CN115477595A - Galanthamine intermediate compound - Google Patents

Galanthamine intermediate compound Download PDF

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CN115477595A
CN115477595A CN202110670852.1A CN202110670852A CN115477595A CN 115477595 A CN115477595 A CN 115477595A CN 202110670852 A CN202110670852 A CN 202110670852A CN 115477595 A CN115477595 A CN 115477595A
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compound
reaction
galanthamine
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stirring
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张贵民
时江华
魏开伟
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Shandong New Time Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a galanthamine intermediate compound. The invention takes 4-methoxy-3- ((2-oxocyclohexyl-3-dilute-1-yl) oxy) benzoate as a starting material to react with (2- ((tert-butoxycarbonyl) (methyl) amino) ethyl) magnesium bromide to obtain a new galanthamine intermediate, namely methyl 3- ((2- ((((tert-butoxycarbonyl) (methyl) amino) methyl) -2-hydroxycyclohexyl-3-dilute-1-yl) oxy) -4-methoxybenzoate.

Description

Galanthamine intermediate compound
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a galanthamine intermediate compound.
Background
Galantamine (Galanthamine) with the chemical name 11-methyl-3-methoxy-4a, 5,9,10,11, 12-hexahydro-6H-benzofuran- [3a,3,2ef][2]Diazepin-6-ol, formula: c 17 H 21 NO 3 (ii) a Molecular weight: 323.81; CAS registry number 357-70-0, structural formula:
Figure BDA0003115636360000011
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 in clinic. Currently, the drug is marketed in various countries and regions of the uk, irish, the united states, china, etc.
The synthesis route of galantamine was first reported by Barton et al in 1962, soc,1962, 806-817, in which p-hydroxybenzaldehyde was used as the starting material and the product was obtained by 10 chemical reactions, wherein the yield of the key intermediate 4 narwedine by oxidative cyclization was only 1.4%, and the total yield was only 0.032%:
Figure BDA0003115636360000012
to further increase the oxidative condensation yield Kita et al (J Org chem.1998,63 (19): 6625-6633) by using PIFA [ phenyliododine (III) bis- (trifluoroacetate) ] as oxidant and trifluoroethanol as solvent, the yield of oxidative condensation is increased to 60%:
Figure BDA0003115636360000021
although the process is the most widely applied route at present, the PIFA catalyst used in the process is expensive and the production process is complex, thereby bringing difficulty to the actual mass production.
In conclusion, in the preparation method of galanthamine, the cyclization yield is low and impurities are easy to generate, so that a cyclization process route which is higher in yield and more suitable for industrial production is still the problem to be solved at present for synthesis of galanthamine.
Disclosure of Invention
In order to solve the problem of low hybridization-cyclization yield in the galanthamine preparation process in the prior art, the invention provides a galanthamine intermediate VI and a preparation method of the compound; the method has the advantages of high cyclization reaction yield, simple and convenient operation, avoidance of use of expensive catalysts, milder reaction, economy, environmental protection, high yield and suitability for industrial production.
The invention provides a novel galanthamine intermediate compound in a first aspect, which has a structure shown in formula VI:
Figure BDA0003115636360000022
the second aspect of the invention provides a preparation method of a galanthamine intermediate compound VI, which comprises the following specific steps: adding the compound IV into the organic solvent A, adding the compound V at low temperature, and continuously stirring at room temperature after the addition is finished until the reaction is finished to obtain an intermediate compound VI, wherein the route is as follows:
Figure BDA0003115636360000023
preferably, the organic solvent A is selected from one or a combination of diethyl ether, acetone and anhydrous tetrahydrofuran, and diethyl ether is particularly preferred.
Preferably, the temperature for adding the compound V is-10 ℃ to 0 ℃.
Preferably, the feeding molar ratio of the compound IV to the compound V is as follows: 1.0 to 2.0, particularly preferably 1.
