CN104496900A - Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline - Google Patents
Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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Abstract
The invention provides a method for synthesizing 2-methoxy-6-one-5,7,8-trihydro-quinoline. The method for synthesizing the 2-methoxy-6-one-5,7,8-trihydro-quinoline comprises the following steps: a step of preparing 2'-methoxy-5',7',8'-trihydro-helix-[1,3-dioxolane-2]-quinoline and preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline. The method comprises the following steps: with 2'-one-5',7',8'-trihydro-helix-[1,3-dioxolane-2]-quinoline as raw material, synthesizing 2'-methoxy-5',7',8'-trihydro-helix-[1,3-dioxolane-2]-quinoline under the action of copper carbonate through iodomethane, deprotecting 2'-methoxy-5',7',8'-trihydro-helix-[1,3-dioxolane-2]-quinoline under an acidic condition, thereby synthesizing 2-methoxy-6-one-5,7,8-trihydro-quinoline. The method is easy to operate, the product yield and purity are high, the method can be used for industrial production, and the compound is an important huperzine A intermediate.
Description
Technical field
The invention belongs to medicine intermediate technical field, be specifically related to the preparation method of selagine intermediate 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline.
Background technology
Along with alzheimer disease patient is increasing, after cardiovascular disorder, neoplastic disease, senile dementia has become the 3rd disease threatening the elderly's life.The decline of acetylcholine function and the forfeiture of learning and memory ability have important relation, and therefore, the research emphasis for the treatment of this disease is searching maincenter choline medicine, and acetylcholinesterase depressant is still current most study, most widely used general.
S-generation acetylcholinesterase depressant selagine; improve outside the acetylcholine concentration between cynapse by acetylcholine esterase inhibition to the hydrolytic action of vagusstoff; also by anti-oxidation stress and anti-apoptotic approach, provide protection is produced to neurone; there is unique pharmacology and hypotoxicity, there is in treatment alzheimer disease field the medicine of bright prospects.
No matter be synthesizing optical selagine or racemization selagine, great majority are all first synthesize 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline.
In prior art, major part synthesis 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline take silver carbonate as catalyzer, and this catalyzer is expensive, reclaims difficulty, is not suitable for scale operation.
Summary of the invention
In order to solve the technical problem in background technology, the invention provides a kind of preparation method of 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline, the method is cheap, simple to operate, product yield and purity high, be applicable to suitability for industrialized production.
The preparation method of this 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline, comprises the following steps:
1] prepare 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline
Under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide join in methylene dichloride (or trichloromethane or tetracol phenixin), stir, 2-12h is reacted under 20-76 DEG C of condition, to be cooled to room temperature, then filter, concentrated, by ethyl acetate and normal hexane pillar layer separation, reconcentration, obtain 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline; Above-mentioned 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide, methylene dichloride (or trichloromethane or tetracol phenixin) is 1:1-3:5-13:46-69; Above-mentioned ethyl acetate, the mol ratio of normal hexane are 1:3;
2] 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline is prepared
Under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline and phosphoric acid are added to the water, and stir, under 25-100 DEG C of condition, react 2-12 hour, to be cooled to room temperature, then add mass concentration be 15% sodium hydroxide solution be adjusted to neutrality, extraction into ethyl acetate, concentrated, ethyl acetate and normal hexane pillar layer separation, reconcentration, both 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline was obtained; Above-mentioned 2 '-methoxyl group-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, phosphoric acid, water is 1:2-8:2-10; The mol ratio of above-mentioned ethyl acetate and normal hexane post is 1:4.
In above-mentioned steps 1, under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide join in methylene dichloride (or trichloromethane or tetracol phenixin), stir, under 30 DEG C of conditions, react 10h, to be cooled to room temperature, filter, concentrated, by ethyl acetate and normal hexane pillar layer separation, concentrated, both 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline; Described 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide, methylene dichloride (or trichloromethane or tetracol phenixin) is 1:2:10:55; Described ethyl acetate, the mol ratio of normal hexane are 1:3;
In above-mentioned steps 2, under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline and phosphoric acid join water, stir, react 7 hours under 70 DEG C of conditions, to be cooled to room temperature, then adding mass concentration is that 15% sodium hydroxide solution is adjusted to neutrality, extraction into ethyl acetate, concentrated, by ethyl acetate and normal hexane pillar layer separation, concentrated, both obtained 2-methoxyl group-6-ketone-5,7,8-, tri-hydrogen-quinoline; Described 2 '-methoxyl group-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, phosphoric acid, water is 1:4:3; The mol ratio of described ethyl acetate and normal hexane post is 1:4.
Technique effect of the present invention:
This 2-methoxyl group-6-ketone-5; the preparation method of 7,8-, tri-hydrogen-quinoline, with 2 '-one-5 '; 7 '; 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline is raw material, by methylation reaction and deprotection reaction; synthesize this compound; simple to operate, product yield and purity high, be applicable to suitability for industrialized production.
