CN102304031A - Benzaldehyde derivative and use thereof in preparation of galanthamine - Google Patents
Benzaldehyde derivative and use thereof in preparation of galanthamine Download PDFInfo
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- CN102304031A CN102304031A CN201110124350A CN201110124350A CN102304031A CN 102304031 A CN102304031 A CN 102304031A CN 201110124350 A CN201110124350 A CN 201110124350A CN 201110124350 A CN201110124350 A CN 201110124350A CN 102304031 A CN102304031 A CN 102304031A
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Abstract
The invention relates to a benzaldehyde derivative and use thereof. The benzaldehyde derivative is obtained by the addition reaction of 6-haloisovanicaline and ethyl vinyl ether. The benzaldehyde derivative provided by the invention can be used for preparing galanthamine or salt thereof by the following steps: by using benzaldehyde derivative as a raw material, performing a Suzuki coupling reaction, an annulations and a reductive amination in turn to obtain racemic narwedine; resolving narwedine raceme to obtain (-)-narwedine; and reducing (-)-narwedine in an asymmetric manner to obtain (-)-galanthamine. The reaction conditions of each reaction are mild, and each reaction is suitable for large-scale preparation.
Description
Technical field
The present invention relates to a kind of benzaldehyde derivative and uses thereof, specifically, relate to a kind of 2,3, substituted phenyl aldehyde of 4-and the application in preparation lycoremine (Galanthamine) or its salt thereof.
Background technology
((-)-Galanthamine) is a kind of Fourth Ring vegeto-alkali that suppresses choline enzyme to (-)-lycoremine reversiblely, and its structure is suc as formula shown in the I.Lycoremine is big 10 to 50 times to the selectivity ratios butyrylcholine esterase of E.C. 3.1.1.7; Be prone to tolerance simultaneously; No liver toxicity; Various chronic diseases (like poliomyelitis sequela, myasthenia gravis, sacroiliitis, fatigue syndrome, manic and schizophrenia etc.) have been used to treat, usually with its hydrobromate administered.
Lycoremine can separation and Extraction obtain from Amaryllidaceae (Amaryllidaceae) plant, like pale reddish brown short-tube lycoris (Lycoris squamigera Maxim) and chrysanthemum short-tube lycoris (Lycoris aurea Herb) etc.Because the big quantity not sufficient of the very little short-tube lycoris in addition of content of lycoremine in the short-tube lycoris, thereby caused the wretched insufficiency of lycoremine output.Therefore, complete synthesis lycoremine enjoys organic chemists' concern.
CN 101674835A, patent documentations such as CN 101239983A and CN 101781305A have been reported the method for a series of complete synthesis lycoremines.The total synthesis method of existing lycoremine is each has something to recommend him, is difficult to the defective of large-scale production but the ubiquity step is tediously long.Given this, provide a kind of step succinct and be easy to the scale preparation lycoremine (method of (-)-Galanthamine) becomes the technical issues that need to address of the present invention.
Summary of the invention
One of the object of the invention is, provides a kind of 2,3, the substituted phenyl aldehyde of 4-, and described phenyl aldehyde has structure shown in the formula II:
Among the formula II, X is Cl, Br or I.
Two of the object of the invention is, the purposes of a kind of above-claimed cpd (compound shown in the formula II) is provided, i.e. its application in preparation lycoremine or its salt.
With compound shown in the formula II is raw material; Can make the Na Weiding ((±)-Narwedine) of racemization successively through Suzuki linked reaction, Cheng Huan (closed loop) reaction and reductive amination process; Folding divides the Na Weiding raceme to get (-)-Na Weiding ((-)-Narwedine); Asymmetric reduction (-)-Na Weiding obtains (-)-lycoremine ((-)-Galanthamine, compound shown in the formula I).Its synthesis strategy is following:
Wherein, X is Cl, Br or I, and TBS is a hydroxy-protective group.
The reaction conditions of above-mentioned each step reaction is all comparatively gentle, and each step reaction all is suitable for scale preparation.
