CN108358912A - A kind of green synthesis process of berberine - Google Patents
A kind of green synthesis process of berberine Download PDFInfo
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- CN108358912A CN108358912A CN201810169875.2A CN201810169875A CN108358912A CN 108358912 A CN108358912 A CN 108358912A CN 201810169875 A CN201810169875 A CN 201810169875A CN 108358912 A CN108358912 A CN 108358912A
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- pepper
- berberine
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- 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 present invention discloses a kind of green synthesis process of berberine, and synthesis technology is：Using catechol in N, in N dimethylformamides, dichloromethane reaction synthesis piperonyl cyclonene is passed through under alkaline condition, it recycles piperonyl cyclonene obtained to prepare pepper propionitrile, pepper propionamide is prepared by pepper propionitrile obtained, homopiperony lamine is obtained by pepper propionamide, N 2 is synthesized by homopiperony lamine again, 3 veratryl homopiperony lamine hydrochlorides, 2,3 veratryl homopiperony lamine hydrochlorides of last N synthetic hydrochloric acid berberine under the conditions of glyoxal, formic acid, copper sulphate.The present invention reduces the formation of black polymer, improve reaction yield, solve the problems, such as that a large amount of black polymers generated in former technique productions cause environmental pollution, reach the green chemical synthesis requirement of national requirements.
Description
Technical field
The present invention relates to pesticide environment-friendly organic synthesis technical field more particularly to a kind of green synthesis process of berberine.
Background technology
Berberine is a kind of important alkaloid, is China's application Chinese medicine for a long time, can from the coptis, Cortex Phellodendri, barberry,
It is extracted in the plants such as Chinese mahonia, there is significant bacteriostasis, common Halomine to be called Berberine hydrochloride, the coptis for it
Element can be to resisting pathogenic microbes, to various bacterias such as shigella dysenteriae, tubercle bacillus, pneumococcus, typhoid bacillus and corynebacterium diphtheriaes
There is inhibiting effect, wherein it is most strong to shigella dysenteriae effect, the disease of digestive tracts such as treatment bacillary dysentery, gastroenteritis are commonly used to,
Clinic is mainly used for treating bacillary dysentery and enterogastritis, Small side effects.
The play-by-play conjunction of berberine in the national bulk pharmaceutical chemicals technique compilation that medicine management general bureau of country in 1980 publishes
At.But the preparation process of these methods is more, and synthetic route is long, using hypertoxic raw material, generates a large amount of black polymers, pollutes ring
Border, product yield is low, of high cost.
The Chinese patent application of Publication No. CN1312250A discloses the preparation side of a kind of Halomine and its esters
Method, the invention use catechol for starting material, and piperonyl cyclonene is obtained through annulation, and pepper acetonitrile is obtained through chlorine cyanogenation, also
It is former that homopiperony lamine obtains Halomine then with 2,3-, bis- benzaldehydes, the jamaicin of hydrogenation, cyclization at salt.The party
Method does raw material using Cymag, and toxicity is big, causes damages to operating personnel and environment.
Have preparation process more in the synthesis technology of existing berberine, synthetic route is long, and raw material toxicity is big, to operation
Personnel and the shortcomings of harmful environment.
Invention content
In view of this, the application provides a kind of green synthesis process of berberine, the synthesis work of existing berberine is solved
With generating, a large amount of black polymers, preparation process is more, synthetic route is long, raw material toxicity is big, to operating personnel and ring in skill
The harmful equal problem in border.
Technical solution provided by the invention is a kind of green synthesis process of berberine, and the synthesis technology is：A kind of Huang
The green synthesis process of Lian Su, the synthesis technology are：Using catechol in n,N-Dimethylformamide, in alkaline condition
Under be passed through dichloromethane reaction synthesis piperonyl cyclonene, recycle piperonyl cyclonene obtained to prepare pepper propionitrile, pass through pepper third obtained
Nitrile prepares pepper propionamide, obtains homopiperony lamine by pepper propionamide, then synthesize N-2,3- dimethoxy benzyls by homopiperony lamine
Base homopiperony lamine hydrochloride, last N-2,3- veratryl homopiperony lamine hydrochlorides are under the conditions of glyoxal, formic acid, copper sulphate
Synthetic hydrochloric acid berberine.