In a preferred scheme, after the reaction is finished, a post-treatment operation is required, specifically, the reaction product is quenched by ice and an HCl (1M) solution, ethyl acetate and purified water are added after the reaction solution is evaporated to dryness, an organic phase is washed by brine and dried by anhydrous sodium sulfate, and the compound VI is obtained by concentration under reduced pressure.
The preparation method of the compound IV comprises the following steps:
adding a compound II and a compound III into an organic solvent B, adding a catalyst, stirring and reacting at a controlled temperature, and detecting to obtain an intermediate compound IV after the reaction is finished, wherein the reaction route is as follows:
Figure BDA0003115636360000031
preferably, the catalyst is selected from one of copper chloride, copper acetate, copper trifluoroacetate, cuprous iodide and rhodium acetate, wherein the copper chloride is particularly preferred.
Preferably, the feeding molar ratio of the compound II, the compound III and the catalyst is 1.
Preferably, the organic solvent B is selected from one of methanol, ethanol, isopropanol, tetrahydrofuran and acetonitrile or a combination thereof.
Preferably, the reaction temperature is 50-75 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: filtering the reaction solution, evaporating to remove the organic solvent in the filtrate, adding purified water and ethyl acetate, decompressing and concentrating the organic layer until the organic layer is dry, and recrystallizing the obtained solid with ethanol at the temperature of-10-0 ℃ to obtain the target compound IV.
The third aspect of the invention provides the application of the compound VI in preparing galanthamine, and the specific preparation method comprises the following scheme: cyclizing the compound VI to obtain a compound VII; the compound VII is reduced and oxidized to obtain galanthamine, and the synthetic route is as follows:
Figure BDA0003115636360000032
preferably, the above steps are described in further detail in the following sections:
preparation of compound VII:
the preparation method of the compound VII comprises the following steps: adding the compound VI into an organic solvent C, stirring to dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate, carrying out temperature-controlled reflux, after the detection reaction is finished, filtering a reaction solution, adding N-hydroxysuccinimide and a condensing agent into a filtrate, and stirring at a controlled temperature until the reaction is finished to obtain a compound VII.
Preferably, the condensing agent is selected from any one of dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, and dicyclohexylcarbodiimide is particularly preferable.
Preferably, the organic solvent C is selected from one or a combination of dichloromethane, tetrahydrofuran, toluene, acetonitrile, DMF, chloroform, with dichloromethane being particularly preferred.
Preferably, the reaction temperature of the condensation reagent is 25 ℃ to 35 ℃.
Preferably, the feeding molar ratio of the compound VI, the 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate, the N-hydroxysuccinimide and the condensing agent is as follows: 1.02-0.1: 1.0 to 2.0, particularly preferably 1.05.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding water and ethyl acetate into the reaction solution, drying the organic layer by anhydrous magnesium sulfate, concentrating, and drying in vacuum to obtain a compound VII.
Preparation of galanthamine
The preparation of galanthamine comprises the following steps: adding the compound VII into an organic solvent D, adding sodium hydride and zinc salt, stirring and reacting at controlled temperature after the addition is finished, and adding a catalyst and an oxidant after the detection reaction is finished, and stirring and reacting at room temperature to obtain the galanthamine.
Preferably, the zinc salt is selected from one of zinc chloride, zinc iodide and zinc bromide, wherein zinc chloride is particularly preferred.
Preferably, the catalyst is selected from F 20 TPPFeCl、F 16 TPPFeCl、F 8 One of TPPFeCl, of which F is particularly preferred 20 TPPFeCl。
Preferably, the oxidizing agent is selected from t-BuOOH, H 2 O 2 、C 6 F 5 One of the IOs, t-BuOOH is particularly preferred.
Preferably, the molar ratio of the compound VII, sodium hydride, zinc salt, catalyst, oxidant fed is 1.0-6.0.
Preferably, the organic solvent D is selected from one or a combination of tetrahydrofuran, methanol, acetonitrile, 1, 2-dichloromethane, toluene, with tetrahydrofuran being particularly preferred.
