CN1033973C - Preparation of vincamine amino acid ester - Google Patents
Preparation of vincamine amino acid ester Download PDFInfo
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- CN1033973C CN1033973C CN 91106219 CN91106219A CN1033973C CN 1033973 C CN1033973 C CN 1033973C CN 91106219 CN91106219 CN 91106219 CN 91106219 A CN91106219 A CN 91106219A CN 1033973 C CN1033973 C CN 1033973C
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- amino acid
- vincamine
- acid ester
- ethanol
- concentrated solution
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Abstract
The present invention provides a new method for preparing a medicine, namely apovincamine ethyl gallate, for treating cerebrovascular diseases. In the method, positive or negative ion exchange resin is added as a dehydrating agent during dehydration and esterification to improve reaction yield by over 15%. Thus, the method cuts off benzene-recrystallization procedure, shortens technological route and reduces handling cost. The present invention has the advantages of convenient operation and great cost reduction, and creates favorable conditions for the industrial production of apovincamine ethyl gallate.
Description
The invention belongs to field of medicaments, is a kind of novel method for the treatment of the medication preparation of cerebrovascular disease.
Vincamine amino acid ester has another name called vinpocetin, is that the indole alkaloid vincamine (VinCamine) that extracts from the little graceful Vinca of Apocynaceae is through structure of modification gained derivative.Its structural formula is as follows:
This product has the supply of promoting and improving brain oxygen, can optionally increase the cerebral lesion regional blood flow, influence little to heart, blood vessel, blood pressure, has the increase erythrocyte deformability, reduce blood viscosity and anticoagulant effect, can improve blood fluidity and microcirculation improvement, the brain of improvement metabolism is arranged.
Be used for clinically both at home and abroad that ischemia hypertensive encephalopathy, cerebral arteriosclerosis, cerebral ischaemia, intermittent cerebral blood flow are under-supply, cerebral vasospasm, early stage cerebral endarteritis, cerebral thrombosis, cerebral embolism form, the treatment of dizzy, aphasia, Meniere's syndrome, and the effect that improves memory, eyesight and old hearing are arranged.
Because this product is treated cerebrovascular disease clinically curative effect is preferably arranged, and has unique pharmacological action, in recent years, cause domestic and international relevant expert's attention, and its synthetic route, preparation technology have been carried out extensive studies.
The preparation method of vincamine amino acid ester, useful chemical process is carried out complete synthesis, and it is also useful that to extract vincamine from the plant that contains vincamine be the semisynthesis that raw material carried out.(Acta Pharmaceutica Sinica 1983,18 (7), 507, CA (100) 103696; Tetrahedron1977, VO133,1803; Synthesis1974,2 (3), 5,354; J, org chem1986, VO151, NO8,1165; Arzmeim-Forsch 1976,26 (10A); Fr2,468,605; Belg879,929; Hung FelieHV24,012; CA (99) 122742.
Contrast two kinds of synthetic methods, it is short that semisynthesis has synthetic route, the yield height, and technology is simply ripe, the advantage that cost is low.Produce the semi-synthetic route of the many employings of vincamine amino acid ester both at home and abroad.It is also more to prepare vincamine amino acid ester report with semi-synthesis method, as: have vincamine elder generation hydrolysis, dehydration, esterification, recrystallization gets the method for finished product again; Also have vincamine elder generation dehydration, hydrolysis, esterification, recrystallization gets the report of finished product again, also has the hydrolysis of vincamine elder generation, resterification, dehydration, recrystallization get the method for finished product at last.
Semi-synthetic route dewatering report is also varied, as: with benzene or its chlorination homologue azeotropic dehydration method; N, the two oxyamides of N-at high temperature dewater; Or (the Richter Gedecon bE2944-036 of company that in the vitriol oil, dewaters; Kugo Masachi cpI CAB 24Dec1986, p5; J961221,187).
Esterification use more ethanol (also useful halogen ethane) in the presence of catalyst with Changchun amino acid or dehydration Changchun acid-respons.Catalyst is used the vitriol oil, organic sulfonic acid, diamino pyridine [Arznei-Fiesch (DrugRes) 1976,26 (10A) 1907 usually; JP8171091; CA (95) 187507; GB2 062,619, and CA (96) 35615; ES8604-956-A; CPI CAB Dec, 1986, p13; ES538923, CA (107) 217094K].
