- Preparation method of vinorelbine tartrate
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The invention discloses a preparation method of vinorelbine tartrate, which comprises the following steps: 1) preparation of dehydrated vinblastine: taking vinblastine sulfate and vindoline as initialraw materials, and carrying out ferric trichloride catalysis and sodium borohydride reduction to obtain dehydrated vinblastine; 2) preparation of bromo-dehydrated vinblastine: carrying out bromination reaction on dehydrated vinblastine and N-bromo-succinimide to obtain a bromo-dehydrated vinblastine crude product; carrying out column purification on the bromo-dehydrated vinblastine crude productto improve the purity of the bromo-dehydrated vinblastine crude product so as to obtain bromo-dehydrated vinblastine; 3) preparation of vinorelbine: carrying out debromination rearrangement on bromo-dehydrated vinblastine and a silver tetrafluoroborate aqueous solution to obtain a vinorelbine crude product; and recrystallizing the vinorelbine crude product to obtain a vinorelbine pure product; and4) preparation of vinorelbine tartrate: carrying out a salt forming reaction on the pure vinorelbine tartrate and tartaric acid to obtain vinorelbine tartrate. The method has the advantages of simpleoperation, few side reactions, great increase of the purity and the yield, reduction of the production cost, and suitableness for large-scale production.
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Paragraph 0078-0085; 0104-0111
(2021/03/30)
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- Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline: Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope
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A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1-10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16′ stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.
- Boon, Byron A.,Boger, Dale L.
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supporting information
p. 14349 - 14355
(2019/10/11)
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- Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance
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A series of 180 vinblastine 20′ amides were prepared in three steps from commercially available starting materials, systematically exploring a typically inaccessible site in the molecule enlisting a powerful functionalization strategy. Clear structure-activity relationships and a structural model were developed in the studies which provided many such 20′ amides that exhibit substantial and some even remarkable enhancements in potency, many that exhibit further improvements in activity against a Pgp overexpressing resistant cancer cell line, and an important subset of the vinblastine analogues that display little or no differential in activity against a matched pair of vinblastine sensitive and resistant (Pgp overexpressing) cell lines. The improvements in potency directly correlated with target tubulin binding affinity, and the reduction in differential functional activity against the sensitive and Pgp overexpressing resistant cell lines was found to correlate directly with an impact on Pgp-derived efflux.
- Lukesh, John C.,Carney, Daniel W.,Dong, Huijun,Cross, R. Matthew,Shukla, Vyom,Duncan, Katharine K.,Yang, Shouliang,Brody, Daniel M.,Brütsch, Manuela M.,Radakovic, Aleksandar,Boger, Dale L.
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p. 7591 - 7604
(2017/09/22)
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- Synthesis and antiproliferativeactivity of new vinca alkaloids containing an α,β-unsaturated aromatic side chain
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A new series of vinca-alkaloids derivatives containing various α,β-unsaturated aromatic side chains was synthesized. Four new vinca-alkaloids derivatives showed selective cytotoxicities against KB tumor cell lines with IC50 value below 0.1 μM, thus comparable with vinblastine.
- Ngo, Quoc Anh,Nguyen, Le Anh,Vo, Ngoc Binh,Nguyen, Thuy Hang,Roussi, Fanny,Nguyen, The Hung,Nguyen, Van Tuyen
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p. 5597 - 5600
(2015/11/17)
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- New insights into the mechanism and an expanded scope of the Fe(III)-mediated vinblastine coupling reaction
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A definition of the scope of aromatic substrates that participate with catharanthine in an Fe(III)-mediated coupling reaction, an examination of the key structural features of catharanthine required for participation in the reaction, and the development of a generalized indole functionalization reaction that bears little structural relationship to catharanthine itself are detailed. In addition to providing insights into the mechanism of the Fe(III)-mediated coupling reaction of catharanthine with vindoline suggesting the reaction conducted in acidic aqueous buffer may be radical mediated, the studies provide new opportunities for the preparation of previously inaccessible vinblastine analogs and define powerful new methodology for the synthesis of indole-containing natural and unnatural products.
- Gotoh, Hiroaki,Sears, Justin E.,Eschenmoser, Albert,Boger, Dale L.
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supporting information; experimental part
p. 13240 - 13243
(2012/09/22)
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- 10′-fluorovinblastine and 10′-fluorovincristine: Synthesis of a key series of modified vinca alkaloids
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A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10′-fluorovinblastine and 10′-fluorovincristine. In addition to defining a pronounced and unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10′, which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC50 = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC50 = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting that the 10′-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions.
