hours, and then the temperature is raised to room temperature and the reaction is continued for 12-18 hours. After the reaction is completed, the mixture is separated and purified to obtain compound 6.

[0025] 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 added amount of tributylphosphine or triphenylphosphine is 1-1.5 times that of 3-hydroxy-2-iodo-4-methoxybenzaldehyde, and the molar ratio of tributylphosphine or triphenylphosphine to the azo compound is 1:1.

[0026] In some embodiments, the third solvent may be selected from at least one of tetrahydrofuran, benzene, toluene, and acetonitrile.

[0027] In some embodiments, the azo compound may be selected from at least one of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.

[0028] According to a third aspect of the present invention, there is provided an intermediate II (i.e., compound 7) for preparing galanthamine having a structure as shown in formula (II):

[0029]

[0030] According to a fourth aspect of the present invention, a method for preparing the intermediate II represented by formula (II) is provided, comprising the following steps:

[0031] Adding intermediate I, catalyst, catalyst ligand, and base to a fourth solvent, heating under reflux for 2-4 hours under nitrogen protection, and separating and purifying after the reaction to obtain intermediate II;

[0032] Calculated by the amount of substance, 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; and the added amount of the base is 200-500% of the intermediate I.

[0033] In some embodiments, the fourth solvent may be at least one selected from acetonitrile, benzene, toluene, dimethylformamide, and 1,4-dioxane.

[0034] In some embodiments, the catalyst can be selected from palladium reagents; specifically, it can be selected from at least one of common palladium reagents such as 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, and palladium trifluoroacetate.

[0035] In some embodiments, the catalyst ligand can be selected from an organic phosphine ligand; specifically, it can be selected from at least one of common organic phosphine ligands such as tri(o-tolyl)phosphine, 1,2-bis(phenylphosphino)ethane, 1,1'-bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane, and 1,1-bis(diphenylphosphino)methane.

[0036] In some embodiments, the base can be selected from at least one of triethylamine, cesium carbonate, potassium carbonate, and sodium carbonate.

[0037] According to a fifth aspect of the present invention, there is provided a method for preparing galanthamine, comprising the following steps:

[0038] (1) Mixing the intermediate II, the first portion of selenium dioxide, the first portion of quartz sand, 1,4-dioxane, and the first portion of pyridine, heating and refluxing the mixture under nitrogen protection for 10-15 hours; then adding the second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine, and continuing the reaction for 18-30 hours. After the reaction is completed, the mixture is separated and purified to obtain the intermediate product I; wherein the molar ratio of the intermediate II, the first portion of selenium dioxide, and the second portion of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of the intermediate II, the first portion of pyridine, and the second portion of pyridine is 1:6:6-1:10:10; the stepwise addition of selenium dioxide, quartz sand, and pyridine is conducive to the complete reaction, thereby improving the reaction yield;

[0039] (2) The intermediate product I and the fifth solvent are mixed, trifluoroacetic acid is added, and the mixture is reacted at 25-35° C. for 2-4 hours under nitrogen protection, and then a formaldehyde aqueous solution is added for reaction, followed by adding sodium cyanoborohydride and continuing to react at 25-35° C. for 12-18 hours. After the reaction is completed, galanthamine is obtained by separation and purification; wherein the mass volume ratio of the intermediate product I to the fifth solvent is (2-6) mg / mL; the volume ratio of the fifth solvent to trifluoroacetic acid is 10:1; the molar ratio of the intermediate product I to formaldehyde is 1:1-1:200; and the molar ratio of the intermediate product I to sodium cyanoborohydride is 1:5-1:20.

[0040] 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.

[0041] According to a sixth aspect of the present invention, there is provided a method for preparing demethylgalanthamine, comprising the following steps:

[0042] The intermediate product I and the sixth solvent are mixed, trifluoroacetic acid is added, and the reaction is carried out under nitrogen protection at 25-35° C. for 2-4 hours. Then, sodium cyanoborohydride is added and the reaction is continued at 25-35° C. for 12-18 hours. After the reaction is completed, the mixture is separated and purified to obtain demethylgalanthamine. 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; and the molar ratio of the intermediate product I to the sodium cyanoborohydride is 1:5-1:20.

