CN103387574A - Synthetic method of epiberberine - Google Patents
Synthetic method of epiberberine Download PDFInfo
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- CN103387574A CN103387574A CN2012101367413A CN201210136741A CN103387574A CN 103387574 A CN103387574 A CN 103387574A CN 2012101367413 A CN2012101367413 A CN 2012101367413A CN 201210136741 A CN201210136741 A CN 201210136741A CN 103387574 A CN103387574 A CN 103387574A
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- methylene
- synthetic method
- epiberberine
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Abstract
The invention discloses a synthetic method of epiberberine. According to the invention, 3,4-dimethoxy phenylethylamine and 2,3-methylenedioxy benzaldehyde are used as initial raw materials and subjected to cyclopolymerization, condensation and loop closure to synthesize the target compound.
Description
Technical field
The present invention relates to a kind of full chemical synthesis process of epiberberine.
Background technology
Epiberberine, another name dehydrogenation suffering is the gram fourth, is a kind of natural quaternary ammonium Protoberberine Alkoloids, be from the coptis (
Coptischinensis) and
Coptistrifolia,
BerberisfloribundaMiddle extraction separation obtains,
Coptisgroenlandica, Coptisjaponica, Thalictrumminus, NandinadomesticaDeng also containing in plant.Epiberberine has multiple pharmacological effect, and as active to the stronger inhibition of cytochrosome P-450 isoforms CYP2D6, it is active that noncompetitive BACE1 suppresses, and suppresses aldose reductase activity, alpha receptor blocking effect, external hypoglycemic activity etc.Content due to epiberberine in the coptis is lower, is about 0.5-2%,, mainly as the assay reference substance, is difficult on the market buy and obtains, and has limited on its pharmacology and further research and the application of the aspect such as clinical.
Bibliographical information has been arranged synthesizing of a kind of epiberberine, reactions steps is as follows:
[Pai, B.R., NataraineS., Rajeswari.S., etal.Studiesinprotoberberinealkaloids:partXIX-synthesisof (±)-thalictrifoline, (±)-sinactine﹠amp; (±)-cavidine.IndianJ.Chem., Sect.B, 1982,21,607-611], in this reaction, epiberberine obtains with by-product form, and the method is economical not, and reactions steps is also more; And used the reagent C H that expensive intermediate and volatility are large, toxicity is stronger
2N
2And PCl
5Deng; The experimental implementation condition is also stricter, needs pressurization to carry out chemical reaction etc.; Do not report yield yet.
Summary of the invention
The object of the invention is to provide a kind of synthetic method of epiberberine, and this synthetic method is comprised of following steps:
Wherein the reaction reagent of reaction (1) is methylene dichloride, methylene bromide, methylene iodide, chloroiodomethane or bromoiodomethane, and acid binding agent is potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate or magnesiumcarbonate; The acid binding agent of reaction (2) is triethylamine, diethylamine, sodium hydroxide, salt of wormwood, sodium carbonate or magnesiumcarbonate; Reaction (3) reductive agent is POTASSIUM BOROHYDRIDE, sodium borohydride, Zn+ concentrated hydrochloric acid or the Fe+ vitriol oil; The reaction reagent of reaction (4) is oxalic dialdehyde, and neutralization bases solution is sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or ammonia solution.
Preferably, the reaction reagent of reaction (1) is methylene bromide, and acid binding agent is salt of wormwood; The acid binding agent of reaction (2) is triethylamine; Reaction (3) reductive agent is sodium borohydride; The reaction reagent of reaction (4) is oxalic dialdehyde, and neutralization bases solution is sodium carbonate.
The comprehensive yield of the inventive method can reach more than 10%.
Embodiment
The present invention is further detailed by following examples, but the present invention is not limited to this.
[0030] embodiment 1:
Synthesizing of (1) 2,3-methylene oxygen benzaldehyde
Add successively 2,3-Dihydroxy benzaldehyde 13.8g (100mmol) in the 500ml three-necked bottle, anhydrous K
2CO
320.8g (151mmol), methylene bromide 28.3g (163mmol), 50mlDMF, magnetic agitation, heating, back flow reaction.Reaction 24h.Ethyl acetate extraction (150ml * 3 time).Merge organic phase, anhydrous Na
2SO
4Dried overnight.Decompression and solvent recovery.The residual solution silica gel mixed sample, through silica gel column chromatography (eluent is sherwood oil: ethyl acetate=20: 1) separate 2,3-methylene oxygen benzaldehyde white crystal 11.2g.Yield 75.0%, m.p.30 ℃-31 ℃.
