CN104788447B - A kind of semi-synthesis method prepares the production technology of vincamine - Google Patents
A kind of semi-synthesis method prepares the production technology of vincamine Download PDFInfo
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- CN104788447B CN104788447B CN201510188608.6A CN201510188608A CN104788447B CN 104788447 B CN104788447 B CN 104788447B CN 201510188608 A CN201510188608 A CN 201510188608A CN 104788447 B CN104788447 B CN 104788447B
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- vincamine
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- vincadifformine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Abstract
The invention discloses a kind of semi-synthesis method and prepare the production technology of vincamine, with tabersonine salt for reaction initiation material, hydrogenated catalysis reduction, enzyme process hydroxylation, rearrangement crystallization obtain vincamine, this process route is brief, and the yield of the vincamine of gained is high, purity is good, and whole production technology low cost, production suitable for industrialized, and carry out enzyme process hydroxylation by oxygenase, and clean and safe, environmentally friendly.
Description
Technical field
The present invention relates to the synthesis technique of chemicals, a kind of semi-synthesis method prepares vincamine
Production technology.
Background technology
Vincamine, Chinese entitled (3 α, 4 β, 16 α)-14,15-dihydro-14-hydroxyl eburnamenine-14-carboxylic acid
Methyl ester, molecular formula is C21H26N2, belong to single indole alkaloids, be mainly used in treating cerebral ischemia, clinical suitable
Answer disease to have and be applicable to cerebrovascular disorders, cerebral embolism, cerebral thrombosis and hemorrhage sequela etc..Due to vincamine
Blood brain barrier can be penetrated, at expansion blood vessel, increase and have good effect in terms of cerebral blood flow, and to heart,
Blood vessel and blood pressure etc., without impact, are the first-line drugs for the treatment of cerebral ischemia.
Vincamine is extraction isolated from apocynaceae plant periwinkle (Vinca minor) the earliest,
But the content of vincamine is only 0.7 ‰ in periwinkle, and Main Resources is distributed in Europe, production cost
Height, limitation is big.From the fifties in last century so far, many scientists are devoted to study the synthesis of vincamine,
Mainly there are semi-synthesis method and two kinds of methods of complete synthesizing process.
With biological extraction tabersonine as initiation material in United States Patent (USP) US3892755, after hydrogenating reduction, between using
Chloroperoxybenzoic acid or Nitrodracylic acid oxidation, then reduce with triphenylphosphine, finally with sour water indexing,
To vincamine.The method metachloroperbenzoic acid or Nitrodracylic acid oxidation, m-chloro peroxide benzene first in product
Acid or Nitrodracylic acid are difficult to remove.
In Spanish patent FR2577926A1, equally with tabersonine as initiation material, after hydrogenated reduction,
Hydrogenation thing is made sulfate, uses single peroxy maleic acid oxidation, then prepare vincamine through reduction indexing.Instead
In Ying, single peroxy maleic acid used needs with system, adds production process.
In Chinese patent CN102276599B, using tabersonine hydrochlorate is raw material, adds through the catalysis of palladium carbon
Hydrogen, single peroxy maleic acid oxidation, by reduction translocation reaction, prepare vincamine.Palladium carbon catalytic hydrogenation efficiency
Relatively low.And this operation also to be used single peroxy maleic acid.
And existing complete synthesizing process, it is all with indole parent nucleus derivant as raw material.The complete synthesis route of vincamine is long,
The gross production rate of these methods all less than 10%, high cost, it is impossible to realize industrialized production.
In sum, produce at present both at home and abroad the method for vincamine and there are following problems: complete synthesis work
Skill route is long, and it is big that manufacturing enterprise undertakes operational risk, produces a large amount of chemical waste the biggest by causing environment
Burden, and all high to producing equipment requirements, relatively costly, and productivity is low.In semisynthesis, easily produce
Raw difficult impurity, needs to use column chromatography and removes, make troubles for industrialized production.
