CN106749229B - A kind of process for purification of pervone - Google Patents
A kind of process for purification of pervone Download PDFInfo
- Publication number
- CN106749229B CN106749229B CN201611187514.8A CN201611187514A CN106749229B CN 106749229 B CN106749229 B CN 106749229B CN 201611187514 A CN201611187514 A CN 201611187514A CN 106749229 B CN106749229 B CN 106749229B
- Authority
- CN
- China
- Prior art keywords
- pervone
- organic solvent
- hours
- added
- crystallization
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of process for purification of pervone in compound field of refinement.It the described method comprises the following steps：(1) in the presence of an organic, pervone crude product is beaten, cool down crystallization, filters, and filter cake is dried to obtain pervone mashing object with organic solvent washing；(2) obtained pervone mashing object is dissolved added with solvent, filtering, filtrate decompression concentration obtains concentrate；(3) organic solvent is added in concentrate, be beaten, cool down crystallization, filters, and filter cake obtains pervone highly finished product with organic solvent washing, drying.This method has the advantages that removing that effect is good, and reaction process is easy to operate, safe, at low cost, products obtained therefrom high income, high-quality to N oxide impurities, being suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of process for purification of pervone in compound field of refinement.
Background technology
Pervone (Vincamine) is a kind of main alkaloid in periwinkle, is in monoterpenoid indole alkaloid
Yaruru bases, its chemical name is (3 α, 14 β, 16 α) -14,15- dihydro -14- hydroxyl eburnamenine -14- carboxylate methyl esters, English
Science of culture title (3a, 14b, 16a)-14,15-Dihydro-14-hydroxyeburnamenine-14-carboxylic
Acid methylester, molecular formula：C21H26N2O3, molecular weight 354.4, structural formula is as follows (formula I)：
Pervone can penetrate blood-brain barrier, so that diseased region brain tissue is maintained and restore the oxidation decomposition metabolism of glucose, make
The generation of lactic acid and the release of carbon dioxide restore normal, to expand cerebral small vessels, improve Brain circlulation, to normal cerebral tissue with
And the blood flow of the normal brain area of patient's brain tissue has no significant effect, while being also the important original of synthesis anticancer drug vinpocetine
Material.At present there are two types of the synthetic methods of pervone：One is complete synthesizing process, another kind is semi-synthesis method.Wherein complete synthesizing process road
Line length cost is higher.It is domestic at present that pervone is mainly prepared using semi-synthesis method, using Voacanga extract tabersonine as raw material,
Hydrogenated, oxidation, resets obtained pervone at reduction.
Tabersonine structure (formula II)：
There are 1 and 2 two nitrogen-atoms in this compound structure, and in semi-synthesis method oxidation step, two nitrogen-atoms are all
It can be aoxidized, oxidation product has following three kinds
Wherein 1 nitrogen-atoms oxidation product A is required target product, can be reduced in the presence of conventional reduction agent, so
Rearrangement reaction occurs afterwards and obtains pervone, but inevitably can all generate the impurity B and C of the oxidation of 2 nitrogen-atoms, this oxidation production
Object is difficult to be reduced since 2 nitrogen-atoms are on indole ring, rearranged to obtain impurity N- oxides, the following (formula of structure
Ⅲ)：
This compound is similar with Changchun amine structure, and polarity is close, it is difficult to be separated off, seriously affect the quality of pervone.
Semi-synthetic used raw material tabersonine source is to be extracted in vegetable seeds Voacanga, causes to contain part in tabersonine
Non- tabersonine plant component so that tabersonine content is low, influences the content of pervone obtained by semisynthesis, need to refine removing.
Therefore, the new issue that a kind of process for purification of pervone is urgently to be resolved hurrily at present is researched and developed.
Invention content
The purpose of the present invention is to provide a kind of process for purification of pervone, remove the N- oxidations that semi-synthetic pervone introduces
The non-tabersonine plant component that object impurity and inorganic salts are introduced with tabersonine raw material, this method is easy to operate, safe, yield
High, at low cost, gained pervone purity is high.
The object of the present invention is achieved like this：A kind of process for purification of pervone, the described method comprises the following steps：
(1) in the presence of an organic, pervone crude product is beaten, after a period of time, cool down crystallization, filters, filter
Cake is dried to obtain pervone mashing object with certain organic solvent washing；
(2) the pervone mashing object obtained step (1) is dissolved added with solvent, filtering, and filtrate decompression concentration must concentrate
Object；
(3) a certain amount of organic solvent is added in the concentrate for obtaining step (2), is beaten at a certain temperature, and cool down crystallization,
It filters, filter cake obtains pervone essence finished product with a certain amount of organic solvent washing, drying.