1H-NMR(CDCl
3，500MHz):δ10.09(1H，s，1-CHO)，7.25(1H，d，
J=7.5Hz，ArH)，7.02(1H，d，
J=6.5Hz，ArH)，6.95(1H，dd，
J=7.5，6.5Hz，ArH)，6.11(2H，s，-OCH
2O-)。
(2) N-(2,3-methylene-dioxy-N-benzyl)-β-(3,4-dimethoxy-benzyl) ethyliminum is synthetic
Add successively step (1) gained 2 in the 500ml three-necked bottle, 3-methylene dioxo group benzaldehyde 8.51g (57mmol), methylene dichloride 100ml, 2,3-dimethoxy-phenylethylamine 10.6g (58mmol), triethylamine 6.82g (67mmol), anhydrous MgSO
410g.Magnetic agitation, heating, back flow reaction.Reaction 5h.Suction filtration, the elimination insolubles.Remove solvent under reduced pressure.Cooling crystallization.Methanol wash, obtain N-(2,3-methylene-dioxy-N-benzyl)-β-(3,4-dimethoxy-benzyl) ethyliminum white crystals 17.6g.Yield 98.7%.
1H-NMR(CDCl
3，500MHz):δ8.23(1H，s)，6.86(1H，s，ArH)，6.85(1H，s，ArH)，6.79(1H，t，J=8.4Hz，ArH)，6.76(2H，d，J=8.0Hz，ArH)，6.04(1H，s，N=CH-Ar)，5.90(2H，s，-OCH
2O-)，3.85(3H，s，-OCH
3)，3.82(3H，s，-OCH
3)，3.85(2H，t，
J=7.0Hz，CH
2)，2.96(2H，t，
J=7.0Hz，CH
2)。
(3) N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(the inferior p-methoxy-phenyl of 3,4-) ethamine is synthetic
In the 500ml three-necked bottle, add step (2) gained N-(2,3-methylene-dioxy-N-benzyl)-β-(3,4-dimethoxy-benzyl) ethyliminum 17.6g (56mmol), dehydrated alcohol 100ml, heating for dissolving.Add sodium borohydride 5.0g (66mmol) in batches.Finish back flow reaction 10h.Remove solvent under reduced pressure.Add water 150ml, (3 * 150ml) extractions, merge organic phase, anhydrous Na to ethyl acetate
2SO
4Dry.Remove solvent under reduced pressure.Obtain N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(the inferior p-methoxy-phenyl of 3,4-) ethamine yellow oily liquid 17.4g.Yield 98.4%.
1H-NMR(CDCl
3，500MHz):δ6.71-6.80(5H，m，ArH)，5.90(2H，s，-OCH
2O-)，3.85(3H，s，-OCH
3)，3.84(3H，s，-OCH
3)，3.79(2H，s，N-CH
2-Ar)，2.87(2H，t，
J=7.0Hz，CH
2)，2.77(2H，t，
J=7.0Hz，CH
2)。
(4) the hydrochloric acid epiberberine is synthetic
In the 500ml three-necked bottle, add CuSO
45H
2O16.1g, NaCl16.3g, 40% oxalic dialdehyde 24.1g, be heated to 70 ℃, the magnetic agitation reaction.After reaction 2h, reactant is added step (3) gained N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(3, the inferior p-methoxy-phenyl of 4-) in ethamine 17.4g (55mmol), add aceticanhydride 30ml, HAc100ml, be heated to 100 ℃, the magnetic agitation reaction.Reaction 20h.Add water 250ml, be heated to 90 ℃, incline and, use saturated NaCO
3Solution is neutralized to pH=7.0.Collecting precipitation, be washed to water lotion and be faint yellow.Throw out is added hydrochloric acid-95% ethanol (5:95) 20ml, heating 1h.Cooling, filter.The filter cake silica gel mixed sample, (eluent is chloroform: methyl alcohol=9: 1) separate, recrystallization (95% ethanol), obtain hydrochloric acid epiberberine 7.3g through silica gel column chromatography.Yield 35.8%, orange amorphous powder.
