Vinpocetine
- CAS No.: 42971-09-5
- Molecular Weight：350.45400
- Modify Date.: 2023-02-09 13:19
- Introduction: A calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) inhibitor
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1. Names and Identifiers
- 1.1 Name
- Vinpocetine
- 1.2 Synonyms
(3A,16A)-EBURNAMENINE-14-CARBOXYLIC ACID ETHYL ESTER (3α,16α)-Eburnamenine-14-carboxylic acid ethyl ester 3A,16A-APOVINCAMINIC ACID ETHYL ESTER CAVINTON EBURNAMENINE EBURNAMENINE-14-CARBOXYLIC ACID ETHYL ESTER Eburnamenine-14-carboxylic acid, ethyl ester, (3ξ,16α)- EINECS 256-028-0 Ethyl (3ξ,16α)-eburnamenine-14-carboxylate ETHYL APOVINCAMIN-22-OATE MFCD00211233 RGH-4405 VINPOCETIN
- 1.3 CAS No.
- 42971-09-5
- 1.4 CID
- 443955
- 1.5 EINECS(EC#)
- 256-028-0
- 1.6 Molecular Formula
- C22H26N2O2 (isomer)
- 1.7 Inchi
- InChI=1S/C22H26N2O2/c1-3-22-11-7-12-23-13-10-16-15-8-5-6-9-17(15)24(19(16)20(22)23)18(14-22)21(25)26-4-2/h5-6,8-9,14,20H,3-4,7,10-13H2,1-2H3/t20-,22+/m1/s1
- 1.8 InChkey
- DDNCQMVWWZOMLN-IRLDBZIGSA-N
- 1.9 Canonical Smiles
- CCC12CCCN3C1C4=C(CC3)C5=CC=CC=C5N4C(=C2)C(=O)OCC
- 1.10 Isomers Smiles
- CC[C@@]12CCCN3[C@@H]1C4=C(CC3)C5=CC=CC=C5N4C(=C2)C(=O)OCC
2. Properties
- 2.1 Density
- 1.28 g/cm3
- 2.1 Melting point
- 147-153ºC dec
- 2.1 Boiling point
- 419.5ºC at 760 mmHg
- 2.1 Refractive index
- 1.6500 (estimate)
- 2.1 Flash Point
- 207.5ºC
- 2.1 Precise Quality
- 350.19900
- 2.1 PSA
- 34.47000
- 2.1 logP
- 4.08620
- 2.1 Solubility
- DMSO: 5?mg/mL
- 2.2 Λmax
- 315nm(EtOH)(lit.)
- 2.3 Appearance
- White Crystalline Solid
- 2.4 Storage
- Ambient temperatures.
- 2.5 Color/Form
- Cryst.
- 2.6 pKa
- 7.87±0.60(Predicted)
- 2.7 Water Solubility
- 35.5 [ug/mL]
- 2.8 Stability
- Photosensitive
- 2.9 StorageTemp
- Sealed in dry,2-8°C
3. Use and Manufacturing
- 3.1 Methods of Manufacturing
- in 500l of reaction kettle sequentially added 200 L of anhydrous ethanol, Reaction raw material vincamine?50 kg, Catalyst Sodium ethoxide 3.0 kg then keep the system pH at about 14 and slowly raised temperature to 70 ° C and allow to react for 3 h. Thin layer chromatography monitoring of raw materials vincamine fully reacted. As the hydrolysis reaction is completed, the product is vincamine acid and dehydrated vincamine mixture. Continue in the same reactor, stirring and cooling below 10 ° C, adjusting ph to about 12 by adding glacial acetic acid then again raise the temperature to reflux and allowed to react for 2h. TLC analysis of vincamine acid point of not more than 5percent, as dehydration reaction is completed. Obtained a product of dehydrating vincamine acid. Continue in the same reactor, stirring down 10 ° C below then the addition of acetic anhydride 14.5 and the reaction of water was generated. Then added acetic acid? to adjust pH , stirred the reaction for 1h and system pH value was about 7. Then add concentrated sulfuric acid to adjust the pH value to about 2, and then heated to 65-75 ° C and allowed to react for 6-8 h. TLC analysis of raw materials dehydrated vincamine acid intermediate reaction completed and completed as ethyl esterification reaction. The reaction system was stirred and cooled below 10 ° C, adjust the pH to about 7 by adding 30percent of sodium hydroxide solution as vinpocetine synthesis steps to complete.. The synthesis step of vincristine ethanol solution into the concentrator, concentrated under reduced pressure recovery of ethanol. Then add 200L methylene chloride and 