CN102702191A - Synthesis method of vinpocetine - Google Patents
Synthesis method of vinpocetine Download PDFInfo
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- CN102702191A CN102702191A CN2012101515595A CN201210151559A CN102702191A CN 102702191 A CN102702191 A CN 102702191A CN 2012101515595 A CN2012101515595 A CN 2012101515595A CN 201210151559 A CN201210151559 A CN 201210151559A CN 102702191 A CN102702191 A CN 102702191A
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- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 title claims abstract description 38
- 229960000744 vinpocetine Drugs 0.000 title abstract description 6
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 238000003756 stirring Methods 0.000 claims abstract description 20
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000005457 ice water Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 8
- 229960002726 vincamine Drugs 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 6
- 230000001105 regulatory effect Effects 0.000 claims abstract description 5
- 235000019441 ethanol Nutrition 0.000 claims abstract description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract 3
- 238000004821 distillation Methods 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 0 CCC1(C(OC)=O)[n]2c(cccc3)c3c(CC[*+]3C(Cc4c(*5C6=C7CCN(CCC8)[C@]6[C@]8(CC)CCC[C@]5C(OC)=O)c7ccc4)CC4)c2[C@@]3[C@]4(C*)C1 Chemical compound CCC1(C(OC)=O)[n]2c(cccc3)c3c(CC[*+]3C(Cc4c(*5C6=C7CCN(CCC8)[C@]6[C@]8(CC)CCC[C@]5C(OC)=O)c7ccc4)CC4)c2[C@@]3[C@]4(C*)C1 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000002087 Endarteritis Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 241000863480 Vinca Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940088033 calan Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 201000009939 hypertensive encephalopathy Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- -1 vinpocetin compound Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of vinpocetine, comprising the following steps: adding vincamine into a three-opening bottle, subsequently, adding methylbenzene, stirring and dropwise adding triethylamine and methylsufonyl chloride in an ice-water bath, slowly heating to room temperature after stirring for 2 h, then continuously stirring for 5 h; stopping reaction, drying solvent by distillation, adding ethanol and water, regulating pH to 12 with saturated potassium carbonate solution, separating out solids, filtering, and drying in vacuum to obtain vinpocetine intermediate; adding absolute ethyl alcohol into the three-opening bottle, stirring in ice-water bath for 1 h, then slowly adding sodium ethoxide, stirring for 0.5 h, then adding the vinpocetine intermediate, subsequently, putting a reaction bottle into an oil bath, setting temperature as 80 degrees centigrade, evaporating most of solvent after reacting for 12 h, then pouring solution into hydrochloric acid, extracting with ethyl acetate, regulating pH to 12 with water phase, separating out solids, filtering and drying to obtain the vinpocetine. According to the synthesis method provided by the invention, reaction steps are short; purity and yield of products are high; energy consumption is low; and environmental pollution is less.
Description
Technical field
The present invention relates to compound method, be specifically related to a kind of compound method of vinpocetin.
Technical background
Vinpocetin (Vinpocetine) be the VALLESIACOTAMIN vincamine that from the Apocynaceae periwinkle, extracts through structure of modification gained verivate, be a kind of good cerebrovascular disease medicament.Vinpocetin has the increase ED; Can improve blood fluidity and microcirculation improvement; Reduce blood viscosity and suppress the platelet aggregation effect, and have the supply of promoting and improving brain oxygen, can optionally increase cerebral lesion RBF and improve the brain metabolism.Be widely used in clinically abroad that ischemia hypertensive encephalopathy, cerebral arteriosclerosis, cerebral ischaemia, intermittent cerebral blood flow are under-supply, treatment of diseases such as cerebral vasospasm, early stage cerebral endarteritis, cerebral embolism, cerebral thrombosis, dizzy, aphasia, Meniere syndrome, and effects such as the memory of improvement, eyesight and old hearing are arranged.
Because vinpocetin is treated cerebrovascular disease clinically curative effect is preferably arranged, and has unique pharmacological action, receive domestic and international relevant expert's attention always.The preparation method of vinpocetin, useful chemical process is carried out complete synthesis, and it is also useful that from the plant that contains vincamine, to extract vincamine be that raw material carries out semisynthetic method.Contrast two kinds of methods, semi-syntheticly have that synthetic route is short, yield is high, simple ripe, a advantage that cost is low of technology, produce that vinpocetin adopts semi-synthetic route more both at home and abroad.The Mondelo patent report be raw material with the Changchun amino acid, acetonitrile is made solvent, 2-fluoro-1,3; The 5-trinitrobenzene is made catalyzer, the synthetic vinpocetin that obtains, and this method yield is high, but catalyzer is rare; Difficult realization industriallization, and it is very big to make solvent toxicity with acetonitrile, not environmental protection.Kuge etc. utilize vincamine to be raw material, obtain Calan through Ti (OEt) 4 catalysis transesterifications, obtain vinpocetin through the methanesulfonic acid catalyzed dehydration again, and this method is that the scale operation of vinpocetin provides thinking, but total recovery is not high.