In addition; The present invention also provides a kind of method for preparing compound shown in the formula II; Said method mainly be: with different 4-hydroxyl-3-methoxylbenxaldehyde (3-hydroxyl-4-methoxybenzaldehyde) is raw material; At first get the different 4-hydroxyl-3-methoxylbenxaldehyde of 6-halo (2-halo-3-hydroxyl-4-methoxybenzaldehyde) through halogenating reaction, then different 4-hydroxyl-3-methoxylbenxaldehyde of 6-halo (2-halo-3-hydroxyl-4-methoxybenzaldehyde) and ethyl vinyl ether are carried out addition reaction and obtain compound shown in the formula II, the synthetic route of said method is as follows:
Wherein said halo refers to the replacement (being that X is Cl, Br or I) of chlorine, bromine or iodine.
Embodiment
In described Suzuki linked reaction, used borane reagent is: 2,4, and 6-three (4-((t-tertiary butyl dimethyl-silicon) oxygen) phenyl)-1,3,5,2,4,6-three oxygen azoles three borines; Used phosphine part is triphenylphosphine or tricyclohexyl phosphine; Used catalyzer is that palladium catalyst is (like Pd
2(dba)
3Or Pd (OAc)
2Deng); The reaction solvent for use is non-proton polar organic solvent; Temperature of reaction is the reflux temperature of solvent for use.
In described Cheng Huan (closed loop) reaction; Compound shown in the formula III is dissolved in the non-proton polar organic solvent of exsiccant; Join then in exsiccant cesium fluoride and sodium sulfate or the vitriolate of tartar solid in 140 ℃ of reactions at least 2 hours, add sodium bicarbonate aqueous solution and ETHYLE ACETATE again, tell organic phase; Organic phase through dry with concentrate after, residuum can get chemical combination shown in the formula IV through separating (like column chromatography etc.).
In described reductive amination process, chemical combination shown in the formula IV, methylamine hydrochloride and diisopropyl ethyl amine were reacted 7 hours in room temperature (15 ℃～25 ℃) in non-proton polar organic solvent at least; And then add sodium cyanoborohydride and acetic acid, be warming up to 50 ℃～60 ℃, and kept at least 10 hours at this state, reaction solution is through cooling, extraction, dry and concentrate after, residuum is the raceme ((±)-Narwedine) of Na Weiding;
Wherein: the mol ratio of chemical combination shown in the formula IV, methylamine hydrochloride, the different basic amine of di-isopropyl and sodium cyanoborohydride is 1: (1～2): (1～2): (1～2).
Divide in the Na Weiding raceme at described folding; The Na Weiding raceme is dissolved in the mixed solvent of being made up of aliphatic monobasic alcohol and alkylamine (can heat in case of necessity and make it to dissolve fully); Add an amount of (-)-Na Weiding crystal (as crystal seed), can obtain (-)-Na Weiding after the gradient cooling.
In described reduction (-)-Na Weiding, (-)-Na Weiding and L-3-sec-butyl lithium borohydride (L-Selectride) are placed non-proton polar organic solvent, kept at least 2 hours at-78 ℃ of states, add C again
1～C
4Monohydroxy-alcohol, be warming up to room temperature (15 ℃～25 ℃), and kept about 20 minutes at this state, steaming desolventizes, residuum gets (-)-Galanthamine (compound shown in the formula I) through (silica gel) column chromatography;
Wherein: (-)-Na Weiding and L-Selectride mol ratio are preferably 1: 2.
In described different 4-hydroxyl-3-methoxylbenxaldehyde (compound shown in the formula VII) halogenating reaction step; Sodium-acetate is being arranged, under the iron powder of catalytic amount and the Glacial acetic acid min. 99.5 existence condition, reacting at least 10 hours in room temperature (15 ℃～25 ℃) by different 4-hydroxyl-3-methoxylbenxaldehyde and halogenating agent (like sulfur oxychloride, NBS or bromine etc.); Reaction solution is poured in the frozen water; Separate out solid, filter and get the different 4-hydroxyl-3-methoxylbenxaldehyde of bullion 6-halo (compound shown in the formula VIII), can get its pure article through recrystallization with the frozen water washing leaching cake;
Wherein: the mol ratio of different 4-hydroxyl-3-methoxylbenxaldehyde, halogenating agent, sodium-acetate and iron powder is preferably 1.0: (1.0～1.5): (1.0～2.0): (0.1～0.5).