Its synthetic route such as formula (1)：
Through the above technical solutions, using catechol in n,N-Dimethylformamide, two are passed through under alkaline condition
The piperonyl cyclonene of chloromethanes reaction synthesis such as Formula II, then leads to hcl reaction by piperonyl cyclonene and acrylonitrile under alchlor effect
As formula III pepper propionitrile, pepper propionitrile be hydrolyzed in sulfuric acid as formula IV pepper propionamide, pepper propionamide is in hydrogen-oxygen
Change and reacted in sodium and aqueous sodium hypochlorite solution, then liquid separation, concentration, distillation obtains the homopiperony lamine such as formula IV, homopiperony lamine with
2,3- dimethoxy benzaldehydes are condensed the N-2 generated such as Formula V, 3- veratryl homopiperony lamines under Raney Ni, hydrogen atmosphere
Hydrochloride, the N-2 of last such as Formula V, the homopiperony lamine hydrochloride of 3- veratryls such as formula IV is in glyoxal, formic acid, copper sulphate
Under the conditions of can synthesize Halomine such as Formula VII.Synthetic route avoids the use of Cymag, zinc amalgam, realizes pair
The close friend of operating personnel and environment, the pepper propionitrile reacted under the conditions of alchlor with acrylonitrile using piperonyl cyclonene, then Hough
Graceful degradation and sulphuric acid hydrolysis obtain homopiperony lamine, and having reached reduces production cost, the effect of technology difficulty is reduced, in condensation reaction
Protected with nitrogen, reduce the formation of black polymer, improve reaction yield, solve generated in former technique productions it is big
The problem of amount black polymer causes environmental pollution, reaches the green chemical synthesis requirement of national requirements.
Preferably, the synthesis technology includes the following steps：
1) catechol is passed through three second of dichloromethane and zephiran chloride in n,N-Dimethylformamide under alkaline condition
Amine, stirring heating, reaction synthesis piperonyl cyclonene；
2) the logical hcl reaction under alchlor effect obtains pepper propionitrile to piperonyl cyclonene with acrylonitrile；
3) then heat preservation solidification after pepper propionitrile hydrolyzes in sulfuric acid adds dissolved matter dissolving, extraction, washing, drying
Up to pepper propionamide；
4) pepper propionamide reacts in sodium hydroxide and aqueous sodium hypochlorite solution, then liquid separation, and pepper is distilled to obtain in concentration
Ethamine；
5) homopiperony lamine and 2,3- dimethoxy benzaldehydes are condensed under Raney Ni, hydrogen atmosphere generates N-2,3- dimethoxies
Benzyl homopiperony lamine hydrochloride；
6) N-2,3- veratryl homopiperony lamine hydrochloride synthetic hydrochloric acid under the conditions of glyoxal, formic acid, copper sulphate are yellow
Lian Su.
In the above synthesis technology, using catechol in n,N-Dimethylformamide, dichloro is passed through under alkaline condition
Methane reaction synthesizes piperonyl cyclonene, and piperonyl cyclonene leads to hcl reaction under alchlor effect with acrylonitrile and obtains pepper propionitrile, pepper
Propionitrile hydrolyzes to obtain pepper propionamide in sulfuric acid, and pepper propionamide reacts in sodium hydroxide and aqueous sodium hypochlorite solution, then
Homopiperony lamine, homopiperony lamine and 2 are distilled to obtain in liquid separation, concentration, and 3- dimethoxy benzaldehydes are condensed under the conditions of Raney Ni generates N-
2,3- veratryl homopiperony lamine hydrochlorides, N-2,3- veratryl homopiperony lamine hydrochlorides are in glyoxal, formic acid, sulfuric acid
It can synthetic hydrochloric acid berberine under the conditions of copper.
More preferably, the reaction temperature of the step 1) is 100-110 DEG C, and the reaction time is 3.5-4 hours, reaction knot
Beam is cooled to room temperature, extraction, liquid separation, and piperonyl cyclonene is distilled to obtain in concentration.
More preferably, the reaction temperature of the step 1) is 110 DEG C, and the reaction time is 4 hours, and reaction terminates to be cooled to
Piperonyl cyclonene is distilled to obtain in room temperature, extraction, liquid separation, concentration.
