Apovincamine

C 4H ( 0 90-44-8) see Maprotiline Melitracen 3-(9-anthryl)proplonic acid (C17H14O2 47034-S3-7) see Maprotiline (-H)-apovincamine... 

Apovincaminic acid ethylester was supplied by Richter Gedeon Co., (-)-dihydroapovincaminic acid ethyl ester was prepared according to the procedure described in (11). fSj-a, -diphcnyl-2-py rro 1 idincmethanol was synthesised as described (12). 2-benzylidene-l-benzosuberone was prepared as described in (13). Isophorone was supplied by Merck. Cinchonidine was purchased from Fluka. 

Solti F, Iskum M and Czako E (1976). Effect of ethyl apovincaminate on the cerebral circulation Studies in patients with obliterative cerebral arterial disease. Arzneimittelforschung, 26, 1945-1947. 

L-Asparagine was used for the synthesis of chiral pipecolates, building blocks for the alkaloid apovincamine. The iodo compound, formed in a multistep transformation from L-asparagine, was cyclized with LDA and ethyl iodide to give the pyridine derivative with a defined configuration (Scheme 36) (85JOC1239). 

Chemical Name Eburnamenine-14-carboxylic acid methyl ester, (3a, 16a)-Common Name Apovincamine Structural Formula ... 

Vinca minor, cultivated in Georgia, USSR, has been shown to contain ( )-vincadifformine and vincine, both already known to occur in this species, together with apovincamine and 11-methoxyvincadifformine.92 Voaphylline, voaphylline hydroxyindolenine, and 11-hydroxytabersonine have been isolated from the leaves of Tabernanthe pubescens,43/ and 5,22-dioxokopsane (177) from the root bark of Alstonia venenata R. Br. 93 this is the first report of an alkaloid of the heptacyclic kopsine group in this species. 

New synthetic work in this sub-group includes syntheses of ( )-eburnamoninem and ( )-apovincamine.112... 

The study of the chromatographic behavior of natural indole alkaloids on cyclodextrin polymers was different, and unexpectedly high retentions were observed in mildly acidic buffer solutions at room temperature, which permitted their separation by inclusion chromatography (25) (Table IV). Figure 7 shows the separation of two Vinca-alkaloids of very similar structure, the (+)-vincamine and (+)-apovincamine. 

Figure 7. Separation of (+)-vincamine (2 mg) and (+)-apovincamine (3 mg) on 6-cyclodextrin polymer (1.6x90 cm, pH 5 citrate buffer, flow rate 80 ml/h, 20 °C).

The hydroxyl group in XXXV could not be acetylated instead, the iV-vinyl indole, the apo compound, XXXVIII was obtained. In fact, simple heating or solution of the alkaloid in strong acid was all that was necessary. The latter experiment, which finds an analogy in eburnamine itself, required the intermediacy of the iminium form (see Chart II). This iminium form was apparently stable in strong acid, since vincamine in 11 N hydrochloric acid had a UV-spectrum with a long wavelength maximum at 360 mp (log e = 3.85) compatible with XXXIX which reverted irreversibly into apovincamine (XXXVIII R = H) upon dilution (18). 

Vincamine showed peaks from M, M-l, M-CH3, M-C2H5, M-COOMe, M-H2O, and M-HCOOCH3. Since the last two peaks were equivalent to apovincamine and eburnamonine, it was not surprising to observe their characteristic fragmentation peaks in the line-rich spectrum. 11-Methoxyvincamine behaved similarly to vincamine, except that the aromatic peaks were displaced by + 30 mass units (18). 

Chart IV. Principal electron—impact products of eburnamenine, apovincamine, and ebumamonine. 

Vincamine is an alkaloid extracted from the plant Vinca minor. Ethyl apovincaminate is a related synthetic ethyl ester of vincaminic acid. These drugs have spasmolytic effects similar to those of reserpine, but also have metabolic effects, including, in high doses, inhibition of phosphodiesterase. Although increased cerebral blood flow has been reported after the intravenous administration of vincamine, there have been no reliable studies of blood flow after oral medication. Improvement in scores on some psychometric tests have been obtained in some patients with cerebrovascular disease, but no clear-cut practical benefit has been demonstrated. 

In the laboratory of A.G. Schultz during the asymmetric total synthesis of two vincane type alkaloids, (+)-apovincamine and (+)-vincamine, it was necessary to construct a crucial c/s-fused pentacyclic diene intermediate. The synthesis began by the Birch reduction-alkylation of a chiral benzamide to give 6-ethyl-1-methoxy-4-methyl-1,4-cyclohexadiene in a >100 1 diastereomeric purity. This cyclohexadiene was first converted to an enantiopure butyrolactone which after several steps was converted to (+)-apovincamine. 

Schultz, A. G., Malachowski, W. P., Pan, Y. 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. J. Org. Chem. 1997, 62, 1223-1229. 

Chrom Q column by Gazdag et al.. Derivatization (silylation with N,0-bis(trimethylsilyl) trifluoroacetamide) was needed for those alkaloids containing free hydroxy groups and/or a carboxylic acid group (vincaminic and apovincaminic acids). In Table 17.6 the retention times and elution temperatures of the vinca alkaloids investigated - as such and as derivatives -are given. 

PolgSr and Vereczkey applied gas chromatography with a glass capillary column for the determination of apovincaminic acid, the main metabolite of apovincaminic acid ethylester (vinpocetine) in human plasma. Apovincaminic acid was recovered from plasma by addition of tetrabutylammonium hydroxide and extraction with chloroform. It was transformed into its... 

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