Preferably, the reaction temperature is 40 to 65 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding purified water into the reaction solution, adding ethyl acetate for extraction, filtering, washing the filtrate with water and alkali, concentrating, and drying in vacuum to obtain the galanthamine.
Compared with the prior art, the invention achieves the following effects
1. Provides a new galanthamine intermediate compound VI and a new method for preparing galanthamine by using the compound simply, conveniently and efficiently, and 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 VI 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, new impurities cannot be generated in a synthesized intermediate, a 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 BDA0003115636360000051
high resolution mass spectrum of compound V: ESI-HRMS: m/z =277.8760[ 2 ] M + H] + ； 1 H-NMR(400MHz,CDCl 3 ):δ7.70(dd,J＝8.0Hz,1.5Hz,1H)，7.43(d,J＝8.5Hz,1H),6.90(d,J＝8.0Hz,1H)，4.69-4.82(m,1H),3.92(s,2H),3.87(s,2H),2.32-2.72(m,3H),1.96-2.14(m,3H),1.65-1.90(m,2H)； 13 C-NMR(400MHz,CDCl 3 )δ176.1,165.2,154.3,150.7,146.1,127.5,123.8,114.6,113.7,97.4,56.2,51.5,32.0,19.6.
Figure BDA0003115636360000052
High resolution mass spectrum of compound VI: ESI-HRMS: m/z =422.1472[ 2 ], [ M + H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ7.22(d,J＝8.5Hz,2H),6.79(s,1H),6.69(d,J＝8.5Hz,2H),6.72-6.58(m,2H),5.95(s,2H),4.83(brs,1H),3.45-3.36(m,2H),3.27(s,2H),2.85-2.65(m,4H),2.17(s,3H),1.45(s,9H)； 13 C-NMR(400MHz,DMSO-d 6 )δ168.5,154.4,147.8,132.7,129.5,123.0,113.8,111.6,92.0,59.4,56.2,51.0,37.1,29.2,28.4,20.6.
Figure BDA0003115636360000061
High resolution mass spectrum of compound VII: ESI-HRMS: m/z =286.1472[ M + H ]] + ； 1 H-NMR(400MHz,CDCl 3 ):δ7.18-7.16(m,2H),6.07(d,J＝8.5Hz,2H),4.25(t,J＝7.9Hz,1H),3.62(dd,J＝8.0,24.1Hz,2H),3.42-3.11(m,2H),3.39-3.28(m,2H),2.17(s,3H),1.72-1.55(m,2H)； 13 C-NMR(400MHz,CDCl3)δ171.5,155.5,146.8,146.4,135.7,133.1,127.8,116.9,116.8,77.5,61.5,56.6,47.5,44.5,40.3,33.7.
Preparation of Compound IV
Example 1
Adding a compound II (12.20g, 0.1mol) into 100ml of methanol solution, stirring to dissolve the compound II, adding a compound III (21.85g, 0.12mol) and copper chloride (0.17g, 1.0mmol), heating to 65 ℃, continuing stirring to react, after the detection reaction is finished, filtering a reaction solution, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of between 5 ℃ below zero and 0 ℃ to obtain a compound IV, wherein the yield is 92.5%, and the HPLC purity is 99.92%.
Example 2
Adding a compound II (12.20g and 0.1mol) into 100ml of methanol solution, stirring to dissolve the compound II, adding a compound III (18.21g and 0.1mol) and copper acetate (0.20g and 1.0mmol), heating to 50 ℃, continuing to stir for reaction, filtering a reaction solution after detection reaction is finished, evaporating an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of-5-0 ℃ to obtain a compound IV, wherein the yield is 88.1%, and the HPLC purity is 99.47%.
Example 3
Adding a compound II (12.20g and 0.1mol) into 100ml of acetonitrile solution, stirring to dissolve the compound II, adding a compound III (36.42g and 0.2mol) and copper trifluoroacetate (0.29g and 1.0mmol), heating to 70 ℃, continuing stirring to react, filtering a reaction solution after detection reaction is finished, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of minus 10-minus 5 ℃ to obtain a compound IV, wherein the yield is 81.3%, and the HPLC purity is 99.44%.