Summary of the invention
The objective of the invention is to: a kind of vinpocetin compound method is provided, and route is simple, and yield is high, and foreign matter content is few, pollutes little.
Technical solution of the present invention is: the chemical structural formula of this vinpocetin is:
.
Wherein, the synthetic route of vinpocetin is:
Wherein, the concrete synthetic route of vinpocetin is:
Wherein, the concrete steps of the synthetic route of vinpocetin are:
The first step: (500g 1.41mol) adds in the there-necked flask of 5L, adds toluene (2L) subsequently with the raw material vincamine; In ice-water bath, stir, and the dropping triethylamine (244.4g, 2.42mol); Slowly drip Methanesulfonyl chloride (176.8g after 10 minutes; 1.55mol), stir after 2 hours in the ice-water bath and slowly be warming up to room temperature, continue again to stir 5 hours; The point plate detects, and raw material transforms fully, termination reaction, directly solvent evaporated; Add second alcohol and water (2000ml:200ml), regulate PH=12 with the unsaturated carbonate potassium solution, have a large amount of solids to separate out direct filtration this moment; Vacuum-drying obtains the vinpocetin midbody, and its reaction formula is following:
；
Second step: absolute ethyl alcohol (3L) is joined in the there-necked flask of 5L, and (180g 2.66mol), stirs adding vinpocetin midbody (578.6g after 0.5 hour in ice-water bath, to stir slow adding sodium ethylate after 1 hour; 1.33mol), subsequently reaction flask being positioned in the oil bath, it is 80 ℃ that temperature is set; React and steam most of solvent after 12 hours, then with solution pour into hydrochloric acid (4mol/L, 800ml) in; With ETHYLE ACETATE 500ml extraction, water is regulated pH value=12, has a large amount of solids to separate out; Filtration drying obtains vinpocetin, and its reaction formula is following:
The reactions step of compound method of the present invention is short, and product purity and yield are high, and energy consumption is low, and environmental pollution is little.
Embodiment
Further specify technical solution of the present invention below in conjunction with embodiment, embodiment can not be interpreted as it is the restriction to technical scheme.
Embodiment:
The first step: (500g 1.41mol) adds in the there-necked flask of 5L, adds toluene (2L) subsequently with the raw material vincamine; In ice-water bath, stir, and the dropping triethylamine (244.4g, 2.42mol); Slowly drip MsCl (176.8g after 10 minutes; 1.55mol), stir after 2 hours in the ice-water bath and slowly be warming up to room temperature, continue again to stir 5 hours; The point plate detects, and raw material transforms fully, termination reaction; Directly solvent evaporated adds second alcohol and water (2000ml:200ml), regulates PH=12 with the unsaturated carbonate potassium solution; Have a large amount of solids to separate out this moment, direct filtration, vacuum-drying; Obtain the vinpocetin midbody (578.6g, 1.33mol), yield reaches 95%;
Second step: absolute ethyl alcohol (3L) is joined in the there-necked flask of 5L, and (180g 2.66mol), stirs adding vinpocetin midbody (578.6g after 0.5 hour in ice-water bath, to stir slow adding sodium ethylate after 1 hour; 1.33mol), subsequently reaction flask being positioned in the oil bath, it is 80 ℃ that temperature is set, and reacts to steam most of solvent after 12 hours; Then with solution pour into hydrochloric acid (4mol/L, 800ml) in, with ETHYLE ACETATE 500ml extraction, water is regulated pH value=12; Have a large amount of solids to separate out, filtration drying, obtain vinpocetin (353g, 1.01mol); Product purity 99%, total recovery 71% need not recrystallization, reaches European standard EP7.0.
The structural identification data of the vinpocetin of embodiment are following:
1H NMR (CDC13,300MHz) δ (ppm); 7.50 (d, lH,
J =5.9Hz), 7.28 (d, IH,
J =4.9Hz), 7.17 (m, 2H), 6.16
(s,LH), 4.49 (m, 2H), 4.18
(s,LH), 3.40-1.50 (12H), 1.44 (t, 3H,
J= 7.1Hz), 1.03 (t, 3H,
J= 7.5Hz).IR?(KBr)?v?max:1720,?1630,?1605,?1455,?1080,?748?cm
-1。
Claims (4)
1. the compound method of vinpocetin is characterized in that the chemical structural formula of this vinpocetin is:
.
