4880-92-6

Usage

Uses

Used in Pharmaceutical Industry:
Apovincamine is used as a chemical precursor for the synthesis of Vinpocetine, a vasodilator with applications in treating conditions related to impaired blood flow in the brain. Its role in the production of Vinpocetine makes it a crucial component in the development of medications aimed at enhancing cerebral circulation and potentially improving cognitive function.
Used in Cerebral Vasodilation:
Apovincamine is used as a vasodilator for promoting blood flow in the cerebral region. Its vasodilating properties help in increasing the diameter of blood vessels, which can lead to improved oxygen and nutrient delivery to the brain. This application is particularly relevant for conditions where enhanced blood flow to the brain is desired, such as in cases of stroke, cognitive decline, or other neurological disorders.

Originator

Apovincamine,GC Promochem

Manufacturing Process

Apovincamine is semisynthethetic derivative of (+)-vincamine. Vincamine is alkaloid of Vinca minor. Alcoloid of Tabernaemontana rigida (Apocynaceae) also is used as raw material for preparing of apovincamine. (+)- Vincamine was transformed into oxime ester by reaction with NaNO2 in acetic acid at 0°C -(+/-)-methyl-3-((12bR)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3- a]quinolizin-1-yl)-2-(hydroxyimino)propanoate, which was resolved on the isomers with dibenzoyl D-tartratic acid. (-)-Methyl 3-((12bR)-1-ethyl- 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl)-2- (hydroxyimino)propanoate was re-crystallized from methanol to afford (-)- methyloxime ester, MP: 195°C. 2 g of above oxime methyl ester was heated in mixture of methanol (37.5 ml) and conc. H2SO4 (13.5 ml) on water bath for 1 hour. The solution was poured into ice-water (80 ml), basified with conc. NH4OH to pH 9, and extracted with CH2Cl2 (3x20 ml). The combined extracts were dried (MgSO4), filtered, evaporated in vacuum and the residue was re-crystallized from MeOH (5 ml) to yield 1.32 g (72.5%) of (+)-apovincamine, MP: 160°-162°C.

Therapeutic Function

Vasodilator

InChI:InChI=1/C21H24N2O2/c1-3-21-10-6-11-22-12-9-15-14-7-4-5-8-16(14)23(18(15)19(21)22)17(13-21)20(24)25-2/h4-5,7-8,13,19H,3,6,9-12H2,1-2H3/t19-,21+/m1/s1

Upstream product

• 55872-13-4 (-)-criocerine 
• 67-56-1 methanol 
• 82398-60-5 (3S,17S)-14-oxo-15-hydroxyimino-E-homoeburnane 
• 66113-74-4 hydroxy-16 dehydro-1 vincadifformine 
• 6835-99-0 14-epivincamine 
• 3389-21-7 3-(2-bromoethyl)-1H-indole 
• 79228-18-5 (10R,11R,11aS,11bR)-11a-Ethyl-11-hydroxy-2,3,4,5,10,11,11a,11b-octahydro-1H-3a,9b-diaza-benzo[cd]fluoranthene-10-carboxylic acid methyl ester 
• 68796-67-8 1-propyl-4,9-dihydro-3H-pyrido<3,4-b>indole 
• 55390-29-9 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolizinium perchlorate 
• 66685-08-3 1-ethyl-2,3,4,6,7,12-hexahydroindolo<2,3-a>quinolizin-4(1H)-one 
• 51152-47-7 (1R*,5S*,12bS*)-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo<2,3-a>quinolizine-1-carbaldehyde 
• 1617-90-9 vincamin 
• 89396-77-0 3-((1S,12bS)-1-Ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizin-1-yl)-2-[(E)-hydroxyimino]-propionic acid methyl ester 
• 70154-93-7 (-)-14-hydroxyamino-14-methoxycarbonyl-eburnan 

Downstream Products

• 27773-65-5 Apovincaminic acid 
• 42971-09-5 Vinpocetine 
• 21019-23-8 (3S,16S,14R)-14-deoxyvincamine 
• 21019-24-9 (3S,16S,14S)-14-deoxyvincamine 
• 95407-52-6 apovincaminic acid methyl mandelate ester 
• 21019-23-8 deoxyvincamine 
• 65825-92-5 6-ketoapovincamine 
• 23173-27-5 (13a-ethyl-2,3,5,6,12,13,13a,13b-octahydro-1H-indolo[3,2,1-de]pyrido[3,2,1-ij][1,5]naphthyridin-12-yl)-methanol 

Relevant academic research and scientific papers

Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity

Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.

Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic β-cells protective agents for the treatment of type 2 diabetes mellitus

A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic β-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic β-cells protective activities and five derivatives were found to exhibit 20–50-fold higher activities than vincamine. Especially for compounds Vin-C01 and Vin-F03, exhibited a remarkable EC50 value of 0.22 μM and 0.27 μM, respectively. Their pancreatic β-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compounds Vin-C01 and Vin-F03 could effectively promote β-cell survival and protect β-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent β-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compounds Vin-C01 and Vin-F03 were two more potent pancreatic β-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.

Pervone derivative and purpose thereof to treatment of diabetes B

The invention relates to the field of medicinal chemistry, in particular to a derivative shown as a general formula (I) and a purpose of a medicine composition containing the derivative to preparationof medicine for treating diabetes B. The compound has the effect of preventing pancreatic island beta cell apoptosis and can be used for treating the diabetes B. The general formula (I) is shown in the description.