Example 4
Adding a compound II (12.20g, 0.1mol) into 100ml of acetonitrile solution, stirring to dissolve the compound II, adding a compound III (40.05g, 0.22mol) and cuprous iodide (0.19g, 1.0mmol) into the mixture, heating to 75 ℃, continuing stirring to react, after the detection reaction is finished, filtering a reaction solution, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at 0-5 ℃ to obtain a compound IV, wherein the yield is 82.1%, and the HPLC purity is 98.36%.
Example 5
Adding a compound II (12.20g and 0.1mol) into 100ml of tetrahydrofuran solution, stirring to dissolve the compound II, adding a compound III (21.85g and 0.12mol) and copper chloride (0.14g and 0.8mmol), heating to 50 ℃, continuing stirring to react, filtering a reaction solution after the detection reaction is finished, evaporating an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of between 5 ℃ below zero and 0 ℃ to obtain a compound IV, wherein the yield is 87.3%, and the HPLC purity is 99.53%.
Example 6
Adding a compound II (12.20g, 0.1mol) into 100ml of ethanol solution, stirring to dissolve the compound II, adding a compound III (21.85g, 0.12mol) and copper chloride (0.26g, 1.5mmol), heating to 75 ℃, continuing to stir for reaction, after the detection reaction is finished, filtering a reaction solution, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of between-10 ℃ and-5 ℃ to obtain a compound IV, wherein the yield is 88.6%, and the HPLC purity is 99.21%.
Example 7
Adding a compound II (12.20g, 0.1mol) into 100ml of isopropanol solution, stirring to dissolve the compound II, adding a compound III (21.85g, 0.12mol) and rhodium acetate (0.17g, 0.6 mmol), heating to 45 ℃, continuing stirring to react, after the detection reaction is finished, filtering a reaction solution, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of between 15 ℃ below zero and 10 ℃ below zero to obtain a compound IV, wherein the yield is 81.9%, and the HPLC purity is 97.35%.
Example 8
Adding a compound II (12.20g and 0.1mol) into 100ml of acetonitrile solution, stirring to dissolve the compound II, adding a compound III (21.85g and 0.12mol) and rhodium acetate (0.48g and 1.7mmol), heating to 80 ℃, continuing to stir for reaction, after the detection reaction is finished, filtering a reaction solution, evaporating to remove an organic solvent, adding ethyl acetate (40 ml) and purified water (50 ml) into the obtained solid, collecting an organic layer, concentrating the organic layer under reduced pressure to dryness, recrystallizing the obtained solid with ethanol (40 ml) at the temperature of between 5 ℃ below zero and 0 ℃ to obtain a compound IV, wherein the yield is 82.4%, and the HPLC purity is 97.10%.
Preparation of Compound VI
Example 9
Adding a compound IV (27.61g, 0.1mol) into diethyl ether (100 ml), cooling the reaction solution to-5 ℃, then slowly adding a compound V (31.32g, 0.12mol), heating the reaction solution to room temperature after the addition is finished, continuously stirring and reacting for 4 hours, cooling the reaction solution to 0 ℃, then adding 1M dilute hydrochloric acid (24 ml) to quench the reaction, evaporating the reaction solution, adding ethyl acetate (20 ml multiplied by 2) and purified water (20 ml multiplied by 2), washing an organic layer by saturated saline (20 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating an organic phase under reduced pressure to obtain a compound VI, wherein the yield is 95.3%, and the HPLC purity is 99.85%.
