CN112521364A - Galanthamine intermediate compound V - Google Patents

Galanthamine intermediate compound V Download PDF

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CN112521364A
CN112521364A CN201910875488.5A CN201910875488A CN112521364A CN 112521364 A CN112521364 A CN 112521364A CN 201910875488 A CN201910875488 A CN 201910875488A CN 112521364 A CN112521364 A CN 112521364A
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galanthamine
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CN112521364B (en
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张贵民
时江华
姜龙
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Lunan Pharmaceutical Group Corp
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a galanthamine intermediate compound V, wherein a new intermediate compound V is synthesized by taking 4- (2- (methylamino) ethyl) phenylacetate, paraformaldehyde and piperonyl as raw materials.

Description

Galanthamine intermediate compound V
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a galanthamine intermediate compound V.
Background
Galantamine (Galanthamine) with chemical name of 11-methyl-3-methoxy-4 a,5,9,10,11, 12-hexahydro-6H-benzofuran- [3a,3,2ef][2]Diazepin-6-ol, formula: c17H21NO3(ii) a Molecular weight: 323.81, respectively; CAS registry number 357-70-0, structural formula as follows:
Figure BDA0002204164120000011
galantamine was first studied and produced by the pharmaceutical company Sopharma, bulgaria under the trade name: nivalin. Pharmacological research proves that the acetylcholinesterase inhibitor is a powerful acetylcholinesterase (AChE) inhibitor, has a good regulating effect on neuronal nicotinic receptors, and is widely used for treating Alzheimer's Disease (AD) and myasthenia gravis and other diseases clinically. Currently, the drug is marketed in various countries and regions of the uk, ireland, the united states, china, etc.
The synthesis of the galanthamine is mainly characterized in that the galanthamine contains a similar dibenzofuran tricyclic framework and a seven-membered nitrogen heterocycle, and has three chiral centers of 4a,6 and 8a, and the synthesis route of the galanthamine is firstly reported by Barton and the like in J Chem Soc,1962:806 and 817 in 1962 by using p-hydroxybenzaldehyde as a starting material through 10 steps of chemical reaction to obtain a product, wherein the oxidation ring combination yield of a key intermediate 4 narwedine is only 1.4%, and the total yield is only 0.032%:
Figure BDA0002204164120000012
in order to further increase the yield of the oxidative cyclization, based on the work of Barton et al, Kametani reported that (J Chem Soc D,1969,8(8):425-426) the yield of the oxidative cyclization was increased to 40% by using bromodiphenol compound 7 as a key intermediate and potassium ferricyanide as an oxidant:
Figure BDA0002204164120000021
although the bromine atom can effectively prevent the side reaction of phenol para-condensation, the reaction route is long, the operation is complex, the product purity and the yield are not high, and the cyanide toxicity is high, so that the method is not suitable for industrial production.
Carroll reports (J heterocyclic Chem,1995,32(1):195-199) that tyramine 9 and isovanillin 10 are used as starting materials, dibromo intermediate 11 is obtained through multi-step reaction, compound 12 is obtained through potassium ferricyanide oxidative cyclization, and finally galantamine is obtained through zinc powder debromination, lithium tri-sec-butylborohydride (L-Selectride) reduction and lithium aluminum hydride reduction:
Figure BDA0002204164120000022
although the L-Selectride is used as a reducing agent to improve the reaction yield, the yield of the key oxidative cyclization compound 12 is only 39%, and potassium ferricyanide is still used as an oxidizing agent, so that the method is not suitable for industrial production.
In order to further increase the yield of oxidative condensation Kita et al (J Org chem.1998,63(19):6625-6633), PIFA [ phenyliododine (III) bis- (trifluoroacetate) ] is used as an oxidizing agent and trifluoroethanol is used as a solvent, so that the yield of oxidative condensation is increased to 60%:
Figure BDA0002204164120000023
in conclusion, galanthamine preparation methods have problems, or long routes, low yield and low purity; or high technical requirements, serious environmental pollution and high production cost; therefore, the problem to be solved at present is to explore a process route for galanthamine, which is simple and convenient to operate, short in production period, high in yield and more suitable for industrial production.
Disclosure of Invention
Aiming at solving the problems of long complicated route, complex operation, low yield and low purity in the galanthamine preparation process in the prior art; or the problems of high technical requirement, serious environmental pollution, high production cost and the like, the invention provides a galanthamine intermediate V and a preparation method of the compound; the method has the advantages of short reaction route, simple and convenient operation, milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.