In the addition reaction step of different 4-hydroxyl-3-methoxylbenxaldehyde of described 6-halo and ethyl vinyl ether, under condition of ice bath, ethyl vinyl ether is added drop-wise in the dichloromethane solution of halogenating agent (like sulfur oxychloride, NBS or bromine etc.); And, add the dichloromethane solution of diisopropyl ethyl amine and the different 4-hydroxyl-3-methoxylbenxaldehyde of 6-halo more successively, and be warming up to room temperature (15 ℃～25 ℃) this state maintenance at least 20 minutes; Kept at least 10 hours at room temperature (15 ℃～25 ℃) state; Reaction solution is poured in the saturated sodium hydrogen carbonate solution into dichloromethane extraction several, combining extraction liquid; Extraction liquid through with saturated common salt washing, dry and concentrate after, residuum is compound shown in the formula II;
Wherein: the mol ratio of the different 4-hydroxyl-3-methoxylbenxaldehyde of 6-halo, ethyl vinyl ether, halogenating agent and diisopropyl ethyl amine is preferably 1: (2～3): (1～2): (2～4).
The described non-proton polar organic solvent of preamble is (but being not limited to): 1, and 4-dioxane, THF or N, dinethylformamide etc.
Through being that embodiment does further elaboration to the present invention, its purpose only is better to understand content of the present invention below.The example of therefore, being lifted does not limit protection scope of the present invention.
In the following example, except that specifying, room temperature is meant: 15 ℃～25 ℃.
Embodiment 1
The preparation of compound shown in the formula IIa.
(1) the different 4-hydroxyl-3-methoxylbenxaldehyde of 6-bromine (compound shown in the formula VIII, wherein X is Br, notes by abridging to be compound VIII preparation a):
Under the room temperature, with the different 4-hydroxyl-3-methoxylbenxaldehyde of 100g, 108g sodium-acetate and 3g iron powder join in the 600mL Glacial acetic acid min. 99.5, slowly drip acetic acid (125mL) solution of 37mL bromine then, the reaction solution stirred overnight.Reaction solution is poured in the frozen water, separated out solid, filter, filter cake is used water washing, and (compound VIII is 112g a), yield 74% to get white solid with ethyl alcohol recrystallization.
1H-NMR(CDCl
3，400MHz)δ10.28(s，1H)，7.60(d，J＝8.4Hz，1H)，6.94(d，J＝8.4Hz，1H)，6.09(s，1H)，4.02(s，3H).
(2) preparation of target compound (compound shown in the formula IIa):
Under condition of ice bath, the 47mL ethyl vinyl ether is added drop-wise in the dichloromethane solution of bromine, reacted 20 minutes, add the 140mL diisopropyl ethyl amine, the different 4-hydroxyl-3-methoxylbenxaldehyde of 23g 6-bromine makes mixed solution rise to room temperature reaction then and spends the night.Reaction solution is used water washing, isolates organic phase, and organic phase removes solvent under reduced pressure through anhydrous sodium sulfate drying, and residuum gets white solid (compound shown in the formula IIa) 30g, yield 79% through silica gel column chromatography (petrol ether/ethyl acetate=10/1 (v/v)).
1H-NMR(CDCl
3，400MHz)δ10.29(s，1H)，7.78(d，J＝8.8Hz，1H)，7.00(d，J＝8.8Hz，1H)，5.47(t，J＝5.2Hz，1H)，3.99(s，3H)，3.94-3.86(m，1H)，3.78-3.70(m，1H)，3.64(q，J＝5.6Hz，2H)，1.22(t，J＝6.8Hz，3H)。
Embodiment 2
The preparation of (-)-lycoremine (preparation of compound shown in the formula I):
(1) preparation of compound shown in the formula III a:
Under the room temperature, with compound shown in 38.2g (0.1mmol) the formula IIa, 23.4g 2,4,6-three (4-((t-tertiary butyl dimethyl-silicon) oxygen) phenyl)-1,3,5,2,4,6-three oxygen azoles three borines, 1.04g triphenylphosphine, 80g potassiumphosphate, 2.3g Pd
2(dba)
3Join in the 1.5L THF, reaction solution is heated to 80 ℃ of reactions 12 hours.The reaction solution cooling is poured in the water, ethyl acetate extraction, and organic phase is dry, removal of solvent under reduced pressure, residuum gets yellow oily liquid 39.2g (compound shown in the formula III a), yield 77% through silica gel column chromatography (petrol ether/ethyl acetate=6/1 (v/v)).