Example 10
Adding a compound IV (27.61g, 0.1mol) into acetone (100 ml), cooling the reaction liquid to-10 ℃, then slowly adding a compound V (26.10g, 0.1mol), heating the reaction liquid to room temperature after the addition is finished, continuously stirring and reacting for 4 hours, cooling the reaction liquid to 0 ℃, then adding 1M dilute hydrochloric acid (24 ml) to quench the reaction, evaporating the reaction liquid, adding ethyl acetate (20 ml multiplied by 2) and purified water (20 ml multiplied by 2), washing an organic layer by saturated saline (20 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating an organic phase under reduced pressure to obtain a compound VI, wherein the yield is 90.8%, and the HPLC purity is 99.45%.
Example 11
Adding a compound IV (27.61g, 0.1mol) into tetrahydrofuran (120 ml), cooling a reaction solution to 0 ℃, then slowly adding a compound V (52.20g, 0.2mol), heating the reaction solution to room temperature after the addition is finished, continuously stirring and reacting for 4 hours, cooling the reaction solution to 0 ℃, then adding 1M dilute hydrochloric acid (24 ml) to quench the reaction, evaporating the reaction solution to dryness, adding ethyl acetate (20 ml multiplied by 2) and purified water (20 ml multiplied by 2), washing an organic layer by saturated saline solution (20 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating an organic phase under reduced pressure to obtain a compound VI, wherein the yield is 89.5%, and the HPLC purity is 99.33%.
Example 12
Adding a compound IV (27.61g, 0.1mol) into tetrahydrofuran (120 ml), cooling a reaction solution to 5 ℃, then slowly adding a compound V (57.42g, 0.22mol), heating the reaction solution to room temperature after the addition is finished, continuously stirring and reacting for 4 hours, cooling the reaction solution to 0 ℃, then adding 1M dilute hydrochloric acid (24 ml) to quench the reaction, evaporating the reaction solution, adding ethyl acetate (20 ml multiplied by 2) and purified water (20 ml multiplied by 2), washing an organic layer by saturated saline (20 ml multiplied by 2), drying by anhydrous sodium sulfate, concentrating an organic phase under reduced pressure to obtain a compound VI, wherein the yield is 84.2%, and the HPLC purity is 97.83%.
Preparation of Compound VII
Example 13
Adding a compound VI (42.12g and 0.1mol) into dichloromethane (120 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate (2.26g and 5.0 mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (13.82g and 0.12mol) and dicyclohexylcarbodiimide (24.76g and 0.12mol) into a filtrate, heating to 30 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution, adding purified water (100 ml) and ethyl acetate (100 ml), drying an organic phase by anhydrous sodium sulfate, concentrating to dryness, and drying the solid at 45 ℃ in vacuum to obtain a compound VII, wherein the yield is 89.6% and the purity is 99.85%.
Example 14
Adding a compound VI (42.12g and 0.1mol) into dichloromethane (120 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate (4.52g and 10.0mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (13.82g and 0.12mol) and N, N' -diisopropylcarbodiimide (15.14g and 0.12mol) into a filtrate, heating to 35 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution, adding purified water (100 ml) and ethyl acetate (100 ml), drying an organic phase by anhydrous sodium sulfate, concentrating to dryness, and drying the solid in vacuum at 45 ℃ to obtain a compound VII, wherein the yield is 84.2%, and the HPLC purity is 99.45%.
Example 15
Adding a compound VI (42.12g and 0.1mol) into trichloromethane (120 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate (0.90g and 2.0mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (13.82g and 0.12mol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (23.90g and 0.12mol) into a filtrate, reacting at 25 ℃, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution, adding purified water (100 ml) and ethyl acetate (100 ml), drying an organic phase by anhydrous sodium sulfate, concentrating to dryness, and drying the solid at 45 ℃ in vacuum to obtain a compound VII, wherein the yield is 83.6%, and the HPLC purity is 98.95%.
Example 16
Adding a compound VI (42.12g and 0.1mol) into DMF (200 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate (0.45g and 1.0mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (13.82g and 0.12mol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (62.45g and 0.12mol) into a filtrate, reacting at 20 ℃, cooling the reaction solution to room temperature after detection reaction is finished, adding purified water (100 ml) and ethyl acetate (100 ml) into the reaction solution, drying an organic phase by anhydrous sodium sulfate and concentrating to dryness, and drying the solid in vacuum at 45 ℃ to obtain a compound VII, wherein the yield is 76.3%, and the HPLC purity is 97.88%.
