- Ozonation in Alkaloid Chemistry: a Mild and Selective Conversion of Vincadifformine into Vincamine
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Vincamine has been obtained in a 'one-pot' method by ozonation of vincadifformine.
- Danieli, Bruno,Lesma, Giordano,Palmisano, Giovanni,Gabetta, Bruno
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- SYNTHESIS OF VINCA ALKALOIDS AND RELATED COMPOUNDS. PART 18. STEREOCHEMICAL INVESTIGATIONS ON SOME INTERMEDIATES LEADING TO (+)-VINCAMINE
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The C-2' absolute configrations of hydroxy esters (1) and (2) have been determined by X-ray analysis.The absolute configurations at C-15 of several compounds with the E-homoeburnane skeleton and the relative configurations at C-14 and -15 of compound (8) have been elucidated.The dominant conformation of compounds (3)-(7) have been established on the basis of 13C n.m.r. and c.d.spectroscopic results.A new method has been elaborated for the preparation of oxime (10), a compound of importance in the synthesis of Vinca alkaloids.
- Szabo, Lajos,Kolonits, Pal,Kalaus, Gyoergy,Szantay, Csaba,Kalman, Alajos,et al.
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- METHYLENE-INDOLINES, INDOLENINES ET INDOLENIUMS-XIII; L'HYDROXY-16 DEHYDRO-1 VINCADIFFORMINE, INTERMEDIAIRE DANS LE REARRANGEMENT BIOMIMETIQUE DE LA VINCADIFFORMINE EN VINCAMINE
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The title compound is a crucial intermediate in the biomimetic conversion of vincadifformine 1 into vincamine 7.Its configuration at C-16 is established by a combination of chemical and spectroscopic evidence.Iodine oxidation converts 14 into the bridged lactam 18, thus proving a β configuration for the hydroxy group at C-16.The same reaction applied to vindoline 19 gives 21 identical with one of the compounds obtained by microbiological transformation of 19.The 13C NMR spectra of derivatives 3 and 8 (obtained by oxidation of vincadifformine) show that oxidation proceeds with introduction of the substituent at C-16, with a β configuration.The alcohol 3 however, posesses a different conformation due to strong hydrogen bonding with N-4.
- Hugel, G.,Massiot, G.,Levy, J.,Men, J. Le
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- Alpneumines A-H, new anti-melanogenic indole alkaloids from Alstonia pneumatophora
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Eight new indole alkaloids, alpneumines A-H (1-8) were isolated from the Malaysian Alstonia pneumatophora (Apocynaceae) and their structures were determined by MS and 2D NMR spectroscopic methods. Alpneumines E and G (5 and 7), vincamine, and apovincamine showed anti-melanogenesis in B16 mouse melanoma cells.
- Koyama, Koichiro,Hirasawa, Yusuke,Hosoya, Takahiro,Hoe, Teh Chin,Chan, Kit-Lam,Morita, Hiroshi
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- Synthesis of vinca alkaloids and related compounds, XV. A new synthetic route to (+)-vincaminic and (+)-apovincaminic esters
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Esters of types 7 and 8, possessing excellent vasodilating effects, have been prepared. A method has been found for the resolution of methyl ester 7c. A new method is described for the preparation of the lactam (+)-10 and its conversion to the oxime (+)-11, from which (+)-vincamine (1a) and the (+)-apovincaminic esters 2a,b were synthesized.
- Szabo,Kalaus,Szantay
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- Synthesis of vinca alkaloids and related compounds LX. A simple transformation of apovincamine into vincamine
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The 15α-chloro-vincamine derivative 2 was prepared and proved to be key intermediate of a two-step transformation of apovincamine into vincamine. The structure of 2 was established via detailed NMR and X-ray investigations.
- Moldvai, Istvan,Szantay Jr., Csaba,Rissanen, Kari,Szantay, Csaba
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- Enantioselective total synthesis of (+)-vincamine
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A catalytic asymmetric total synthesis of (+)-vincamine is presented. Key features of the synthesis include a Pd-catalyzed enantioselective decarboxylative allylation to form the C20 quaternary stereogenic center and a stereoselective iminium reduction to install the critical cis-C20/C21 relative stereochemisty.
