CN107880012A - The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' - Google Patents
The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' Download PDFInfo
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- CN107880012A CN107880012A CN201711097183.3A CN201711097183A CN107880012A CN 107880012 A CN107880012 A CN 107880012A CN 201711097183 A CN201711097183 A CN 201711097183A CN 107880012 A CN107880012 A CN 107880012A
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- China
- Prior art keywords
- veratryl
- synthetic method
- homopiperony
- homopiperony lamine
- hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
Abstract
The present invention discloses the synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ', comprises the following steps：2,3 dimethoxy benzaldehyde contracting homopiperony lamines（Ⅱ）Ethanol solution, zinc chloride catalysis under, with hydrazine hydrate aqueous solution occur reduction reaction, obtain the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 '（Ⅰ）.Compared with existing synthetic method, this method has a simple synthetic method, and catalytic activity is high, and product is easily isolated purifying, and product purity height, high income, potential safety hazard is small, the advantages that suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, is related to N-2 ', the synthesis of 3 '-veratryl homopiperony lamine hydrochloride
Method.
Background technology
Berberine hydrochloride, also known as Halomine, chemistry are entitled：5,6- dihydro -9,10- dimethoxy benzo [g]-l, 3- benzene
And dioxolanes [5,6- α] quinolizine hydrochloride dihydrate, molecular formula：C20H18ClNO4 • 2H20, structural formula is：
Berberine hydrochloride is the isoquinoline alkaloid being present in plant, can be extracted from various plants, as the coptis, golden cypress,
Barberry, barberry, greater celandine, nandina, barberry, iron sheet lotus etc..Berberine hydrochloride is a kind of broad spectrum antibiotic, clinically extensively
It is general to be used to treat tuberculosis, diarrhoea, dysentery, enteritis.
Numerous studies and clinical practice show in recent years, and Berberine hydrochloride also has antitumor, antiviral, anti AIDS virus
(HIV), diabetes, anti-obesity, anti-malarial, antirheumatic, anti-aging, antianxiety, anti-Living organ transplantation rejection etc. are made
With, while it is comprehensive available for inflammation, cardioprotection, the effect for reducing pain and the improvement polycystic ovary for reducing abdominal postoperative
Simulator sickness, treatment angiocardiopathy.In addition, Berberine hydrochloride has, toxicity is low, side effect is smaller, antimicrobial spectrum is relatively wide and clinical demand
Measure the features such as big.But it is available for the natural plant resource of extraction limited.Therefore, people are directed to studying Berberine hydrochloride always
Synthesis technique, it is expected to obtain a simplicity, green, the synthetic route of economy.
Chinese patent【CN011068089.1】Report homopiperony lamine and the 4-hydroxyl-3-methoxylbenxaldehyde condensation reaction first of methyl ortho position obtains
Schiff bases, then it is dissolved in autoclave with methanol and is catalyzed with active nickel, leads to hydrogen（4MPa）Reduction, then plus acidic alcohol into
Salt, obtain N-2', 3'- veratryl homopiperony lamine hydrochlorides；Then acetic acid, acetic anhydride, copper chloride, sodium chloride and glyoxal
Reaction, prepares berberine mantoquita, then with ammonia decopper(ing), obtains berberine wet product；Wet product is dissolved with water, adds carbon decoloring, uses salt
Acid for adjusting pH, cooling obtain Berberine hydrochloride.
The process route of other document reports and above-mentioned technique are also basically identical, wherein N-2', 3'- veratryl peppers
Ethylamine hydrochloride is key intermediate.Its synthetic method is：Homopiperony lamine and methyl ortho position 4-hydroxyl-3-methoxylbenxaldehyde prepare schiff bases 2 first,
3- dimethoxy benzaldehyde contracting homopiperony lamines, then in methanol or ethanol, are catalyzed in autoclave with active nickel, lead to hydrogen
（About 4MPa）Reduction, then plus acidic alcohol is into salt, obtains N-2', 3'- veratryl homopiperony lamine hydrochlorides.Reaction needs
Completed in autoclave, equipment requirement is high, and investment is big；Oxidation reaction, or even spontaneous combustion can occur in atmosphere for active nickel exposure；Hydrogen
Gas can form explosive mixture with air, and heat or naked light explode.Risk safe to use is larger, once deal with possibility improperly
Serious accident.
Chen Cheng etc.【Organic chemistry, 2016,36,1426-1430】The height of active nickel and hydrogen is replaced with sodium borohydride reduction
Press reduction reaction.Reaction time is up to 10 hours, reaction terminate after, it is necessary to be evaporated under reduced pressure removing methanol, then with ether dissolution,
Extraction, wash, dry, filter, the step such as concentration obtains N-2', 3'- veratryl homopiperony lamine grease.Sodium borohydride into
This is higher, and aftertreatment technology is cumbersome, it is necessary to make solvent using dangerous larger ether, is not suitable for industrialized production.
