Preparation method of galanthamine and intermediate thereof

Abstract

The invention discloses a preparation method of galanthamine and an intermediate thereof, and belongs to the technical field of organic chemical synthesis. The chemical structural formulas of the intermediates for synthesis of galanthamine are as shown in formulas (I)-(IV). According to the invention, 2-cyclohexenone, acrylic ester, 3-hydroxy-2-halo-4-methoxybenzaldehyde and the like are used as starting raw materials, and the intermediate required for preparing the galanthamine is synthesized in sequence through a plurality of reactions such as Sentian-Bellies-Hilmann reaction, Corey-Barksh-Chai-field reaction, Mitsunobu reaction and the like; and then the galanthamine is synthesized by using the intermediates. The synthesis method is low in raw material and reagent price, low in production cost, short in synthesis route, easy and convenient to operate, high in yield and suitable for large-scale production, and the problems that an existing galanthamine synthesis process is complex, high in cost, low in yield and the like are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a preparation method of galanthamine and an intermediate thereof. Background Art

[0002] Galanthamine is a polycyclic alkaloid extracted and isolated from plants in the Amaryllidaceae family, including Lycoris, Amaryllis, Narcissus, and Leucojum. Pharmacologically, it is a selective, reversible, and competitive acetylcholinesterase inhibitor and an allosteric modulator of acetylcholine nicotinic receptors. It is widely used clinically to treat mild to moderate Alzheimer's disease with sleep disorders, myasthenia gravis, angle-closure glaucoma, and post-polio syndrome.

[0003] Traditionally, galanthamine is produced by isolating and extracting it from plants of the Amaryllidaceae family. However, due to limited plant resources, the diverse and complex structures of plant components, and the low natural content of galanthamine in plants, the extraction and purification processes are complex, and production costs are high, resulting in a persistently high price for galanthamine. Numerous chemical synthesis routes for galanthamine have been published, but asymmetric synthesis methods for galanthamine remain relatively rare. Most of these methods suffer from varying degrees of lengthy synthetic routes, cumbersome steps, and low yields. Some synthetic methods also require extensive use of unavailable raw materials and precious metal catalysts, resulting in high production costs and hindering industrial production. A nine-step method for preparing (-)-galanthamine via a biomimetic intramolecular phenol oxidative coupling process (Org. Process. Res. Dev. 1999, 3, 425-431) was reported. However, the key biomimetic phenol oxidative coupling step only yields approximately 40%, resulting in a total yield of only 12.4% for the entire synthetic route. Literature (WO 2023 / 221022 A1, CN 117751125 A) reports that ( S )-2-iodo-2-cyclohexene-1-ol was used as the raw material and (-)-galanthamine was synthesized with a total yield of 15.2% through six steps. S)-2-iodo-2-cyclohexen-1-ol requires reduction of 2-cyclohexenone with a difficult-to-obtain chiral borane. The subsequent palladium-catalyzed coupling reaction with N-tert-butyloxycarbonylvinylamine requires the use of an excessive amount of the expensive borane 9-BBN and triphenylarsin ligand, significantly increasing production costs. A study (Chem. Sci. 2024, 15, 19851-19857) reported the preparation of (-)-galanthamine from 2-ethoxycarbonylmethyl-1-cyclohexenone via a six-step reaction. However, the synthetic yield of the raw material 2-ethoxycarbonylmethyl-1-cyclohexenone used in this route was only 55%-70%, and column chromatography separation and purification were required, making it difficult to apply to actual industrial production.

[0004] In summary, the prior art still lacks a method for synthesizing galanthamine that is economical in steps, simple to operate, and low in cost. Summary of the Invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide a method for preparing galanthamine and its intermediates, so as to solve the problem that the existing method for preparing galanthamine lacks economical steps, simple operation, low cost and high total yield.

[0006] The technical solution of the present invention to solve the above technical problems is as follows: The first aspect of the present invention provides an intermediate I for preparing galanthamine, the structural formula of which is shown in formula (I): Formula (I): ; In formula (I), X is a halo group; R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

[0007] Furthermore, X is a bromine atom or an iodine atom.

[0008] The second aspect of the present invention provides a method for preparing intermediate I for preparing galanthamine represented by formula (I), comprising the following steps: First, 2-cyclohexenone and acrylate were subjected to a Morita-Bells-Hillman reaction, and then the product of the Morita-Bells-Hillman reaction was subjected to a Corey-Bakshi-Shibata reaction. Finally, the product of the Corey-Bakshi-Shibata reaction was subjected to a Mitsunobu reaction with 3-hydroxy-2-halogenated-4-methoxybenzaldehyde to prepare intermediate I.

[0009] Furthermore, the Morita-Bells-Hillman reaction specifically includes the following steps: 2-Cyclohexenone and a solvent were mixed, 1,8-diazabicyclo[5.4.0]undec-7-ene was added, and the mixture was stirred vigorously. Finally, acrylic acid ester was added and the mixture was heated under reflux to obtain compound 2.

[0010] Furthermore, the structural formula of compound 2 is shown in formula (2): Formula (2): ; In formula (2), R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

[0011] Furthermore, the solvent in the Morita-Bells-Hillman reaction is DMF; the vigorous stirring time is 10-20 min; and the heating reflux temperature is 70-90° C. and the time is 20-30 h.

[0012] Furthermore, the Kori-Bakshi-Shibata reaction specifically comprises the following steps: Compound 2 solution was added dropwise to the S )-2-methyl-CBS-oxazaborolidine and borane tetrahydrofuran mixed solution, reacted in a protective gas atmosphere to prepare compound 3.

[0013] Furthermore, the structural formula of compound 3 is shown in formula (3): Formula (3): ; In formula (3), R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

[0014] Furthermore, the solvent of the solution of compound 2 in the Kori-Bakshi-Shibata reaction includes at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, benzene, n-hexane, and n-heptane; containing ( S The solvent of the mixed solution of )-2-methyl-CBS-oxazaborolidine and borane tetrahydrofuran includes at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, benzene, n-hexane, and n-heptane.

[0015] Furthermore, in the Kori-Bakshi-Shibata reaction, the temperature of the compound 2 solution during the dropwise addition is -20 ~ 0 °C; the reaction temperature is -30 ~ -10 °C, and the reaction time is 10-20 h.

[0016] Furthermore, the molar ratio of compound 2 to borane tetrahydrofuran in the Kori-Bakshi-Shibata reaction is 1:1-1.5, and compound 2 and ( S The molar ratio of )-2-methyl-CBS-oxazaborolidine is 1:0.1-0.3.

[0017] Furthermore, borane tetrahydrofuran can be replaced by borane dimethyl sulfide, borane triethylamine or borane pyridine.

[0018] Furthermore, the Mitsunobu reaction specifically includes the following steps: First, compound (3) and 3-hydroxy-2-halogenated-4-methoxybenzaldehyde are mixed in a solvent, and then tri-n-butylphosphine and an azo compound are added to react to obtain intermediate II.

[0019] Furthermore, the reaction conditions of Mitsunobu are to first react at -30 ~ -10 ℃ for 20-40 min, and then continue the reaction at room temperature for 10-20 h.

[0020] Furthermore, in the Mitsunobu reaction, the molar ratio of compound (3) to 3-hydroxy-2-halogeno-4-methoxybenzaldehyde is 1:1-2.5; the molar ratio of tributylphosphine to 3-hydroxy-2-halogeno-4-methoxybenzaldehyde is 1:1-1.5; and the molar ratio of tributylphosphine to the azo compound is 1:0.8-1.2.