Embodiment
The preparation method of 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline:
Embodiment 1
Under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 20.7g, copper carbonate 25.0g, methyl iodide 14.2g joins in 300mL methylene dichloride, stir, react 10 hours under 30 DEG C of conditions, 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, copper carbonate, be 1:2:10:55 with the mol ratio of methylene dichloride, be cooled to room temperature, filter, concentrated, ethyl acetate: normal hexane=1:3 pillar layer separation, concentrated, both 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, yield: 90.3%, purity: 98.3%.
Embodiment 2
Under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 20.7g, copper carbonate 37.5g, methyl iodide 11.4g joins in 450mL trichloromethane, stir, 50 DEG C are reacted 8 hours, 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, copper carbonate, be 1:3:8:69 with the mol ratio of trichloromethane, be cooled to room temperature, filter, concentrated, ethyl acetate: normal hexane=1:3 pillar layer separation, concentrated, both 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, yield: 81.4%, purity: 97.1%.
Embodiment 3
Under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 20.7g, copper carbonate 50.0g, methyl iodide 21.3g joins in 600 tetracol phenixin, stir, 65 DEG C are reacted 6 hours, 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, copper carbonate, be 1:4:15:92 with the mol ratio of tetracol phenixin, be cooled to room temperature, filter, concentrated, ethyl acetate: normal hexane=1:3 pillar layer separation, concentrated, both 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, yield: 61.4%, purity: 97.3%.
Embodiment 4
Under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 22.1g, phosphoric acid 21mL, join in 60mL water, stir, 70 DEG C are reacted 7 hours, 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, the mol ratio of phosphoric acid and water is 1:4:3, be cooled to room temperature, 15% sodium hydroxide solution is adjusted to neutrality, extraction into ethyl acetate, concentrated, ethyl acetate: normal hexane=1:4 pillar layer separation, concentrated, both 2-methoxyl group-6-ketone-5 was obtained, 7, 8-tri-hydrogen-quinoline, yield: 93.4%, purity: 98.6%.
Embodiment 5
Under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 22.1g, phosphoric acid 26.2mL, join in 100mL water, stir, 60 DEG C are reacted 6 hours, 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, the mol ratio of phosphoric acid and water is 1:5:5, be cooled to room temperature, 15% sodium hydroxide solution is adjusted to neutrality, extraction into ethyl acetate, concentrated, ethyl acetate: normal hexane=1:4 pillar layer separation, concentrated, both 2-methoxyl group-6-ketone-5 was obtained, 7, 8-tri-hydrogen-quinoline, yield: 81.3%, purity: 96.2%.
Embodiment 6
Under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline 22.1g, phosphatase 24 2mL, join in 200mL water, stir, 60 DEG C are reacted 6 hours, 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1, 3-dioxolane-2]-quinoline, the mol ratio of phosphoric acid and water is 1:8:10, be cooled to room temperature, 15% sodium hydroxide solution is adjusted to neutrality, extraction into ethyl acetate, concentrated, ethyl acetate: normal hexane=1:4 pillar layer separation, concentrated, both 2-methoxyl group-6-ketone-5 was obtained, 7, 8-tri-hydrogen-quinoline, yield: 81.3%, purity: 96.2%.
Due to experimental procedure 1 prepare 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline is a most key step.In order to determine optimum material proportion and the optimised process step of this step, carried out a large amount of laboratory study tests, various test situation is as follows:
1, temperature of reaction to preparation 2 '-methoxyl group-5 ', 7 ', the impact of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline product yield
According to 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2] mol ratio of-quinoline, copper carbonate, methyl iodide and methylene dichloride is 1:2:10:55, respectively 20,30,40,50,65,76 DEG C of reactions 10 hours, preparation 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, calculates its yield.Test-results is in table 1.
Table 1 temperature of reaction is on the impact of product yield
From table 1,20 ~ 40 DEG C of reaction purity of 5 hours products therefroms and yield all higher, wherein the purity of 30 DEG C of reactions, 10 hours products therefroms and yield the highest.
2, the reaction times to preparation 2 '-methoxyl group-5 ', 7 ', the impact of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline yield
According to 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2] mol ratio of-quinoline, copper carbonate, methyl iodide and methylene dichloride is 1:2:10:55, respectively 30 DEG C of reactions 5,6,7,8,10,12,14 hours, preparation 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, calculates its yield.Test-results is in table 2.
Table 2 reaction times is on the impact of product yield
From table 2,30 DEG C of reaction 8-16 hour, the purity of products therefrom and yield are all higher, and wherein the reaction times is 10 constantly little, and purity and the yield of products therefrom are the highest.
Comprehensive test 1 and 2, the present invention selects 20 ~ 76 DEG C to react 6 ~ 16 hours, and preferably 20 ~ 40 DEG C are reacted 8 ~ 16 hours, and the best is 30 DEG C of reactions 10 hours.
3, catalyst levels to preparation 2 '-methoxyl group-5 ', 7 ', the impact of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline product yield
Respectively according to according to 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide and methylene dichloride is 1:1:10:55; 1:2:10:55; 1:3:10:55; 1:4:10:55; 1:5:10:55, reaction conditions is: 30 DEG C of reactions 10 hours, preparation 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, calculates its yield.Test-results is in table 3.