200L water, into the extraction tank for extraction and separation, dichloromethane extraction separation twice, the organic phase, dried with anhydrous sodium sulfate. And then transferred to the mixer with a mixer to recover dichloromethane to dry, get vinca cis-crude. Then add 450L of anhydrous ethanol to dissolve, fine filter, the filtrate into the crystallization tank with a concentrator. After evaporation of 300 L of ethanol under reduced pressure, the mixture was cooled to below 10 ° C for 2 h, filtered and dried to obtain 43.2 kg of vincristine and 86.4percent by weight. HPLC detection purity of 99.3percent, the external standard method measured content of 99.5percent.Example 6 While stirring, 3.80 kg of aprichengchun amine and 46 L of anhydrous ethanol were put into a 100 L reaction kettle, Heated to ethanol reflux, until the material is basically clear, Then add ethanol sodium ethanol solution 1.45L, The reaction was stirred at reflux for 1 hour. The sample was monitored by HPLC and the reflux was stopped when the starting apache amine content was 0.659percent (less than 3percent). With tap water cooled to about 40 , all solvents were removed under reduced pressure to obtain solid, and then re-added 46L of fresh ethanol, and then heated to reflux until clear, ethanol solution of sodium ethoxide 0.35L, and then refluxed reaction 30 minute. Re-monitoring, when the raw material apricot amine content less than 0.3percent immediately end the reaction. Add ethanol 40-60L, reflux and clear. With preheated to 60-70 D40 stainless steel porous quick filter hot filtered reaction solution to remove insoluble. The filtrate was transferred to a clean and dry 100L reactor, the material will precipitate, and then defrost after steamed some of the ethanol, control the remaining amount of ethanol in the reactor 35-43L. Under stirring, after about 10-12 hours of natural cooling to cool down to near normal temperature, and then open the jacket tap water and continue stirring for 2 hours aging crystallization. The material was drained, drained, and thoroughly rinsed with 6L × 2 portions of absolute ethanol, drained and dried to collect the filter cake, which was crude vinpocetine
- 3.2 Usage
- A calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) inhibitor
4. Safety and Handling
- 4.1 Symbol
- GHS07
- 4.1 Hazard Codes
- Xn
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- R22
- 4.1 Safety Statements
- S36
- 4.1 Hazard Declaration
- H302
- 4.1 RIDADR
- NONH for all modes of transport
- 4.1 Caution Statement
- P301 + P312 + P330
- 4.1 WGK Germany
- 3
- 4.1 RTECS
- JW4792000
- 4.1 Safety
-
Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion. Experimental teratogenic and reproductive effects. When heated to decomposition it emits toxic fumes of NOx.
Hazard Codes: 
Xn
Risk Statements: 22
22:? Harmful if swallowed?
Safety Statements: 36
36:? Wear suitable protective clothing?
WGK Germany: 3
RTECS: JW4792000
- 4.2 Specification
-
? Vinpocetinum , with CAS number of 42971-09-5, can be called Ethyl (+)-cis-apovincaminate ; Ethyl(+)-apovincaminate ; cis-Apovincaminic acid ethylester ; Apovincaminic acid ethyl ester ; (+)-cis-Apovincaminic acid ethyl ester ; 1H-Indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridine,eburnamenine-14-carboxylic acid deriv ; (+)-Apovincaminic acid ethyl ester . It is a?white crystalline solid,?Vinpocetinum (CAS NO.42971-09-5) is used as a vasodilator.