Relevant vincamine amino acid ester process for purification [RichterGedeonArznei-Forsch (Drug Re) 1976,26 (10A) 1907] gets finished product with the benzene recrystallization.The vincamine amino acid ester specification of quality is by Japanese military field medicine Co., Ltd. product standard, and fusing point is controlled at 149.5-153 ℃, and apovincamine is no more than 1.1%, and Vincaminic acid ethyl ester must not be higher than 0.5%, and remaining other impurity summation must not be greater than 0.1%.These impurity are difficult to remove with the process for purification of reported in literature, and quality problems can not be solved for a long time.
The objective of the invention is to keep when semisynthesis prepares the vincamine amino acid ester advantage provides a kind of cost lower, and technology is simple, and step is short, and dewatering agent is cheap and easy to get, the novel method of the preparation vincamine amino acid ester of ensuring the quality of products qualified.
The ion exchange resin of catalysis dual function was dewatering agent when utilization of the present invention had not only had dehydration but also had esterification, reaction solution through routine handle the vincamine amino acid ester concentrated solution, in concentrated solution, add organic solvent ethanol or methyl alcohol, propyl alcohol, Virahol, ether, acetonitrile crystallization, slice off with benzene recrystallization operation.Added positive or negative ion exchange resin dewatering agent is reusable edible also, reaches with this to reduce cost, and shortens operation, guarantees the purpose that final product quality is qualified simultaneously.
For this reason, abundant male in source or negative ion exchange resin have been selected for use, particularly the anionite-exchange resin of the Zeo-karb of sulfonic acid type or polystyrene and Changchun amino acid carry out the new preparation method that dehydration reaction adds the ethyl esterification single stage method, the vincamine amino acid ester reaction solution that makes, through routine handle its concentrated solution, this concentrated solution organic solvent crystallization obtains up-to-standard vincamine amino acid ester finished product.
The object of the present invention is achieved like this:
In the amino acid of Changchun, add dehydrated alcohol, the vitriol oil, add a spot of Zeo-karb or anionite-exchange resin, its weight ratio is the Changchun amino acid: dehydrated alcohol: the vitriol oil: ion exchange resin=1: 30-40: 4-7: 0.15-0.5, under the reflux condition, dewater, esterification 5-20 hour, get the vincamine amino acid ester reaction solution, its reaction solution is handled through routine, get the vincamine amino acid ester concentrated solution, in concentrated solution, add single organic solvent ethanol or ethanol and methylene dichloride mixing organic solvent crystallization, also concentrated solution can be added in the single organic solvent ethanol or ethanol and methylene dichloride mixing organic solvent in crystallization, the vincamine amino acid ester finished product.Its reaction formula is as follows:
Changchun amino acid vincamine amino acid ester reaction solution
Vincamine amino acid ester concentrated solution vincamine amino acid ester finished product
Advantage of the present invention and positively effect:
1, the present invention makes dewatering agent owing to adding male or negative ion exchange resin in dehydration, esterification, it has the effect of taking off water in the vincamine acid molecule, the effect that has the moisture that contains in moisture that absorption reaction takes off and the esterifying agent ethanol simultaneously, therefore this reaction not only had dehydration but also have katalysis, promote reaction to carry out to the right, make yield surpass the prior art level, be increased to elaboration yield 79.5-80.5% of the present invention by prior art crude product yield 73%, and added ion exchange resin reusable edible also, cost reduces more than 1/4.
2, esterification of the present invention requires anhydrous response, and commercially available esterifying agent dehydrated alcohol, water content must processing treatment could be used more than 0.2%, otherwise influences yield and quality product.Owing to add the ion exchange resin with dual function, esterifying agent need not to handle and can use, and save energy and processing costs are for suitability for industrialized production creates conditions.
3, the vincamine amino acid ester concentrated solution with this method preparation adds organic solvent crystallizatioies such as ethanol, has sliced off with benzene recrystallization operation, has shortened operation, simplified operation, particularly removed the impurity in the finished product, ensured the quality of products, gone into operation for this product and created condition.Utilize this cloudy method for preparing vincamine amino acid ester in a word, synthetic route is short, and is easy to operate, the yield height, and cost is low, guarantees quality product, for suitability for industrialized production creates favorable conditions.