The technique of chemical method synthetic hydrochloric acid jamaicin comes into industrialized production at present, but process route is complicated, production
Cost is higher.In order to further reduce the production cost of Berberine hydrochloride, it is badly in need of developing new synthesis technique.
The content of the invention
The technical problem to be solved in the present invention is to provide N-2 ', the synthesis side of 3 '-veratryl homopiperony lamine hydrochloride
Method.Compared with existing synthetic method, this method has simple synthetic method, and catalytic activity is high, and product is easily isolated purifying, produces
Product purity is high, and high income, potential safety hazard is small, the advantages that suitable for industrialized production.
To overcome the weak point of existing synthetic method, the present invention provides following technical scheme.
N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, 2,3- dimethoxy benzaldehyde contracting pepper second
Amine（Ⅱ）Ethanol solution, zinc chloride catalysis under, with hydrazine hydrate aqueous solution occur reduction reaction, obtain N-2 ', 3 '-dimethoxy
Benzyl homopiperony lamine hydrochloride（Ⅰ）, reaction equation is as follows：
。
N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, described zinc chloride and formula（Ⅱ）Weight
The ratio of dosage is 0.005：1~0.015：1.
N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, the concentration of described hydrazine hydrate aqueous solution are
Hydrazine hydrate percentage by weight is 40%, hydrazine hydrate aqueous solution and formula（Ⅱ）Weight consumption ratio be 0.3：1~0.6：1.
N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, described reduction reaction temperature are 20~75
℃。
Each optimum condition in the synthetic method of the present invention can be combined each preferred embodiment for producing the present invention.
The present invention has the following advantages that compared with prior art：
1）The use of autoclave, hydrogen and active nickel, and the use of dangerous larger ether are eliminated, reduces work
The security implication of skill, is easy to industrialized production；
2）The go back original reagent sodium borohydride of costliness is eliminated, catalyst amount is few, and catalytic activity and selectivity are high；
3）Aftertreatment technology is simple to operate, and product purity is high, high income.
Embodiment
Schiff bases prepared by homopiperony lamine and 2,3- dimethoxy benzaldehyde, the synthesis of reference literature method：Add in reaction bulb
Enter homopiperony lamine 108g and 2,3- dimethoxy benzaldehyde 108g, maintain 100~110 DEG C, react 0.5h.Room temperature is down to, is added
Ethanol 500g, it is made into the ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines（Wherein contain 2,3- dimethoxy benzene first
Aldehyde contracting homopiperony lamine 200g）, the raw material as following examples.
Following examples are the further explanations to the present invention, but should not serve to the limitation to this patent.Embodiment
1：
The ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines is added in reaction bulb（Wherein contain 2,3- dimethoxy benzenes
Formaldehyde contracting homopiperony lamine 200g）, zinc chloride 1g and hydrazine hydrate aqueous solution 140g.65~75 DEG C of reaction 6h.Cooling, is concentrated under reduced pressure into
It is dry, hydrogen chloride/ethanol solution is added dropwise to pH 4~5, is cooled to less than 0 DEG C, crystallization, filters, dry, obtain N-2', 3'- diformazans
Oxygen benzyl homopiperony lamine hydrochloride 203g, yield 95.9%, 144.4~145.6 DEG C of fusing point, HPLC purity 98.9%.
Embodiment 2：
The ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines is added in reaction bulb（Wherein contain 2,3- dimethoxy benzenes
Formaldehyde contracting homopiperony lamine 200g）, zinc chloride 1.8g and hydrazine hydrate aqueous solution 110g.40~50 DEG C of reaction 5h.Cooling, is concentrated under reduced pressure
To dry, dropwise addition hydrogen chloride/ethanol solution to pH 4~5, less than 0 DEG C is cooled to, crystallization, is filtered, dries, obtains N-2', 3'- bis-
Methoxybenzyl homopiperony lamine hydrochloride 204g, yield 96.4%, 144.3~145.2 DEG C of fusing point, HPLC purity 99.1%.
Embodiment 3：
The ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines is added in reaction bulb（Wherein contain 2,3- dimethoxy benzenes
Formaldehyde contracting homopiperony lamine 200g）, zinc chloride 3g and hydrazine hydrate aqueous solution 90g.20~30 DEG C of reaction 8h.Cooling, is concentrated under reduced pressure into
It is dry, hydrogen chloride/ethanol solution is added dropwise to pH 4~5, is cooled to less than 0 DEG C, crystallization, filters, dry, obtain N-2', 3'- diformazans
Oxygen benzyl homopiperony lamine hydrochloride 206g, yield 97.3%, 144.2~145.3 DEG C of fusing point, HPLC purity 99.3%.