ANALOGS OF VINCAMINE AND USES THEREOF

The present disclosure provides compounds of any one of Formulae (I'), (I), (IA), (II'), (II), (IIA), (IIIA), (III"), (III'), (III), (IIIA), (IV), (V'), (V), (VI), (VII), (VIII'), (VIII), (ΙΧ'), (IX), and (X). The compounds described herein may be useful in treating and/or preventing a broad range of diseases (e.g., proliferative disease (e.g., cancers (e.g., non-small cell lung cancer, or glioma), inflammatory diseases, autoimmune diseases), CNS disorder (e.g., drug addiction), metabolic disorder (e.g., diabetes), or infectious disease (e.g., bacterial infection or parasitic infection (e.g., malaria))). Also provided in the present disclosure are pharmaceutical compositions, methods of synthesis of a compound described herein, kits, methods, and uses including or using a compound described herein.

Method for preparing vinpocetine

The invention relates to a method for preparing a compound, specifically to a method for preparing vinpocetine. The method comprises the following steps: 1) preparation of a vinpocetine crude product, including, mixing an apovincamine ethanol solution and a sodium ethoxide ethanol solution for a reflux reaction, removing the solvent, adding ethanol, carrying out a reflux reaction of the sodium ethoxide ethanol solution, when the residual content of apovincamine is less than 0.3% of the added apovincamine raw material, performing hot filtration, removing a part of solvent of the filtered liquid, and performing cooling crystallization, solid-liquid separation, washing and drying to obtain the vinpocetine crude product; and 2) refining of vinpocetine, including adding active carbon, performing hot filtration, and performing recrystallization with ethanol for refining to obtain vinpocetine. The method is short and simple in process. The prepared vinpocetine is high in yield and purity, meets the standard of the European Pharmacopoeia (EP) 6.0, and is easy for industrial production.

Studies on the synthesis, structural characterization, Hirshfeld analysis and stability of apovincamine (API) and its co-crystal (terephthalic acid: Apovincamine = 1:2)

Apovincamine and the corresponding co-crystal have been synthesized and characterized by single crystal XRD, FT-IR, UV, TGA/DSG. Components of the crystalline phase have also been investigated in terms of their corresponding Hirshfeld surface. In the crystal lattice, a three-dimensional hydrogen-bonded network is observed in the co-crystal, including the formation of a two-dimensional molecular scaffold. Hirshfeld surfaces and fingerprint plots indicate that the structures are stabilized by H???H, C-H???π, C-H???O and O-H???N intermolecular interactions. In this work, the co-crystal strategy has been applied successfully to apovincamine. One important parameter, i.e. solubility in water, has also been significantly improved, which proves to be an important factor for bioavailability. Furthermore, DSC/TGA analysis indicates that the co-crystal maintains its crystallinity up to 200 °C, suggesting a higher stability of the co-crystal compared to apovincamine.

Process for the preparation of vinpocetine and apovincamine

A process for the preparation of vinpocetine and apovincamine, wherein said process comprises the steps of: (1) preparing a solution of the compound of formula (II) below and an organic or inorganic base in a polar aprotic solvent, and (2) adding an alkyl haloacetate to the solution of step (1) under controlled temperature conditions.

Synthesis of vinca alkaloids and related compounds. Part 97. Epimerization with the aid of iodine

(-)-15β-Hydroxy-14,15-dihydroeburnamenine (6) has been epimerized at the C(3) position with the aid of iodine. Octahydroindoloquinolizine derivatives containing hydroxyl group (11, 14, 17) gave the appropriate epimeric alcohols (13,16, 19) via pentacyclic intermediates (12, 15, 18).

Asymmetric Total Synthesis of (+)-Apovincamine and a Formal Synthesis of (+)-Vincamine. Demonstration of a Practical "Asymmetric Linkage" between Aromatic Carboxylic Acids and Chiral Acyclic Substrates

Asymmetric syntheses of (+)-apovincamine (la) and (+)-vincamine (2) are described. Construction of the pentacyclic diene lactam 14, a pivotal intermediate for synthesis of the cis-fused vincane-type alkaloids, began by Birch reduction - alkylation of the chiral benzamide 3 to give the 6-ethyl-l-methoxy-4-methyl-l,4-cyclohexadiene 4. Conversion of 4 to 2,5-cyclohexadienone 5 (92percent overall yield from 3) and HPLC analysis of 5 demonstrated the diastereomeric purity resulting from the Birch reduction - alkylation to be > 100:1. Dienone 5 was converted to butyrolactone 9 (47percent overall yield from 3), and 9 was coupled with tryptamine (10) to give the amide lia. Amido keto aldehyde 13 was obtained from 11a, and acid-catalyzed tricyclization and subsequent base-induced elimination of MeOH provided the desired cis-fused pentacyclic diene lactam 14. Examination of the two-step process 13 -14 revealed a novel base-induced epimerization at C(21) which served to interconvert 14 and 17, possibly by the involvement of a homoenolate. Diene lactam 14 was converted to (+)-apovincaminal 20a, an intermediate in the synthesis of (+)-apovincamine (la) reported by Winterfeldt and co-workers. A new procedure for conversion of 20a to la involves conversion of 20a to the acetal 20b and treatment of 20b with NBS/AIBN in CCl4. The conversion of la to vincamine (2) has been reported by Oppolzer and co-workers.

A facile one-pot synthesis of vinpocetine

A one-pot synthesis of vinpocetine from vincamine was established. Lewis acids caused transesterification and/or dehydration of vincamine in EtOH. FeCl3 catalyzed both transesterification and dehydration while Ti(OEt)4 selectively catalyzed transesterification.