[0021] Furthermore, 3-hydroxy-2-halogenated-4-methoxybenzaldehyde is 3-hydroxy-2-iodo-4-methoxybenzaldehyde or 3-hydroxy-2-bromo-4-methoxybenzaldehyde.

[0022] Furthermore, the solvent in the Mitsunobu reaction includes at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, toluene, benzene and acetonitrile.

[0023] Furthermore, the azo compound in the Mitsunobu reaction includes at least one of ethyl azodicarboxylate, propyl azodicarboxylate and tetramethylazodicarbonamide.

[0024] The third aspect of the present invention provides an intermediate II for preparing galanthamine, the structural formula of which is shown in formula (II): Formula (II): ; In formula (II), R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

[0025] The fourth aspect of the present invention provides a method for preparing intermediate II for preparing galanthamine represented by formula (II), comprising the following steps: The intermediate I according to claim 1, a catalyst, a catalyst ligand and a base are subjected to heating reflux reaction to obtain an intermediate II.

[0026] Furthermore, the heating reflux reaction temperature is 80-120° C. and the time is 2-4 h.

[0027] Furthermore, based on the percentage of 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.

[0028] Furthermore, the reaction solvent includes at least one of acetonitrile, benzene, toluene, dimethylformamide and 1,4-dioxane.

[0029] Furthermore, the catalyst is a palladium catalyst.

[0030] Furthermore, the palladium catalyst includes at least one of 1,1-bis(diphenylphosphino)ferrocene-dichloropalladium(II)dichloromethane complex, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium dichloride, tris(diphenyleneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium and palladium trifluoroacetate.

[0031] Furthermore, the catalyst ligand is an organic phosphine ligand.

[0032] Furthermore, the organic phosphine ligand includes at least one of tri(o-tolyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane and 1,1-bis(diphenylphosphino)methane.

[0033] Furthermore, the base includes at least one of triethylamine, cesium carbonate, potassium carbonate and sodium carbonate.

[0034] The fifth aspect of the present invention provides an intermediate III for preparing galanthamine, the structural formula of which is shown in formula (III): Formula (III): .

[0035] The sixth aspect of the present invention provides a method for preparing intermediate III for preparing galanthamine represented by formula (III), comprising the following steps: First, the intermediate II described in claim 3 is reacted with an inorganic base to obtain an organic acid, and then the organic acid, triethylamine and diphenylphosphoryl azide are refluxed to obtain the intermediate III.

[0036] Furthermore, the reaction temperature of intermediate II and the inorganic base is room temperature, and the reaction time is 10-20 h.

[0037] Furthermore, the reflux reaction temperature is 80-120° C., and the time is 10-20 h.

[0038] Furthermore, the solvent for the reaction of intermediate II and the inorganic base is a mixed solvent of an organic solvent and water.

[0039] Furthermore, the volume ratio of the organic solvent to water is 1:1-5.

[0040] Preferably, the volume ratio of the organic solvent to water is 1:1-2.

[0041] Furthermore, the organic solvent includes at least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, acetone, dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether.

[0042] Furthermore, the inorganic base includes at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide.

[0043] The seventh aspect of the present invention provides an intermediate IV for preparing galanthamine, the structural formula of which is shown in formula (IV): Formula (IV): .

[0044] In an eighth aspect of the present invention, a method for preparing an intermediate IV for preparing galanthamine represented by formula (IV) is provided, comprising the following steps: The intermediate III described in claim 5 is fully reacted with a metal hydride, and then iodomethane is added to continue the reaction to obtain the intermediate IV.

[0045] Furthermore, the intermediate III and the excess metal hydride are fully reacted at room temperature until the raw materials are completely consumed.

[0046] Furthermore, the reaction is continued at room temperature for 10-20 h.

[0047] Furthermore, the reaction solvent includes at least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethylformamide and dimethylacetamide.

[0048] Furthermore, the metal hydride includes at least one of lithium hydride, sodium hydride, potassium hydride and magnesium hydride.

[0049] The ninth aspect of the present invention provides the use of the intermediate I, intermediate II, intermediate III, or intermediate IV in the preparation of galanthamine.

[0050] The tenth aspect of the present invention provides a method for preparing galanthamine, comprising the following steps: First, the intermediate IV represented by formula (IV), selenium dioxide, quartz sand, 1,4-dioxane and pyridine are mixed and heated under reflux reaction, and then the reflux reaction product is mixed with lithium aluminum hydride to react to prepare galanthamine.

[0051] Furthermore, selenium dioxide, quartz sand, 1,4-dioxane and pyridine are added in two portions during the heating reflux reaction.

[0052] Furthermore, when selenium dioxide, quartz sand, 1,4-dioxane and pyridine are added for the first time, the reflux reaction is carried out for 10-15 hours at a temperature of 80-120°C; when selenium dioxide, quartz sand, 1,4-dioxane and pyridine are added for the second time, the reflux reaction is carried out for 18-40 hours at a temperature of 80-120°C.

[0053] Furthermore, the molar ratio of intermediate IV, the first added selenium dioxide, and the second added selenium dioxide is 1:1-2:1-2; the molar ratio of intermediate IV, the first added pyridine, and the second added pyridine is 1:3-10:3-10.

[0054] The beneficial effect of adopting the above further technical solution is that the present invention facilitates the complete reaction of the raw materials by adding the reaction materials in batches, thereby improving the reaction product.

[0055] Furthermore, the molar ratio of the heated reflux reaction product to lithium aluminum hydride is 1:1-5.

[0056] Furthermore, the temperature of the mixed reaction is 60-70° C., and the time is 5-7 h.

[0057] Furthermore, the solvent of the mixed reaction includes at least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether.

[0058] The present invention has the following beneficial effects: The present invention uses cheap and readily available commercial compounds as starting materials and provides an asymmetric synthesis method for (-)-galanthamine with a small number of synthetic steps and a high yield. The synthetic method has low raw materials and reagents, low production costs, a short synthetic route, simple operation, and is suitable for large-scale production. The total yield is as high as 17.6%. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 The following is a synthetic route diagram of (-)-galanthamine and its intermediates of the present invention. DETAILED DESCRIPTION

[0060] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples are only used to explain the present invention and are not intended to limit the scope of the invention. In the embodiments, if specific conditions are not specified, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0061] Example 1: Synthesis of Compound 2a The structural formula of compound 2a is: ; It is prepared by Morita-Baylis-Hillman reaction of 2-cyclohexenone and acrylate, which specifically includes the following steps: 2-Cyclohexenone (19.2 g, 200 mmol) and DMF (200 mL) were added to a 500 mL round-bottom flask, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (6.1 g, 40 mmol). The mixture was stirred vigorously for 15 min, and then methyl acrylate (22.4 g, 260 mmol) was added. The mixture was heated under reflux at 80 °C for 24 h. The reaction system was cooled to room temperature and poured into 150 mL of ice water. The mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and washed twice with 50 mL of 1 mol / L hydrochloric acid, and once with 100 mL and 50 mL of saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was distilled under reduced pressure to obtain 32.8 g of compound 2a as a light yellow oil in a yield of 90%.