Organic solvent described in step (1) is anhydrous organic solvent, and the anhydrous organic solvent is selected from ethyl alcohol, N, N-
One or more of dimethylformamide, methanol, acetone, ethyl acetate；The washing is that polarity is organic with organic solvent
Solvent, the one kind of the polar organic solvent in methanol, ethyl alcohol, isopropanol；The temperature being beaten described in step (1)
It it is 40 DEG C -90 DEG C, the time of the mashing is -8 hours 4 hours；The temperature being preferably beaten described in step (1) is 60
DEG C, the time of the mashing is 7 hours；The cooling crystallization is divided into first stage and second stage, the first stage
Recrystallization temperature is 20 DEG C -30 DEG C, and the crystallization time is -8 hours 4 hours, and the second stage recrystallization temperature is -5 DEG C -5 DEG C, analysis
The brilliant time is -4 hours 2 hours；The preferred first stage recrystallization temperature is 25 DEG C, and the crystallization time is 8 hours, described
Second stage recrystallization temperature is 0 DEG C, and the crystallization time is 4 hours；The volume of organic solvent and pervone described in step (1) are thick
The mass ratio of product is 3-10:1, the volume unit is milliliter, and the mass unit is gram；Preferably in step (1)
The volume of the organic solvent is 5 with the mass ratio of pervone crude product:1, the volume unit is milliliter, the quality list
Position is gram；Organic solvent described in step (2) is dichloromethane or chloroform；The volume of the organic solvent and pervone
Mass ratio is 20-40:1, the volume unit is milliliter, and the mass unit is gram；The preferred organic solvent
The mass ratio of volume and pervone is 100:3, the volume unit is milliliter, and the mass unit is gram；In step (3)
Described in organic solvent be methanol, ethyl alcohol, dichloromethane, one or more of acetone, preferred organic solvent is dichloromethane
Alkane and methanol mixed solvent；The volume of the organic solvent is 3-10 with pervone mashing amount of substance ratio in the step (2):1,
The volume unit is milliliter, and the mass unit is gram；The volume and the step (2) of the preferred organic solvent
Middle pervone mashing amount of substance ratio is 5:1, the volume unit is milliliter, and the mass unit is gram；The dichloromethane
In alkane and methanol mixed solvent, the volume ratio of dichloromethane and methanol is 1:0.5-6, the volume of preferred dichloromethane and methanol
Than being 1:2；The temperature being beaten described in step (3) is 40 DEG C -60 DEG C, and the time of mashing is -4 hours 2 hours；The crystallization
Temperature be 20 DEG C -30 DEG C, time of crystallization is -9 hours 6 hours；The temperature being preferably beaten described in step (3) is 60
DEG C, the time of mashing is 3 hours；The temperature of the crystallization is 21 DEG C, and the time of crystallization is 7 hours；
In step (1), the pervone crude product is prepared by the following method：
A. the preparation of tabersonine：
30.0g tabersonines hydrochloride and 325.0g petroleum ethers are added into 1000mL four-hole bottles, stirs lower dropwise addition 12.3g ammonia
Water, drop stir 0.5 hour after finishing at 25 DEG C, add 330g saturated sodium bicarbonate solutions and stir 0.5 hour；Reaction finishes
Afterwards, liquid separation, water layer 2 × 65g petroleum ether extractions 2 times；Merge organic phase, 5g anhydrous magnesium sulfates be added and dry 2 hours, filter,
Petroleum ether is removed under reduced pressure at 50 DEG C, obtains tabersonine；
B. the preparation of vincadifformine
26.0g tabersonines are added into the 1000ml four-hole bottles equipped with threeway, the dissolving of 208.0g methanol is added with stirring
2.6gPd/C, 99.9% nitrogen displaced air 3 times, then with after the displacement three times of 99.5% hydrogen, it is continually fed into hydrogen, it is anti-at 25 DEG C
It should be monitored less than raw material point up to TLC；After completion of the reaction, it filters, filter cake 2 × 9.0g organic solvent washings；At 40 DEG C of filtrate
Vacuum distillation, is evaporated off methanol, obtains vincadifformine；
C. the preparation of single peroxy maleic acid
53.6g maleic anhydrides, 96.4gN, dinethylformamide, stirring and dissolving are added into 1000mL four-hole bottles
After be cooled to -5~0 DEG C, 30% hydrogen peroxide 29.2g is added dropwise, drop finishes, and continues to stir 15min.Temperature is slowly increased to 30 DEG C again