The invention is realized by the following technical scheme:
a galanthamine intermediate compound represented by formula V:
Figure BDA0002204164120000031
a preparation method of a galanthamine intermediate compound V comprises the following steps: adding a compound II, a compound III paraformaldehyde, a compound IV 1, 3-benzodioxole (piperonyl), acid and an organic solvent into a three-neck flask connected with a water diversion device, heating to reflux, stopping heating after detection reaction is finished, and slowly cooling to room temperature to obtain an intermediate compound V, wherein the reaction route is as follows:
Figure BDA0002204164120000032
preferably, the acid is an organic acid, and may be one of or a combination of p-toluenesulfonic acid, benzoic acid, acetic acid, oxalic acid and trifluoromethanesulfonic acid, wherein p-toluenesulfonic acid is particularly preferred.
In a preferable embodiment, the feeding molar ratio of the compound II, the compound III paraformaldehyde and the compound IV 1, 3-benzodioxole (piperonyl cycloate) is 1: 1.1-2.5: 1.1-2.0, and particularly preferably 1:1.5: 1.2.
In a preferable embodiment, the feeding molar ratio of the compound II to the acid is 1: 0.2-0.6, and particularly preferably 1: 0.2.
Preferably, the organic solvent is selected from one or a combination of toluene, benzene, xylene, dichloromethane and cyclohexane.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding an extracting agent into the reaction liquid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain an intermediate compound V; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
The use of the above compound V for the preparation of galanthamine.
The compound V is used for preparing galanthamine, and the preparation method comprises the following steps: step 1, obtaining an intermediate VI from the compound V under the action of an oxidant; step 2, reacting the intermediate VI with methyl iodide to obtain an unseparated intermediate VII, and reducing the intermediate VII to obtain galanthamine; the synthetic route is as follows:
Figure BDA0002204164120000041
preferably, the above steps are described in further detail in the following sections:
step 1 preparation of compound vi:
the preparation method of the compound VI comprises the following steps: adding the compound V into an organic solvent, stirring to dissolve the solid, adding an oxidant at a low temperature, and continuously stirring at a controlled temperature until the reaction is finished to obtain an intermediate compound VI.
Preferably, the oxidant is selected from one or the combination of di (trifluoroacetic acid) iodobenzene, hydroxytoluenesulfonyliodobenzene, iodobenzene diacetic acid and 2-iodoxybenzoic acid, and the di (trifluoroacetic acid) iodobenzene is particularly preferred.
Preferably, the organic solvent is selected from one or a combination of dichloromethane, trichloromethane, acetonitrile and toluene, and dichloromethane is particularly preferred.
In a preferred scheme, the temperature of the oxidant is-5 ℃ to 5 ℃.
Preferably, the feeding molar ratio of the compound V to the oxidant is as follows: 1:1.1 to 2.0, particularly preferably 1: 1.2.
In a preferred scheme, after the reaction is finished, the post-treatment operation is needed, specifically, the reaction solution is added with an organic solvent for extraction, the extract liquid is dried by anhydrous sodium sulfate, filtered, the filtrate is decompressed and concentrated to obtain a crude product, and the crude product is further separated by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) obtaining an intermediate VI; the organic extraction solvent is: one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Step 2 preparation of compound I:
the preparation method of the compound I comprises the following steps: adding the compound VI into a dehydrated organic solvent, stirring to dissolve the solid, adding alkali and methyl iodide at low temperature, gradually heating to room temperature, stirring for reaction, and after the detection reaction is finished, adding a reducing agent into the reaction liquid, and continuing the reaction until the reaction is finished to obtain the galanthamine I.
In a preferred embodiment, the base is selected from one or two of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide, and sodium hydride is particularly preferred.
Preferably, the reducing agent is selected from one or a combination of lithium tri-sec-butyl borohydride, sodium borohydride, lithium triethylborohydride and lithium aluminum hydride, and lithium tri-sec-butyl borohydride is particularly preferred.
In a preferred scheme, the temperature of the alkali and the iodomethane is-5 ℃ to 5 ℃.
Preferably, the reaction organic solvent is one or a combination of tetrahydrofuran, acetonitrile, toluene and 1, 4-dioxane, and tetrahydrofuran is particularly preferred.