[0062] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ: 6.76 (dd, J = 4.4, 4.4 Hz,1H), 3.63(s, 3H), 2.52-2.37 (m, 6H), 2.36-2.29 (m, 2H), 1.99-1.91 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ: 199.1, 173.1, 146.2, 138.0, 51.3,38.4, 33.2, 25.9, 25.4, 22.9. HR-MS (EI) m / z Calcd for C 10 H 14 O3 + [M+Na + ] 182.0943, found 182.0935.

[0063] Example 2: Synthesis of Compound 2b The structural formula of compound 2a is: ; It is prepared by Morita-Baylis-Hillman reaction of 2-cyclohexenone and acrylate, which specifically includes the following steps: 2-Cyclohexenone (19.2 g, 200 mmol) and DMF (200 mL) were added to a 500 mL round-bottom flask, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (6.1 g, 40 mmol). The mixture was stirred vigorously for 15 min, and then ethyl acrylate (26.0 g, 260 mmol) was added. The mixture was heated under reflux at 80 °C for 24 h. The reaction system was cooled to room temperature and poured into 150 mL of ice water. The mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and washed twice with 50 mL of 1 mol / L hydrochloric acid, and once with 100 mL and 50 mL of saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was distilled under reduced pressure to obtain 34.5 g of compound 2b as a light yellow oil in a yield of 88%.

[0064] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ:6.75 (t, J = 4.3 Hz, 1H), 4.08 (q, J =7.1 Hz, 2H), 2.51 - 2.43 (m, 2H), 2.43 - 2.35 (m, 4H), 2.32 (td, J = 5.9, 4.3Hz, 2H), 1.94 (p, J = 6.2 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ: 199.1, 173.1, 146.2, 138.0, 60.2, 38.4, 33.2, 25.9, 25.4, 22.9, 14.2. HR-MS (ESI) m / z Calcd for C 11 H 16 O3 + [M+Na + ] 219.0992, found 219.0993.

[0065] Example 3: Synthesis of Compound 2c The structural formula of compound 2c is: ; It is prepared by Morita-Baylis-Hillman reaction of 2-cyclohexenone and acrylate, which specifically includes the following steps: 2-Cyclohexenone (19.2 g, 200 mmol) and DMF (200 mL) were added to a 500 mL round-bottom flask, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (6.1 g, 40 mmol). The mixture was stirred vigorously for 15 min, and then tert-butyl acrylate (33.3 g, 260 mmol) was added. The mixture was heated under reflux at 80 °C for 24 h. The reaction system was cooled to room temperature and poured into 150 mL of ice water. The mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and washed twice with 50 mL of 1 mol / L hydrochloric acid, and once with 100 mL and 50 mL of saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was distilled under reduced pressure to obtain 36.8 g of compound 2c as a light yellow oil in a yield of 82%.

[0066] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 6.75 (t, J = 4.3 Hz, 1H), 2.51 - 2.43(m, 2H), 2.43 - 2.35 (m, 4H), 2.32 (td, J = 5.9, 4.3 Hz, 2H), 1.94 (p, J = 6.2Hz, 2H), 1.44(s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 199.3, 172.6, 146.2, 138.4, 80.3,38.6, 34.6, 28.3, 26.2, 25.8, 23.2. HR-MS (ESI) m / z Calcd for C 13 H 20 O3 + [M+Na +] 247.1305, found 247.1311.

[0067] Example 4: Synthesis of Compound 2d The structural formula of compound 2c is: ; It is prepared by Morita-Baylis-Hillman reaction of 2-cyclohexenone and acrylate, which specifically includes the following steps: 2-Cyclohexenone (19.2 g, 200 mmol) and DMF (200 mL) were added to a 500 mL round-bottom flask. 1,8-diazabicyclo[5.4.0]undec-7-ene (6.1 g, 40 mmol) was then added to the system. The mixture was vigorously stirred for 15 min, and then benzyl acrylate (32.4 g, 260 mmol) was added to the system. The mixture was heated to reflux at 80 °C for 24 h. Finally, the reaction system was cooled to room temperature and poured into 150 mL of ice water. The mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and washed twice with 50 mL of 1 mol / L hydrochloric acid, and once with 100 mL and 50 mL of saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was distilled under reduced pressure to obtain 43.9 g of compound 2d as a light yellow oil in 85% yield.

[0068] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 7.29 - 7.36 (m,5H), 6.75 (t, J = 4.3Hz, 1H), 5.13 (s, 2H), 2.51 - 2.43 (m, 2H), 2.43 - 2.35 (m, 4H), 2.32 (m,2H), 1.94 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 199.3, 172.6, 146.2, 139.2, 138.4,130.6, 130.5, 130.4, 80.3, 68.5, 38.6, 34.6, 28.3, 26.2, 25.8, 23.2. HR-MS (ESI) m / z Calcd for C 16 H 18 O3+ [M+Na + ] 281.1149, found 281.1150.

[0069] Example 5: Synthesis of Compound 3a The structural formula of compound 3a is: ; The compound 2a is prepared by subjecting it to Corey-Bakshi-Shibata reduction, which specifically includes the following steps: Will( S )-2-Methyl-CBS-oxazaborolidine (10.2 g, 36.9 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -20 °C under argon atmosphere. Then, 1 mol / L borane tetrahydrofuran solution (2.6 g, 185.0 mmol) was added dropwise to the above reaction system and stirred for 1 h. Subsequently, compound 2a (33.6 g, 184.5 mmol) dissolved in 10 mL of tetrahydrofuran solution was added to the reaction system at -20 °C and the reaction was continued at this temperature for 16 h. The reaction was quenched with 150 mL of methanol and concentrated under reduced pressure to remove the solvent. The product was then dissolved in 300 mL of ethyl acetate and washed with 100 mL of 1 mol / L hydrochloric acid. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain 31.0 g colorless oily product compound 3a, yield 85%, 90% ee.

[0070] The results of NMR, mass spectrometry and gas chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 5.54 (t, J = 4.0 Hz, 1H), 4.04 (t, J =4.4 Hz, 1H), 3.63 (s, 3H), 2.52 - 2.33 (m, 4H), 2.16 (s, 1H), 2.02 (dd, J =18.3, 4.9 Hz, 1H), 1.91 (d, J = 19.0 Hz, 1H), 1.73 (m, 2H), 1.63 (h, J = 6.8 Hz,1H), 1.53 (dt, J = 12.6, 5.6 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.8, 137.9, 125.8, 66.8, 51.6, 33.2, 32.1, 29.3, 25.4, 18.0. HR-MS (ESI) m / z Calcd for C 10 H 16 O3 + [M+Na + ] 207.0992, found 207.0993. GC conditions: chiral β-Dex 120 column (30 m × 0.25 μm × 0.25 mm), t R = 35.003min (minor), 35.475min (major). [α] D 27.5 = +37.80 ( c = 0.06, CHCl3).

[0071] Example 6: Synthesis of Compound 3b The structural formula of compound 3b is: ; The compound 2b was prepared by subjecting it to Corey-Bakshi-Shibata reduction, which specifically includes the following steps: Will( S )-2-Methyl-CBS-oxazaborolidine (10.2 g, 36.9 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -20 °C under argon atmosphere. Then, 1 mol / L borane tetrahydrofuran solution (2.6 g, 185.0 mmol) was added dropwise to the above reaction system and stirred for 1 h. Subsequently, compound 2b (36.2 g, 184.5 mmol) dissolved in 10 mL of tetrahydrofuran solution was added to the reaction system at -20 °C and the reaction was continued at this temperature for 16 h. The reaction was quenched with 150 mL of methanol and concentrated under reduced pressure to remove the solvent. The product was then dissolved in 300 mL of ethyl acetate and washed with 100 mL of 1 mol / L hydrochloric acid. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain 35.1 g Colorless oily product compound 3b, yield 96%, 97% ee.