Example 17
Adding a compound VI (42.12g and 0.1mol) into toluene (220 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate (5.43g and 12.0 mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (25.32g and 0.22mol) and dicyclohexylcarbodiimide (45.39g and 0.22mol) into a filtrate, reacting at 40 ℃, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution to dryness, adding purified water (100 ml) and ethyl acetate (100 ml), drying an organic phase by anhydrous sodium sulfate, concentrating to dryness, and drying the solid at 45 ℃ in vacuum to obtain a compound VII with the yield of 75.1% and the purity of HPLC of 97.05%.
Example 18
Adding a compound VI (42.12g, 0.1mol) into tetrahydrofuran (120 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamyl phenyl aniline trifluoromethanesulfonate (2.26g, 5.0mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (11.51g, 0.10mol) and dicyclohexylcarbodiimide (20.63g, 0.10mol) into a filtrate, heating to 30 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution, adding purified water (100 ml) and ethyl acetate (100 ml) into a solid, drying an organic phase through anhydrous sodium sulfate, concentrating to be dry, and drying the solid at 45 ℃ in vacuum to obtain a compound VII, wherein the yield is 85.3%, and the purity is 99.25% through HPLC.
Example 19
Adding a compound VI (42.12g, 0.1mol) into acetonitrile (120 ml), starting stirring to completely dissolve a solid, adding 4-benzylcarbamyl phenyl aniline trifluoromethanesulfonate (2.26g, 5.0mmol), heating and refluxing, filtering a reaction solution after detection reaction is finished, adding N-hydroxysuccinimide (23.02g, 0.20mol) and dicyclohexylcarbodiimide (41.26g, 0.10mol) into a filtrate, heating to 30 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction is finished, evaporating the reaction solution, adding purified water (100 ml) and ethyl acetate (100 ml) into a solid, drying an organic phase by anhydrous sodium sulfate, concentrating to dryness, and drying the solid at 45 ℃ in vacuum to obtain a compound VII with the purity of 84.4% and the purity of 98.75% by HPLC.
Preparation of galanthamine
Example 20
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml of tetrahydrofuran, adding sodium hydride (1.2g, 0.05mol) and zinc chloride (3.41g, 0.025 mol) while stirring, heating to 55 ℃ for reaction, detecting the reaction completion, cooling the reaction liquid to room temperature, adding F 20 TPPFeCl (26.79mg, 0.05mmol), t-BuOOH (45.06mg, 0.5 mmol) is slowly dropped at the same time, the reaction is stirred at room temperature for 4 hours after the dropping is finished, purified water (50 ml) and ethyl acetate (50 ml) are added after the reaction liquid is evaporated under reduced pressure, an organic layer is collected, the organic layer is filtered, washed by water and alkali, and concentrated to be dry to obtain galanthamine, the yield is 97.8%, and the HPLC purity is 99.89%.
Example 21
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml of tetrahydrofuran, adding sodium hydride (0.72g, 0.03mol) and zinc chloride (2.04g, 0.015mol) while stirring, heating to 55 ℃ for reaction, detecting the reaction completion, cooling the reaction liquid to room temperature, adding F 16 TPPFeCl (22.99mg, 0.05mmol) with H slowly added dropwise 2 O 2 (17.0mg0.5 mmol), reacting for 4 hours at room temperature under stirring after the dripping, distilling off the reaction solution under reduced pressure, adding purified water (50 ml) and ethyl acetate (50 ml), collecting the organic layer, filtering, washing with water and alkali, concentrating to dryness to obtain galanthamine, wherein the yield is 92.9%, and the HPLC purity is 98.99%.