Stirring 5 hours is cooled to 0 DEG C after completion of the reaction, and it is spare that the dilution of 323.8g cold methanols is added；
D. the preparation of pervone
24.0g vincadifformines are added into 1000mL four-hole bottles, 133.0g methanol makes it dissolve, and is cooled to -5-0 DEG C,
The dropwise addition mono- peroxy maleic acids of 119.0g in lower 2.5 hours are stirred, drop stirs 40min after finishing, and continues that the mono- peroxide horses of 119.1g are added dropwise
It is next sour, it is dripped off in 2.5 hours, continues stirring 3 hours.After completion of the reaction, 40% Sodium Metabisulfite solution is added dropwise to starch KI
Test paper no longer changes colour, and continues to stir 10min, is warming up to 40 DEG C and stirs 3 hours；After completion of the reaction, 433.9g water is added, is cooled to
25 DEG C, it is 8.5-9 that ammonium hydroxide, which is added dropwise, and adjusts pH value of solution, continues stirring and is cooled to 0-5 DEG C, and crystallization filters after 2 hours, and filter cake is used
57.0g cold methanols wash, 150g water washings, and after draining, filter cake is added in 500mL single port bottles, and 300g water is added, and stir lower heating
It is beaten 2 hours, filters to 60 DEG C, after 40 DEG C of vacuum drying, obtain pervone.
The present invention is characterized by a kind of process for purification of pervone, and pharmacy principle is：(1) by step (1)
The optimization of organic solvent type and reaction temperature can get good effect for the removal of N- oxide impurities, and solvent is used
It measures less, mild condition, is suitable for industrialized production；(2) being removed by way of organic solvent dissolution filter influences product content
Inorganic matter and plant component, mild condition can get good effect to the raising of content；(3) by being mixed in step (3)
The optimization of solvent ratio has good result for impurity removal and yield；(4) reaction raw materials are to be added at one time, and are simplified
Operation；(5) it is high to obtain pervone purity by the present invention.
Good, reaction process that a kind of process for purification of pervone removes effect compared with prior art, to N- oxide impurities
It is easy to operate, safe, at low cost, products obtained therefrom high income, high-quality, it the advantages that being suitable for industrialized production, will be extensive
Ground is applied in the field of refinement of pervone.
Specific implementation mode
Following embodiment will be helpful to the understanding to the present invention, but these embodiments are only for being illustrated the present invention,
The present invention is not limited to these contents.
Embodiment one
Step 1：12.0g pervone crude products are added into 100ml single port bottles, 60ml anhydrous organic solvents are described organic molten
The selection situation of agent is shown in Table 1, and 60 DEG C are warming up under stirring and is beaten 7 hours, is down to 25 DEG C and stirs 8 hours, then is down to 0 DEG C of crystallization 4
Hour, it filters, filter cake is washed with 12ml cold methanols, and 40 DEG C are 6-9 hours dry.White pervone mashing object is obtained, N- oxides are miscellaneous
Matter, purity and yield situation are shown in Table 1.
Step 2：6.0g pervones are added into 500ml single port bottles and are beaten object, 200ml dichloromethane stirs lower dissolving,
Filtering, filtrate decompression concentration, obtains concentrate.
Step 3：Concentrate is added into 250ml three-necked bottles, 10ml dichloromethane is added, 20ml methanol is heated to 60 DEG C
Mashing 3 hours is down to 21 DEG C and is stirred 7 hours, a large amount of white crystals are precipitated, filters, and filter cake is washed with 9ml cold methanols, 40 DEG C of dryings
6-9 hours, obtain white pervone finished product 5.4g, molar yield 89.5%.
Table 1：The selection of organic solvent changes with N- oxide impurities, purity and yield
Embodiment two
Step 1：12.0g pervone crude products, 60ml n,N-Dimethylformamide, stirring are added into 100ml single port bottles
Under be warming up to certain temperature and be beaten 7 hours, the selection situation of the temperature is shown in Table 2, is down to 25 DEG C and stirs 8 hours, then is down to 0 DEG C
Crystallization 4 hours filters, and filter cake is washed with 12ml cold methanols, and 40 DEG C 6-9 hours dry.Obtain white pervone mashing object, N- oxidations
Object impurity, purity and yield situation are shown in Table 2.