Summary of the invention
It is an object of the invention to provide a kind of semi-synthesis method and prepare the production technology of vincamine, this production technology gram
Take the shortcoming in existing vincamine synthetic technology, it is provided that a kind of high yield, high-quality tabersonine salt are semi-synthetic
The industrialization process route of vincamine, and environmental friendliness, low cost, concise in technology.
For reaching above-mentioned purpose, the technical solution used in the present invention is: a kind of semi-synthesis method prepares vincamine
Production technology, is embodied as step as follows:
Step 1): tabersonine salt is put in reactor, add organic solvent dissolved, and backward instead
Answer addition hydrogenation catalyst in still, under 1～3atm, be hydrogenated with room temperature reaction, to reaction completely, obtain Changchun Buddhist
Bright；
Step 2): in reactor, carry out the acid solution of described vincadifformine pH4～5 being dissolved to completely
Dispersion, adds oxygenase and carries out catalytic reaction, and reaction temperature controls at 20～50 DEG C, to reaction completely, stops
Only reaction, acid unnecessary in removal system, extract organic facies, described organic facies drying, concentrating under reduced pressure
After, obtain 16-hydroxyl-vincadifformine；
Step 3): described 16-hydroxyl-vincadifformine is joined in reactor, adds organic acid, stir,
To being completely dissolved, add photocatalyst and carry out photochemical reaction, to reaction completely, add afterwards and organic acid etc.
The frozen water of amount, and regulation system pH is to 8～9, then carries out extracting organic facies, described organic facies is concentrated, de-
Color, filter, crystallize, obtain target product vincamine after recrystallization.
Here, the synthetic route of this production technology is as follows:
Wherein: formula 1 is tabersonine salt；Formula 2 is vincadifformine；Formula 3 is 16-hydroxyl-vincadifformine；Formula 4
For vincamine.
Preferably, step 1) in organic solvent be 40%～100% methanol or 50%～95% ethanol.Certainly
Here organic solvent solubilized tabersonine salt.
It is further preferred that described step 1) in the w/v of organic solvent and tabersonine salt be 4～15:
1。
Preferably, described step 1) in hydrogenation catalyst be Raney's nickel, nickel borides, Pd/C, Pd-CaCO3,
Chlorine three (triphenyl phasphine) closes rhodium, chlorine three (triphenyl phasphine) closes the combination of one or more in rubidium.
Preferably, described step 2) in oxygenase be hydroxylase.
Preferably, described step 3) in organic acid be glacial acetic acid, formic acid, propanoic acid, halo glacial acetic acid, halogen
Combination for one or more in propanoic acid.
Preferably, described step 1) in tabersonine salt be hydrochloric acid tabersonine salt or sulphuric acid tabersonine salt.
Due to the utilization of technique scheme, the present invention compared with prior art has the advantage that the present invention
Semi-synthesis method prepare the production technology of vincamine, its technique is simple, have employed with natural Renewable resource
Extract isolated tabersonine salt, then through reduction, be hydroxylated and rearrangement obtains vincamine.In this production technology
The equipment used is simple, and have employed oxygenase and carry out enzyme process hydroxylation as catalyst so that in whole preparation
During clean, safe and environmentally friendly, the purity of the vincamine prepared is high.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is further elaborated.Should be understood that
These embodiments for the ultimate principle of the present invention, principal character and advantage be described, and the present invention by with
The restriction of lower embodiment.The implementation condition used in embodiment can do adjustment further according to specific requirement,
Not marked implementation condition is usually the condition in normal experiment.Embodiment is raw materials used is industrial goods.