- Liu, Hengmao,Liu, Xiao-Yu,Qin, Yong,Song, Hao,Wang, Rui,Xue, Fanglin,Zhang, Dan
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- Intermediate, preparation method and application of intermediate in synthesis of vincamine
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The invention relates to the technical field of chemical drug synthesis, and discloses an intermediate, a preparation method and application of the intermediate in synthesis of vincamine. A modular synthesis strategy is adopted, and a compound 1 with a D ring structure and a C20 quaternary carbon center and a tryptophol derivative 7 (namely the compound 7) with an indole ring are adopted as synthesis blocks for synthesis. The synthesis method is efficient; each step of the synthesis route is simple in reaction; the used reagent and solvent are cheap and easy to obtain; the operation is simple and convenient; the yield is high; and large-scale production is easy.
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- Preparation method of vincamine
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The invention provides a green preparation method of vincamine, which comprises the following steps: (1) reduction: introducing a tabersonine methanol solution and hydrogen into a micro-channel reactor through a charging pump to react, and filtering, concentrating and extracting the reaction solution twice after the reaction is finished, thereby obtaining an extracting solution; (2) oxidation: catalyzing an organic phase in the extraction liquid in the step (1) by using peroxy acid to carry out oxidation reaction, neutralizing by using a sodium bicarbonate solution after the reaction is finished, extracting and concentrating; and (3) rearrangement: dissolving the concentrated solid obtained in the step (2) with ethanol, rearranging in the presence of a catalyst, adjusting the pH value after the reaction is completed, filtering, washing and crystallizing the filter cake, and separating out the solid, namely vincamine. The preparation method is safe, environmentally friendly and capable of achieving continuous production, the product purity is 99% or above, automatic equipment can be adopted for continuous production, and the industrial production efficiency is improved.
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Paragraph 0044-0047
(2021/04/21)
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- Preparation method of high-purity vinpocetine (by machine translation)
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The preparation method, of the high-purity vinpocetine :S1. comprises, following steps: preparing vinpocstine, by dissolving; in toluene as a solvent; in toluene as a solvent ;S2. and carrying out an ester exchange reaction, to obtain the intermediate vinpocstine nitrogen oxide, in a toluene as a solvent, and carrying out an ester exchange reaction to obtain a product impurity at least ;S3. purity S2 and, % by mass of a solvent . The preparation method of the vinpocstine nitrogen oxide reaction solution in step, is adopted as a catalyst for carrying out an ester exchange reaction to obtain a long spring cavoniflorac sodium/vinpocstine . The process production operation is, simple, avoids the high, 99.9% toxicity reagent, to obtain a, long spring cavonift, nitrogen oxide reaction, solution to, obtain a product, impurity at a time of acid. (by machine translation)
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Paragraph 0041; 0043-0044; 0051-0056
(2020/04/17)
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- Vincamine preparation method
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The invention relates to a vincamine preparation method in the field of compound preparation. The vincamine preparation method includes the steps of (1), tabersonine preparation, (2), vincadifformine preparation, (3), monoperoxy maleic acid preparation and (4), vincamine preparation. The vincamine preparation method has the advantages of easy availability to raw materials, simplicity and convenience in reaction process operation, high safety, low cost, high product yield, high quality and suitability for industrial production.
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Paragraph 0052; 0053; 0064; 0065; 0076-0079; 0088-0094
(2017/08/29)
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- Compounds and compositions for treating infection
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Compounds from 14 Kenyan plants, including from the root of Dovyalis abyssinica and Clutia robusta have been characterized and isolated, and their uses are disclosed.
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- Synthesis of 18-hydroxyvincamines and epoxy-1,14-secovincamines; A new proof for the aspidospermane-eburnane rearrangement
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Chemical transformations started from tabersonine were studied. A one-pot oxidative ring-transformation with permaleic acid in methanol yielded 17,18-dehydrovincamine. Hydroboration-oxidation of the latter compound led to alkaloid 17,18-dehydrovincamone. Hydroboration-oxidation of tabersonine resulted 14β-hydroxyvincadifformine and 15β-hydroxyvincadifformine. Allowing 14β- and 15β- hydroxyvincadifformines to react with permaleic acid/methanol provided 1,14-secovincamines, serving as new evidence for the mechanism of the aspidospermane-eburnane transformation. On the other hand 18β-hydroxyvincamine was obtained from 14β-hydroxyvincadifformine by reaction with 3-chloroperbenzoic acid and successive treatment with triphenylphosphine/aqueous acetic acid.