In a preferred scheme, the feeding molar ratio of the reaction compound VI to the methyl iodide to the alkali is as follows: 1: 1.1-2.0, especially preferably 1:1.2: 1.2.
In a preferred scheme, the feeding molar ratio of the reaction compound VI to the reducing agent is as follows: 1:1.8 to 2.5, particularly preferably 1: 2.0.
In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, water and ethyl acetate are added into the reaction liquid, and the organic layer is dried by anhydrous magnesium sulfate, concentrated and dried in vacuum to obtain the galanthamine.
Compared with the prior art, the invention has the following technical effects:
1. provides a new galanthamine intermediate compound V and a new method for preparing galanthamine by using the compound simply, conveniently and efficiently, the whole synthesis method has simple and convenient operation, high reaction yield and high purity of the obtained product;
2. the obtained new intermediate compound V has simple structure, no new impurity in the next step of oxidation cyclization reaction, high yield and high purity.
In conclusion, the invention provides a new compound and a new method for synthesizing galanthamine by using the compound, the method avoids using dangerous chemical reagents, the synthesized intermediate does not generate new impurities, the traditional catalyst is replaced by a green catalyst, the reaction is milder, the economic performance and the environmental protection are realized, the yield is higher, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The structure of the novel compound obtained by the invention is confirmed:
Figure BDA0002204164120000051
high resolution mass spectrum of compound V: ESI-HRMS: M/z 286.1472[ M + H ]]+；1H-NMR(400MHz,CDCl3):δ8.13(s,1H),7.01(d,J＝8.5Hz,2H),6.79(s,1H),6.69(d,J＝8.5Hz,2H),6.67-6.52(m,2H),5.89(s,2H),3.27(s,2H),2.85-2.65(m,4H),2.17(s,3H)；13C-NMR(400MHz,CDCl3)δ156.1,148.2,147.3,133.7,130.1,129.5,123.8,115.6,114.7,95.4,62.2,58.0,39.1,35.2.
Preparation of Compound V
Example 1
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (14.64g, 0.12mol), p-toluenesulfonic acid (3.44g, 0.02mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 92.5% and an HPLC purity of 99.92%.
Example 2
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (9.91g, 0.11mol), compound IV (14.64g, 0.12mol), benzenesulfonic acid (3.16g, 0.02mol), and 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. Adding 100mL of dichloromethane, violently shaking and standing, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain white solid powder with the yield of 85.1% and the HPLC purity of 99.87%.
Example 3
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (9.01g, 0.10mol), compound IV (14.64g, 0.12mol), acetic acid (1.20g, 0.02mol), 80mL of benzene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. Adding 100mL of trichloromethane, shaking vigorously, standing, collecting an organic phase, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain white solid powder with the yield of 81.3% and the HPLC purity of 99.44%.
Example 4
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (22.52g, 2.5mol), compound IV (14.64g, 0.12mol), oxalic acid (1.80g, 0.02mol), 100mL of xylene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. Adding 100mL of trichloromethane, shaking vigorously, standing, collecting an organic phase, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating under reduced pressure to obtain white solid powder with the yield of 86.1% and the HPLC purity of 99.76%.
Example 5
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (23.42g, 2.6mol), compound IV (14.64g, 0.12mol), trifluoromethanesulfonic acid (3.0g, 0.02mol), 100mL cyclohexane. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, the organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to give a white solid powder with a yield of 81.4% and an HPLC purity of 99.51%.
Example 6
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (13.42g, 0.11mol), p-toluenesulfonic acid (3.44g, 0.02mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 89.6% and an HPLC purity of 99.78%.
Example 7
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (12.20g, 0.10mol), p-toluenesulfonic acid (3.44g, 0.02mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 83.9% and an HPLC purity of 99.65%.
Example 8
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (24.40g, 0.20mol), p-toluenesulfonic acid (3.44g, 0.02mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 88.9% and an HPLC purity of 99.65%.
Example 9
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (25.62g, 0.21mol), p-toluenesulfonic acid (3.44g, 0.02mol), 100mL of cyclohexane. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 81.5% and an HPLC purity of 98.65%.
Example 10
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (14.64g, 0.12mol), p-toluenesulfonic acid (1.72g, 0.01mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 88.2% and an HPLC purity of 99.75%.