Embodiment 1
This example provides the preparation method of a kind of vincamine, be embodied as follows:
1) weigh in the stainless steel cauldron that hydrochloric acid tabersonine salt 5.0kg puts into 100L, add 75% ethanol
50L, is stirred at room temperature to hydrochloric acid tabersonine salt and is completely dissolved, and adds 250g Raney's nickel in backward reactor,
It is passed through hydrogen, stirs after 0.5h, and control Hydrogen Vapor Pressure under 1.1atm, room temperature, react 8h.React
Cheng Hou, is passed through nitrogen 10min, Filtration of catalyst Raney's nickel, is concentrated to give the thick product of vincadifformine, then
With ethyl acetate-ethanol, this thick product is crystallized to obtain the purity hydrochloric acid vincadifformine 4.8kg more than 99.0%；
2) by step 1) in prepare hydrochloric acid vincadifformine put in 100L stainless steel cauldron, add
The aqueous acetic acid 60L of pH=4.5, is stirred at room temperature and dissolves to hydrochloric acid vincadifformine, is filled with nitrogen protection afterwards,
Lucifuge room temperature reaction 8h.TLC detects reaction process, disappears to vincadifformine intermediate, and generation 16-hydroxyl-
Vincadifformine, and backward reactant liquor adds 5%NaHCO3Solution, regulates pH to 8, separates organic facies, and
It is extracted twice with 20L dichloromethane, merges organic facies, be dried overnight with anhydrous sodium sulfate 500g, decompression
It is concentrated to give the 16-hydroxyl-vincadifformine crude product for oily mater.16-is obtained again with dichloromethane-acetone crystallization
Hydroxyl-vincadifformine 4.0kg；
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add
Enter glacial acetic acid 70L, dissolving is stirred at room temperature, add photocatalyst rose-red 350g, open tungsten lamp.TLC
Detection reaction process, disappears substantially to 16-hydroxyl-vincadifformine, adds frozen water 70L, then with 1%NaOH
Adjust pH to 8, extract secondary with dichloromethane, merge organic facies and be concentrated into 20L volume, add activated carbon and take off
Color 30min.Filtering to obtain organic facies, be dried overnight with anhydrous sodium sulfate 500g, mother solution adds a certain amount of methanol
Crystallization, obtains vincamine crude product.Crude product is again with dichloromethane and methanol system recrystallization, and obtaining purity is 99.1%
Vincamine sterling 2.9kg.
Embodiment 2
This example provides the preparation method of a kind of vincamine, be embodied as follows:
1) weigh in the L stainless steel cauldron that sulphuric acid tabersonine salt 5.0kg puts into 100, add 40% first
Alcohol 100L, is stirred at room temperature and is completely dissolved to sulphuric acid tabersonine salt, be subsequently adding 50g nickel borides, be passed through hydrogen,
Stir after 0.5h, and control Hydrogen Vapor Pressure at 1.1atm, reaction 12h.After having reacted, it is passed through nitrogen 10
Min, Filtration of catalyst nickel borides, it is concentrated to give the thick product of vincadifformine, then crystallizes with ethyl acetate-ethanol
Obtain the purity sulphuric acid vincadifformine 4.0kg more than 99.0%；
2) by step 1) in the sulphuric acid vincadifformine of gained be placed in 100L stainless steel cauldron, add pH=5
Aqueous acetic acid 80L, is stirred at room temperature dissolving, is filled with nitrogen protection, lucifuge room temperature reaction about 12h afterwards.
TLC detects reaction process, disappears to vincadifformine intermediate, generates 16-hydroxyl-vincadifformine.To reaction
Liquid adds 5%NaHCO3Solution, regulates pH to 8.Separate organic facies, then extract two with 20L dichloromethane
Secondary, merge organic facies, be dried overnight with anhydrous sodium sulfate 500g, concentrating under reduced pressure must be the 16-of oily mater
Hydroxyl-vincadifformine crude product.16-hydroxyl-vincadifformine 3.7kg is obtained again with dichloromethane-acetone crystallization；
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add
Entering trichloroacetic acid 60L, dissolving is stirred at room temperature, add rose-red 250g, open tungsten lamp, TLC detection is anti-
Answer process, substantially disappear to 16-hydroxyl-vincadifformine, add frozen water 60L, then adjust pH with 1%NaOH
To 8, extract secondary with dichloromethane, merge organic facies and be concentrated into 20L volume, add decolorizing with activated carbon 30min.