Example 22
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml of tetrahydrofuran, adding sodium hydride (1.44g, 0.06mol) and zinc chloride (4.08g, 0.03mol) while stirring, heating to 55 ℃, cooling the reaction liquid to room temperature after the reaction is detected, adding F 8 TPPFeCl (15.39mg, 0.05mmol) with slow addition of C 6 F 5 IO (0.15g, 0.5mmol), stirring at room temperature for 4 hours after the addition, distilling off the reaction liquid under reduced pressure, adding purified water (50 ml) and ethyl acetate (50 ml), collecting the organic layer, filtering, washing with water and alkali, concentrating to dry to obtain galanthamine, wherein the yield is 93.6%, and the HPLC purity is 98.87%.
Example 23
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml of methanol, adding sodium hydride (0.48g, 0.02mol) and zinc chloride (1.77g, 0.013mol) while stirring, heating to 35 ℃ for reaction, detecting the reaction completion, cooling the reaction liquid to room temperature, adding F 16 TPPFeCl (0.37mg, 0.8umol) with slow dropwise addition of H 2 O 2 (0.27mg, 8.0umol), stirring at room temperature for reaction for 4 hours after dripping, distilling under reduced pressure to remove a reaction solution, adding purified water (50 ml) and ethyl acetate (50 ml), collecting an organic layer, filtering, washing with water, washing with alkali, concentrating to dryness to obtain galanthamine, wherein the yield is 86.9%, and the HPLC purity is 97.55%.
Example 24
Adding compound VII (2.85g, 0.01mol) into a reaction flask containing 150ml of toluene, adding sodium hydride (1.92g, 0.08mol) and zinc chloride (5.45g, 0.04mol) while stirring, heating the reaction to 70 ℃, cooling the reaction solution to room temperature after the reaction is detected, and adding F 16 TPPFeCl (45.98mg, 0.1mmol) with H slowly added dropwise 2 O 2 (34.0 mg,1.0 mmol), after dropping, stirring at room temperature for 4 hours, evaporating the reaction solution under reduced pressure, and adding purified water (50 ml) and acetic acidEthyl ester (50 ml), collect the organic layer, filter, water wash, alkali wash, concentrate to dry to get galanthamine, yield 84.4%, purity by HPLC 97.21%.
Example 25
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml of acetonitrile, adding sodium hydride (1.2g, 0.05mol) and zinc iodide (7.98g, 0.025 mol) while stirring, heating to 40 ℃ for reaction, detecting the reaction completion, cooling the reaction liquid to room temperature, adding F 20 TPPFeCl (23.0mg, 50.0umol), t-BuOOH (17.0mg, 0.5mmol) is slowly dripped at the same time, the mixture is stirred at room temperature for reaction for 4 hours after dripping is finished, purified water (50 ml) and ethyl acetate (50 ml) are added after the reaction liquid is evaporated under reduced pressure, an organic layer is collected, the organic layer is filtered, washed by water and alkali, and concentrated to be dry to obtain galanthamine, the yield is 92.2%, and the HPLC purity is 98.95%.
Example 26
Adding compound VII (2.85g, 0.01mol) into a reaction bottle containing 50ml1, 2-dichloromethane, adding sodium hydride (1.2g, 0.05mol) and zinc bromide (5.63g, 0.025mol) while stirring, heating to 40 ℃ for reaction, cooling the reaction liquid to room temperature after the reaction is detected, adding F 20 TPPFeCl (36.79mg, 80.0umol), t-BuOOH (27.21mg, 0.8mmol) is slowly dripped at the same time, the mixture is stirred at room temperature for reaction for 4 hours after dripping is finished, purified water (50 ml) and ethyl acetate (50 ml) are added after the reaction liquid is evaporated under reduced pressure, an organic layer is collected, and the organic layer is filtered, washed by water and alkali and concentrated to be dry to obtain galanthamine, wherein the yield is 93.6 percent, and the HPLC purity is 98.77 percent.