Step 2：6.0g pervones are added into 500ml single port bottles and are beaten object, 200ml dichloromethane stirs lower dissolving,
Filtering, filtrate decompression concentration, obtains concentrate.
Step 3：Concentrate is added into 250ml three-necked bottles, 10ml dichloromethane is added, 20ml methanol is heated to 60 DEG C
Mashing 3 hours is down to 21 DEG C and is stirred 7 hours, a large amount of white crystals are precipitated, filters, and filter cake is washed with 9ml cold methanols, 40 DEG C of dryings
6-9 hours, obtain white pervone finished product 5.4g, molar yield 89.5%
Table 2：The selection of temperature changes with N- oxide impurities, purity and yield
Embodiment three
Step 1：12.0g pervone crude products, 60ml n,N-Dimethylformamide, stirring are added into 100ml single port bottles
Under be warming up to 60 DEG C and be beaten 7 hours, be down to 25 DEG C and stir 8 hours, then be down to 0 DEG C of crystallization 4 hours, filter, filter cake is cold with 12ml
Methanol is washed, and 40 DEG C 6-9 hours dry.Obtain white pervone mashing object 10.4g, molar yield 87.0%.
Step 2：6.0g pervones are added into 500ml single port bottles and are beaten object, 200ml organic solvents, the organic solvent
Selection situation be shown in Table 3, stir lower dissolving, filtering, filtrate decompression concentration obtains concentrate.
Step 3：Concentrate is added into 250ml three-necked bottles, 10ml dichloromethane and 20ml methanol mixed solvents is added,
It is heated to 60 DEG C to be beaten 3 hours, is down to 21 DEG C and stirs 7 hours, filter, a large amount of white crystals, filter cake 9ml cold methanols is precipitated
It washes, 40 DEG C 6-9 hours dry, obtains white pervone finished product, and finished product content and yield situation are shown in Table 3
Table 3：The selection of organic solvent and finished product content and yield situation
Example IV
Step 1：12.0g pervone crude products, 60ml n,N-Dimethylformamide, stirring are added into 100ml single port bottles
Under be warming up to 60 DEG C and be beaten 7 hours, be down to 25 DEG C and stir 8 hours, then be down to 0 DEG C of crystallization 4 hours, filter, filter cake is cold with 12ml
Methanol is washed, and 40 DEG C 6-9 hours dry.Obtain white pervone mashing object 10.4g, molar yield 87.0%.
Step 2：6.0g pervones are added into 500ml single port bottles and are beaten object, 200ml dichloromethane stirs lower dissolving,
Filtering, filtrate decompression concentration, obtains concentrate.
Step 3：It is added concentrate into 250ml three-necked bottles, dichloromethane and methanol mixed solvent 30ml is added, it is described
The selection situation of dichloromethane and methanol mixed proportion is shown in Table 4, is heated to 60 DEG C and is beaten 3 hours, is down to 21 DEG C and stirs 7 hours,
A large amount of white crystals are precipitated, filter, filter cake is washed with 9ml cold methanols, and 40 DEG C 6-9 hours dry, obtains white pervone finished product, N-
Oxide impurity, purity and yield situation are shown in Table 4.
Table 4：Mixed solvent ratio selects to change with N- oxide impurities, purity and yield
Embodiment five
Pervone crude product in the embodiment of the present invention one to four is prepared by the following method：
A. the preparation of tabersonine：
30.0g (80.4mmol) tabersonine hydrochlorides and 325.0g petroleum ethers are added into 1000mL four-hole bottles, under stirring
12.3g (87.7mmol) ammonium hydroxide is added dropwise, drop stirs 0.5 hour after finishing at 25 DEG C, adds 330g saturated sodium bicarbonate solutions
Stirring 0.5 hour.After completion of the reaction, liquid separation, water layer 2 × 65g petroleum ether extractions 2 times.Merge organic phase, the anhydrous sulphur of 5g is added
Sour magnesium is dried 2 hours, is filtered, and is removed petroleum ether under reduced pressure at 50 DEG C, is obtained 27.0g tabersonines, mass yield 90%.