Example 11
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (14.64g, 0.12mol), p-toluenesulfonic acid (1.55g, 0.009mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 82.4% and an HPLC purity of 99.65%.
Example 12
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (14.64g, 0.12mol), p-toluenesulfonic acid (10.33g, 0.06mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with a yield of 88.4% and an HPLC purity of 99.78%.
Example 13
To a three-necked flask were added compound II (19.3g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), compound IV (14.64g, 0.12mol), p-toluenesulfonic acid (12.05g, 0.07mol), 100mL of toluene. Stirring to dissolve, heating to reflux, removing generated water from the reaction system by using a water separator, stopping heating when the water in the water separator is not increased any more, and slowly cooling to room temperature. 100mL of ethyl acetate was added, followed by vigorous shaking and standing, and the organic phase was collected and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and concentrated under reduced pressure to give a white solid powder with yield 80.4% and HPLC purity 99.46%.
Preparation of Compound VI:
example 14
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with iodobenzene bis (trifluoroacetic acid) (51.60g, 0.12mol), allowed to warm to room temperature slowly after the addition was complete, and stirred overnight. Adding 100mL of dichloromethane, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 96.8% yield and 99.96% HPLC purity.
Example 15
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with iodobenzene bis (trifluoroacetic acid) (47.30g, 0.11mol), and after the addition was complete, slowly warmed to room temperature and stirred overnight. Adding 100mL chloroform, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 92.6% yield with HPLC purity 99.76％。
Example 16
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with iodobenzene bis (trifluoroacetic acid) (43.0g, 0.10mol), allowed to warm to room temperature slowly after the addition was complete, and stirred overnight. Adding 100mL acetonitrile, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 87.6% yield and 99.54% HPLC purity.
Example 17
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with iodobenzene bis (trifluoroacetic acid) (86.1g, 0.20mol), allowed to warm to room temperature slowly after the addition was complete, and stirred overnight. Adding 100mL toluene, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 90.5% yield and 99.67% HPLC purity.
Example 18
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with iodobenzene bis (trifluoroacetic acid) (90.3g, 0.21mol), and after the addition was complete, slowly warmed to room temperature and stirred overnight. Adding 100mL toluene, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 84.5% yield with HPLC purity 99.33%.
Example 19
Compound V (28.51g, 0.10mol), 100mL methylene chloride was added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with hydroxytoluenesulfonyliodobenzene (47.06g, 0.12mol), slowly warmed to room temperature after the addition was complete, and stirred overnight. Adding 100mL of toluene, shaking vigorously, standing, and collecting organic substancesDrying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating with silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 91.5% yield and 99.75% HPLC purity.
Example 20
Compound V (28.51g, 0.10mol), 100mL methylene chloride were added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and then added iodobenzene diacetic acid (38.65g, 0.12mol) slowly, after the addition was complete, slowly warmed to room temperature and stirred overnight. Adding 100mL toluene, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 92.3% yield and 99.77% HPLC purity.
Example 21
Compound V (28.51g, 0.10mol), 100mL methylene chloride was added to a three-necked flask, stirred to full solution, cooled to 0 deg.C and slowly added with 2-iodoxybenzoic acid (33.60g, 0.12mol), allowed to warm to room temperature slowly after addition, and stirred overnight. Adding 100mL toluene, shaking vigorously, standing, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating by silica gel column chromatography (V)Methylene dichloride：VMethanol50: 1) compound VI was obtained in 90.8% yield and 99.79% HPLC purity.
Preparation of galanthamine
Example 22
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding solid sodium hydride (2.88g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding lithium tri-sec-butyl borohydride (38.02g, 0.2mol) at 0 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a white solid, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 90.6%, and the purity of HPLC is 99.95%.
Example 23
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to-5 ℃, adding potassium tert-butoxide (13.47g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (15.61g, 0.11mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at-5 ℃, stirring for 2.0 hours, gradually heating to room temperature, detecting by TLC after the reaction is finished, slowly adding lithium tri-sec-butyl borohydride (38.02g, 0.2mol) at-5 ℃, keeping the temperature at-5 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), violently shaking, standing, removing the aqueous phase, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a white solid, and drying at 40 ℃ in vacuum to obtain galantamine yield of 84.5% and HPLC purity of 99.85%.