Claims (10)

1. A galanthamine intermediate compound is characterized in that the structure is shown as formula VI:
Figure FDA0003115636350000011
2. a process for the preparation of galanthamine intermediate compound VI according to claim 1, comprising the steps of: adding the compound IV into an organic solvent A, adding the compound V at a low temperature, and continuously stirring at room temperature until the reaction is finished to obtain an intermediate compound VI, wherein the route is as follows:
Figure FDA0003115636350000012
3. the preparation method according to claim 2, wherein the compound IV and the compound V are fed in a molar ratio of: 1.0-2.0 parts by weight.
4. The preparation method according to claim 2, wherein the organic solvent A is selected from one or a combination of diethyl ether, acetone and anhydrous tetrahydrofuran; the temperature for adding the compound V is-10 ℃ to 0 ℃.
5. The process according to claim 2, wherein the process for the preparation of compound IV comprises the steps of: adding a compound II and a compound III into an organic solvent B, adding a catalyst, stirring and reacting at a controlled temperature, and detecting to obtain an intermediate compound IV after the reaction is finished, wherein the reaction route is as follows:
Figure FDA0003115636350000013
6. the preparation method of claim 5, wherein the catalyst is selected from one of copper chloride, copper acetate, copper trifluoroacetate, cuprous iodide and rhodium acetate; the feeding molar ratio of the compound II to the compound III to the catalyst is 1.0-2.0; the organic solvent B is selected from one or the combination of methanol, ethanol, isopropanol, tetrahydrofuran and acetonitrile; the reaction temperature is 50-75 ℃.
7. Use of compound v I according to claim 1 for the preparation of galanthamine.
8. Use of the galanthamine intermediate compound VI according to claim 1 for the preparation of galanthamine, wherein the preparation process comprises the steps of:
step (1): adding the compound VI into an organic solvent C, stirring to dissolve solids, adding 4-benzylcarbamyl phenyl aniline trifluoromethanesulfonate, controlling the temperature and refluxing, after the detection reaction is finished, adding N-hydroxysuccinimide and a condensing agent, controlling the temperature and stirring until the reaction is finished to obtain a compound VII,
step (2): adding the compound VII into an organic solvent D, adding sodium hydride and zinc salt, stirring and reacting at controlled temperature after the addition is finished, adding a catalyst and an oxidant after the detection reaction is finished, stirring and reacting at room temperature to obtain galanthamine,
the synthetic route is as follows:
Figure FDA0003115636350000021
9. the use according to claim 8, wherein the condensing agent of step (1) is selected from any one of dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate; the feeding molar ratio of the compound VI to the 4-benzylcarbamoylphenylaniline trifluoromethanesulfonate to the N-hydroxysuccinimide to the condensing agent is as follows: 1.02-0.1: 1.0 to 2.0; the organic solvent C is selected from one or the combination of dichloromethane, tetrahydrofuran, toluene, acetonitrile, DMF and chloroform; the reaction temperature of the condensation reagent is 25-35 ℃.
10. The use according to claim 8, wherein the zinc salt of step (2) is selected from one of zinc chloride, zinc iodide, zinc bromide; the catalyst is selected from F 20 TPPFeCl、F 16 TPPFeCl、F 8 One in TPPFeClSeed growing; the oxidant is selected from t-BuOOH and H 2 O 2 、C 6 F 5 One of IO; the feeding molar ratio of the compound VII, sodium hydride, zinc salt, catalyst and oxidant is (1.0-3.0); the organic solvent D is one or the combination of tetrahydrofuran, methanol, acetonitrile, 1, 2-dichloromethane and toluene; the reaction temperature is 40-65 ℃.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113292420A (en) * 2021-05-27 2021-08-24 神隆医药（常熟）有限公司 Method for recovering galanthamine intermediate raw material 2-bromo-5-hydroxy-4-methoxybenzoic acid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113292420A (en) * 2021-05-27 2021-08-24 神隆医药（常熟）有限公司 Method for recovering galanthamine intermediate raw material 2-bromo-5-hydroxy-4-methoxybenzoic acid

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