B. the preparation of vincadifformine
26.0g (77.3mmol) tabersonine is added into the 1000ml four-hole bottles equipped with threeway, the dissolving of 208.0g methanol is stirred
Lower addition 2.6gPd/C, 99.9% nitrogen displaced air 3 times are mixed, then with after the displacement three times of 99.5% hydrogen, is continually fed into hydrogen,
Until TLC is monitored, (solvent is petroleum ether for reaction at 25 DEG C：Ethyl acetate=5:1) less than raw material point.After completion of the reaction, mistake
Filter, filter cake 2 × 9.0g organic solvent washings.It is evaporated under reduced pressure at 40 DEG C of filtrate, methanol is evaporated off, obtain vincadifformine 24.7g,
Mass yield is 95.0%.
C. the preparation of single peroxy maleic acid
53.6g (546.6mmol) maleic anhydride, 96.4gN, N- dimethyl formyls are added into 1000mL four-hole bottles
Amine is cooled to -5~0 DEG C after stirring and dissolving, and 30% hydrogen peroxide 29.2g (257.6mmol) is added dropwise, and drop finishes, continues to stir
15min.Temperature is slowly increased to 30 DEG C again to stir 5 hours, after completion of the reaction, 0 DEG C is cooled to, the dilution of 323.8g cold methanols is added
It is spare.
D. the preparation of pervone
24.0g (70.9mmol) vincadifformine is added into 1000mL four-hole bottles, 133.0g methanol makes it dissolve, and cools down
To -5-0 DEG C, the single peroxy maleic acids of 119.0g (60.9mmol) are added dropwise in stirring in lower 2.5 hours, and drop stirs 40min after finishing, continues
The single peroxy maleic acids of 119.1g (60.9mmol) are added dropwise, is dripped off in 2.5 hours, continues stirring 3 hours.After completion of the reaction, it is added dropwise
40% Sodium Metabisulfite solution to starch KI test paper no longer changes colour, and continues to stir 10min, is warming up to 40 DEG C and stirs 3 hours.Instead
After answering, 433.9g water is added, is cooled to 25 DEG C, it is 8.5-9 that ammonium hydroxide, which is added dropwise, and adjusts pH value of solution, continues stirring and is cooled to 0-5
DEG C, crystallization filters after 2 hours, and filter cake is washed with 57.0g cold methanols, 150g water washings, and after draining, 500mL single port is added in filter cake
In bottle, 300g water is added, 60 DEG C are heated under stirring and is beaten 2 hours, is filtered, after 40 DEG C of vacuum drying, obtains pervone
18.8g, mass yield 78.3%.
Claims (7)
1. a kind of process for purification of pervone, it is characterised in that：It the described method comprises the following steps：
(1) in the presence of an organic, pervone crude product is beaten, after a period of time, cool down crystallization, filter, filter cake with
Certain organic solvent washing is dried to obtain pervone mashing object；
(2) the pervone mashing object obtained step (1) is dissolved added with solvent, filtering, and filtrate decompression concentration obtains concentrate；
(3) a certain amount of organic solvent is added in the concentrate for obtaining step (2), is beaten at a certain temperature, and cool down crystallization, takes out
Filter, filter cake obtain pervone essence finished product with a certain amount of organic solvent washing, drying；
Organic solvent described in step (1) is anhydrous organic solvent, and the anhydrous organic solvent is selected from ethyl alcohol, N, N- diformazans
One or more of base formamide, methanol, acetone, ethyl acetate；The washing is polar organic solvent with organic solvent,
The one kind of the polar organic solvent in methanol, ethyl alcohol, isopropanol；
The temperature being beaten described in step (1) is 40 DEG C -90 DEG C, and the time of the mashing is -8 hours 4 hours；The drop
Warm crystallization is divided into first stage and second stage, and the first stage recrystallization temperature is 20 DEG C -30 DEG C, and the crystallization time is 4 small
When -8 hours, the second stage recrystallization temperature be -5 DEG C -5 DEG C, the crystallization time be -4 hours 2 hours；
The mass ratio of the volume of organic solvent described in step (1) and pervone crude product is 3-10:1, the volume unit
For milliliter, the mass unit is gram；
Organic solvent described in step (2) is dichloromethane or chloroform；The volume of the organic solvent and the matter of pervone
Amount is than being 20-40:1, the volume unit is milliliter, and the mass unit is gram；
The organic solvent described in step (3) is methanol, ethyl alcohol, dichloromethane, one or more of acetone, described organic molten
The volume of agent is 3-10 with pervone mashing amount of substance ratio in the step (2):1, the volume unit is milliliter, described
Mass unit is gram；In the dichloromethane and methanol mixed solvent, the volume ratio of dichloromethane and methanol is 1:0.5-6；
The temperature being beaten described in step (3) is 40 DEG C -60 DEG C, and the time of mashing is -4 hours 2 hours；The temperature of the crystallization
Degree is 20 DEG C -30 DEG C, and the time of crystallization is -9 hours 6 hours；
The pervone crude product is semi-synthetic pervone.
