CN106543171A - A kind of berberine synthesis technique - Google Patents
A kind of berberine synthesis technique Download PDFInfo
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- CN106543171A CN106543171A CN201610956902.1A CN201610956902A CN106543171A CN 106543171 A CN106543171 A CN 106543171A CN 201610956902 A CN201610956902 A CN 201610956902A CN 106543171 A CN106543171 A CN 106543171A
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- berberine
- homopiperony lamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
Abstract
The invention discloses a kind of berberine synthesis technique, synthetic route is as follows：With catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent, synthesizes piperonyl cyclonene.Piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method.Piperonal reacts nitration by Henry and generates 3,4 dioxy methine styrene of β nitros.3,4 dioxy methine styrene of β nitros generates homopiperony lamine by Clemensen reduction.Homopiperony lamine and the condensation of 2,3 dimethoxy benzaldehydes restore generation 2,3 veratryl homopiperony lamine hydrochlorides of N.2,3 veratryl homopiperony lamine hydrochlorides of N are cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.The synthetic route of the present invention, it is to avoid cyanogenation, reduces toxicity.H is replaced using zinc amalgam2Ni and LiAlH4, cost is substantially reduced, technology difficulty is reduced, product yield is improved.
Description
Technical field
The invention belongs to medicine organic synthesis field, and in particular to a kind of berberine synthesis technique.
Background technology
Berberine is a kind of important alkaloid, is China's application Chinese medicine for a long time.Can be from the coptis, golden cypress, barberry etc.
Extract in plant.It has significant bacteriostasis.Conventional Halomine is called Berberine hydrochloride, and berberine can be to disease-resistant
Pathogenic microorganism, has suppression to various bacteria such as shigella dysenteriae, tubercle bacillus, pneumococcus, typhoid bacillus and corynebacterium diphtheriae etc.
Effect, wherein acting on shigella dysenteriae most strong, is commonly used to treat the disease of digestive tracts such as bacterial gastroenteritis, dysentery.It is clinical main
For treating bacillary dysentery and enterogastritis, its side effect is less.
National bulk drug technique that medicine management general bureau of country in 1980 publishes collect in also play-by-play berberine
Synthesis.But the preparation process route of these methods is very long, cause production cost height, product yield low.
The Chinese patent application of Publication No. CN 1312250A discloses the preparation method of a kind of berberine and its esters,
Catechol is adopted in the invention for initiation material, Jing annulations obtain piperonyl cyclonene, Jing chlorine cyanogenations obtain pepper acetonitrile, Jing
Condensation, catalysis, hydrogenation obtain condensation product hydrochloride, and Jing ring-closure reactions obtain berberine crude product, and Jing is alkalized, hydrochloric acid Huang is obtained into salt
Lian Su.In the method, catechol is adopted for initiation material, hence it is evident that reduce synthetic route, but there is cyanogenation, toxicity is big,
Operating personnel and environment are worked the mischief.
The content of the invention
The present invention seeks to a kind of berberine synthesis technique, solves original berberine synthesis technique high cost, technique is difficult
Degree is big, and low yield is the big problem of toxicity.
The technical scheme is that：A kind of berberine synthesis technique, synthetic route are as follows：
Further, it is the dimethyl sulfoxide in the basic conditions, with catechol and dichloromethane as raw material that formula I arrives formula II
For solvent, at 95-120 DEG C, synthesize piperonyl cyclonene.
Further, formula II is that piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method to formula III.
Further, formula III is that piperonal reacts nitration generation β-nitro -3,4- dioxies time first by Henry to formula IV
Base styrene.
Further, formula IV is β-nitro -3 to formula V, and 4- dioxy methine styrene is by Clemensen reduction generation
Homopiperony lamine.
Further, formula V is that homopiperony lamine and the condensation of 2,3- dimethoxy benzaldehyde restore generation N-2,3- to formula VI
Veratryl homopiperony lamine hydrochloride.
Further, formula VI is N-2 to formula VII, and 3- veratryl homopiperony lamine hydrochlorides are in glyoxal, formic acid, sulfuric acid
Halomine is cyclized under the conditions of copper.
Specifically, synthetic route is：
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, in 95-120
DEG C, synthesize piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride in c, piperonal and nitromethane
Generate β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes under the conditions of Pd/C ammonium formates, formic acid
45-60 DEG C of reaction generates N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized hydrochloric acid under the conditions of glyoxal, formic acid, copper sulphate
Berberine.
The present invention core be：Piperonyl cyclonene synthesizes piperonal, pepper by ViLsmeiar formylateds method by piperonyl cyclonene
Aldehyde reacts nitration by Henry and generates β-nitro -3,4- dioxy methine styrene, β-nitro -3,4- dioxy methine benzene
Ethene generates homopiperony lamine by Clemensen reduction.Above-mentioned steps avoid cyanogenation step, and adopt zinc amalgam generation
For H2Ni and LiAlH4, it is possible to decrease technology difficulty, it is cost-effective.