Table 3 oxygenant consumption is on the impact of product yield
From table 3: 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2] mol ratio of-quinoline, copper carbonate, methyl iodide and methylene dichloride is when being 1:2 ~ 3:10:55, the yield of products therefrom and purity are all higher, wherein 2 '-one-5 ', 7 ', when 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide and methylene dichloride mol ratio is 1:2:10:55, purity and the yield of products therefrom are all the highest.
4, solvent load to preparation 2 '-methoxyl group-5 ', 7 ', the impact of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline product yield
Respectively according to 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide and methylene dichloride is 1:2:10:46; 1:2:10:55; 1:2:10:65; 1:2:10:75; 1:2:10:92; Reaction conditions is: 30 DEG C are reacted 10 hours, compound 2 '-methoxyl group-5 shown in preparation formula III ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, and calculate its yield.Test-results is in table 4.
Table 4 solvent load is on the impact of product yield
From table 4: 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2] mol ratio of-quinoline, copper carbonate, methyl iodide and methylene dichloride is when being 1:2:10:46 ~ 65, the yield of product is higher, wherein 2 '-one-5 ', 7 ', when the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide and methylene dichloride is 1:2:10:55, the purity of product is high, yield is also high.
The result of comprehensive test 3 and 4, selecting type 2 '-methoxyl group of the present invention-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide and methylene dichloride mol ratio be 1:1-5:10:46-92, preferred molar ratio is 1:2-3:10:46-65, and optimum mole ratio is 1:2:10:55.
Claims (3)
1. the preparation method of 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline, is characterized in that, comprise the following steps:
1] prepare 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline
Under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide join in methylene dichloride (or trichloromethane or tetracol phenixin), stir, 2-12h is reacted under 20-76 DEG C of condition, to be cooled to room temperature, then filter, concentrated, by ethyl acetate and normal hexane pillar layer separation, reconcentration, obtain 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline; Described 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide, methylene dichloride (or trichloromethane or tetracol phenixin) is 1:1-3:5-13:46-69; Described ethyl acetate, the mol ratio of normal hexane are 1:3;
2] 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline is prepared
Under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline and phosphoric acid are added to the water, and stir, under 25-100 DEG C of condition, react 2-12 hour, to be cooled to room temperature, then add mass concentration be 15% sodium hydroxide solution be adjusted to neutrality, extraction into ethyl acetate, concentrated, ethyl acetate and normal hexane pillar layer separation, reconcentration, both 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline was obtained; Described 2 '-methoxyl group-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, phosphoric acid, water is 1:2-8:2-10; The mol ratio of described ethyl acetate and normal hexane post is 1:4.
2. the preparation method of 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline according to claim 1, is characterized in that:
In described step 1, under magnetic stirring, by 2 '-one-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide join in methylene dichloride (or trichloromethane or tetracol phenixin), stir, under 30 DEG C of conditions, react 10h, to be cooled to room temperature, filter, concentrated, by ethyl acetate and normal hexane pillar layer separation, concentrated, both 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline; Described 2 '-one-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, copper carbonate, methyl iodide, methylene dichloride (or trichloromethane or tetracol phenixin) is 1:2:10:55; Described ethyl acetate, the mol ratio of normal hexane are 1:3.
3. the preparation method of 2-methoxyl group-6-ketone-5,7,8-tri-hydrogen-quinoline according to claim 1, is characterized in that:
In described step 2, under magnetic stirring, by 2 '-methoxyl group-5 ', 7 ', 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline and phosphoric acid join water, stir, react 7 hours under 70 DEG C of conditions, to be cooled to room temperature, then adding mass concentration is that 15% sodium hydroxide solution is adjusted to neutrality, extraction into ethyl acetate, concentrated, by ethyl acetate and normal hexane pillar layer separation, concentrated, both obtained 2-methoxyl group-6-ketone-5,7,8-, tri-hydrogen-quinoline; Described 2 '-methoxyl group-5 ', 7 ', the mol ratio of 8 '-three hydrogen-spiral shell-[1,3-dioxolane-2]-quinoline, phosphoric acid, water is 1:4:3; The mol ratio of described ethyl acetate and normal hexane post is 1:4.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716449A (en) * | 2022-04-12 | 2022-07-08 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline |
| CN115232138A (en) * | 2022-08-09 | 2022-10-25 | 杭州师范大学 | Huperzine A intermediate and nontoxic synthesis process of raw materials thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716449A (en) * | 2022-04-12 | 2022-07-08 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene ketal-5, 7, 8-trihydroquinoline |
| CN114716449B (en) * | 2022-04-12 | 2023-09-29 | 浙江工业大学 | Preparation method of 2-methoxy-6-ethylene glycol ketal-5, 7, 8-trihydroquinoline |
| CN115232138A (en) * | 2022-08-09 | 2022-10-25 | 杭州师范大学 | Huperzine A intermediate and nontoxic synthesis process of raw materials thereof |
| CN115232138B (en) * | 2022-08-09 | 2024-01-30 | 杭州师范大学 | Huperzine A intermediate and nontoxic synthesis process of raw materials thereof |
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