Example 24 (methyl iodide, 1.1 below)
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 5 ℃, adding sodium tert-butoxide (12.69g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (14.2g, 0.10mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at 5 ℃, stirring for 2.0 hours, gradually heating to room temperature, detecting by TLC (thin layer chromatography), after the reaction is finished, slowly adding sodium borohydride (7.57g, 0.2mol) at 5 ℃, keeping the temperature at 5 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating a white solid obtained by reducing pressure of a filtrate, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 79.4% and the purity is 99.67% by HPLC.
Example 25
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding lithium diisopropylamide (14.14g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (28.4g, 0.20mol), dissolving in 20mL of anhydrous tetrahydrofuran, dripping the reaction solution into the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, detecting by TLC (thin layer chromatography), after the reaction is finished, slowly adding sodium borohydride (7.57g, 0.2mol) at 5 ℃, keeping the temperature at 5 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating a white solid obtained by decompressing a filtrate, drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 81.6%, and the purity is 99.77% by HPLC.
Example 26
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding lithium bis (trimethylsilyl) amide (20.08g, 0.12mol), stirring until no bubbles are generated, weighing iodomethane (29.81g, 0.21mol) and dissolving in 20mL of anhydrous tetrahydrofuran, dripping the reaction solution into the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding sodium borohydride (7.57g, 0.2mol) at 0 ℃ and keeping the temperature at 0 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a white solid, and drying at 40 ℃ in vacuum to obtain galantamine with the yield of 74.6% and the purity of HPLC of 99.57%.
Example 27
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding solid sodium hydride (2.64g, 0.11mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding lithium triethylborohydride (21.19g, 0.2mol) at 0 ℃ to keep the temperature for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating a white solid obtained by reducing pressure of a filtrate, and drying in vacuum at 40 ℃ to obtain galantamine, wherein the yield is 84.2%, and the purity is 99.75% by HPLC.
Example 28
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to-6 ℃, adding solid sodium hydride (2.40g, 0.10mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving the methyl iodide in 20mL of anhydrous tetrahydrofuran, dripping the reaction solution into the reaction solution, keeping the temperature at-6 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is completed, slowly adding lithium triethylborohydride (7.59g, 0.2mol) at 0 ℃ to keep the temperature at 0 ℃ for continuous reaction, after the reaction is completed, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a white solid, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 80.8%, and the purity of HPLC is 99.75%.
Example 29
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous acetonitrile into a three-necked flask, stirring until the compound VI and the anhydrous acetonitrile are completely dissolved, cooling to 0 ℃, adding solid sodium hydride (4.80g, 0.20mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving the methyl iodide in 20mL of anhydrous acetonitrile, dripping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, slowly adding lithium tri-sec-butyl borohydride (38.02g, 0.2mol) at 0 ℃ after TLC detection reaction is finished, keeping the temperature at 0 ℃ for continuous reaction, adding purified water (100mL) and ethyl acetate (100mL) after the reaction is finished, shaking, standing, removing an aqueous phase, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating a white solid obtained by decompressing a filtrate, vacuum drying at 40 ℃ to obtain galantamine, wherein the yield is 85.2% and the purity is 99.65% by HPLC.
Example 30
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous toluene into a three-neck flask, stirring until the mixture is completely dissolved, cooling to 0 ℃, adding solid sodium hydride (5.04g, 0.21mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving the methyl iodide in 20mL of anhydrous toluene, dropping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding lithium tri-sec-butyl borohydride (38.02g, 0.2mol) at 0 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), shaking, standing, removing an aqueous phase, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating a white solid obtained by reducing pressure of a filtrate, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 80.7%, and the purity is 99.58% by HPLC.
Example 31
Adding compound VI (27.11g, 0.1mol) and 100mL of anhydrous 1, 4-dioxane into a three-neck flask, stirring until the mixture is completely dissolved, cooling to 0 ℃, adding solid sodium bis (trimethylsilyl) amide (22.00g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol) and dissolving in 20mL of anhydrous 1, 4-dioxane, dropwise adding a reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is completed, slowly adding lithium tri-sec-butylborohydride (34.22g, 0.18mol) at-6 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and ethyl acetate (100mL), standing after violent shaking, removing an aqueous phase, drying an organic phase with anhydrous sodium sulfate, filtering, decompressing and concentrating a white solid filtrate, and vacuum drying at 40 ℃ to obtain galantamine, yield 84.7% and HPLC purity 99.77%.