The present invention is had the advantage that compared with prior art：
1st, synthetic route of the invention, it is to avoid cyanogenation, reduces toxicity.
2nd, the present invention adds sodium acetate, methylamine hydrochloride in prepared by nitro compound, makes reaction in suitable pH environment,
It is easy to nitrification to carry out, in nitro compound reduction reaction, H is replaced using zinc amalgam2Ni and LiAlH4, cost is substantially reduced, is subtracted
Few technology difficulty, improves product yield.
Specific embodiment
A kind of berberine synthesis technique, synthetic route are as follows：
Formula I is that with catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent in the basic conditions to formula II,
95-120 DEG C, synthesize piperonyl cyclonene.Formula II is that piperonyl cyclonene synthesizes piperonal by ViLsmeiar formylateds method to formula III.Formula III is arrived
Formula IV is that piperonal reacts nitration generation β-nitro -3,4- dioxy methine styrene by Henry.Formula IV to formula V be β-
Nitro -3,4- dioxy methine styrene generates homopiperony lamine by Clemensen reduction.Formula V to formula VI be homopiperony lamine with
The condensation of 2,3- dimethoxy benzaldehydes restores generation N-2,3- veratryl homopiperony lamine hydrochlorides.It is N- that formula VI arrives formula VII
2,3- veratryl homopiperony lamine hydrochlorides are cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.
Embodiment
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, in 95-120
DEG C, synthesize piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride in c, piperonal and nitromethane
Generate β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes under the conditions of Pd/C ammonium formates, formic acid
45-60 DEG C of reaction generates N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized hydrochloric acid under the conditions of glyoxal, formic acid, copper sulphate
Berberine.
Wherein, the method detailed of step c is：At room temperature by 2000g piperonals, 5000ml nitromethanes, 410g acetic acid
Sodium, 410g methylamine hydrochlorides are dissolved in putting reactor, are stirred 2 hours, after the completion of reaction, are stopped reaction, plus 30000nl water, are placed in
Divide in liquid ware, add 20000ml dichloromethane to extract every time 3 times, organic phase is dried with magnesium sulfate, elimination drier distills back
Solvent is received, yellow crystal is obtained, is recrystallized with absolute ethyl alcohol, less than 80 DEG C dry β-nitro -3,4- dioxy methine styrene
2330g, yield 91%, mp：152-155℃.
The method detailed of Step d is：The β of 2330g-nitro -3,4- dioxy methine styrene, 95% ethanol of 83000ml
It is placed in the zinc amalgam for just having made, stirs under room temperature, once adds 2300ml concentrated hydrochloric acids, temperature voluntarily to rise to 60-70 DEG C, so
Stir 1.5h afterwards under room temperature, reactant becomes colourless, decompression steams ethanol, remain about 15000ml, filter out cadmia, cool down,
With in ammoniacal liquor and alkaline pH 8-9, with chloroform extraction 3 times, once, organic phase magnesium sulfate dry filter steams chloroform, obtains for washing
Yellow oil, plus 10% anhydrous hydrochloric acid-ethanol is neutralized to neutrality, has white crystal to separate out, suction filtration, filter cake are washed with a small amount of ether
Wash, be dried, obtain homopiperony lamine hydrochloride 1048.5g, yield 54%, mp：153-155℃.
Embodiment described above only expresses the specific embodiment of the application, and its description is more concrete and detailed, but and
Therefore the restriction to the application protection domain can not be interpreted as.It should be pointed out that for one of ordinary skill in the art
For, on the premise of conceiving without departing from technical scheme, some deformations and improvement can also be made, these belong to this
The protection domain of application.
Claims (8)
1. a kind of berberine synthesis technique, it is characterised in that synthetic route is as follows：
2. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula I to formula II is in alkalescence condition
Under, with catechol and dichloromethane as raw material, dimethyl sulfoxide is solvent, at 95-120 DEG C, synthesizes piperonyl cyclonene.
3. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula II passes through to formula III for piperonyl cyclonene
ViLsmeiar formylateds method synthesizes piperonal.
4. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula III passes through to formula IV for piperonal
Henry reaction nitrations generate β-nitro -3,4- dioxy methine styrene.
5. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula IV to formula V is β-nitro -3,
4- dioxy methine styrene generates homopiperony lamine by Clemensen reduction.
6. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula V to formula VI be homopiperony lamine with
The condensation of 2,3- dimethoxy benzaldehydes restores generation N-2,3- veratryl homopiperony lamine hydrochlorides.
7. a kind of berberine synthesis technique according to claim 1, it is characterised in that formula VI to formula VII is N-2,3- diformazans
Oxygen benzyl homopiperony lamine hydrochloride is cyclized into Halomine under the conditions of glyoxal, formic acid, copper sulphate.