For a better understanding of the present invention, preferentially select following most preferred embodiment for use:
Embodiment 1
Reflux exchanger is being housed, agitator, temperature is taken into account in the three-necked bottle of addition funnel, add 1.2g Changchun amino acid, the 30g dehydrated alcohol splashes into the 4g vitriol oil under stirring, add 0.3g polystyrene sulfonic acid ion exchange resin, reflux 12 hours, cooling, filter, filtrate concentrates in an amount of frozen water of back impouring, transfer PH to 9 with alkali, with 50ml dichloromethane extraction 2-3 time, united extraction liquid is used the salt of wormwood drying, filter, filtrate concentrates, in concentrated solution, add the ethanol crystallization, or, filter crystallization in the concentrated solution impouring ethanol, use the small amount of ethanol washing leaching cake, drying gets the vincamine amino acid ester finished product, yield 79.5%.
Embodiment 2
With the same method of embodiment 1, in three-necked bottle, add 1.2g Changchun amino acid, the 32g dehydrated alcohol, 3.5g the vitriol oil, the anionite-exchange resin of 0.25g strong-basicity styrene series, stirring heating refluxed 13 hours, reaction solution gets concentrated solution with embodiment 1 same method after routine is handled, concentrated solution is added crystallization in ethanol and the methylene dichloride mixed solvent, get the vincamine amino acid ester finished product, yield 80.5%.
Embodiment 3
With the same method of embodiment 1, in three-necked bottle, add 1.2g Changchun amino acid, the 35g dehydrated alcohol, 3.2g the vitriol oil, the Zeo-karb of 0.2g macrovoid polystyrene sulfonic acid type, stirring heating refluxed 14 hours, reaction solution gets concentrated solution with embodiment 1 same method after routine is handled, concentrated solution is added crystallization in the ethanol, get the vincamine amino acid ester finished product, yield 81.5%.
Embodiment 4
With the same method of embodiment 1, in three-necked bottle, add 1.2g Changchun amino acid, the 38g dehydrated alcohol, 4.5g the vitriol oil adds macrovoid polystyrene strongly basic anion exchange resin, stirring heating refluxed 12 hours, reaction solution gets concentrated solution with embodiment 1 same method after routine is handled, the organic solvent Virahol is added crystallization in the concentrated solution, get the vincamine amino acid ester finished product, yield 78.5%.
With the vincamine amino acid ester finished product that the inventive method makes, through ultimate analysis, four big its structural formulas of spectrum resolution and standard substance are in full accord.Test data is as follows:
Test with DEF-1 type CHN+O element automatic analyser
C% H% N% theoretical value 75.42 7.48 7.99 example value 73.3 7.22 8.17
Record MS figure with the Britain 70SE of VG company type mass spectrograph
Peak value m/e (%) 350 (M
+The peak).Its main fragment ion peak m/e 321 (m
+-C2H5)
m/e(％)280(M
+-CH2-CH2-CH2-NCH2)
Scheming as can be known by MS, m/e 350 is M
+It is 350 that the peak meets the vincamine amino acid ester molecular weight.Main fragment ion peak is by its structure crack, and this product and standard quality spectrogram are in full accord.
H nucleus magnetic resonance (H NMR) is resolved the nuclear magnetic resonance spectrometer with WH-90 Sweden, is that solvent is measured its result with CDCL3:
δ PPM
Standard substance: quartet 1.9 and 4.4, triplet 1.0 and 1.4, single
Peak 4.1 and 6.1
The peak area ratio of δ 4.4,4.1,6.11=2: 1: 1 wherein
This product: quartet 1.92 and 4.43, triplet 1.02 and 1.39,
Unimodal 4.15 and 6.11
The peak area ratio of δ 4.43,4.15,6.11=2: 1: 1 wherein
In two sample molecules between each group the number of H conform to, the coupling relation meets rule between each group, the δ value is similar.Illustrate that two sample structures are identical.
Use the PE-684 determination of infrared spectroscopy, the characteristic peak and the relevant peaks infared spectrum of this product and the main group of standard substance result are in full accord, its peak position cm, 1718,1625,1280,1360,1075,740.Illustrate that two samples have identical functional group, each functional group environment of living in is in full accord.