- 4.3 Toxicity
- LD50 in mice, rats (mg/kg): 534, 503 orally; 240, 133.8 i.p.; 58.7, 42.6 i.v. (Pálosi, Szporny), also reported as 161.2 mg/kg i.p. in mice (Cholnoky, Dmk)
5. MSDS
2.Hazard identification
2.1 Classification of the substance or mixture
Acute toxicity - Oral, Category 4
2.2 GHS label elements, including precautionary statements
| Pictogram(s) |  |
| Signal word | Warning |
| Hazard statement(s) | H302 Harmful if swallowed |
| Precautionary statement(s) | |
| Prevention | P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product. |
| Response | P301+P312 IF SWALLOWED: Call a POISON CENTER/doctor/\u2026if you feel unwell. P330 Rinse mouth. |
| Storage | none |
| Disposal | P501 Dispose of contents/container to ... |
2.3 Other hazards which do not result in classification
none
7. Synthesis Route
42971-09-5Total: 15 Synthesis Route
9. Other Information
- 9.0 Merck
- 14,9991
- 9.1 Cerebral Vasodilator
- Vinpocetine is a cerebrovascular expansion drug and has a relatively stronger function than Vincamine. It can selectively increase cerebral blood flow, enhance and improve brain oxygen supply, promote metabolism, enhance the capacity of deformation for red blood cells, reduce blood viscosity, inhibit platelet aggregation, improve tissue metabolism. Vinpocetine is mainly used in the treatment of cerebral infarction sequela, cerebral hemorrhage sequelae, cerebral arteriosclerosis, etc. It can also used in the treatment of retinal vascular sclerosis and blood vessel spasm, the elderly deafness, and dizziness.
Vinpocetine is a half synthetic Vincamine derivative, and has the similar effect with Vincamine. It has a stronger expansion function for cerebrovascular selectively. Pharmacological effects are as follows:
①Inhibit the activity of calcium dependency phosphodiesterase, increase the content of cAMP which can relax vascular smooth muscle, then relax vascular smooth muscle, and further increase cerebral blood flow.
②Enhance the capacity of deformation of red blood cells, reduce blood viscosity, inhibit platelet aggregation, and thus improve blood flow and microcirculation.
③Promote the brain tissue to absorb glucose, and promote the transformation of brain monoamine metabolism.
④Inhibit the increase of brain lactic acid during cerebral ischemia, increase the ATP content, inhibit the generation of lipid peroxide in the brain, delay the occurring of spasm caused by cerebral ischemia, have the function of improving cerebral metabolism and protecting brain.
Figure 1 is the structural formula of vinpocetine.
- 9.2 Pharmacokinetics
- Vinpocetine is of high fat-solubility, easy to be absorbed by the organization, and widely distributed. It can through the blood brain barrier, mainly metabolism to Vinpocetine in the liver, and be excreted by the kidney.
- 9.3 Medicinal properties and Application
- Vinpocetine is also called Ethyl apovincaminate, Conway, Karan and Vinpocetine. It is a kind of natural medicine extracted from small vinca flower, and belongs to the indole alkaloids. Can be synthetic now. The mechanism of its pharmacological action is to inhibit the activity of calcium dependency phosphodiesterase, increase the content of CGMP which can relax vascular smooth muscle, then relax vascular smooth muscle, and further increase cerebral blood flow; Enhance the capacity of deformation of red blood cells, reduce blood viscosity, inhibit platelet aggregation, and thus improve blood flow and microcirculation; Promote the brain tissue to absorb glucose, and promote the transformation of brain monoamine metabolism; Inhibit the increase of brain lactic acid during cerebral ischemia, increase the ATP content, increase thedegree of oxygen dissociation in hemoglobin; Increase the resistance capacity for cerebral anoxia and occurring of spasm caused by cerebral ischemia, inhibit the generation of lipid peroxide in the brain. Oral absorption effectively, reach peak at 1 h, then metabolize into Vinpocetine in the body. The half-life of plasma elimination is about 1 hour. For 4 weeks in a row, no accumulation in the body. Clinical used in cerebral infarction sequela, cerebral hemorrhage sequelae, cerebral arteriosclerosis, cerebral vasospasm, brain endarteritis caused vertigo, tinnitus, headache, dizziness, limb numbness, incontinence and other clinical manifestations, depression, anxiety, sleep disorder and other mental symptoms. Clinical experience has shown that it is effective regardless of the length of the course of the disease, and the symptom is fixed or not.
- 9.4 Indications
- 1.Neurology: all kinds of cerebrovascular disease and its sequelae.
2.Cardiology: coronary heart disease, hardening of the arteries and blood clotting abnormalities, etc.
3.Eye: all kinds of views of visual impairment caused by poor circulation, etc.