[0072] The results of NMR, mass spectrometry and gas chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 5.54 (t, J = 4.0 Hz, 1H), 4.11 (q, J =7.1 Hz, 2H), 4.04 (t, J = 4.4 Hz, 1H), 2.52 - 2.33 (m, 4H), 2.16 (s, 1H), 2.02(dd, J = 18.3, 4.9 Hz, 1H), 1.91 (d, J = 19.0 Hz, 1H), 1.73 (m, 2H), 1.63 (h, J =6.8 Hz, 1H), 1.53 (dt, J = 12.6, 5.6 Hz, 1H), (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.8, 137.9, 125.8, 66.8, 60.3,33.2, 32.1, 29.3, 25.4, 18.0, 14.2. HR-MS (ESI) m / z Calcd for C 11 H 18 O3 + [M+Na + ] 221.1149, found 221.1150. GC conditions: chiral β-Dex 120 column (30 m × 0.25 μm × 0.25 mm), t R = 35.305min (minor), 35.775min (major). [α] D 27.5 = +37.60 ( c = 0.06, CHCl3).

[0073] Example 7: Synthesis of Compound 3c The structural formula of compound 3c is: ; The compound 2c was prepared by subjecting it to Corey-Bakshi-Shibata reduction, which specifically includes the following steps: Will( S )-2-Methyl-CBS-oxazaborolidine (10.2 g, 36.9 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -20 °C under argon atmosphere. Then, 1 mol / L borane tetrahydrofuran solution (2.6 g, 185.0 mmol) was added dropwise to the above reaction system and stirred for 1 h. Subsequently, compound 2c (36.2 g, 184.5 mmol) dissolved in 10 mL of tetrahydrofuran solution was added to the reaction system at -20 °C and the reaction was continued at this temperature for 16 h. The reaction was quenched with 150 mL of methanol and concentrated under reduced pressure to remove the solvent. The product was then dissolved in 300 mL of ethyl acetate and washed with 100 mL of 1 mol / L hydrochloric acid. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain 37.2 g Colorless oily product compound 3c, yield 89%, 96% ee.

[0074] The results of NMR, mass spectrometry and gas chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 5.54 (t, J = 4.0 Hz, 1H), 4.04 (t, J =4.4 Hz, 1H), 2.52 - 2.33 (m, 4H), 2.16 (s, 1H), 2.02 (dd, J = 18.3, 4.9 Hz,1H), 1.91 (d, J = 19.0 Hz, 1H), 1.73 (m, 2H), 1.63 (h, J = 6.8 Hz, 1H), 1.53 (dt, J = 12.6, 5.6 Hz, 1H), 1.44(s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.8, 137.9, 125.8, 80.3, 66.8,51.6, 33.2, 32.1, 29.3, 25.4, 18.2. HR-MS (ESI) m / z Calcd for C 13 H 22 O3 + [M+Na + ] 249.1462, found 249.1463. GC conditions: chiral β-Dex 120 column (30 m × 0.25 μm × 0.25 mm), t R = 37.254min (minor), 37.728min (major). [α] D 27.5 = +38.50 ( c = 0.06, CHCl3).

[0075] Example 8: Synthesis of Compound 3d The structural formula of compound 3d is: ; The compound 2d is prepared by subjecting it to Corey-Bakshi-Shibata reduction, which specifically comprises the following steps: Will( S )-2-Methyl-CBS-oxazaborolidine (10.2 g, 36.9 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -20 °C under argon atmosphere. Then, 1 mol / L borane tetrahydrofuran solution (2.6 g, 185.0 mmol) was added dropwise to the above reaction system and stirred for 1 h. Subsequently, compound 2d (36.2 g, 184.5 mmol) dissolved in 10 mL of tetrahydrofuran solution was added to the reaction system at -20 °C and the reaction was continued at this temperature for 16 h. The reaction was quenched with 150 mL of methanol and concentrated under reduced pressure to remove the solvent. The product was then dissolved in 300 mL of ethyl acetate and washed with 100 mL of 1 mol / L hydrochloric acid. The aqueous phase was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by flash column chromatography to obtain 44.1 g The product compound 3d was a colorless oil with a yield of 92% and 96% ee.

[0076] The results of NMR, mass spectrometry and gas chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 7.29 - 7.36 (m,5H), 5.54 (t,J = 4.0Hz, 1H), 5.13 (s, 2H), 4.04 (t, J = 4.4 Hz, 1H), 2.52 - 2.33 (m, 4H), 2.16 (s,1H), 2.02 (dd, J = 18.3, 4.9 Hz, 1H), 1.91 (d, J = 19.0 Hz, 1H), 1.73 (m, 2H), 1.63 (h, J = 6.8 Hz, 1H), 1.53 (dt, J = 12.6, 5.6 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.0, 138.4, 137.8, 130.2, 130.2, 130.0, 124.9, 70.7, 68.1, 34.9, 34.2, 31.7, 28.1, 22.0. HR-MS (ESI) m / z Calcd for C 16 H 20 O3 + [M+Na + ] 283.1305, found 283.1305. GC conditions: chiral β-Dex 120 column (30 m × 0.25 μm × 0.25 mm), t R = 36.226min (minor), 26.695min (major). [α] D 27.5 = +39.20 ( c = 0.06, CHCl3).

[0077] Example 9: Synthesis of Intermediate I (Compound 5aa) The structural formula of compound 5aa is: ; The compound 3a and compound 4a (3-hydroxy-2-iodo-4-methoxybenzaldehyde) were reacted to obtain the product through Mitsunobu reaction, which specifically includes the following steps: Compound 3a (6.1 g, 33.0 mmol) and compound 4a (18.5 g, 66.0 mmol) were dissolved in 100 mL of tetrahydrofuran. Under an argon atmosphere, the reactant was cooled to -10 °C. Tributylphosphine (13.3 g, 57.2 mmol) was then added to the system and stirred at -10 °C for 15 min. N,N,N',N' A solution of 1-tetramethylazodicarbonamide (11.4 g, 66 mmol) dissolved in 250 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 h. Finally, the mixture was filtered through celite, and the filter cake was washed three times with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to remove the solvent and then redissolved in 300 mL of dichloromethane. The organic phase was washed twice with 50 mL of 1 mol / L sodium hydroxide solution and once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford 10.4 g of compound 5aa as a white solid in 70% yield and 89% ee.