2. the process for purification of pervone according to claim 1, it is characterised in that：The temperature being beaten described in step (1)
Degree is 60 DEG C, and the time of the mashing is 7 hours；The first stage recrystallization temperature is 25 DEG C, and the crystallization time is 8 hours,
The second stage recrystallization temperature is 0 DEG C, and the crystallization time is 4 hours.
3. the process for purification of pervone according to claim 1, it is characterised in that：The organic solvent described in step (1)
The mass ratio of volume and pervone crude product be 5:1, the volume unit is milliliter, and the mass unit is gram.
4. the process for purification of pervone according to claim 1, it is characterised in that：In step (2), described is organic molten
The mass ratio of agent volume and pervone is 100:3, the volume unit is milliliter, and the mass unit is gram.
5. the process for purification of pervone according to claim 1, it is characterised in that：The organic solvent described in step (3)
For dichloromethane and methanol mixed solvent；The volume of the organic solvent is beaten amount of substance ratio with pervone in the step (2)
It is 5:1, the volume unit is milliliter, and the mass unit is gram；In the dichloromethane and methanol mixed solvent, two
The volume ratio of chloromethanes and methanol is 1:2.
6. the process for purification of pervone according to claim 1, it is characterised in that：The temperature being beaten described in step (3)
Degree is 60 DEG C, and the time of mashing is 3 hours；The temperature of the crystallization is 21 DEG C, and the time of crystallization is 7 hours.
7. the process for purification of pervone according to claim 1, it is characterised in that：In step (1), the pervone
Crude product is prepared by the following method：
A. the preparation of tabersonine：
30.0g tabersonines hydrochloride and 325.0g petroleum ethers are added into 1000mL four-hole bottles, stirs lower dropwise addition 12.3g ammonium hydroxide,
Drop stirs 0.5h after finishing at 25 DEG C, adds 330g saturated sodium bicarbonate solutions stirring 0.5h；After completion of the reaction, liquid separation, water
Layer 2 × 65g petroleum ether extractions 2 times；Merge organic phase, 5g anhydrous magnesium sulfates are added and dry 2h, filter, are removed under reduced pressure at 50 DEG C
Petroleum ether obtains tabersonine；
B. the preparation of vincadifformine
26.0g tabersonines are added into the 1000ml four-hole bottles equipped with threeway, the dissolving of 208.0g methanol is added with stirring 2.6g
Pd/C, 99.9% nitrogen displaced air 3 times, then with after the displacement three times of 99.5% hydrogen, be continually fed into hydrogen, react straight at 25 DEG C
It is monitored to TLC less than raw material point；After completion of the reaction, it filters, filter cake 2 × 9.0g organic solvent washings；It is depressurized at 40 DEG C of filtrate
Distillation, is evaporated off methanol, obtains vincadifformine；
C. the preparation of single peroxy maleic acid
53.6g maleic anhydrides are added into 1000mL four-hole bottles, 96.4g n,N-Dimethylformamide drops after stirring and dissolving
30% hydrogen peroxide 29.2g is added dropwise to -5~0 DEG C in temperature, and drop finishes, and continues to stir 15min；Temperature is slowly increased to 30 DEG C of stirrings again
5h is cooled to 0 DEG C after completion of the reaction, and it is spare that the dilution of 323.8g cold methanols is added；
D. the preparation of pervone
24.0g vincadifformines are added into 1000mL four-hole bottles, 133.0g methanol makes it dissolve, and is cooled to -5-0 DEG C, stirring
The mono- peroxy maleic acids of 119.0g are added dropwise in lower 2.5h, drop stirs 40min after finishing, and continues that the mono- peroxy maleic acids of 119.1g are added dropwise,
It is dripped off in 2.5h, continues to stir 3h；After completion of the reaction, 40% Sodium Metabisulfite solution to starch KI test paper is added dropwise no longer to become
Color continues to stir 10min, is warming up to 40 DEG C of stirring 3h；After completion of the reaction, 433.9g water is added, is cooled to 25 DEG C, ammonium hydroxide is added dropwise
Adjusting pH value of solution is 8.5-9, continues stirring and is cooled to 0-5 DEG C, is filtered after crystallization 2h, filter cake is washed with 57.0g cold methanols, 150g