More preferably, in step 1), the mass ratio of the catechol and n,N-Dimethylformamide is 1.1: 3, step
It is rapid 2) in, the mass ratio of the piperonyl cyclonene and acrylonitrile is 1: 1.1, in step 3), the mass ratio of the sulfuric acid and pepper propionitrile
It is 1: 1.2, in step 5), the mass ratio of the homopiperony lamine and 2,3- dimethoxy benzaldehydes is 1: 0.9610.
More preferably, the alkali in the step 1) is any one in sodium hydroxide, potassium hydroxide.
More preferably, the sulfuric acid in the step 3) is the sulfuric acid of 86%-87%.
More preferably, the heat preservation solidification temperature in the step 3) is 80 DEG C, and the dissolved matter is chloroform, ice water and ammonia
The mixture of water.
Based on above-mentioned elaboration, compared with prior art, advantage is technical scheme：(1) of the invention
Synthetic route avoids the use of Cymag, zinc amalgam, environmentally friendly；(2) piperonyl cyclonene of the present invention and acrylonitrile are in tri-chlorination
The pepper propionitrile reacted under aluminium, then Hofmann degradation and sulphuric acid hydrolysis obtain homopiperony lamine, reduce production cost, reduce work
Skill difficulty；(3) present invention is protected with nitrogen in the condensation reaction, reduces the formation of black polymer, is improved reaction and is received
Rate solves the problems, such as that a large amount of black polymers generated in former technique productions cause environmental pollution, reaches the green of national requirements
Colour chemistry synthesis requires.
Specific implementation mode
Embodiment 1
Step 1)：The synthesis of piperonyl cyclonene
It takes catechol 100g (0.2mol) to be dissolved in n,N-Dimethylformamide (300g) and nitrogen in autoclave is added
Displacement adds the 500ml aqueous solutions dissolved with 130g potassium hydroxide, and nitrogen is charged to 5atm, and stirring is warming up to 100-110 DEG C of reaction
3.5-4 hours, reaction, which is finished, to be cooled to room temperature, and is adjusted PH=8, liquid separation, water layer to be extracted with 750ml*3 dichloromethane, is merged organic phase,
Dry, recycling design collects 172-174 DEG C/Hg fractions and obtains faint yellow piperonyl cyclonene.
Step 2)：The synthesis of pepper propionitrile
In the 2000ml four-hole bottles equipped with blender, reflux condensing tube, dropping funel and thermometer, step 1) system is added
The piperonyl cyclonene 270g obtained, is added portionwise aluminum trichloride (anhydrous) 300g in≤10 DEG C under stirring, control temperature is no more than 30 DEG C, finishes
After be cooled to 15 DEG C, acrylonitrile 240g is added dropwise, control temperature is no more than 30 DEG C, is then passed through dry hydrogen chloride 1 at 15 DEG C or less
Hour, remove to continue after ice-water bath to be passed through hydrogen chloride and do not rise to reacting liquid temperature, after to be heated to 65 DEG C of insulated and stirreds reactions 6 small
When, it is poured into 1000g trash ices after reaction solution cooling, liquid separation, water layer is extracted with 100ml*3 chloroforms, merges organic phase, in being washed to
Property, it is dry, chloroform is recycled, after being evaporated under reduced pressure out methylenedioxybenzene benzene and chloroethyl nitrile (80-115 DEG C/25-80mmHg), is received
Collect 132-180 DEG C/Hg fraction about 190g, as pepper propionitrile, yield 70%.
Step 3)：The synthesis of pepper propionamide
In the 1000ml four-hole bottles equipped with blender, reflux condensing tube, dropping funel and thermometer, 86%- is added
87% sulfuric acid 73g is added with stirring pepper propionitrile 90g made from step 2), and temperature rises to 50 DEG C or so naturally, after be heated to 80
DEG C hydrolysis, insulation reaction to reactant all cure, and are cooled to 30 DEG C hereinafter, chloroform 250ml, ice water 200ml and ammonium hydroxide is added
300ml, stirring makes complete molten, liquid separation, water layer be extracted with 100ml chloroforms, merges organic phase, be washed to neutrality, dry, recycles chloroform
Obtain residue 75g, as pepper propionamide, yield 80-82%.