[0043] In some embodiments, the sixth solvent may be selected from at least one of dichloromethane, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, dimethyl sulfoxide,

[0044] The present invention uses simple, inexpensive, and readily available commercial compounds as starting materials to provide an asymmetric synthesis method for galanthamine and its derivatives with a few synthetic steps and high yield. The galanthamine synthesis method provided by the present invention has low production costs, a short synthetic route, and is easy to implement for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The present invention provides a synthetic route for galanthamine, demethylgalanthamine and their intermediates. DETAILED DESCRIPTION

[0046] The present invention will be further described in detail below with reference to the following embodiments. The examples are provided for illustrative purposes only and are not intended to limit the present invention in any way. Unless otherwise specified, the raw materials and reagents used in the examples are commercially available conventional products; experimental methods without specific conditions in the examples are conventional methods and conditions well known in the art.

[0047] Example 1: Synthesis of Compound 4

[0048]

[0049] To the first round-bottom flask, tert-butyl vinylcarbamate (compound 3, 1917 mg, 13.39 mmol) was added and dissolved in 20 ml of degassed dry tetrahydrofuran. 9-Borabicyclo[3.3.1]nonane dimer [recrystallized from a hot solution of 1,2-dimethoxyethane] (1635 mg, 13.39 mmol) was added dropwise at room temperature to the solution. After 0.5 hour of reaction, the solution became clear and transparent.

[0050] In a second round-bottom flask, compound 2 (2000 mg, 8.93 mmol), 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (367 mg, 0.45 mmol), and triphenylarsine (273 mg, 0.89 mmol) were dissolved in 40 mL of degassed dry tetrahydrofuran, and then degassed sodium hydroxide solution (3 mol / L, 12 mL) was added to the mixture.

[0051] The solution in the first round-bottom flask was added to the second round-bottom flask at room temperature and then stirred under nitrogen for 0.5 hours. Once the thin-layer chromatography monitored that compound 2 had been consumed, the light orange reaction mixture was diluted with ethyl acetate (20 ml) and then added to saturated brine (60 ml), followed by aqueous hydrogen peroxide solution (9.8 mol / L, 1.2 ml). The aqueous solution was extracted with ethyl acetate (3×60 ml), and the combined organic phases were dried (anhydrous sodium sulfate), concentrated under reduced pressure, and purified by silica gel column chromatography (gradient elution, ethyl acetate: petroleum ether = 1:5-1:3) to obtain 1980 mg of colorless oily compound 4 (R f =0.25, petroleum ether:ethyl acetate=1:3), yield 92%.

[0052] 1 H-NMR (500MHz, CDCl3) 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,1 H),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 groupproton not observed];

[0053] 13 C-NMR (126MHz, CDCl3) δ156.6,136.0,127.9,79.3,67.5,39.7,36.6,32.6,28.4,25.7,17.9.

[0054] IRν max 3337,2929,1683,1520,1364,1277,1250,1167,1050,985cm-1 .

[0055] HRMS(ESI,+ve)[M+Na]calculated for C 13 H 23 NO3Na 264.1576,found264.1570.

[0056] Example 2: Synthesis of Compound 6 (Intermediate I)

[0057]

[0058] 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 mmol) were added sequentially to a -20°C round-bottom flask in 5 ml of dry, degassed tetrahydrofuran. Tributylphosphine (0.91 ml, 1.91 mmol) and tetramethylazodicarbonamide (327 mg, 1.91 mmol) were then added to the reaction mixture. The reaction mixture was stirred at this temperature for one hour, then warmed to room temperature and stirred for another 16 hours. After completion of the reaction, the mixture was diluted with 15 ml of ethyl acetate and filtered through silica gel. The resulting solution was concentrated under reduced pressure, followed by the addition of 15 ml of dichloromethane and extraction three times with 15 ml of 3 mol sodium hydroxide solution. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 330 mg of a foamy white compound in a 70% yield.

[0059] 1 H-NMR (500MHz, CDCl3) δ10.03(s,1H),7.66(d,J=8.6Hz,1H),6.95(d,J=8.6Hz,1H),5.77(t,J=3.4Hz,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).