Embodiment 4：
The ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines is added in reaction bulb（Wherein contain 2,3- dimethoxy benzenes
Formaldehyde contracting homopiperony lamine 200g）, zinc chloride 1.5g and hydrazine hydrate aqueous solution 120g.50~65 DEG C of reaction 5h.Cooling, is concentrated under reduced pressure
To dry, dropwise addition hydrogen chloride/ethanol solution to pH 4~5, less than 0 DEG C is cooled to, crystallization, is filtered, dries, obtains N-2', 3'- bis-
Methoxybenzyl homopiperony lamine hydrochloride 203g, yield 95.9%, 144.5~145.4 DEG C of fusing point, HPLC purity 99.2%.
Embodiment 5：
The ethanol solution of 2,3- dimethoxy benzaldehyde contracting homopiperony lamines is added in reaction bulb（Wherein contain 2,3- dimethoxy benzenes
Formaldehyde contracting homopiperony lamine 200g）, zinc chloride 2.4g and hydrazine hydrate aqueous solution 70g.30~40 DEG C of reaction 4h.Cooling, is concentrated under reduced pressure
To dry, dropwise addition hydrogen chloride/ethanol solution to pH 4~5, less than 0 DEG C is cooled to, crystallization, is filtered, dries, obtains N-2', 3'- bis-
Methoxybenzyl homopiperony lamine hydrochloride 204g, yield 96.4%, 144.2~145.1 DEG C of fusing point, HPLC purity 99.0%.
Embodiment described above is only that the preferred embodiment for the present invention is described, not to the design of the present invention
It is defined with scope, on the premise of design philosophy of the present invention is not departed from, ordinary skill technical staff is to this hair in this area
The various modifications and improvement that bright technical scheme is made, all should belong to protection scope of the present invention.
Claims (4)
1.N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, it is characterised in that：2,3- dimethoxy benzene first
Aldehyde contracting homopiperony lamine（Ⅱ）Ethanol solution, zinc chloride catalysis under, with hydrazine hydrate aqueous solution occur reduction reaction, obtain N-
2 ', 3 '-veratryl homopiperony lamine hydrochloride（Ⅰ）, reaction equation is as follows：
。
2.N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, it is characterised in that：Described zinc chloride and formula
（Ⅱ）Weight consumption ratio be 0.005：1~0.015：1.
3.N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, it is characterised in that：Described hydrazine hydrate is water-soluble
The concentration of liquid is that hydrazine hydrate percentage by weight is 40%, hydrazine hydrate aqueous solution and formula（Ⅱ）Weight consumption ratio be 0.3：1~
0.6：1.
4.N-2 ', the synthetic method of 3 '-veratryl homopiperony lamine hydrochloride, it is characterised in that：Described reduction reaction temperature
Spend for 20~75 DEG C.
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Cited By (1)
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101245064A (en) * | 2007-02-14 | 2008-08-20 | 常州亚邦制药有限公司 | Process for producing hydrochloric berberine |
| CN106543171A (en) * | 2016-10-28 | 2017-03-29 | 佑华制药（乐山）有限公司 | A kind of berberine synthesis technique |
-
2017
- 2017-11-09 CN CN201711097183.3A patent/CN107880012A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101245064A (en) * | 2007-02-14 | 2008-08-20 | 常州亚邦制药有限公司 | Process for producing hydrochloric berberine |
| CN106543171A (en) * | 2016-10-28 | 2017-03-29 | 佑华制药（乐山）有限公司 | A kind of berberine synthesis technique |
Non-Patent Citations (3)
| Title |
|---|
| HÜSEYIN KÖKSAL等: "Copper(II), cobalt(III), nickel(II), palladium(II), and zinc(II) complexes of the Schiff base ligands derived from 2,6-diacetylpyridine and phthaldialdehyde", 《SYNTHESIS AND REACTIVITY IN INORGANIC AND METAL-ORGANIC CHEMISTRY》 * |
| JASON B. CRAWFOR等: "AMD070, a CXCR4 Chemokine Receptor Antagonist: Practical Large-Scale Laboratory Synthesis", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| MARIAGRAZIA ROSELLI等: "Synthesis and evaluation of berberine derivatives and analogs as", 《PHYTOCHEMISTRY LETTERS》 * |
Cited By (2)
| 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 |
| 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 |
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