2. the compound method of vinpocetin according to claim 1 is characterized in that the synthetic route of vinpocetin is:
.
3. the compound method of vinpocetin according to claim 2 is characterized in that the concrete synthetic route of vinpocetin is:
4. the compound method of vinpocetin according to claim 3 is characterized in that the concrete steps of the synthetic route of vinpocetin are:
The first step: (500g 1.41mol) adds in the there-necked flask of 5L, adds toluene (2L) subsequently with the raw material vincamine; In ice-water bath, stir, and the dropping triethylamine (244.4g, 2.42mol); Slowly drip Methanesulfonyl chloride (176.8g after 10 minutes; 1.55mol), stir after 2 hours in the ice-water bath and slowly be warming up to room temperature, continue again to stir 5 hours; The point plate detects, and raw material transforms fully, termination reaction, directly solvent evaporated; Add second alcohol and water (2000ml:200ml), regulate PH=12 with the unsaturated carbonate potassium solution, have a large amount of solids to separate out direct filtration this moment; Vacuum-drying obtains the vinpocetin midbody, and its reaction formula is following:
；
Second step: absolute ethyl alcohol (3L) is joined in the there-necked flask of 5L, and (180g 2.66mol), stirs adding vinpocetin midbody (578.6g after 0.5 hour in ice-water bath, to stir slow adding sodium ethylate after 1 hour; 1.33mol), subsequently reaction flask being positioned in the oil bath, it is 80 ℃ that temperature is set, and reacts after 12 hours; Steam most of solvent, then with solution pour into hydrochloric acid (4mol/L, 800ml) in; With ETHYLE ACETATE 500ml extraction, water is regulated pH value=12, has a large amount of solids to separate out; Filtration drying obtains vinpocetin, and its reaction formula is following:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210151559.5A CN102702191B (en) | 2012-05-16 | 2012-05-16 | Synthesis method of vinpocetine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210151559.5A CN102702191B (en) | 2012-05-16 | 2012-05-16 | Synthesis method of vinpocetine |
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| Publication Number | Publication Date |
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| CN102702191A true CN102702191A (en) | 2012-10-03 |
| CN102702191B CN102702191B (en) | 2014-05-07 |
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|---|---|---|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911171A (en) * | 2012-10-15 | 2013-02-06 | 绍兴民生医药有限公司 | Semisynthesis method of vinpocetine |
| CN102952128A (en) * | 2012-10-30 | 2013-03-06 | 河南中帅医药科技发展有限公司 | Refining method of vinpocetine |
| CN103265541A (en) * | 2013-06-17 | 2013-08-28 | 长沙理工大学 | Synthetic method of vinpocetine intermediate |
| CN103554102A (en) * | 2013-11-22 | 2014-02-05 | 长沙理工大学 | Simple synthetic method of vinpocetine |
| CN103664934A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Preparation method for vinpocetine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10311850A1 (en) * | 2003-03-17 | 2004-09-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparation of vinpocetin used as vasodilator and nootropic agent, comprises dehydrating vincamine ester to apovincamine derivative and transesterifying |
-
2012
- 2012-05-16 CN CN201210151559.5A patent/CN102702191B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10311850A1 (en) * | 2003-03-17 | 2004-09-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Preparation of vinpocetin used as vasodilator and nootropic agent, comprises dehydrating vincamine ester to apovincamine derivative and transesterifying |
Non-Patent Citations (1)
| Title |
|---|
| 姜华等: "长春西汀的半合成工艺", 《暨南大学学报（自然科学版）》》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911171A (en) * | 2012-10-15 | 2013-02-06 | 绍兴民生医药有限公司 | Semisynthesis method of vinpocetine |
| CN102911171B (en) * | 2012-10-15 | 2015-03-04 | 绍兴民生医药有限公司 | Semisynthesis method of vinpocetine |
| CN102952128A (en) * | 2012-10-30 | 2013-03-06 | 河南中帅医药科技发展有限公司 | Refining 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 |
| CN103265541A (en) * | 2013-06-17 | 2013-08-28 | 长沙理工大学 | Synthetic method of vinpocetine intermediate |
| CN103554102A (en) * | 2013-11-22 | 2014-02-05 | 长沙理工大学 | Simple synthetic method of vinpocetine |
| CN103664934A (en) * | 2013-12-06 | 2014-03-26 | 湖南科源生物制品有限公司 | Preparation method for vinpocetine |
| CN103664934B (en) * | 2013-12-06 | 2015-10-28 | 湖南科源生物制品有限公司 | A kind of preparation method of vinpocetin |
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| Publication number | Publication date |
|---|---|
| CN102702191B (en) | 2014-05-07 |
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