[0078] The results of NMR, mass spectrometry and liquid chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 10.05 (s, 1H), 7.67 (d, J = 8.6 Hz,1H), 6.96 (d, J = 8.6 Hz, 1H), 5.75 (t, J = 3.8 Hz, 1H), 4.96 (t, J = 3.9 Hz, 1H),3.94 (s, 3H), 3.63 (s, 3H), 2.69 - 2.50 (m, 4H), 2.20 -2.13 (m, 1H), 2.12 -1.96 (m, 2H), 1.94 - 1.87 (m, 1H), 1.57 - 1.43 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 195.7, 173.6, 157.2, 146.9, 135.5,129.3, 128.1, 126.4, 111.7, 101.6, 80.4, 57.1, 52.6, 33.6, 29.7, 28.4, 25.4,18.7. HR-MS (ESI) m / z Calcd for C 18 H 21 IO5 + [M+Na + ]467.0327, found 467.0328. HPLC conditions (OD-H, isopropanol / n-hexane = 33 / 57, flow rate = 1.0 mL / min, wavelength = 309 nm), t R = 13.306 min (minor), 16.557 min (major). [α] D 27.5 = -8.60 ( c = 0.05, CHCl3).

[0079] Example 10: Synthesis of Intermediate I (Compound 5ba) The structural formula of compound 5ba is: ; The product was prepared by Mitsunobu reaction of compound 3b and compound 4a (3-hydroxy-2-iodo-4-methoxybenzaldehyde), which specifically includes the following steps: Compound 3b (6.5 g, 33.0 mmol) and compound 4a (18.5 g, 66.0 mmol) were dissolved in 100 mL of tetrahydrofuran. Under an argon atmosphere, the reaction was cooled to -10 °C. Tributylphosphine (13.3 g, 57.2 mmol) was then added to the system and stirred at -10 °C for 15 min. N,N,N',N' A solution of 1-tetramethylazodicarbonamide (11.4 g, 66 mmol) dissolved in 250 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 h. Finally, the mixture was filtered through celite, and the filter cake was washed three times with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to remove the solvent and then redissolved in 300 mL of dichloromethane. The organic phase was washed twice with 50 mL of 1 mol / L sodium hydroxide solution and once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford 11.4 g of compound 5ba as a white solid in 75% yield and 99% ee.

[0080] The results of NMR, mass spectrometry and liquid chromatography are shown below: 1 H NMR (400 MHz, Chloroform-d ) δ 10.05 (s, 1H), 7.67 (d, J = 8.6 Hz,1H), 6.96 (d, J = 8.6 Hz, 1H), 5.75 (t, J = 3.8 Hz, 1H), 4.96 (t, J = 3.9 Hz, 1H),4.12 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 2.69 - 2.50 (m, 4H), 2.20 -2.13 (m,1H), 2.12 - 1.96 (m, 2H), 1.94 - 1.87 (m, 1H), 1.57 - 1.43 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 195.7, 173.6, 157.2, 146.9, 135.5,129.3, 128.1, 126.4, 111.7, 101.6, 77.0, 60.2, 55.9, 33.6, 29.7, 28.4, 25.4,18.7, 14.3. HR-MS (ESI) m / z Calcd for C 19 H 23 IO5 + [M+Na + ]481.0483, found 481.0484. HPLC conditions (OD-H, isopropanol / n-hexane = 33 / 57, flow rate = 1.0 mL / min, wavelength = 309 nm), t R = 12.973 min (minor), 16.239 min (major). [α] D 27.5 = -8.00 ( c = 0.05 , CHCl3).

[0081] Example 11: Synthesis of Intermediate I (Compound 5bb) The structural formula of compound 5bb is: ; The product was prepared by Mitsunobu reaction of compound 3b and compound 4b (3-hydroxy-2-bromo-4-methoxybenzaldehyde), which specifically includes the following steps: Compound 3b (6.5 g, 33.0 mmol) and compound 4b (15.2 g, 66.0 mmol) were dissolved in 100 mL of tetrahydrofuran. Under an argon atmosphere, the reactant was cooled to -10 °C. Tributylphosphine (13.3 g, 57.2 mmol) was then added to the system and stirred at -10 °C for 15 min. N,N,N',N' A solution of 1-tetramethylazodicarbonamide (11.4 g, 66 mmol) dissolved in 250 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 h. Finally, the mixture was filtered through celite, and the filter cake was washed three times with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to remove the solvent and then redissolved in 300 mL of dichloromethane. The organic phase was washed twice with 50 mL of 1 mol / L sodium hydroxide solution and once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford 9.5 g of compound 5bb as a white solid in a 70% yield and 99% ee.

[0082] The results of NMR, mass spectrometry and liquid chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 10.00 (s, 1H), 7.66 (d, J = 8.6 Hz,1H), 6.94 (d, J = 8.6 Hz, 1H), 5.73 (t, J = 3.8 Hz, 1H), 4.95 (t, J = 3.9 Hz, 1H),4.10 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 2.69 - 2.50 (m, 4H), 2.20 -2.13 (m,1H), 2.12 - 1.96 (m, 2H), 1.94 - 1.87 (m, 1H), 1.57 - 1.43 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 194.3, 173.5, 157.1, 147.0, 135.4,129.1, 128.0, 126.5, 111.7, 101.6, 77.0, 60.2, 55.9, 33.6, 29.7, 28.4, 25.4,18.7, 14.3. HR-MS (ESI) m / z Calcd for C 19 H 23 BrO5 + [M+Na + ] 433.0621, found 433.0624. HPLC conditions (OD-H, isopropanol / n-hexane = 33 / 57, flow rate = 1.0 mL / min, wavelength = 309 nm), t R = 13.554 min (minor), 16.427 min (major). [α] D 27.5 = -7.90 ( c = 0.05, CHCl3).

[0083] Example 12: Synthesis of Intermediate I (Compound 5ca) The structural formula of compound 5ca is: ; The product was prepared by Mitsunobu reaction of compound 3c and compound 4a (3-hydroxy-2-iodo-4-methoxybenzaldehyde), which specifically includes the following steps: Compound 3c (7.5 g, 33.0 mmol) and compound 4a (18.5 g, 66.0 mmol) were dissolved in 100 mL of tetrahydrofuran. Under an argon atmosphere, the reaction was cooled to -10 °C. Tributylphosphine (13.3 g, 57.2 mmol) was then added to the system and stirred at -10 °C for 15 min. N,N,N',N'A solution of 1-tetramethylazodicarbonamide (11.4 g, 66 mmol) dissolved in 250 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 h. Finally, the mixture was filtered through celite, and the filter cake was washed three times with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to remove the solvent, and the mixture was redissolved in 300 mL of dichloromethane. The organic phase was washed twice with 50 mL of 1 mol / L sodium hydroxide solution and once with 100 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford 10.6 g of compound 5ca as a white solid in a 67% yield and 99% ee.

[0084] The results of NMR, mass spectrometry and liquid chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 10.05 (s, 1H), 7.67 (d, J = 8.6 Hz,1H), 6.96 (d, J = 8.6 Hz, 1H), 5.75 (t, J = 3.8 Hz, 1H), 4.96 (t, J = 3.9 Hz, 1H),3.95 (s, 3H), 2.69 - 2.45 (m, 4H), 2.20 -2.13 (m, 1H), 2.12 - 1.96 (m, 2H),1.94 - 1.87 (m, 1H), 1.57 - 1.43 (m, 2H), 1.48 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 194.9, 173.6, 157.2, 146.9, 135.5,129.3, 128.1, 126.4, 111.7, 101.6, 81.1, 80.4, 57.1, 34.3, 32.7, 32.4, 28.7,27.3, 21.7. HR-MS (ESI) m / z Calcd for C 21 H 27 IO5 + [M+Na + ]509.0796, found 509.0798. HPLC conditions (OD-H, isopropanol / n-hexane = 33 / 57, flow rate = 1.0 mL / min, wavelength = 309 nm), t R = 12.602 min (minor), 15.943 min (major). [α] D 27.5 = -8.25 ( c = 0.05, CHCl3).