- Gotoh, Hiroaki,Duncan, Katharine K.,Robertson, William M.,Boger, Dale L.
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scheme or table
p. 948 - 952
(2012/02/01)
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- Synthesis of anti-tumor dimeric indole alkaloids in catharanthus roseus was promoted by irradiation with near-ultraviolet light at low temperature
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We have found that coupling between catharanthine and vindoline occurs non-enzymatically in the presence of flavin mononucleotide and manganese ions with near- ultraviolet light irradiation in vitro. The present study found that the concentrations of cath
- Asano, Mamiko,Harada, Kazuo,Yoshikawa, Tomoaki,Bamba, Takeshi,Hirata, Kazumasa
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body text
p. 386 - 389
(2010/10/03)
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- Catharanthine C16 substituent effects on the biomimetic coupling with vindoline: Preparation and evaluation of a key series of vinblastine analogues
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The examination of the catharanthine C16 substituent effects on the Fe(III)-promoted biomimetic coupling reaction with vindoline is detailed, confirming the importance of the presence of a C16 electron-withdrawing substituent, and establishing an unanticipated unique role (>10-fold) that the C16 methyl ester plays in the expression of the natural product properties. Thus, replacement of the vinblastine C16′ methyl ester with an ethyl ester (10-fold), a cyano group (100-fold), an aldehyde (100-fold), a hydroxymethyl group (1000-fold) or a primary carboxamide (>1000-fold) led to surprisingly large reductions in cytotoxic activity.
- Tam, Annie,Gotoh, Hiroaki,Robertson, William M.,Boger, Dale L.
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supporting information; scheme or table
p. 6408 - 6410
(2010/12/18)
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- Process for the preparation of bisindole alkaloid derivatives
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A process for the coupling of catharantine and vindoline catalyzed by Laccases is described. The coupling produces anhydrovinblastine and anhydrovinblastine eniminium, which can be transformed to vinblastine or vinorelbine.
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Page/Page column 6
(2009/12/28)
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- Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids
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Ten hybrids of vinca alkaloids and phomopsin A have been synthesized by linking the octahydrophomopsin lateral chain to the tertiary amine of the cleavamine moiety of anhydrovinblastine (AVLB) and vinorelbine. These compounds have been elaborated in order
- Ngo, Quoc Anh,Roussi, Fanny,Cormier, Anthony,Thoret, Sylviane,Knossow, Marcel,Guenard, Daniel,Gueritte, Frangoise
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scheme or table
p. 134 - 142
(2009/09/06)
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- VINCA DERIVATIVES
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The present invention relates to derivatives of vinca alkaloids. Pharmaceutical compositions containing these compounds as well as processes of preparation and treatment of various conditions are also disclosed.
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Page/Page column 42-43
(2008/06/13)
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- Concise synthesis of anhydrovinblastine from leurosine.
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[reaction: see text] The Cp(2)TiCl-mediated deoxygenation of leurosine (1) afforded anhydrovinblastine (4) in good yield. Furthermore, as the reaction proceeded via a carbon-centered radical intermediate, this transient was also trapped by a hydrogen-atom donor to afford selectively reduced alkaloid 10.
- Hardouin, Christophe,Doris, Eric,Rousseau, Bernard,Mioskowski, Charles
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p. 1151 - 1153
(2007/10/03)
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- Selective deoxygenation of leurosine: Concise access to anhydrovinblastine
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Straightforward access to anhydrovinblastine starting from the parent alkaloid leurosine is reported. The key deoxygenation step was first optimized on a model substrate. However, applied to leurosine, only the low-valent CP2TiCl gave satisfactory results.