[0060] 13 C-NMR (126MHz, CDCl3) δ195.62,157.08,155.97,146.56,133.98,129.73,129.29,126 .38,111.70,101.57,78.80,55.97,39.24,34.69,28.39,28.38,28.20,25.43,18.63.

[0061] IRν max 3360,3188,2920,2849,1682,1572,1471,1271,1246,1170,1020cm -1 .

[0062] HRMS(ESI,+ve)[M+Na]calculated for C 21 H 28 INO5 524.0910,found524.0904.

[0063] Example 3: Synthesis of Compound 7 (Intermediate II)

[0064]

[0065] Compound 6 (540 mg, 1.08 mmol), tris(dibenzylidene)acetonepalladium (110 mg, 0.12 mmol), tri(o-tolyl)phosphine (73 mg, 0.24 mmol), and triethylamine (0.33 ml, 4.47 mmol) were added sequentially to a dry, degassed 10 ml acetonitrile solution. The reaction solution was heated under reflux for 3 hours under nitrogen. After completion of the reaction, the reaction solution was filtered through celite, and the filter cake was washed three times with 10 ml of ethyl acetate (or dichloromethane). 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 foamy compound with a yield of 81%.

[0066] 1 H-NMR (300MHz, CDCl3) 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).

[0067] 13 C-NMR (75MHz, CDCl3) δ190.91,155.68,149.85,148.54,133.04,130.27,129.09,128 .08,126.81,110.12,86.24,79.09,56.01,49.21,37.13,36.91,28.33,24.42,19.01.

[0068] IRν max 3359,3184,2920,2849,1687,1607,1570,1505,1409,1435,1365,1248,1284,1169,765,723cm -1 .

[0069] HRMS(ESI,+ve)[M+Na]calculated for C 21 H 27 NO5Na 396.1787,found396.1781.

[0070] Example 4: Synthesis of Compounds 8 & 9 (Intermediate Product I)

[0071]

[0072] To a dry, nitrogen-protected round-bottom flask were added compound 7 (60 mg, 0.16 mmol), finely ground selenium dioxide (18 mg, 0.16 mmol), oven-dried quartz sand (300 mg), 2 mL of dry 1,4-dioxane solution, and dry pyridine (0.1 mL, 1.29 mmol). The reaction mixture was heated under reflux for 12 hours. Finely ground selenium dioxide (18 mg, 0.16 mmol), oven-dried quartz sand (300 mg), and dry pyridine (0.1 mL, 1.29 mmol) were then added to the reaction mixture and the reaction continued for 24 hours. After completion of the reaction, the reaction mixture was filtered through Celite, and the filter cake was washed three times with 2 mL of ethyl acetate each time. The organic phases were combined and then washed three times with saturated sodium bicarbonate solution (10 mL each), and then three times with saturated brine (10 mL each). 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%. The molar ratio of compound 8 to compound 9 was approximately 1:10.

[0073] The spectral data of compound 9 are as follows:

[0074] 1H-NMR (300MHz, CDCl3) δ9.86 (s, 1H), 7.40 (d, J = 8.4Hz, 1H), 6.90 (d, J = 8.3Hz, 1H), 6.17 (d,J=10.2Hz,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).

[0075] 13 C-NMR (75MHz, CDCl3) δ191.09,155.67,150.24,147.74,131.77,131.40,129.65, 128.99,126.88,110.47,85.52,79.26,62.32,56.10,49.55,36.90,32.11,28.35.

[0076] IRν max 3359,2921,2851,1687,1607,1506,1435,1366,1285,1169,1067,967,764cm -1 .

[0077] HRMS(ESI,+ve)[M+Na]calculated for C 21 H 27 HO6Na 412.1736,found412.1731.

[0078] Example 5: Synthesis of Compound 1 (Galantamine)

[0079]

[0080] To a dry, nitrogen-protected round-bottom flask, intermediate I (33 mg, 0.08 mmol) and 7.5 mL of dichloromethane were added dropwise at room temperature. 0.75 mL of trifluoroacetic acid (dichloromethane:trifluoroacetic acid = 10:1, volume ratio) was then added dropwise. The reaction was monitored by thin-layer chromatography. Once compound 9 had reacted completely, formaldehyde (10 mmol, 3.25 mL, 37% aqueous solution) was added. Sodium cyanoborohydride (27 mg, 0.42 mmol) was then added over 5 minutes. The resulting mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, 10 mL of saturated sodium bicarbonate solution was added dropwise. The mixture was extracted with ethyl acetate three times (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to yield 13 mg of compound 1 in a 53% yield.