Filtering to obtain organic facies, be dried overnight with anhydrous sodium sulfate 500g, mother solution adds a certain amount of methanol crystallization, obtains length
Spring amine crude product, this crude product with dichloromethane and methanol system recrystallization, obtains the vincamine that purity is 99.0% pure again
Product 2.8kg,.
Embodiment 3
This example provides the preparation method of a kind of vincamine, be embodied as follows:
1) weigh hydrochloric acid tabersonine salt 5.0kg to put in 100L stainless steel cauldron, add 95% ethanol 80L,
It is stirred at room temperature and is completely dissolved to hydrochloric acid tabersonine salt, be subsequently adding 500g PdCO3, it is passed through hydrogen, after 0.5h
Stirring, and control Hydrogen Vapor Pressure 1.1atm, react 8h, after having reacted, be passed through nitrogen 10min, mistake
Filter catalyst PdCO3, it is concentrated to give the thick product of vincadifformine, then crystallizes to obtain purity with ethyl acetate-ethanol
Hydrochloric acid vincadifformine 4.6kg more than 99.0%；
2) by step 1) the hydrochloric acid vincadifformine of gained is placed in 100L stainless steel cauldron, adds pH=4
Aqueous acetic acid 50L, is stirred at room temperature dissolving, is filled with nitrogen protection, lucifuge room temperature reaction about 10h afterwards.
TLC detects reaction process, disappears to vincadifformine intermediate, generates 16-hydroxyl-vincadifformine, to reaction
Liquid adds 5%NaHCO3Solution, regulates pH to 8, separates organic facies, then extracts two with 20L dichloromethane
Secondary, merge organic facies, be dried overnight with anhydrous sodium sulfate 500g, concentrating under reduced pressure must be the 16-of oily mater
Hydroxyl-vincadifformine crude product, then obtain 16-hydroxyl-vincadifformine 3.4kg with dichloromethane-acetone crystallization；
3) by step 2) in the 16-hydroxyl-vincadifformine of gained be placed in 100L stainless steel cauldron, add
Enter propanoic acid 90L, dissolving be stirred at room temperature, add rose-red 450g, open tungsten lamp, TLC detection react into
Journey, disappears substantially to 16-hydroxyl-vincadifformine, adds frozen water 90L, then adjusts pH to 9 with 1%NaOH,
Extract secondary with dichloromethane, merge organic facies and be concentrated into 20L volume, add decolorizing with activated carbon 30min,
Filtering to obtain organic facies, be dried overnight with anhydrous sodium sulfate 500g, mother solution adds a certain amount of methanol crystallization, obtains length
Spring amine crude product.Crude product with dichloromethane and methanol system recrystallization, obtains the sterling that purity is 99.2% vincamine again
2.8kg。
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow and is familiar with this skill
The personage of art will appreciate that present disclosure and is carried out, and can not limit the protection model of the present invention with this
Enclose, all equivalence changes made according to spirit of the invention or modification, all should contain the protection in the present invention
In the range of.
Claims (6)
1. a semi-synthesis method prepares the production technology of vincamine, it is characterised in that be embodied as step as follows:
Step 1): put in reactor by tabersonine salt, adds organic solvent and is dissolved, and add hydrogenation catalyst in backward reactor, under 1 ~ 3atm, is hydrogenated with room temperature reaction, to reaction completely, obtains vincadifformine；
Step 2): in reactor, carry out being dissolved to be completely dispersed by the acid solution of described vincadifformine pH4 ~ 5, add hydroxylase and carry out catalytic reaction, reaction temperature controls at 20 ~ 50 DEG C, to reaction completely, and stopped reaction, acid unnecessary in removal system, extraction organic facies, after described organic facies drying, concentrating under reduced pressure, obtains 16-hydroxyl-vincadifformine；
Step 3): described 16-hydroxyl-vincadifformine is joined in reactor, add organic acid, stirring, to being completely dissolved, add rose-red and carry out photochemical reaction, to reaction completely, add the frozen water with organic acid equivalent afterwards, and regulation system pH is to 8 ~ 9, then carrying out extracting organic facies, described organic facies is concentrated, decolour, filter, crystallize, obtain target product vincamine after recrystallization.