1H-NMR(DMSO-
d 6)δ:9.91(1H，s，H-8)，9.04(1H，s，H-13)，8.03(1H，d，
J=8.43Hz，H-11)，7.86(1H，d，
J =8.4Hz，H-12)，7.71(1H，s，H-l)，7.09(1H，s，H-4)，6.55(2H，s，-OCH
2O-)，4.94(2H，t，
J=5.6Hz，H-6)，3.95(3H，s，2-OCH
3)，3.88(3H，s，3-OCH
3)，3.22(2H，t，
J=5.6Hz，H-5)。
Embodiment 2:
Synthesizing of (1) 2,3-methylene oxygen benzaldehyde
Add successively 2,3-Dihydroxy benzaldehyde 13.8g (100mmol) in the 500ml three-necked bottle, anhydrous MgCO
312.8g (151mmol), methylene iodide 43.7g (163mmol), 50mlDMF, magnetic agitation, heating, back flow reaction.Reaction 24h.Ethyl acetate extraction (150ml * 3 time).Merge organic phase, anhydrous Na
2SO
4Dried overnight.Decompression and solvent recovery.The residual solution silica gel mixed sample, through silica gel column chromatography (eluent is sherwood oil: ethyl acetate=20: 1) separate 2,3-methylene dioxo group benzaldehyde white crystal 11.1g.Yield 74.0%.
(2) N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(the inferior p-methoxy-phenyl of 3,4-) ethamine is synthetic
Add successively step (1) gained 2 in the 500ml three-necked bottle, 3-methylene dioxo group benzaldehyde 8.51g (57mmol), methylene dichloride 100ml, 2,3-dimethoxy-phenylethylamine 10.6g (58mmol), triethylamine 4.90g (67mmol), anhydrous MgSO
410g.Magnetic agitation, heating, back flow reaction.Reaction 5h.Suction filtration, the elimination insolubles.Remove solvent under reduced pressure.Product is without separation.Add dehydrated alcohol 100ml, heating for dissolving.Add POTASSIUM BOROHYDRIDE 3.6g (66mmol) in batches.Finish back flow reaction 10h.Remove solvent under reduced pressure.Add water 150ml, (3 * 150ml) extractions, merge organic phase, anhydrous Na to ethyl acetate
2SO
4Dry.Remove solvent under reduced pressure.Obtain N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(the inferior p-methoxy-phenyl of 3,4-) ethamine yellow oily liquid 17.2g.Yield 71.9%.
(3) the hydrochloric acid epiberberine is synthetic
In the 500ml three-necked bottle, add CuSO
45H
2O16.1g, NaCl16.3g, 40% oxalic dialdehyde 24.1g, be heated to 70 ℃, the magnetic agitation reaction.After reaction 2h, reactant is joined step (2) gained N-(the inferior methoxyl group of 2,3--N-benzyl)-β-(3, the inferior p-methoxy-phenyl of 4-) in ethamine 17.2g (54mmol), add aceticanhydride 30ml, HAc100ml, be heated to 100 ℃, the magnetic agitation reaction.Reaction 20h.Add water 250ml, be heated to 90 ℃, incline and, with saturated NaOH solution, be neutralized to pH=7.0.Collecting precipitation, be washed to water lotion and be faint yellow.Throw out is added hydrochloric acid-95% ethanol (5:95) 15ml, heating 2h.Cooling, filter.The filter cake silica gel mixed sample, (eluent is chloroform: methyl alcohol=9: 1) separate, recrystallization (95% ethanol), obtain hydrochloric acid epiberberine 5.0g through silica gel column chromatography.Yield 24.7%, orange amorphous powder.
Embodiment 3:
Synthesizing of (1) 2,3-methylene oxygen benzaldehyde
Add successively 2,3-Dihydroxy benzaldehyde 13.8g (100mmol) in the 500ml three-necked bottle, anhydrous MgCO
312.8g (151mmol), chloroiodomethane 28.8g (163mmol), 50mlDMF, magnetic agitation, heating, back flow reaction.Reaction 24h.Ethyl acetate extraction (150ml * 3 time).Merge organic phase, anhydrous Na
2SO
4Dried overnight.Decompression and solvent recovery.The residual solution silica gel mixed sample, through silica gel column chromatography (eluent is sherwood oil: ethyl acetate=20: 1) separate 2,3-methylene oxygen benzaldehyde white crystal
111.1g.Yield 74.0%.