- Hardouin, Christophe,Doris, Eric,Rousseau, Bernard,Mioskowski, Charles
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p. 6571 - 6574
(2007/10/03)
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- Synthesis and oxidative fragmentation of catharanthine analogs. Comparison to the fragmentation - Coupling of catharanthine and vindoline
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Two new analogs of catharanthine have been synthesized in racemic form. They differ from catharanthine in the fusion of the indole ring to the non- aromatic portion of the iboga skeleton, with the [2,3] fusion present in catharanthine being replaced by [2,1] and [3,2] fusions. The corresponding deethyl analogs were also and methodological improvements were applied to an existing synthesis of deethylcatharanthine and a formal synthesis of racemic catharanthine. The reactivity of the catharanthine analogs toward coupling with vindoline was examined. Coupling was attempted by both the amine oxide fragmentation (Potier) and Fe3+ methods. Under Potier conditions the [2,1] fused analogs give low yields of coupling products in which vindaline is attached to the 3-position of the indole ring. The [3,2] isomers undergo fragmentation of the C16-C21 bond, as observed for catharanthine, but no coupling to vindoline occurs. The reactivity, oxidation potentials and conformation of the analogs are compared with catharanthine, deethylcatharanthine and N-methylcatharanthine.
- Sundberg, Richard J.,Hong, Jian,Smith, Stanton Q.,Sabat, Michal,Tabakovic, Ibro
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p. 6259 - 6292
(2007/10/03)
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- Borane Complexes of Vinblastine Type Diindole Derivatives
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While investigating the ferric chloride mediated coupling of catharanthine (1) with vindoline (3) and their derivatives (2, 4), the borane complexes of 15',20'-anhydrovinblastine (AVLB), 20'-deethyl-AVLB and N-demethyl-AVLB (9, 10, 11) have been synthesized.The corresponding bases (6, 7 and 8) have also been obtained in high yield. Key Words: Anhydrovinblastine; 20'-deethyl-AVLB; N-demethyl-AVLB; borane complexes; FeCl3 coupling.
- Balazs, Mihaly,Szantay, Csaba,Boelcskei, Hedvig,Szantay, Csaba
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p. 4397 - 4398
(2007/10/02)
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- Synthesis of vinca alkaloids and related compounds. Part LVI. 15′,20′-Anhydrovinblastine borane complex. Structural investigations using NMR methods
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In the course of coupling catharanthine 1 to vindoline 2, the 3 borane complex of anhydrovinblastine, a new diindole derivative was isolated. The structure of this compound was studied by detailed NMR investigations. Full 1H and 13C assignments for both the 3 borane complex and anhydrovinblastine are given.
- Szantay, Csaba,Balazs, Mihaly,Boelcskei, Hedvig,Szantay, Csaba
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p. 1265 - 1274
(2007/12/18)
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- A HIGHLY EFFICIENT AND COMMERCIALLY IMPORTANT SYNTHESIS OF THE ANTITUMOR CATHARANTHUS ALKALOIDS VINBLASTINE AND LEUROSIDINE FROM CATHARANTHINE AND VINDOLINE
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Extensive studies of various reaction parameters for the chemical coupling of catharanthine (1) and vindoline (2) followed by evaluation of highly unstable intermediates by careful reaction control have provided essentially a quantitative yield in this coupling reaction.Subsequent regioselective reduction of the resultant intermediate 3 by select NADH models affords a high yield of an enamine (5) which, without isolation, is selectively oxidized to unstable iminium intermediates 6 and 7 and the latter, again without isolation, are finally reduced to vinblastine (8, 40percent), leurosidine (10, 16percent), and 3',4'-anhydrovinblastine (4, 12percent).The entire process of five steps (1->11+2->3->5->6,7->8,10,4) can be achieved in a one-pot operation and the high overall yield of vinblastine (8) requires that each reaction must proceed in yields in excess of 80percent.
- Kutney, James Peter,Choi, Lewis Siu Leung,Nakano, Jun,Tsukamoto, Hiroki,McHugh, Michael,Boulet, Camille Andre
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p. 1845 - 1854
(2007/10/02)
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- ALKALOID PRODUCTION IN CATHARANTHUS ROSEUS (L.) G. DON CELL CULTURES, XV. SYNTHESIS OF BISINDOLE ALKALOIDS BY USE OF IMMOBILIZED ENZYME SYSTEMS
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Affinity gel bound enzyme systems obtained from Catharanthus roseus cell cultures were employed to establish a high yielding enzymatic system for the coupling of catharanthine (1) and vindoline (2) to 3',4'-anhydrovinblastine (3) and leurosine (4).Long term enzymatic activity can be preserved by this technique, an aspect which may prove important in subsequent utilization of such systems in large scale production.
- Kutney, James Peter,Boulet, Camille Andre,Choi, Lewis Siu Leung,Gustowski, Wlodzimierz,McHugh, Michael,et al.
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p. 621 - 628
(2007/10/02)
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