[0085] Example 13: Synthesis of Intermediate I (Compound 5da) The structural formula of compound 5da is: ; The compound 3d and compound 4a (3-hydroxy-2-iodo-4-methoxybenzaldehyde) were reacted via Mitsunobu reaction, which specifically includes the following steps: Compound 3d (7.5 g, 33.0 mmol) and compound 4a (18.5 g, 66.0 mmol) were dissolved in 100 mL of tetrahydrofuran. Under an argon atmosphere, the reactant was cooled to -10 °C. Tributylphosphine (13.3 g, 57.2 mmol) was then added to the system and stirred at -10 °C for 15 min. N,N,N',N' A solution of 1-tetramethylazodicarbonamide (11.4 g, 66 mmol) dissolved in 250 mL of tetrahydrofuran was added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 h. Finally, the mixture was filtered through celite, and the filter cake was washed three times with 100 mL of ethyl acetate. The combined filtrates were concentrated under reduced pressure to remove the solvent, and the mixture was redissolved in 300 mL of dichloromethane. The organic phase was washed twice with 50 mL of 1 mol / L sodium hydroxide solution and once with 100 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography to afford 10.6 g of compound 5da as a white solid in a 67% yield and 99% ee.

[0086] The results of NMR, mass spectrometry and liquid chromatography are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 10.05 (s, 1H), 7.67 (d, J = 8.6 Hz,1H), 7.53 - 7.31 (m, 5H), 6.96 (d, J= 8.6 Hz, 1H), 5.75 (t, J = 3.8 Hz, 1H),5.17 (s, 2H), 4.96 (t, J = 3.9 Hz, 1H), 3.94 (s, 3H), 2.62 - 2.47 (m, 4H), 2.18- 2.03 (m, 3H), 1.97 - 1.85 (m, 1H), 1.84 - 1.74 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 195.7, 173.1, 154.8, 150.4, 137.3,137.1, 129.6, 129.5, 129.5, 129.3, 127.8, 123.9, 114.8, 97.2, 80.4, 67.4,57.1, 33.7, 32.8, 32.4, 27.3, 21.7. HR-MS (ESI) m / z Calcd for C 24 H 25 IO5 + [M+Na + ]543.3528, found 543.3529. HPLC conditions (OD-H, isopropanol / n-hexane = 33 / 57, flow rate = 1.0 mL / min, wavelength = 309 nm), t R = 13.177 min (minor), 16.549 min (major). [α] D 27.5 = -8.70 ( c = 0.05, CHCl3).

[0087] Example 14: Synthesis of Intermediate II (Compound 6a) The structural formula of compound 6a is: ; The intermediate I, a catalyst, a catalyst ligand and a base are subjected to a heating reflux reaction in a solvent to obtain the product, which specifically comprises the following steps: Compound 5aa (8.4 g, 19 mmol) was dissolved in 150 mL of DMF. Under an argon atmosphere, palladium acetate (0.43 g, 1.9 mmol), 1,2-bis(diphenylphosphino)ethane (1.52 g, 3.8 mmol), and silver carbonate (15.72 g, 57 mmol) were added sequentially to the system. The reaction system was then heated to 100 °C and refluxed for 16 h. After complete conversion of the starting materials, the reaction was cooled to room temperature and the insoluble matter was filtered through celite. The solid impurities were washed three times with 30 mL of ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 4.6 g of compound 6a as a colorless oil in a yield of 76%.

[0088] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 9.89 (s, 1H), 7.60 (d, J = 8.4 Hz,1H), 7.02 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H), 5.72 (dt, J = 8.9, 4.6 Hz,1H), 4.66 (dd, J = 5.5, 2.6 Hz, 1H), 3.95 (s, 3H), 3.63 (s, 3H), 2.49 (ddd, J =13.5, 10.6, 5.3 Hz, 1H), 2.32 - 2.05 (m, 5H), 1.97 (dq, J = 16.6, 5.1, 4.4 Hz,1H), 1.91 - 1.73 (m, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 190.5, 173.4, 147.8, 144.6, 133.7,132.9, 130.7, 126.9, 125.2, 113.5, 87.1, 55.6, 50.9, 48.4, 33.9, 28.3, 23.9,22.6. HR-MS (ESI) m / z Calcd for C 18 H 20 O5 + [M+Na +]339.1204, found 339.1206. [α] D 28.0 = -70.20 ( c = 0.02, CHCl3).

[0089] Example 15: Synthesis of Intermediate II (Compound 6b) The structural formula of compound 6b is: ; The intermediate I, a catalyst, a catalyst ligand and a base are subjected to a heating reflux reaction in a solvent to obtain the product, which specifically comprises the following steps: Compound 5ba (8.7 g, 19 mmol) was dissolved in 150 mL of DMF. Under an argon atmosphere, palladium acetate (0.43 g, 1.9 mmol), 1,2-bis(diphenylphosphino)ethane (1.52 g, 3.8 mmol), and silver carbonate (15.72 g, 57 mmol) were added sequentially to the system. The reaction system was then heated to 100 °C and refluxed for 16 h. After complete conversion of the raw materials, the reaction was cooled to room temperature and the insoluble matter was filtered through celite. The solid impurities were washed three times with 30 mL of ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 5.1 g of compound 6b as a colorless oil in an 81% yield.

[0090] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 9.89 (s, 1H), 7.36 (d, J = 8.4 Hz,1H), 6.88 (d, J = 8.4 Hz, 1H), 6.10 (d, J = 10.0 Hz, 1H), 5.87 (ddd, J = 10.2, 5.4,2.8 Hz, 1H), 4.79 (t, J = 4.0 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 2.49 (ddd, J = 13.5, 10.6, 5.3 Hz, 1H), 2.32 - 2.05 (m, 5H), 1.97 (dq, J= 16.6,5.1, 4.4 Hz, 1H), 1.91 - 1.73 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 190.5, 173.1, 149.8, 148.6, 133.2,129.6, 129.3, 128.4, 126.9, 110.3, 86.0, 60.4, 56.0, 50.0, 32.3, 30.3, 24.6,19.2, 14.1. HR-MS (ESI) m / z Calcd for C 19 H 22 O5 + [M+Na + ]353.1360, found 353.1361. [α] D 28.0 = -70.00 ( c = 0.02, CHCl3).

[0091] Example 16: Synthesis of Intermediate II (Compound 6b) The structural formula of compound 6b is: ; The intermediate I, a catalyst, a catalyst ligand and a base are subjected to a heating reflux reaction in a solvent to obtain the product, which specifically comprises the following steps: Compound 5bb (7.8 g, 19 mmol) was dissolved in 150 mL of DMF. Under an argon atmosphere, palladium acetate (0.43 g, 1.9 mmol), 1,2-bis(diphenylphosphino)ethane (1.52 g, 3.8 mmol), and silver carbonate (15.72 g, 57 mmol) were added sequentially to the system. The reaction system was then heated to 100 °C and refluxed for 16 h. After complete conversion of the raw materials, the reaction was cooled to room temperature and the insoluble matter was filtered through celite. The solid impurities were washed three times with 30 mL of ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 4.7 g of compound 6b as a colorless oil in a yield of 75%.