[0081] 1 H-NMR (500MHz, CDCl3) δ6.67(d,J=8.2Hz,1H),6.63(d,J=8.2Hz,1H),6.05(dd,J=10.3,1.5Hz,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,3 H),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).

[0082] 13 C-NMR (126MHz, CDCl3) δ146.02,144.46,133.14,127.98,126.78,122.41,111.44,88.87,62.20,56.08,53.85,48.30,30.08,29.85.

[0083] IRν max 3387,3024,2920,2850,1624,1507,1439,1282,1230,1202,1167,1067,1045,990,801,764,663cm -1 .

[0084] HRMS(ESI,+ve)[M+H]calculated for C 17 H 22 NO3 288.1600,found288.1594.

[0085] Example 6: Synthesis of Compound 1' (Demethylgalanthamine)

[0086] To a dry, nitrogen-protected round-bottom flask, intermediate I (33 mg, 0.08 mmol) and 7.5 mL of dichloromethane were added dropwise at room temperature. 0.75 mL of trifluoroacetic acid (dichloromethane:trifluoroacetic acid = 10:1, volume ratio) was then added dropwise. The reaction was monitored by thin-layer chromatography. Once compound 9 had reacted completely, sodium cyanoborohydride (27 mg, 0.42 mmol) was added over 5 minutes. The resulting mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, 10 mL of saturated sodium bicarbonate solution was added dropwise. The mixture was extracted with chloroform three times (10 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to yield 13 mg of compound 1' in a 56% yield.

[0087] 1 H-NMR (300MHz, CDCl3): 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).

[0088] 13 C-NMR (75MHz, CDCl3):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.

[0089] The above are only some embodiments of the present invention. For those skilled in the art, several modifications and improvements can be made without departing from the inventive concept of the present invention, which all fall within the scope of protection of the present invention.

Claims

1. An intermediate I for preparing galanthamine, characterized in that: The structural formula is shown in formula (I):

2. The method for preparing the intermediate I according to claim 1, wherein The steps include: With vinyl carbamic acid tert-butyl ester and compound 2 Compound 4 was synthesized via Suzuki cross-coupling reaction Compound 4 was reacted with 3-hydroxy-2-iodo-4-methoxybenzaldehyde to synthesize intermediate I.

3. The method for preparing the intermediate I according to claim 2, characterized in that: The preparation method of compound 4 comprises the following steps: Dissolving tert-butyl vinyl carbamate in a first solvent, adding borane at room temperature and reacting until the solution becomes clear and transparent, thereby obtaining a solution I; wherein the molar ratio of tert-butyl vinyl carbamate to borane is 1:1-1:2; Dissolving compound 2, a palladium reagent, and triphenylarsenic in a second solvent, and then adding an alkaline solution to obtain a solution II; wherein, based on the amount of substance, the amount of the palladium reagent added is 5-25% of compound 2, and the amount of triphenylarsenic added is 9-50% of compound 2; Solution I was added to solution II, and the mixture was reacted for 0.5-1 hour under nitrogen protection. Compound 4 was obtained after separation and purification.

4. The method for preparing the intermediate I according to claim 3, characterized in that: The first solvent is selected from at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, benzene, dimethylformamide, and dimethyl sulfoxide; The borane is selected from at least one of 9-borane bicyclo[3.3.1]nonane dimer, diisopinocampheyl chloroborane, diethylmethoxyborane, dimethylborane, and catechol borane; The palladium reagent is selected from at least one of 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, 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 alkaline solution is 2-5 mol / L, and the added volume is 0.2-0.5 times the volume of solution II.