Semi-synthesis method the most according to claim 1 prepares the production technology of vincamine, it is characterised in that: the organic solvent in step 1) is 40% ~ 100% methanol or 50% ~ 95% ethanol.
Semi-synthesis method the most according to claim 1 and 2 prepares the production technology of vincamine, it is characterised in that: the organic solvent in described step 1) is 4 ~ 15:1 with the envelope-bulk to weight ratio of tabersonine salt.
Semi-synthesis method the most according to claim 1 prepares the production technology of vincamine, it is characterised in that: the hydrogenation catalyst in described step 1) is Raney's nickel, nickel borides, Pd/C, Pd-CaCO3, chlorine three (triphenyl phasphine) closes rhodium, chlorine three (triphenyl phasphine) closes the combination of one or more in rubidium.
Semi-synthesis method the most according to claim 1 prepares the production technology of vincamine, it is characterised in that: the organic acid in described step 3) is the combination of one or more in glacial acetic acid, formic acid, propanoic acid, halo glacial acetic acid, halopropanoic acid.
Semi-synthesis method the most according to claim 1 prepares the production technology of vincamine, it is characterised in that: the tabersonine salt in described step 1) is hydrochloric acid tabersonine salt or sulphuric acid tabersonine salt.
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| CN106749229B (en) * | 2016-12-20 | 2018-08-17 | 东北制药集团股份有限公司 | A kind of process for purification of pervone |
| CN113321643B (en) * | 2021-06-17 | 2023-06-20 | 四川大学 | Intermediate, preparation method and application thereof in synthesizing vincamine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| BE763730R (en) * | 1971-01-15 | 1971-08-02 | Omnium Chimique Sa | PROCESS FOR PREPARING NATURAL VINCAMINE FROM LATABERSONIN AND INDOLIC DERIVATIVES |
| CH664153A5 (en) * | 1985-02-28 | 1988-02-15 | Arysearch Arylan Ag | PROCEDURE FOR THE PREPARATION OF THE VINCAMINA. |
| CN102108082A (en) * | 2009-12-23 | 2011-06-29 | 广州斯威森科技有限公司 | Industrialized semisynthesis of medicine-vincamine for treating cerebral ischemia |
| CN102040606B (en) * | 2011-01-26 | 2012-10-03 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of vinpocetine |
| CN102276599B (en) * | 2011-08-18 | 2012-10-17 | 张家口市格瑞高新技术有限公司 | Process for preparing vincamine by semisynthetic method |
| CN103232452A (en) * | 2013-05-14 | 2013-08-07 | 彭学东 | Industrialized semi-synthesis process of vincamine |
| CN103664941B (en) * | 2013-12-06 | 2015-12-02 | 湖南科源生物制品有限公司 | A kind of preparation method of vinpocetine analogue |
| CN104327073B (en) * | 2014-10-16 | 2016-05-04 | 广州普星药业有限公司 | A kind of semi-synthetic production method of vinpocetine |
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Denomination of invention: A production process of vinblastine by semi synthetic method Effective date of registration: 20210930 Granted publication date: 20160831 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |
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Date of cancellation: 20221031 Granted publication date: 20160831 Pledgee: Agricultural Bank of China Limited Zhangjiagang branch Pledgor: ZHANG JIA GANG VINSCE BIO-PHARM Co.,Ltd. Registration number: Y2021320010400 |
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