1H?NMR(400MHz，CDCl
3)δ9.65(s，1H)，7.87(d，J＝8.8Hz，1H)，7.26(d，J＝8.4Hz，2H)，7.05(d，J＝8.8Hz，1H)，6.94(d，J＝8.4Hz，2H)，5.02-5.01(m，1H)，3.99(s，3H)，3.63-3.56(m，1H)，3.38-3.31(m，1H)，3.12-3.05(m，2H)，1.06(t，J＝6.8Hz，3H)，1.02(s，m?9H)，0.25(s，6H).
(2) preparation of compound shown in the formula IV:
Under the room temperature, with the 280mL N of compound shown in 19.8g (38.8mmol) the formula III a, N '-dimethyl formamide solution joins the 17.7g cesium fluoride; In the 55g sodium sulfate; Reaction solution was 140 ℃ of reactions 2 hours, and cooling reaction liquid is poured reaction solution in the saturated sodium bicarbonate aqueous solution of 2L into; Ethyl acetate extraction repeatedly merges organic phase.Organic phase is used the saturated common salt water washing respectively, anhydrous sodium sulfate drying, be evaporated to dried, residuum through silica gel column chromatography (petrol ether/ethyl acetate=2/1 (v/v)) faint yellow solid 8.6g (compound shown in the formula IV), yield 70%.
1H?NMR(400MHz，CDCl
3)δ9.95(s，1H)，7.76(dd，J
1＝1.6Hz，J
2＝10.0Hz，1H)，7.65(d，J＝8.4Hz，1H)，7.06(dd，J
1＝2.0Hz，J
2＝10.0Hz，1H)，6.98(d，J＝8.4Hz，1H)，6.38(d，J＝10.0Hz，1H)，6.32(d，J＝10.0Hz，1H)，5.52(s，1H)，3.99(s，3H)，4.05-3.89(m，2H)，3.74-3.67(m，1H)，2.41(d，J＝14.0Hz，1H)，2.03(d，J＝14.0Hz，1H)，1.23(t，J＝7.2Hz，3H).
(3) preparation of compound shown in the formula V:
Under the room temperature, compound shown in 15.7g (50mmol) the formula IV is joined 250mL 1, in the 4-dioxane; Add the 4g methylamine hydrochloride then, the 10mL diisopropyl ethyl amine reacted 7 hours; Add 30mL acetic acid then, 4.7g sodium cyanoborohydride, reaction solution are warming up to 60 ℃ of reactions and spend the night.Saturated sodium bicarbonate aqueous solution is poured in the reaction solution cooling into, and methylene dichloride repeatedly extracts; Merge organic phase; Organic phase is again with saturated common salt washing, anhydrous sodium sulfate drying, concentrating under reduced pressure; Residuum gets light brown solid 12.8g (compound shown in the formula V), yield 90% through silica gel column chromatography (methylene chloride/triethylamine=100/5/1 (v/v)).
1H?NMR(400MHz，CDCl
3)δ6.95(dd，J
1＝1.6Hz，J
2＝10.4Hz，1H)，6.70(d，J＝8.0Hz，1H)，6.61(d，J＝8.0Hz，1H)，6.03(dd，J
1＝0.8Hz，J
2＝10.0Hz，1H)，4.72-4.70(m，1H)，4.08(d，J＝16.0Hz，1H)，3.82(s，3H)，3.72(d，J＝16.0Hz，1H)，3.27-3.10(m，3H)，2.75(dd，J
1＝4.0Hz，J
2＝17.2Hz，1H)，2.43(s，3H)，2.28(m，1H)，1.84(dd，J
1＝2.0Hz，J
2＝14.0Hz，1H).
(4) preparation of (-)-Na Weiding (compound shown in the formula VI):
5.7g (2mmol) racemization Na Weiding (compound shown in the formula V) is joined in 100mL ethanol/triethylamine mixed solvent (9: 1 (V/V)), and solution is heated to 80 ℃ and stirred 1 hour, and after treating to dissolve fully, temperature is reduced to 60 ℃; Add 142mg (-)-Na Weiding crystal (as crystal seed), continue to be cooled to 40 ℃, under this temperature, stirred 15 hours; Again reacting liquid temperature is reduced to 20 ℃ and stirred 2 hours, standing and reacting liquid filters; Collect crystallization and get white solid 5.1g, (compound shown in the formula VI), [α]
D 20=-400 °, (c 1.1, CHCl
3), yield 90%.