- Nemes, Andras,Szantay Jr., Csaba,Czibula, Laszlo,Greiner, Istvan
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p. 2347 - 2362
(2008/09/18)
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- Stereocontrolled elaboration of quaternary carbon centers through the asymmetric Michael-type alkylation of chiral imines/secondary enamines: Enantioselective synthesis of (+)-vincamine
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An enantioselective synthesis of (+)-vincamine (1) has been developed. The key strategic element was the stereocontrolled elaboration of a quaternary carbon center (future C-20 center of 1) by using the asymmetric Michael reaction involving chiral imines/secondary enamines under neutral conditions. Thus, addition of enaminolactam (S)-12, derived from ketolactam 7 (itself prepared in four steps from commercially available tryptamine) and (S)-1-phenylethylamine, to methyl acrylate led, after hydrolytic workup, to adduct (R)-6 with a 90% stereoselectivity. The critical removal of the additional keto group of 6 was then examined. After extensive experimentation, we finally established that the most efficient deoxygenation procedure was the Wolff-Kishner reduction of the corresponding keto acid, which proceeded with a 55% yield. The cornerstone [ABD]-tricyclic lactam ester 38 thus obtained was next cyclized under Bischler-Napieralski reaction conditions to afford, after catalytic hydrogenation of the intermediary iminium perchlorate salt, a mixture of the desired, known indoloquinolizidine 5 and its epimer 39, in a ratio of 6:1, respectively. Basic treatment of 5 led to (+)-homoeburnamonine 4, which was finally converted, according to a known procedure, into our goal (+)-vincamine (1). Thus, synthesis of (+)-vincamine (1) has been achieved by a linear sequence of 15 chemical operations, starting from tryptamine, with an overall yield of 1.2%.
- Desmaele, Didier,Mekouar, Khalid,D'Angelo, Jean
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p. 3890 - 3901
(2007/10/03)
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- Syntheses and Cardiovascular Activity of Stereoisomers and Derivatives of Eburnane Alkaloids
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The synthesis of all the possible isomers of the eburnamenine-vincamine type alkaloids 1b, 2a*, 3a and derivatives 4, 8, 9, 10 is described.Structures were determined by 1H- and 13C-NMR spectroscopy including special techniques such as DR, DEPT, DNOE, and 2D-HSC.In contrast to the known cerebrovascular effects of cis-(3S,16S) compounds, trans-(3S,16R) derivatives show a significant peripheral vasodilator effect. Key Word: Eburnanes / Alkaloids / Cardiovascular effects / Indoloquinolizines
- Czibula, Laszlo,Nemes, Andras,Visky, Gyoergy,Farkas, Maria,Szombathelyi, Zsolt,et al.
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p. 221 - 230
(2007/10/02)
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- ALTERNATIVE ROUTES TO VINCAMINE
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The preparation of vincamine (1a) via indoloquinolizine propionic esters (7) is discussed.A new synthesis of the starting material methyl 2-acetoxyacrylate and an oxidative transformation of 7b to 1a are described and an alternative, more efficient route is reported.
- Nemes, Andras,Czibula, Laszlo,Visky, Gyorgy,Farkas, Maria,Kreidl, Janos
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p. 2329 - 2338
(2007/10/02)
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- SYNTHESIS OF VINCA ALKALOIDS AND RELATED COMPOUNDS, XLIX. AROMATIC SUBSTITUENT EFFECTS IN THE C-14 EPIMERIZATION
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Some A-ring substituted vincamine derivatives and their C-14 epimers have been prepared and the aromatic substituent effects on the epimeric equilibrium of these compounds investigated.
- Moldvai, Istvan,Vedres, Andras,Szantay, Csaba,Toth, Gabor,Szantay, Csaba
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p. 109 - 118
(2007/10/02)
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- IMINOIMIDAZOLIDINES USEFUL IN LOWERING INTRAOCULAR PRESSURE
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Antiglaucoma compounds having beta adrenoreceptor antagonist properties and alpha adrenoreceptor antagonist properties are described. The compounds comprise a beta blocker-derived moiety designed to provide beta antagonist properties and an imidazolidine moiety designed to provide alpha-antagonist properties. Methods of synthesizing the compounds are also described. The compounds are useful in the treatment of glaucoma due to their ability to lower elevated intraocular pressure.