(2) the hydrochloric acid epiberberine is synthetic
Add successively step (1) gained 2 in the 500ml three-necked bottle, 3-methylene dioxo group benzaldehyde 8.51g (57mmol), methylene dichloride 100ml, 2,3-dimethoxy-phenylethylamine 10.6g (58mmol), triethylamine 4.90g (67mmol), anhydrous MgSO
410g.Magnetic agitation, heating, back flow reaction.Reaction 5h.Suction filtration, the elimination insolubles.Remove solvent under reduced pressure.Product is without separation.Add methyl alcohol 100ml, heating for dissolving.Add POTASSIUM BOROHYDRIDE 3.6g (66mmol) in batches.Finish back flow reaction 10h.Remove solvent under reduced pressure.Add water 150ml, (3 * 150ml) extractions, merge organic phase, anhydrous Na to ethyl acetate
2SO
4Dry.Remove solvent under reduced pressure.Product is without separation.CuSO
45H
2O16.1g, NaCl16.3g, 40% oxalic dialdehyde 24.1g, be heated to 70 ℃, the magnetic agitation reaction.After reaction 2h, reactant is joined in the previous step product, add aceticanhydride 30ml, HAc100ml, be heated to 100 ℃, the magnetic agitation reaction.Reaction 20h.Add water 250ml, be heated to 90 ℃, incline and, with saturated NaOH solution, be neutralized to pH=7.0.Collecting precipitation, be washed to water lotion and be faint yellow.Throw out is added hydrochloric acid-95% ethanol (5:95) 15ml, heating 2h.Cooling, filter.The filter cake silica gel mixed sample, (eluent is chloroform: methyl alcohol=9: 1) separate, recrystallization (95% ethanol), obtain hydrochloric acid epiberberine 5.0g through silica gel column chromatography.Yield 24.7%, orange amorphous powder.
Claims (3)
1. the synthetic method of an epiberberine, this synthetic method is comprised of following steps:
。
2. synthetic method according to claim 1, the reaction reagent that it is characterized in that reaction (1) is methylene dichloride, methylene bromide, methylene iodide, chloroiodomethane or bromoiodomethane, and acid binding agent is potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate or magnesiumcarbonate; The acid binding agent of reaction (2) is triethylamine, diethylamine, sodium hydroxide, salt of wormwood, sodium carbonate or magnesiumcarbonate; Reaction (3) reductive agent is POTASSIUM BOROHYDRIDE, sodium borohydride, Zn+ concentrated hydrochloric acid or the Fe+ vitriol oil; The reaction reagent of reaction (4) is oxalic dialdehyde, and neutralization bases solution is sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or ammonia solution.
3. synthetic method according to claim 2, is characterized in that the reaction reagent of reaction (1) is methylene bromide, and acid binding agent is salt of wormwood; The acid binding agent of reaction (2) is triethylamine; Reaction (3) reductive agent is sodium borohydride; The reaction reagent of reaction (4) is oxalic dialdehyde, and neutralization bases solution is sodium carbonate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705512A (en) * | 2014-01-21 | 2014-04-09 | 西南大学 | Method for extracting epiberberine and application thereof |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
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| US5420308A (en) * | 1991-10-07 | 1995-05-30 | Bayer Aktiengesellschaft | 2,2-difluorobenzo (1,3)-dioxole-carbaldehydes and new intermediate products |
| WO2009146910A1 (en) * | 2008-06-04 | 2009-12-10 | Spear Therapeutics Limited De Montfort University | 4, 6-diphenylpyrid-2-0nes against cancer |
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
-
2012
- 2012-05-07 CN CN2012101367413A patent/CN103387574A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5420308A (en) * | 1991-10-07 | 1995-05-30 | Bayer Aktiengesellschaft | 2,2-difluorobenzo (1,3)-dioxole-carbaldehydes and new intermediate products |
| WO2009146910A1 (en) * | 2008-06-04 | 2009-12-10 | Spear Therapeutics Limited De Montfort University | 4, 6-diphenylpyrid-2-0nes against cancer |
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
Non-Patent Citations (3)
| Title |
|---|
| PENG YANG等: "Synthesis and structure–activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XIAOLI,BIAN等: "Synthesis and antihyperglycemic evaluation of various protoberberine derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 何菱等: "小檗碱类衍生物的全合成及抗癌活性的研究", 《华西药学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705512A (en) * | 2014-01-21 | 2014-04-09 | 西南大学 | Method for extracting epiberberine and application thereof |
| CN103705512B (en) * | 2014-01-21 | 2016-04-06 | 西南大学 | Extract method and the application of epiberberine |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
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Inventor after: Lv Ziming Inventor after: Zhao Shaohua Inventor after: Liang Junqing Inventor after: Wang Hongtao Inventor after: Li Xiangjun Inventor after: Tian Shuyan Inventor after: Wu Yiling Inventor before: Lv Ziming Inventor before: Zhao Shaohua Inventor before: Liang Junqing Inventor before: Wang Hongtao Inventor before: Li Xiangjun Inventor before: Tian Shuyan Inventor before: Wu Yiling |
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Application publication date: 20131113 |