1H?NMR(400MHz，CDCl
3)δ6.95(d，J＝10.4Hz，1H)，6.67(d，J＝8.4Hz，2H)，6.00(d，J＝10.4Hz，1H)，4.72(bs，1H)，4.07(d，J＝15.2Hz，1H)，3.81(s，3H)，3.74(d，J＝15.2Hz，1H)，3.12-3.10(m，3H)，2.74(dd，J1＝3.6Hz，J2＝18.0Hz，1H)，2.42(s，3H)，2.27(td，J1＝2.8Hz，J2＝13.2Hz，1H)，1.85(d，J＝14.0Hz，1H).
The preparation of (5) (-)-lycoremine (compound shown in the formula I):
Under-78 ℃ of conditions, slowly drip L-Selectride (20mL, 1N in THF) in 90 milliliters of tetrahydrofuran solutions of compound shown in 2.85g (10mmol) the formula VI; Kept 2 hours at this state; With its join 100 ml methanol in, be warming up to 20 ℃ and stirred 20 minutes, dried solvent is revolved in decompression; Residuum gets white solid 2.82g (compound shown in the formula I), [α] through silica gel column chromatography (methylene chloride/triethylamine=100/10/1 (v/v))
D 20=-94.0 °, (c 1, CHCl
3), yield 99%.
1H?NMR(400MHz，CDCl
3)δ6.67(q，J＝8.4Hz，2H)，6.00-5.99(m，2H)，4.61(bs，1H)，4.15(bs，1H)，4.09(d，J＝15.2Hz，1H)，3.84(s，3H)，3.70(d，J＝15.2Hz，1H)，3.27(t，J＝13.8Hz，1H)，3.05(d，J＝14.4Hz，1H)，2.69(dd，J
1＝2.0Hz，J
2＝16.0Hz，1H)，2.47(bs，1H)，2.40(s，3H)，2.05-2.04(m，2H)，1.45(dd，J
1＝2.0Hz，J
2＝14.0Hz，1H)。
Claims (10)
1. benzaldehyde derivative, it has structure shown in the formula II:
Among the formula II, X is Cl, Br or I.
2. its application in preparation lycoremine or its salt of benzaldehyde derivative as claimed in claim 1.
3. application as claimed in claim 2 is characterized in that, wherein said lycoremine has structure shown in the formula I:
4. application as claimed in claim 3; It is characterized in that; Wherein the key step by the described benzaldehyde derivative preparation of claim 1 (-)-lycoremine is: with compound shown in the formula II is raw material; Get compound shown in compound shown in the formula III, the formula III makes racemization successively through annulation and reductive amination process Na Weiding through the Suzuki linked reaction, folding divides a Na Weiding raceme to get (-)-Na Weiding, and asymmetric reduction (-)-Na Weiding obtains (-)-lycoremine:
Wherein, X is Cl, Br or I, and TBS is a hydroxy-protective group.
5. application as claimed in claim 4 is characterized in that, in described Suzuki linked reaction, used borane reagent is: 2,4, and 6-three (4-((t-tertiary butyl dimethyl-silicon) oxygen) phenyl)-1,3,5,2,4,6-three oxygen azoles three borines; Used phosphine part is triphenylphosphine or tricyclohexyl phosphine; Used catalyzer is a palladium catalyst; The reaction solvent for use is non-proton polar organic solvent; Temperature of reaction is the reflux temperature of solvent for use.
6. application as claimed in claim 5 is characterized in that wherein said palladium catalyst is Pd
2(dba)
3Or Pd (OAc)
2
7. application as claimed in claim 4 is characterized in that, in described annulation; Compound shown in the formula III is dissolved in the non-proton polar organic solvent of exsiccant; Join then in exsiccant cesium fluoride and sodium sulfate or the vitriolate of tartar solid in 140 ℃ of reactions at least 2 hours, add sodium bicarbonate aqueous solution and ETHYLE ACETATE again, tell organic phase; Organic phase is through drying with after concentrating, and residuum can get chemical combination shown in the formula IV through separating:
Wherein, X is Cl, Br or I, and TBS is a hydroxy-protective group.