8. a kind of berberine synthesis technique according to claim 1, it is characterised in that synthetic route is：
A, first with catechol and dichloromethane as raw material, under the conditions of NaOH, dimethyl sulfoxide is solvent, at 95-120 DEG C,
Synthesis piperonyl cyclonene；
B, piperonyl cyclonene and dimethylformamide are in POCl3Under the conditions of occur formyl be combined to piperonal；
There is Henry reaction nitrations under the conditions of sodium acetate, 95% ethanol, methylamine hydrochloride and generate in c, piperonal and nitromethane
β-nitro -3,4- dioxy methine styrene；
D, β-nitro -3,4- dioxy methine styrene is reduced into homopiperony lamine by zinc amalgam in 95% ethanol solution；
E, homopiperony lamine and 2,3- dimethoxy benzaldehydes are in Raney Ni, H2Under the conditions of condensation hydrogenation generate N-2,3- dimethoxy benzyls
Base homopiperony lamine hydrochloride or homopiperony lamine and 2,3- dimethoxy benzaldehydes are under the conditions of Pd/C ammonium formates, formic acid in 45-60
DEG C reaction generate N-2,3- veratryl homopiperony lamine hydrochlorides；
F, N-2,3- veratryl homopiperony lamine hydrochloride is cyclized the hydrochloric acid coptis under the conditions of glyoxal, formic acid, copper sulphate
Element.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880012A (en) * | 2017-11-09 | 2018-04-06 | 华中药业股份有限公司 | The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' |
| CN108164498A (en) * | 2018-02-08 | 2018-06-15 | 河南普瑞制药有限公司 | A kind of preparation method of berberine and dopamine intermediate homopiperony lamine |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
| CN109232556A (en) * | 2018-10-08 | 2019-01-18 | 佑华制药（乐山）有限公司 | A kind of Berberine hydrochloride production technology |
| CN109320492A (en) * | 2018-11-30 | 2019-02-12 | 湖北文理学院 | The method for preparing homopiperony lamine hydrochloride and berberine |
| CN109666016A (en) * | 2019-01-09 | 2019-04-23 | 沈阳化工大学 | A method of homopiperony lamine is prepared by raw material of catechol |
| CN110563693A (en) * | 2019-09-30 | 2019-12-13 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
| CN112341454A (en) * | 2020-11-24 | 2021-02-09 | 四川大学华西医院 | Berberine derivative, preparation method thereof and application thereof as p300 HAT small molecule inhibitor |
| CN113072548A (en) * | 2021-03-19 | 2021-07-06 | 四川大学 | Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
| CN113831318A (en) * | 2021-09-10 | 2021-12-24 | 四川大学 | Synthetic method of piperonylethylamine |
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| CN1312250A (en) * | 2001-01-19 | 2001-09-12 | 东北制药总厂 | Preparation of berberine and its salts |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880012A (en) * | 2017-11-09 | 2018-04-06 | 华中药业股份有限公司 | The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' |
| CN108164498A (en) * | 2018-02-08 | 2018-06-15 | 河南普瑞制药有限公司 | A kind of preparation method of berberine and dopamine intermediate homopiperony lamine |
| CN109160915A (en) * | 2018-09-07 | 2019-01-08 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of ortho vanillin |
| CN109232556A (en) * | 2018-10-08 | 2019-01-18 | 佑华制药（乐山）有限公司 | A kind of Berberine hydrochloride production technology |
| CN109320492A (en) * | 2018-11-30 | 2019-02-12 | 湖北文理学院 | The method for preparing homopiperony lamine hydrochloride and berberine |
| CN109666016A (en) * | 2019-01-09 | 2019-04-23 | 沈阳化工大学 | A method of homopiperony lamine is prepared by raw material of catechol |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
| CN110563693A (en) * | 2019-09-30 | 2019-12-13 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN110563693B (en) * | 2019-09-30 | 2022-10-21 | 苏州弘森药业股份有限公司 | Preparation method of pepper ring |
| CN112341454A (en) * | 2020-11-24 | 2021-02-09 | 四川大学华西医院 | Berberine derivative, preparation method thereof and application thereof as p300 HAT small molecule inhibitor |
| CN112341454B (en) * | 2020-11-24 | 2022-02-11 | 四川大学华西医院 | Berberine derivative, preparation method thereof and application thereof as p300 HAT small molecule inhibitor |
| CN113072548A (en) * | 2021-03-19 | 2021-07-06 | 四川大学 | Method for preparing 5, 8-dihydro-6H-isoquinoline [3, 2-alpha ] isoquinoline based on micro-reaction system |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
| CN113831318A (en) * | 2021-09-10 | 2021-12-24 | 四川大学 | Synthetic method of piperonylethylamine |
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