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- SYNTHESIS OF VINCA ALKALOIDS AND RELATED COMPOUNDS XLII TRANSFORMATION OF VINCAMONE INTO VINCAMINES VIA DIAZOMETHANE ASSISTED HOMOLOGIZATION. APPLICATION OF(1)H-NOE MEASUREMENTS FOR THE CONFIGURATIONAL ASSIGMENT OF THE SPIRO-OXIRANE RING
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The α-oxo-acids 4 and 5 derived from vincamone (1) were transformed into vincamines 2,9,10, respectively by methylene insertion with diazomethane.Homologization of 3 and 6 dioxo compounds led to oxirane derivatives 8,16,11,13, 18, respectively.Configuration of the oxiranes was determined by (1)H-NOE measurements.
- Sapi, Janos,Szabo, Lajos,Baitz-Gacs, Eszter,Kalaus, Gyoergy,Szantay, Csaba
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p. 4619 - 4630
(2007/10/02)
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- 4-alkylindolonaphthyridines and their therapeutical application
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The present invention is concerned with derivatives of 2,3,3a,4,5,6-hexahydro-1H-indolo(3,2,1-de)(1,5)naphthyridine of the formula STR1 in the form of base or acid addition salts, preferably with pharmaceutically acceptable acids, wherein one of the groups R1 and R2 represents a lower alkyl group and the other represents a hydrogen atom or R1 and R2 represent each independently an alkyl group or, together an alkanediyl group having from 4 to 6 carbon atoms. R3 represents a lower alkyl group, a hydrogen atom or a benzyl group. And either R5 represents a lower carboalkoxy group or a hydrogen atom and R6 represents with R4 an additional carbon-carbon bond; or R4 represents a hydrogen atom and R6 and R5 represent together an oxygen atom or respectively a hydrogen atom and a hydroxyl group.
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- Nouvelles hemisyntheses de la (+)vincamine et de la (-)vincamone
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A new course in the hemisynthesis of (+)vincamine 2a and (-)vincamone 3 indole alkaloids of medicinal interest from (-)apovincamine 1a is described.Apovincamine itself was obtained from vincadifformine 4 by an original process recently related (N-chlorosuccinimide in pure CF3COOH or HCOOH).The conversion of apovincamine into vincamine involves three steps, with or without isolation of the intermediate compounds: a) addition of bromine in methanol to the double bond (C-16)-(C-17) b) catalytic hydrogenolysis of the (C-17)-Br bond in vincamine O-methyl ether 9 c) hydrolysis of 9 resulting in a mixture of vincamine 2a and 16-epivincamine 2b.The conversion of apovincamine into vincamone is carried out after saponification to apovincaminic acid 1b.Addition of bromine in aqueous medium, and further acidification and heating yields vincamone by a single step process.
- Lewin, Guy,Poisson, Jacques
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p. 435 - 437
(2007/10/02)
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- Process for the preparation of vincaminic acid esters
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The invention relates to a new process for the preparation of apovincaminic acid esters. More particularly, the invention concerns a process for preparing racemic and optionally active vincaminic acid esters of the formula (I) STR1 in which R1 and R2 independently stand for alkyl having from one to 6 carbon atoms, and 14-epimers thereof. According to the invention an octahydroindolo[2,3-a]quinolizine-oxime ester of the formula (II) STR2 in which R1 and R2 have the same meaning as defined above, is reacted with an aqueous solution of sulfurous acid or a salt thereof at a temperature of 80° to 110° C. and the 14-epimeric mixture obtained is epimerized or separated in a known manner and if desired, the racemic vincaminic acid esters are resolved. The valuable, pharmaceutically active compounds of the formula (I) can be prepared according to the invention in a considerably improved yield and the undesired side reactions can be suppressed and/or the by-products can easily be converted into other pharmaceutically active materials.