5. The method for preparing the intermediate I according to any one of claims 2 to 4, characterized in that: The steps of synthesizing intermediate I by Mitsunobu reaction of compound 4 and 3-hydroxy-2-iodo-4-methoxybenzaldehyde include: Compound 4 is mixed with 3-hydroxy-2-iodo-4-methoxybenzaldehyde and a third solvent at -20°C under nitrogen protection, and then tributylphosphine and an azo compound, or triphenylphosphine and an azo compound, are added. The mixture is reacted at -20°C for 0.5-1.5 hours, and then the temperature is raised to room temperature and the reaction is continued for 12-18 hours. After the reaction is completed, the mixture is separated and purified to obtain intermediate I. The molar ratio of compound 4 to 3-hydroxy-2-iodo-4-methoxybenzaldehyde is 1:1-1:2.5; the molar ratio of tributylphosphine or triphenylphosphine to 3-hydroxy-2-iodo-4-methoxybenzaldehyde is 1:1-1.5:1; and the molar ratio of tributylphosphine or triphenylphosphine to the azo compound 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 of ethyl azodicarboxylate, diisopropyl azodicarboxylate, and tetramethylazodicarbonamide.

6. An intermediate II for preparing galanthamine, characterized in that: The structural formula is shown in formula (II):

7. The method for preparing intermediate II according to claim 6, characterized in that: The steps include: Add the intermediate I described in claim 1, a catalyst, a catalyst ligand, and a base to a fourth solvent, and heat under reflux for 2-4 hours under nitrogen protection. After the reaction is completed, the intermediate II is obtained by separation and purification; Calculated by the amount of substance, 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; and the added amount of the base is 200-500% of the intermediate I.

8. The method for preparing 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 palladium reagent; the catalyst ligand is selected from organic phosphine ligand; and the base is selected from at least one of triethylamine, cesium carbonate, potassium carbonate, and sodium carbonate.

9. A method for preparing galanthamine, characterized in that: The steps include: (1) The intermediate II described in claim 6, the first portion of selenium dioxide, the first portion of quartz sand, 1,4-dioxane, and the first portion of pyridine are mixed and heated under reflux for reaction for 10-15 hours under nitrogen protection; then the second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine are added and the reaction is continued for 18-30 hours. After the reaction is completed, the intermediate product I is obtained by separation and purification; wherein the molar ratio of the intermediate II, the first portion of selenium dioxide, and the second portion of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of the intermediate II, the first portion of pyridine, and the second portion of pyridine is 1:6:6-1:10:10; (2) mixing the intermediate product I and the fifth solvent, adding trifluoroacetic acid, reacting under nitrogen protection at 25-35°C for 2-4 hours, then adding formaldehyde aqueous solution to react, then adding sodium cyanoborohydride and continuing to react at 25-35°C for 12-18 hours, and separating and purifying after the reaction to obtain galanthamine; wherein the mass volume ratio of the intermediate product I to the fifth solvent is (2-6) mg / mL; the volume ratio of the fifth solvent to trifluoroacetic acid is 10:1; the molar ratio of the intermediate product I to formaldehyde is 1:1-1:200; and the molar ratio of the 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.

10. A method for preparing demethylgalanthamine, characterized in that: The steps include: (1) The intermediate II described in claim 6, the first portion of selenium dioxide, the first portion of quartz sand, 1,4-dioxane, and the first portion of pyridine are mixed and heated under reflux for reaction for 10-15 hours under nitrogen protection; then the second portion of selenium dioxide, the second portion of quartz sand, and the second portion of pyridine are added and the reaction is continued for 18-30 hours. After the reaction is completed, the intermediate product I is obtained by separation and purification; wherein the molar ratio of the intermediate II, the first portion of selenium dioxide, and the second portion of selenium dioxide is 1:1:1-1:1.5:1.5; the molar ratio of the intermediate II, the first portion of pyridine, and the second portion of pyridine is 1:6:6-1:10:10; (2) mixing the intermediate product I and the sixth solvent, adding trifluoroacetic acid, reacting under nitrogen protection at 25-35° C. for 2-4 hours, then adding sodium cyanoborohydride and continuing to react at 25-35° C. for 12-18 hours. After the reaction is completed, separating and purifying to obtain demethylgalanthamine; 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; and the molar ratio of the intermediate product I to the 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.

Images