4.Otolaryngology: hearing loss, tinnitus, vestibular dysfunction, etc.
5.Neurosurgery: all kinds of craniocerebral surgery back function rehabilitation.
- 9.5 Side Effects
- Nervous system: head heavy, dizziness, occasional tiredness and side limb numbness, etc.
Digestive system: nausea, vomiting, loss of appetite, abdominal pain, diarrhea, etc.
Circulatory system: facial blushing, dizziness and other symptoms.
Blood system: white blood cells reduction.
Liver reaction: AST, ALT elevations, rare elevation of alkaline phosphatase.
Kidney reaction: blood urea nitrogen increasing.
Sometimes allergic reactions like skin rash, urticarial and pruritus may appear, then drug should be discontinued. Occasional mild lowering blood pressure, tachycardia, etc.
- 9.6 Chemical Properties
- White crystal powder, odourless and tasteless. Soluble in chloroform or 96% ethanol, insoluble in water. The melting point is 147-147 oC (decomposition). [α]D20+114°(C=1，pyridine). UV maximum absorption (96% ethanol): 229,275,315 nm (ε28200120, 00710). Acute toxicity LD50 in mice and rats (mg/kg): 534503 oral; 240133.8 intraperitoneal injection; 58.7, 42.6 intravenous injection.
- 9.7 Usage
- Cerebrovascular drug. A alkaloid extracted from apocynaceae plant, Vincamine derivatives. Selectively inhibit vascular smooth muscle calcium dependency phosphodiesterase, and increase the content of cGMP, expanse cerebral vascular, which in turn increase cerebral blood flow, improve cerebral circulation, but has little effects on the cardiovascular and blood pressure. Effectively, good tolerance, less adverse reaction. Used for dizziness, headache, memory disorders, movement disorder, aphasia, hypertensive encephalopathy, etc.. Can also be used in brain blood circulation obstacle caused by mental or neurological symptoms.
This information is edited by Xiao Nan.
- 9.8 Production Method
- Vincamine extracted from small periwinkle (Vinca mino) of apocynaceae plant as raw material, dehydration to Apovincamine, then hydrolysis to Apovincaminic acid. Dissolved the acid (1.0 g, 0.003 mo1) and 1.0 g of potassium hydroxide in 80 ml of drying ethanol, add bromine ethane (0.4 g, 0.0036 mol), reflux 3 h. After the completion of reaction, cooling, evaporation to dry. Dissolve the leftovers in 500 ml of 2% sulfuric acid, and adjust the Ph to 8. Extracted with methylene chloride, drying with potassium carbonate, after the majority of methylene chloride has been evaporated, add in ethanol. Be placed overnight At 0 oC, filter the collected precipitation crystallization, washing with cold ethanol, drying, 0.66 g of Vinpocetine could be obtained. Tabersonine extracted from apocynaceae plant willow small licorice leaf or periwinkle seed can also be as raw material, through multi-step synthesis.
- 9.9 Chemical Properties
- White Crystalline Solid
- 9.10 Uses
- A calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) inhibitor
- 9.11 Uses
- A derivative of Vincamine with vasodilating activity. Vasodilator (cerebral).
- 9.12 Uses
- calcium regulator
- 9.13 Uses
- Gleevec metabolite, tyrosine kinase inhibitor
- 9.14 Biological Activity
- Phosphodiesterase inhibitor, selective for PDE1 (IC 50 = 21 μ M). Also blocks voltage-gated Na + channels.
- 9.15 Biochem/physiol Actions
- Ca2+-calmodulin-dependent phosphodiesterase I (PDE1) inhibitor.