Spectrum resolution is with Lambda-and spectrophotometric determination this product and the following value of standard substance maximum absorbance in methyl alcohol in addition:
Standard substance Max=228nm-230nm
274nm-275nm
274nm(E
1％ 1cm)330-343
This product Max=229.4nm
274.6nm?274nm(E
1％ 1cm)338.5nm
313.6nm
Two absorption of sample peak positions of result and relative intensity are in full accord, and identical spectrophotometric spectra is arranged, and illustrate that identical color development is the colour system identical conjugated degree of unifying.
Comprehensive above ultimate analysis, it is in full accord with Ah the pouncing on's vinpocetine structure and the standard substance of this inventive method preparation that mass spectrum (ms), nuclear-magnetism (NMR), infrared (IR) ultraviolet (UV) are analyzed conclusive evidence.
0.49-153 ℃ of this product fusing point, specific rotation [α]
20 D+ 127-134 (the 1g dry product be dissolved in DMF (100ml, 100mm).
Meet the requirements with the limit of impurities that HPLC limited:
As: apovincamine acid 1.1%
Vincaminic acid ethyl ester＜0.5%
Other impurity summation＜0.1%
Claims (1)
1, a kind of sulfuric acid of using, ethanol and vincamine acid-respons prepare the method for vincamine amino acid ester, it is characterized in that: in the amino acid of Changchun, add dehydrated alcohol, the vitriol oil, add a spot of Zeo-karb or anionite-exchange resin, its weight ratio is the Changchun amino acid: dehydrated alcohol: the vitriol oil: ion exchange resin=1: 30-40: 4-7: 0.15-0.5, under the reflux condition, dewater, esterification 5-20 hour, get the vincamine amino acid ester reaction solution, its reaction solution is handled through routine, get the vincamine amino acid ester concentrated solution, in concentrated solution, add single organic solvent ethanol or ethanol and methylene dichloride mixing organic solvent crystallization, also concentrated solution can be added in the single organic solvent ethanol or crystallization in ethanol and the methylene dichloride mixed solvent, the vincamine amino acid ester finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91106219 CN1033973C (en) | 1991-08-30 | 1991-08-30 | Preparation of vincamine amino acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 91106219 CN1033973C (en) | 1991-08-30 | 1991-08-30 | Preparation of vincamine amino acid ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1058966A CN1058966A (en) | 1992-02-26 |
| CN1033973C true CN1033973C (en) | 1997-02-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 91106219 Expired - Fee Related CN1033973C (en) | 1991-08-30 | 1991-08-30 | Preparation of vincamine amino acid ester |
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| CN (1) | CN1033973C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875547A (en) * | 2011-07-15 | 2013-01-16 | 海南灵康制药有限公司 | Vinpocetine compound and its preparation method |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721361B (en) * | 2009-12-08 | 2013-06-26 | 李荣立 | Pervone vincamine injection and preparation process thereof |
| 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 |
| CN102311432B (en) * | 2011-08-26 | 2012-10-17 | 贺金凤 | Stable vinpocetine compound and pharmaceutical composition thereof |
| CN102911171B (en) * | 2012-10-15 | 2015-03-04 | 绍兴民生医药有限公司 | Semisynthesis method of vinpocetine |
| CN102952128B (en) * | 2012-10-30 | 2015-01-21 | 河南中帅医药科技股份有限公司 | Refining method of vinpocetine |
| CN103910722B (en) * | 2013-01-07 | 2015-12-23 | 长春海悦药业有限公司 | A kind of Vinpocetine compound and preparation method thereof |
| CN103121998B (en) * | 2013-02-06 | 2015-03-04 | 北京康瑞达彤医药科技有限公司 | Vinpocetine compound and drug composition thereof |
| CN103304563A (en) * | 2013-06-17 | 2013-09-18 | 长沙理工大学 | Method for efficiently synthesizing vinpocetine from vincamine |
| CN103333166B (en) * | 2013-06-26 | 2016-07-06 | 上海交通大学 | The method utilizing solid acid alkali catalytic synthesis vinpocetine |
-
1991
- 1991-08-30 CN CN 91106219 patent/CN1033973C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875547A (en) * | 2011-07-15 | 2013-01-16 | 海南灵康制药有限公司 | Vinpocetine compound and its preparation method |
| CN102875547B (en) * | 2011-07-15 | 2015-05-27 | 海南灵康制药有限公司 | Vinpocetine compound and its preparation method |
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| Publication number | Publication date |
|---|---|
| CN1058966A (en) | 1992-02-26 |
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