Step 4)：The synthesis of homopiperony lamine
In the 1000ml four-hole bottles equipped with blender, chlorine tube and thermometer, 10% sodium hydroxide solution is added
500ml, stirring are cooled to 5 DEG C, are slowly passed through 15.6-16g chlorine about 1 hour, and pepper made from step 3) is then once added
Propionamide 40g, after removing ice-water bath, temperature rises naturally, and 75 DEG C of continuation are warming up to again after 1 hour in 30-40 DEG C of insulation reaction
Reaction 1 hour is cooled to room temperature rear reaction solution and pours into liquid separation in separatory funnel, and water layer is extracted with chloroform 50ml*4, is merged organic
Phase is washed, dry, recycles vacuum distillation collection 130-138 DEG C/7mmHg fraction 36g, as homopiperony lamine after chloroform, yield
90%
Step 5)：The synthesis of N-2,3- veratryl homopiperony lamine hydrochloride
Homopiperony lamine 175g and 2,3- dimethoxy benzaldehydes are added in the 500ml Claisen flasks equipped with thermometer
180g shakes up to obtain muddy grease, is heated 1 hour at 110 DEG C and depressurizes the moisture content for steaming generation, until room temperature obtains clear oil
Grease is transferred in autoclave by object with absolute ethyl alcohol 2000ml, and 30gReny nickel, nitrogen displacement is added, and hydrogen is replaced,
Hydrogen is filled with to 20-30atm, 60-65 DEG C is heated to and reacts 2 hours, be cooled to room temperature, filter, be concentrated to give viscous shape liquid, use chlorine
To change ethanolic hydrogen tune PH=2 and crystallization is precipitated, ethyl alcohol washs to obtain white crystals, and mother liquor concentrations must crystallize, and merge to obtain 291g, as N-2,
3- veratryl homopiperony lamine hydrochlorides, yield 82%.
Step 6)：The synthesis of Halomine
Acetic acid 280g, copper sulphate 28g, chlorine are added in the 500ml three-necked flasks equipped with blender, condenser pipe and thermometer
Change sodium 20g, 50% glyoxal 14g, N-2,3- veratryl homopiperony lamine hydrochloride 34g made from step 5) be then added,
It is heated to 85 DEG C to be stirred to react 6 hours, water pump is evaporated under reduced pressure recovery of acetic acid, and residue is added 200ml water and is heated to 90 DEG C, cold
But it filters, washes afterwards, filter cake adds water and is heated to 90 DEG C, with saturated solution of sodium carbonate tune PH=8-8.5, filters while hot, is used in combination 1
: the acidification of 1 hydrochloric acid, filtrate crystallisation by cooling, filtering, dry 30.9g, yield 91%.
Can be seen that the berberine synthesized by the way of the application from the data of above example and measurement has conjunction
Operating personnel's body is not damaged at process, and environmentally friendly, reduce production cost, reduce technology difficulty, reduced
The formation of black polymer, improves reaction yield, solves a large amount of black polymers generated in former technique productions and cause
The problem of environmental pollution, reaches the green chemical synthesis requirement of national requirements.
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be subject to claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, several improvements and modifications can also be made, these change
Protection scope of the present invention is also should be regarded as into retouching.
Claims (9)
1. a kind of green synthesis process of berberine, it is characterised in that：The synthesis technology is：Using catechol in N, N- bis-
In methylformamide, it is passed through dichloromethane reaction synthesis piperonyl cyclonene under alkaline condition, piperonyl cyclonene obtained is recycled to prepare recklessly
Green pepper propionitrile prepares pepper propionamide by pepper propionitrile obtained, obtains homopiperony lamine by pepper propionamide, then pass through pepper
Ethamine synthesizes N-2, and 3- veratryl homopiperony lamine hydrochlorides, last N-2,3- veratryl homopiperony lamine hydrochlorides are in second
Synthetic hydrochloric acid berberine under the conditions of dialdehyde, formic acid, copper sulphate.
2. a kind of green synthesis process of berberine according to claim 1, it is characterised in that：The synthesis technology includes
Following steps：
1) catechol is passed through dichloromethane and chlorinating benzyl triethylamine in n,N-Dimethylformamide under alkaline condition,
Stirring heating, reaction synthesis piperonyl cyclonene；
2) the logical hcl reaction under alchlor effect obtains pepper propionitrile to piperonyl cyclonene with acrylonitrile；
3) then heat preservation solidification after pepper propionitrile hydrolyzes in sulfuric acid adds dissolved matter and dissolves, extracts, washes, is drying to obtain
Pepper propionamide；
4) pepper propionamide reacts in sodium hydroxide and aqueous sodium hypochlorite solution, then liquid separation, and pepper second is distilled to obtain in concentration
Amine；
5) homopiperony lamine and 2,3- dimethoxy benzaldehydes are condensed under Raney Ni, hydrogen atmosphere generates N-2,3- veratryls
Homopiperony lamine hydrochloride；
6) N-2,3- veratryl homopiperony lamine hydrochloride synthetic hydrochloric acid berberine under the conditions of glyoxal, formic acid, copper sulphate.
3. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：The reaction of the step 1)
Temperature is 100-110 DEG C, and the reaction time is 3.5-4 hours, and reaction terminates to be cooled to room temperature, and extracts, liquid separation, and concentration is distilled
Piperonyl cyclonene.
4. a kind of green synthesis process of berberine according to claim 3, it is characterised in that：The reaction of the step 1)
Temperature is 110 DEG C, and the reaction time is 4 hours, and reaction terminates to be cooled to room temperature, and extracts, liquid separation, and piperonyl cyclonene is distilled to obtain in concentration.
5. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：Three in the step 2)
Aluminium chloride is aluminum trichloride (anhydrous), and controls temperature no more than 30 DEG C after alchlor is added in reaction process, is then cooled down again
To 15 DEG C.
6. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：In step 1), the neighbour
Benzenediol and the mass ratio of n,N-Dimethylformamide are 1.1: 3, and in step 2), the mass ratio of the piperonyl cyclonene and acrylonitrile is
1: 1.1, in step 3), the mass ratio of the sulfuric acid and pepper propionitrile is 1: 1.2, in step 5), the homopiperony lamine and 2,3-
The mass ratio of dimethoxy benzaldehyde is 1: 0.9610.
7. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：Alkali in the step 1)
For any one in sodium hydroxide, potassium hydroxide.
8. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：Sulphur in the step 3)
Acid is the sulfuric acid of 86%-87%.
9. a kind of green synthesis process of berberine according to claim 2, it is characterised in that：Guarantor in the step 3)
Warm solidification temperature is 80 DEG C, and the dissolved matter is the mixture of chloroform, ice water and ammonium hydroxide.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109001342A (en) * | 2018-09-30 | 2018-12-14 | 东北制药集团股份有限公司 | A kind of efficient liquid phase method detecting N-2,3- veratryl homopiperony lamine and its salt content |
| 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 |
| CN109608448A (en) * | 2019-01-09 | 2019-04-12 | 沈阳化工大学 | A method of using guaiacol as the fully synthetic jamaicin of raw material |
| CN109651361A (en) * | 2019-01-09 | 2019-04-19 | 沈阳化工大学 | A method of using catechol as the fully synthetic jamaicin of raw material |
| 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 |
| CN109705113A (en) * | 2019-01-09 | 2019-05-03 | 沈阳化工大学 | A method of using catechol as the fully synthetic berberrubine of raw material |
| CN109705114A (en) * | 2019-01-09 | 2019-05-03 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of guaiacol |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109001342A (en) * | 2018-09-30 | 2018-12-14 | 东北制药集团股份有限公司 | A kind of efficient liquid phase method detecting N-2,3- veratryl homopiperony lamine and its salt content |
| CN109001342B (en) * | 2018-09-30 | 2021-06-29 | 东北制药集团股份有限公司 | High performance liquid chromatography method for detecting N-2, 3-dimethoxybenzyl piperonylethylamine and salt content thereof |
| 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 |
| CN109608448A (en) * | 2019-01-09 | 2019-04-12 | 沈阳化工大学 | A method of using guaiacol as the fully synthetic jamaicin of raw material |
| CN109651361A (en) * | 2019-01-09 | 2019-04-19 | 沈阳化工大学 | A method of using catechol as the fully synthetic jamaicin of raw material |
| 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 |
| CN109705113A (en) * | 2019-01-09 | 2019-05-03 | 沈阳化工大学 | A method of using catechol as the fully synthetic berberrubine of raw material |
| CN109705114A (en) * | 2019-01-09 | 2019-05-03 | 沈阳化工大学 | A method of berberrubine is prepared by raw material of guaiacol |
| CN111499626A (en) * | 2019-01-31 | 2020-08-07 | 西南大学 | Synthetic method and application of epiberberine |
| CN113735847A (en) * | 2021-09-10 | 2021-12-03 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
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Application publication date: 20180803 |