- 9.16 Storage Conditions
- in 500l of reaction kettle sequentially added 200 L of anhydrous ethanol, Reaction raw material vincamine?50 kg, Catalyst Sodium ethoxide 3.0 kg then keep the system pH at about 14 and slowly raised temperature to 70 ° C and allow to react for 3 h. Thin layer chromatography monitoring of raw materials vincamine fully reacted. As the hydrolysis reaction is completed, the product is vincamine acid and dehydrated vincamine mixture. Continue in the same reactor, stirring and cooling below 10 ° C, adjusting ph to about 12 by adding glacial acetic acid then again raise the temperature to reflux and allowed to react for 2h. TLC analysis of vincamine acid point of not more than 5percent, as dehydration reaction is completed. Obtained a product of dehydrating vincamine acid. Continue in the same reactor, stirring down 10 ° C below then the addition of acetic anhydride 14.5 and the reaction of water was generated. Then added acetic acid? to adjust pH , stirred the reaction for 1h and system pH value was about 7. Then add concentrated sulfuric acid to adjust the pH value to about 2, and then heated to 65-75 ° C and allowed to react for 6-8 h. TLC analysis of raw materials dehydrated vincamine acid intermediate reaction completed and completed as ethyl esterification reaction. The reaction system was stirred and cooled below 10 ° C, adjust the pH to about 7 by adding 30percent of sodium hydroxide solution as vinpocetine synthesis steps to complete.. The synthesis step of vincristine ethanol solution into the concentrator, concentrated under reduced pressure recovery of ethanol. Then add 200L methylene chloride and 200L water, into the extraction tank for extraction and separation, dichloromethane extraction separation twice, the organic phase, dried with anhydrous sodium sulfate. And then transferred to the mixer with a mixer to recover dichloromethane to dry, get vinca cis-crude. Then add 450L of anhydrous ethanol to dissolve, fine filter, the filtrate into the crystallization tank with a concentrator. After evaporation of 300 L of ethanol under reduced pressure, the mixture was cooled to below 10 ° C for 2 h, filtered and dried to obtain 43.2 kg of vincristine and 86.4percent by weight. HPLC detection purity of 99.3percent, the external standard method measured content of 99.5percent.Example 6 While stirring, 3.80 kg of aprichengchun amine and 46 L of anhydrous ethanol were put into a 100 L reaction kettle, Heated to ethanol reflux, until the material is basically clear, Then add ethanol sodium ethanol solution 1.45L, The reaction was stirred at reflux for 1 hour. The sample was monitored by HPLC and the reflux was stopped when the starting apache amine content was 0.659percent (less than 3percent). With tap water cooled to about 40 , all solvents were removed under reduced pressure to obtain solid, and then re-added 46L of fresh ethanol, and then heated to reflux until clear, ethanol solution of sodium ethoxide 0.35L, and then refluxed reaction 30 minute. Re-monitoring, when the raw material apricot amine content less than 0.3percent immediately end the reaction. Add ethanol 40-60L, reflux and clear. With preheated to 60-70 D40 stainless steel porous quick filter hot filtered reaction solution to remove insoluble. The filtrate was transferred to a clean and dry 100L reactor, the material will precipitate, and then defrost after steamed some of the ethanol, control the remaining amount of ethanol in the reactor 35-43L. Under stirring, after about 10-12 hours of natural cooling to cool down to near normal temperature, and then open the jacket tap water and continue stirring for 2 hours aging crystallization. The material was drained, drained, and thoroughly rinsed with 6L × 2 portions of absolute ethanol, drained and dried to collect the filter cake, which was crude vinpocetine
- 9.17 Mesh
- Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)|Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. (See all compounds classified as Neuroprotective Agents.)|Drugs used to specifically facilitate learning or memory, particularly to prevent the cognitive deficits associated with dementias. These drugs act by a variety of mechanisms. (See all compounds classified as Nootropic Agents.)|Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. (See all compounds classified as Phosphodiesterase Inhibitors.)
- 9.18 Usage
- Specific calcium-calmodulin-dependent phosphodiesterase inhibitor
10. Computational chemical data
- Molecular Weight: 350.45400g/mol
- Molecular Formula: C22H26N2O2
- Compound Is Canonicalized: True
- XLogP3-AA: 4.1
- Exact Mass: 350.199428076
- Monoisotopic Mass: 350.199428076
- Complexity: 617
- Rotatable Bond Count: 4
- Hydrogen Bond Donor Count: 0
- Hydrogen Bond Acceptor Count: 3
- Topological Polar Surface Area: 34.5
- Heavy Atom Count: 26
- Defined Atom Stereocenter Count: 2
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADceB7MAAAAAAAAAAAAAAAAAAAAWAAAAA8WIEAAAAAAFix8AAAHgAAAAAADijhngYyyPMMFACoAyTyTACCgCAhAiAImCC4ZNgKZOLAsbGXMAhggADY6YcQgMAPgAAAAAACAAAAAAAAAAQAAAAAAAAAAA==
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