[0092] The NMR and mass spectrometry results are the same as those in Example 15.

[0093] Example 17: Synthesis of Intermediate II (Compound 6c) The structural formula of compound 6c is: ; The intermediate I, a catalyst, a catalyst ligand and a base are subjected to a heating reflux reaction in a solvent to obtain the product, which specifically comprises the following steps: Compound 5ca (9.2 g, 19 mmol) was dissolved in 150 mL of DMF. Under an argon atmosphere, palladium acetate (0.43 g, 1.9 mmol), 1,2-bis(diphenylphosphino)ethane (1.52 g, 3.8 mmol), and silver carbonate (15.72 g, 57 mmol) were added sequentially to the system. The reaction system was then heated to 100 °C and refluxed for 16 h. After complete conversion of the raw materials, the reaction was cooled to room temperature and the insoluble matter was filtered through celite. The solid impurities were washed three times with 30 mL of ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 5.1 g of compound 6c as a colorless oil in a yield of 57%.

[0094] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 9.89 (s, 1H), 7.60 (d, J = 8.4 Hz,1H), 7.02 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H), 5.72 (dt, J = 8.9, 4.6 Hz,1H), 4.66 (dd, J = 5.5, 2.6 Hz, 1H), 3.95 (s, 3H), 2.49 (ddd, J = 13.5, 10.6, 5.3Hz, 1H), 2.32 - 2.05 (m, 5H), 1.97 (dq, J = 16.6, 5.1, 4.4 Hz, 1H), 1.91 - 1.73(m, 1H), 1.50 (s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 190.5, 173.1, 147.8, 144.6, 133.7,132.9, 130.7, 126.9, 125.2, 113.5, 87.1, 79.6, 55.6, 48.4, 33.8, 29.6, 27.2,23.9, 22.6. HR-MS (ESI) m / z Calcd for C 21 H 26 O5 + [M+Na + ]381.1673, found 381.1674. [α] D 28.0 = -69.60 ( c = 0.02, CHCl3).

[0095] Example 18: Synthesis of Intermediate II (Compound 6d) The structural formula of compound 6d is: ; The intermediate I, a catalyst, a catalyst ligand and a base are subjected to a heating reflux reaction in a solvent to obtain the product, which specifically comprises the following steps: Compound 5da (9.9 g, 19 mmol) was dissolved in 150 mL of DMF. Under an argon atmosphere, palladium acetate (0.43 g, 1.9 mmol), 1,2-bis(diphenylphosphino)ethane (1.52 g, 3.8 mmol), and silver carbonate (15.72 g, 57 mmol) were added sequentially to the system. The reaction system was then heated to 100°C and refluxed for 16 h. After complete conversion of the starting materials, the reaction was cooled to room temperature and the insoluble matter was filtered through celite. The solid impurities were washed three times with 30 mL of ethyl acetate. The filtrates were combined and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain 4.8 g of compound 6d as a colorless oil in a yield of 64%.

[0096] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 9.89 (s, 1H), 7.60 (d, J = 8.4 Hz,1H), 7.47 - 7.34 (m, 5H), 7.02 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.8 Hz, 1H),5.72 (dt,J = 8.9, 4.6 Hz, 1H), 5.20 (s, 2H), 4.66 (dd, J = 5.5, 2.6 Hz, 1H), 3.95 (s, 3H), 2.49 (ddd, J = 13.5, 10.6, 5.3 Hz, 1H), 2.32 - 2.05 (m, 5H), 1.97(dq, J = 16.6, 5.1, 4.4 Hz, 1H), 1.91 - 1.73 (m, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 190.5, 172.4, 147.8, 144.6, 135.5,133.7, 132.9, 130.7, 128.0, 128.0, 127.8, 126.9, 125.2, 113.5, 87.1, 65.9,55.6, 48.4, 33.9, 28.7, 23.9, 22.6. HR-MS (ESI) m / z Calcd for C 24 H 24 O5 + [M+Na + ]415.1517, found 415.1518. [α] D 28.0 = -70.80 ( c = 0.02, CHCl3).

[0097] Example 19: Synthesis of Intermediate III (Compound 7) The structural formula of compound 7 is: ; The method comprises the following steps: firstly reacting intermediate II with an inorganic base to obtain an organic acid, and then mixing the organic acid, triethylamine and diphenylphosphoryl azide to carry out a reflux reaction. Compound 6b (4.0 g, 12.4 mmol) was dissolved in 120 mL of a mixture of tetrahydrofuran and water (the volume ratio of tetrahydrofuran to water was 1:1). LiOH·H2O (1.0 g, 24.7 mmol) was then added portionwise and reacted at room temperature for 16 h. TLC confirmed the complete reaction of the starting material. The solvent was removed by concentration under reduced pressure to obtain a yellow-brown solid. The solid was then dissolved in 100 mL of water and washed twice with 100 mL of ethyl acetate. The aqueous phase was acidified with 50 mL of 1 mol / L hydrochloric acid solution and extracted four times with 100 mL of ethyl acetate. The organic phases were combined, washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product, which was used directly in the next reaction.

[0098] The above crude product, triethylamine (2.5 g, 24.7 mmol) and tert-butanol (40 mL) were added to a 100 mL three-necked flask, and the argon atmosphere was replaced. Under ice bath conditions, diphenylphosphoryl azide (4.4 g, 16 mmol) was added dropwise through a constant pressure dropping funnel. After the addition was complete, the ice bath was removed, and the reaction was heated to 100 °C and refluxed for 16 hours. TLC showed that the raw material had completely reacted. The solvent was removed by concentration under reduced pressure, and ethyl acetate (300 mL) was added to dissolve the mixture. Subsequently, the mixture was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by silica gel flash column chromatography to obtain 3.2 g of white solid product compound 7 with a yield of 69%.

[0099] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 9.85 (s, 1H), 7.33 (d, J = 8.4 Hz,1H), 6.86 (d, J = 8.3 Hz, 1H), 6.06 (d, J = 10.1 Hz, 1H), 5.83 (ddd, J = 9.7, 5.5,2.5 Hz, 1H), 4.92 (t, J = 3.8 Hz, 1H), 4.52 (m, 1H), 3.94 (s, 3H), 3.19 - 3.05(m, 1H), 2.92 (s, 1H), 2.34 (ddd, J= 13.4, 10.7, 5.5 Hz, 1H), 2.29 - 2.19 (m,1H), 2.19 - 2.01 (m, 2H), 2.00 - 1.89 (m, 1H), 1.90 - 1.79 (m, 1H), 1.40 (s,9H). 13 C NMR (101 MHz, Chloroform- d ) δ 190.9, 155.7, 149.9, 148.6, 133.1,130.2, 129.2, 128.1, 126.9, 110.2, 86.3, 79.1, 56.0, 49.3, 37.0, 28.3, 26.9,24.5, 19.1. HR-MS (ESI) m / z Calcd for C 21 H 27 NO5 + [M+Na + ]396.1782, found 396.1783. [α] D 28.1 = -72.60 ( c = 0.01, CHCl3).