8. application as claimed in claim 4 is characterized in that, in described reductive amination process, with chemical combination shown in the formula IV, methylamine hydrochloride and diisopropyl ethyl amine in non-proton polar organic solvent in 15 ℃～25 ℃ reactions at least 7 hours; And then add sodium cyanoborohydride and acetic acid, be warming up to 50 ℃～60 ℃, and kept at least 10 hours at this state, reaction solution is through cooling, extraction, dry and concentrate after, residuum is the Na Weiding raceme;
Wherein: the mol ratio of chemical combination shown in the formula IV, methylamine hydrochloride, the different basic amine of di-isopropyl and sodium cyanoborohydride is 1: (1～2): (1～2): (1～2).
9. application as claimed in claim 4; It is characterized in that, divide in the Na Weiding raceme, the Na Weiding raceme is dissolved in the mixed solvent of forming by aliphatic monobasic alcohol and alkylamine at described folding; Add an amount of (-)-Na Weiding crystal, get (-)-Na Weiding after the gradient cooling.
10. application as claimed in claim 4 is characterized in that, in described asymmetric reduction (-)-Na Weiding; (-)-Na Weiding and L-3-sec-butyl lithium borohydride are placed non-proton polar organic solvent, kept at least 2 hours, add the monohydroxy-alcohol of C1～C4 again at-78 ℃ of states; Be warming up to 15 ℃～25 ℃; And kept about 20 minutes at this state, steaming desolventizes, residuum behind column chromatography (-)-lycoremine;
Wherein: (-)-Na Weiding and L-3-sec-butyl lithium borohydride mol ratio are 1: 2.
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| CN201110124350A CN102304031A (en) | 2011-05-13 | 2011-05-13 | Benzaldehyde derivative and use thereof in preparation of galanthamine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592243A (en) * | 2014-12-19 | 2015-05-06 | 北京大学 | Asymmetric synthesis method of galanthamine and lycoramine |
Citations (5)
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|---|---|---|---|---|
| CN1050380A (en) * | 1989-09-22 | 1991-04-03 | 默里尔药物公司 | New substituted alkyl piperidines and as the application of cholesterol synthesis inhibitor |
| EP0906314B1 (en) * | 1996-05-24 | 2002-09-25 | Janssen Pharmaceutica N.V. | Optical resolution of narwedine-type compounds |
| US20090326219A1 (en) * | 2008-06-26 | 2009-12-31 | Sanochemia Pharmazeutika Ag | Process for manufacturing extremely pure benzazepine derivatives |
| EP1885727B1 (en) * | 2005-05-03 | 2010-03-03 | Medichem, S.A. | Syntheses and preparations of narwedine and related novel compounds |
| US20100292466A1 (en) * | 2009-05-12 | 2010-11-18 | Board Of Regents The University Of Texas System | Efficient Synthesis Of Galanthamine |
-
2011
- 2011-05-13 CN CN201110124350A patent/CN102304031A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1050380A (en) * | 1989-09-22 | 1991-04-03 | 默里尔药物公司 | New substituted alkyl piperidines and as the application of cholesterol synthesis inhibitor |
| EP0906314B1 (en) * | 1996-05-24 | 2002-09-25 | Janssen Pharmaceutica N.V. | Optical resolution of narwedine-type compounds |
| EP1885727B1 (en) * | 2005-05-03 | 2010-03-03 | Medichem, S.A. | Syntheses and preparations of narwedine and related novel compounds |
| US20090326219A1 (en) * | 2008-06-26 | 2009-12-31 | Sanochemia Pharmazeutika Ag | Process for manufacturing extremely pure benzazepine derivatives |
| US20100292466A1 (en) * | 2009-05-12 | 2010-11-18 | Board Of Regents The University Of Texas System | Efficient Synthesis Of Galanthamine |
Non-Patent Citations (1)
| Title |
|---|
| 刘涛等: "外消旋加兰他敏全合成研究", 《浙江大学学报(工学版)》, no. 03, 28 March 2006 (2006-03-28) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592243A (en) * | 2014-12-19 | 2015-05-06 | 北京大学 | Asymmetric synthesis method of galanthamine and lycoramine |
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