Example 32
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 6 ℃, adding solid potassium bis (trimethylsilyl) amide (23.94g, 0.12mol), stirring until no bubbles are generated, weighing iodomethane (17.03g, 0.12mol) and dissolving in 20mL of anhydrous tetrahydrofuran, dripping the reaction solution into the solution, keeping the temperature at 6 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is completed, slowly adding lithium tri-sec-butyl borohydride (32.32g, 0.17mol) at 0 ℃ and keeping the temperature at 0 ℃ for continuous reaction, after the reaction is completed, adding purified water (100mL) and dichloromethane (100mL), standing after violent shaking, removing an aqueous phase, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a white solid, and drying in vacuum at 40 ℃ to obtain galantamine, wherein the yield is 79.3%, and the HPLC purity is 99.48%.
Example 33
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding solid sodium hydride (2.88g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding tri-sec-butyl lithium borohydride (47.53g, 0.25mol) at 6 ℃ to keep 6 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and trichloromethane (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating a white solid obtained by reducing pressure of a filtrate, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 85.3%, and the purity is 99.75% by HPLC.
Example 34
Adding a compound VI (27.11g, 0.1mol) and 100mL of anhydrous tetrahydrofuran into a three-necked flask, stirring until the compound VI and the anhydrous tetrahydrofuran are completely dissolved, cooling to 0 ℃, adding solid sodium hydride (2.88g, 0.12mol), stirring until no bubbles are generated, weighing methyl iodide (17.03g, 0.12mol), dissolving in 20mL of anhydrous tetrahydrofuran, dropping the reaction solution, keeping the temperature at 0 ℃, stirring for 2.0 hours, gradually heating to room temperature, after TLC detection reaction is finished, slowly adding tri-sec-butyl lithium borohydride (49.43g, 0.26mol) at 0 ℃ for continuous reaction, after the reaction is finished, adding purified water (100mL) and trichloromethane (100mL), shaking, standing, removing an aqueous phase, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating a white solid by reducing pressure, and drying at 40 ℃ in vacuum to obtain galantamine, wherein the yield is 77.6%, and the purity is 98.98% by HPLC.

Claims (10)

1. A galanthamine intermediate compound represented by formula V:
Figure FDA0002204164110000011
2. an intermediate compound iv according to claim 1, characterized in that the preparation process comprises the following steps: adding a compound II, a compound III, paraformaldehyde, a compound IV 1, 3-benzodioxole, acid and an organic solvent into a three-neck flask connected with a water-dividing device, heating to reflux, stopping heating after detection reaction is finished, and slowly cooling to room temperature to obtain an intermediate compound V, wherein the reaction route is as follows:
Figure FDA0002204164110000012
3. the method according to claim 2, wherein the acid is an organic acid, and may be one or a combination of p-toluenesulfonic acid, benzoic acid, acetic acid, oxalic acid and trifluoromethanesulfonic acid.
4. The preparation method according to claim 2, wherein the feeding molar ratio of the compound II, the compound III, the compound IV and the acid is 1: 1.1-2.5: 1.1-2.0: 0.2 to 0.6.
5. The method according to claim 2, wherein the organic solvent is one of toluene, benzene, xylene, dichloromethane, cyclohexane, or a combination thereof.
6. Use of compound v according to claim 1 for the preparation of galanthamine.
7. A process for the preparation of galanthamine from compound V according to claim 1, comprising the steps of:
step 1: the compound V is used for obtaining an intermediate VI under the action of an oxidant;
step 2: the intermediate VI reacts with methyl iodide under the action of alkali to obtain an unseparated intermediate VII, and the intermediate VII is reacted with a reducing agent to obtain galanthamine I, wherein the synthetic route is as follows:
Figure FDA0002204164110000013
8. the preparation method according to claim 7, wherein the oxidizing agent in step 1 is one or two selected from the group consisting of iodobenzene bis (trifluoroacetate), hydroxytoluenesulfonyliodobenzene, iodobenzene diacetic acid, and 2-iodoxybenzoic acid.
9. The method according to claim 7, wherein the base used in step 2 is one or two selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, and potassium bis (trimethylsilyl) amide.
10. The method according to claim 7, wherein the reducing agent in step 2 is selected from one of lithium tri-sec-butylborohydride, sodium borohydride, lithium triethylborohydride, lithium aluminum hydride or a combination thereof.
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Citations (2)

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