[0100] Example 20: Synthesis of Intermediate IV (Compound 8) The structural formula of compound 8 is: ; The intermediate III is reacted with a metal hydride, and then iodomethane is added to continue the reaction to obtain the product, which specifically comprises the following steps: Compound 7 (5.0 g, 13.4 mmol) was dissolved in 400 mL of tetrahydrofuran at room temperature, and then 60% by weight of sodium hydride (5.4 g, 133.9 mmol) was added. The reaction mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the conversion of the initial raw material was complete, iodomethane (3.6 g, 25 mmol) was added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the excess sodium hydride was carefully quenched with water, and then the mixture was fully extracted three times with 100 mL of dichloromethane. The organic phases were combined and washed once with 200 mL of water and once with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain 3.4 g of nearly pure white solid product compound 8 with a yield of 90%.

[0101] The results of NMR and mass spectrometry are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.38 (d, J = 8.4 Hz, 1H), 6.84 (d, J =8.5 Hz, 1H), 5.64 (dd, J = 9.9, 5.7 Hz, 1H), 5.41 (dt, J = 9.9, 2.7 Hz, 1H), 4.70(t, J = 1.9 Hz, 1H), 3.90 (s, 3H), 3.75 (td, J = 14.4, 2.9 Hz, 1H), 3.21 - 3.09(m, 4H), 2.38 (td, J = 13.8, 3.8 Hz, 2H), 2.27 (ddt, J = 14.3, 5.2, 2.6 Hz, 1H),1.93 (dt, J = 17.7, 5.9 Hz, 1H), 1.82 (dt, J = 14.5, 2.7 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.9, 146.6, 146.3, 132.4, 131.4,124.6, 123.67, 123.3, 111.5, 89.9, 55.9, 49.8, 47.9, 40.3, 34.9, 22.0, 18.4. HR-MS (ESI) m / z Calcd for C 17 H 20 NO3 + [M+H + ]286.1438, found 286.1440. [α] D 28.3 = -68.00 ( c = 0.01, CHCl3).

[0102] Example 21: Synthesis of (-)-Galantamine The structural formula of (-)-galantamine is: ; The method comprises first mixing intermediate IV, selenium dioxide, quartz sand, 1,4-dioxane and pyridine, heating and refluxing the mixture, and then mixing the reflux reaction product with lithium aluminum hydride to react the mixture, and specifically comprising the following steps: Compound 8 (2.0 g, 7.0 mmol), selenium dioxide (1.6 g, 14.0 mmol), quartz sand (1.6 g), 1,4-dioxane (60 mL) and pyridine (2.2 g, 28.0 mmol) were first added to a dry 100 mL three-necked flask and refluxed at 100 °C for 16 h under argon atmosphere. Then, the second portion of the reaction material was added to the reaction system: selenium dioxide (1.6 g, 14.0 mmol), quartz sand (1.6 g), 1,4-dioxane (60 mL) and pyridine (2.2 g, 28.0 mmol). The reaction was refluxed again at 100 °C for 32 h. The conversion of the raw materials was complete after TLC monitoring. The reaction mixture was cooled to room temperature, filtered through celite, and filtered with 20 The filter cake was washed with 1 mL of dichloromethane, and the filtrate was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain 1.42 g of intermediate V as a white solid. The yield was 67% and the diastereoselectivity ratio of the product was 5:1.

[0103] Intermediate V (1.0 g, 3.3 mmol) was dissolved in 60 mL of tetrahydrofuran. Lithium aluminum hydride (0.63 g, 16.6 mmol) was slowly added to the solution at 0°C. After the addition was complete, the reaction was incubated at 65°C for 6 h. TLC monitored the complete consumption of the starting material. The reaction mixture was cooled in an ice bath and diluted with 60 mL of ethyl acetate. The reaction was quenched with a 10% (mass fraction) aqueous sodium hydroxide solution and then extracted twice with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography to obtain 0.87 g of a white solid product, (-)-galanthamine, with a yield of 92%.

[0104] The NMR and mass spectrometry results are shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 6.63 (q, J = 8.2 Hz, 2H), 6.09 - 5.95(m, 2H), 4.61 (t, J = 2.6 Hz, 1H), 4.13 (s, 1H), 4.08 (d, J = 15.2 Hz, 1H), 3.82(s, 3H), 3.68 (d, J= 15.6 Hz, 1H), 3.26 (td, J = 13.7, 12.8, 1.9 Hz, 1H), 3.05(dt, J = 14.5, 3.7 Hz, 1H), 2.68 (ddt, J = 15.7, 3.3, 1.5 Hz, 1H), 2.40 (s, 3H), 2.08 (td, J = 13.2, 3.2 Hz, 1H), 2.00 (ddd, J = 15.7, 5.0, 2.5 Hz, 1H), 1.57(ddd, J = 13.8, 4.1, 1.9 Hz, 1H). 13 C NMR (101 MHz, Chloroform- d ) δ 145.8, 144.1, 133.0, 129.3, 127.6,126.8, 122.0, 111.2, 88.7, 62.0, 60.6, 55.9, 53.8, 48.2, 42.1, 33.8, 29.9. HR-MS (ESI) m / z Calcd for C 17 H 22 NO3 + [M+H + ]288.1594, found 288.1596. [α] D 28.5 = -80.00 ( c = 0.01, CHCl3).

[0105] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in 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): Formula (I): ; In formula (I), X is a halo group; R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

2. The method for preparing the intermediate I for preparing galanthamine according to claim 1, wherein The following steps are involved: First, 2-cyclohexenone and acrylate were subjected to a Morita-Bells-Hillman reaction, and then the product of the Morita-Bells-Hillman reaction was subjected to a Corey-Bakshi-Shibata reaction. Finally, the product of the Corey-Bakshi-Shibata reaction was subjected to a Mitsunobu reaction with 3-hydroxy-2-halogenated-4-methoxybenzaldehyde to prepare intermediate I.

3. An intermediate II for preparing galanthamine, characterized in that, The structural formula is shown in formula (II): Formula (II): ; In formula (II), R includes any one of an alkyl group, a halogenated alkyl group, an alkoxyalkyl group, and an aryl group.

4. The method for preparing the intermediate II for preparing galanthamine according to claim 3, characterized in that: The following steps are involved: The intermediate I according to claim 1, a catalyst, a catalyst ligand and a base are subjected to heating reflux reaction to obtain an intermediate II.

5. An intermediate III for preparing galanthamine, characterized in that, The structural formula is shown in formula (III): Formula (III): .

6. The method for preparing the intermediate III for preparing galanthamine according to claim 5, characterized in that: The following steps are involved: First, the intermediate II described in claim 3 is reacted with an inorganic base to obtain an organic acid, and then the organic acid, triethylamine and diphenylphosphoryl azide are refluxed to obtain the intermediate III.

7. An intermediate IV for preparing galanthamine, characterized in that, The structural formula is shown in formula (IV): Formula (IV): .

8. The method for preparing the intermediate IV for preparing galanthamine according to claim 7, characterized in that: The following steps are involved: The intermediate III described in claim 5 is fully reacted with a metal hydride, and then iodomethane is added to continue the reaction to obtain the intermediate IV.

9. Use of the intermediate I according to claim 1, the intermediate II according to claim 3, the intermediate III according to claim 5, or the intermediate IV according to claim 7 in the preparation of galanthamine.

10. A method for preparing galanthamine, characterized in that: The following steps are involved: First, the intermediate IV described in claim 7, selenium dioxide, quartz sand, 1,4-dioxane and pyridine are mixed and heated under reflux reaction, and then the reflux reaction product is mixed with lithium aluminum hydride to react to obtain galanthamine.

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