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- THERMAL REARRANGEMETS OF SOME INDOLE ALKALOID DERIVATIVES
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Under both static and flow thermolysis conditions, several compounds with an "aspidosperma" framework rearranged to "vinca" derivatives.Thus (-)1,2-dehydroaspidospermidine (4) rearranged to (-)aspidospermidine and compound 17 on pyrolysis (200 deg C) while flow termolysis (580 deg C) gave vincane (14).Compound 6 rearranged to vincamine (13a) and 16-epivincamine (13b) under either condition; increasing the temperature resulted in formation of apovincamine (19) (pyrolysis) or vincamone (16) (flow thermolysis).
- Hugel, Georgette,Levy, Jean
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p. 1067 - 1074
(2007/10/02)
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- Synthesis of vinca alkaloids and related compounds. XVI. New route to the stereoselective synthesis of (+)-vincamine, (-)-vincamone and (+)-apovincaminic acid esters
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A stereoselective methods has been elaborated for the synthesis of oxime esters, from which, as common intermediates, (+)-apovincaminic acid esters, (+)-vincamine and (-)-vincamone can be prepared.
- Szabo,Sapi,Kalaus,et al.
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p. 3737 - 3747
(2007/10/02)
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- Dye-sensitized Photo-oxygenation of the Aspidosperma Alkaloids Vincadifformine and Tabersonine. A New, Convenient Approach to Vincamine
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The dye-sensitized photo-oxygenation of (-)-vincadifformine (1) and (-)-tabersonine (3) is discribed.Reaction takes place through the intermediate formation of 16-hydroperoxyindolenines, which decompose to give 2,16-seco-products or which can be efficently trapped by reductants to give a new stereoselective synthesis of the 16-hydroxy-indoles (10) and (14).These compounds are the key precursors to the eburnane alcaloids vincamine (4) and Δ14-vincamine (6).Suitable experimental conditions give compounds (4) and (6) in good yields directly from their Aspidosperma precursor.
- Calabi, Luisella,Danieli, Bruno,Lesma, Giordano,Palmisano, Giovanni
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p. 1371 - 1380
(2007/10/02)
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- Synthesis of vincaminic acid derivatives
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Vincaminic acid derivatives of formula (A) STR1 useful in treating cerebral insufficiency, are prepared by reacting 1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3-a]quinolizine with the 2,4-DNP hydrazone of ethyl or methyl bromopyruvate followed by (i) reduction of the C=N bond and (ii) simultaneous cyclization with removal of the ketone-protecting group in either order.
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- OXIDATION OF THE 2,16 DOUBLE BOND OF VINCADIFFORMINE
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Chemical vs photochemical oxidation of the 2,16 double bond of vincadifformine 1 and 3-oxo vincadifformine 2 yielded inter alia, respectively the ketooexindoles 7 and 8.Attempts of partial synthesis of vincatine 15 from these derivatives were unsuccessful, The structure of the LAH reduction product of vincatine is revised to 21.The stereochemical course of an earlier total synthesis of vincadifformine is examined.
- Hugel, Georgette,Laronze, Jean-Yves,Laronze, Jacqueline,Levy, Jean
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p. 581 - 590
(2007/10/02)
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- Process for the preparation of cis-vincamine
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A process is provided for the preparation of cis-vincamine by oxidising trans-vincamine with tertiary butyl hypochlorite to obtain dehydrovincamine chloride, reducing the dehydrovincamine chloride with a metal in an aqeous acidic medium and neutralising the product, and separating cis-vincamine from the resulting mixture of cis- and trans-vincamines. Cis-vincamine is useful for the treatment of circulatory disorders.
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- Process for the preparation of vincamine and other indole alkaloids
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The invention relates to the preparation of vincamine and similar indole alkaloids, capable of being easily converted to vincamine, by oxydating a starting alkaloid selected between tabersonine and vincadifformine with oxygen, the reaction mixture being added with an essential amount of an inorganic or organic salt of a metal selected among Cu, Fe and Co.
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- Vincamine 2-ketoglutarate and compositions containing vincamine 2-ketoglutarate
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The new compound vincamine 2-ketoglutarate of the formula: SPC1 Is disclosed and is prepared by mixing 2-ketoglutaric acid and vincamine or a salt thereof in a solvent and recovering the resulting vincamine 2-ketoglutarate which has interesting properties as a vasodilator and brain oxygenator. The vincamine may be prepared by allowing a mixture of a solution of 16-epivincamine and a quaternary ammonium hydroxide to stand whereafter the vincamine is recovered.
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