Water washing, after draining, filter cake is added in 500mL single port bottles, and 300g water is added, and 60 DEG C of mashing 2h are heated under stirring, are filtered, 40
DEG C vacuum drying after, obtain pervone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611187514.8A CN106749229B (en) | 2016-12-20 | 2016-12-20 | A kind of process for purification of pervone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611187514.8A CN106749229B (en) | 2016-12-20 | 2016-12-20 | A kind of process for purification of pervone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106749229A CN106749229A (en) | 2017-05-31 |
| CN106749229B true CN106749229B (en) | 2018-08-17 |
Family
ID=58894240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611187514.8A Active CN106749229B (en) | 2016-12-20 | 2016-12-20 | A kind of process for purification of pervone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106749229B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110950859B (en) * | 2019-10-23 | 2021-04-30 | 广州一品红制药有限公司 | Preparation method of vinpocetine |
| CN113121466B (en) * | 2019-12-31 | 2023-12-15 | 成都迪康药业股份有限公司 | Recrystallizing solvent of acotiamide hydrochloride and refining method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276599A (en) * | 2011-08-18 | 2011-12-14 | 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 |
| CN104788447A (en) * | 2015-04-21 | 2015-07-22 | 张家港威胜生物医药有限公司 | Production process using semi-synthetic method to prepare vincamine |
| US20160340334A1 (en) * | 2015-05-19 | 2016-11-24 | Joseph Robert Knight | Method for isolation of alkaloids and amino acids, and compositions containing isolated alkaloids and amino acids |
-
2016
- 2016-12-20 CN CN201611187514.8A patent/CN106749229B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276599A (en) * | 2011-08-18 | 2011-12-14 | 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 |
| CN104788447A (en) * | 2015-04-21 | 2015-07-22 | 张家港威胜生物医药有限公司 | Production process using semi-synthetic method to prepare vincamine |
| US20160340334A1 (en) * | 2015-05-19 | 2016-11-24 | Joseph Robert Knight | Method for isolation of alkaloids and amino acids, and compositions containing isolated alkaloids and amino acids |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106749229A (en) | 2017-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105061416B (en) | A kind of method for preparing flumioxazin | |
| CN101092421B (en) | New technique for extracting sesamin | |
| CN106749229B (en) | A kind of process for purification of pervone | |
| CN113717176B (en) | Method for preparing remazolam | |
| CN115011661B (en) | Synthesis method of 3 beta-ursodeoxycholic acid | |
| CN111116692A (en) | Synthesis method of high-purity selamectin | |
| CN108752415B (en) | Synthesis and purification method of finasteride chiral impurity (5 β -finasteride) | |
| KR101418620B1 (en) | Process for production of mirtazapine | |
| CN106749230B (en) | A kind of preparation method of pervone | |
| CN103450201B (en) | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine | |
| CN111943937A (en) | Synthesis method of triphenyl candesartan | |
| CN113549031A (en) | Method for refining dipheny hydrochloride | |
| CN113480480B (en) | Synthesis method of (R) -5' -methoxy laudan | |
| CN106008660B (en) | The preparation method of deflazacort | |
| EP2414378B1 (en) | Separation of 4-aza-androst-1-ene-17-oic acid from 4-aza-androstan-17-oic acid | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN109232530B (en) | Preparation method of sitafloxacin hydrate | |
| CN109608511B (en) | Chemical synthesis process of prednisolone valerate acetate | |
| KR101485418B1 (en) | A synthetic method of high purity mirtazapine | |
| CN106336411A (en) | Preparation method and use of CDK4/6 inhibitor palbociclib highly-pure raw drug | |
| CN106187864A (en) | A kind of method being prepared high-purity bupivacaine alkali by bupivacaine hydrochloride | |
| CN113214267B (en) | Refining method for preparing pure and optically enriched eszopiclone | |
| CN115433135B (en) | Gefitinib method for purifying nylon | |
| CN105330652B (en) | A kind of preparation method of Afatinib | |
| CN115991655B (en) | Synthesis method and product of m-hydroxylamine bitartrate and key intermediate enantiomer thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |