[slideshare id=26643487&style=border:1px solid #CCC;border-width:1px 1px 0;margin-bottom:5px&sc=no]
Like LSD, the microtubule toxin vincristine allegedly causes not-unpleasant visual hallucinations in humans. Other side-effects of vincristine include depression, agitation, and insomnia. Very small doses are needed for the effects of LSD or vincristine, for example, these drugs are active at concentrations of 4.3E-7 M-1 vincristine and 1.0E-8 M-1 LSD.
- ^ "Pharmacognosy of Vinca Alkaloids".
- Graf, W. D.; Chance, P. F.; Lensch, M. W.; Eng, L. J.; Lipe, H. P.; Bird, T. D. (1996). "Severe Vincristine Neuropathy in Charcot-Marie-Tooth Disease Type 1A". Cancer 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515.
- Qweider, M.; Gilsbach, J. M.; Rohde, V. (2007). "Inadvertent Intrathecal Vincristine Administration: A Neurosurgical Emergency. Case Report". Journal of Neurosurgery: Spine 6 (3): 280–283. doi:10.3171/spi.2007.6.3.280. PMID 17355029.
- Jake Hooker and Walt Bogdanich (January 31, 2008). "Tainted Drugs Tied to Maker of Abortion Pill". New York Times.
- Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. (1963). "The Vinca Alkaloids: A New Class of Oncolytic Agents" (pdf). Cancer Research 23 (8 Part 1): 1390–1427.PMID 14070392.
- Vincristine chemotherapy
- Vincristine and vinblastine
- Description and Natural History of the Periwinkle
- The Boger Route to (-)-Vindoline
- U.S. National Library of Medicine: Drug Information Portal - Vincristine
- Cytostatic Vinca alkaloids rosea L. Catharanthus roseus G.Don) are now well known anticancer and particularly useful. Given the small amount of vincristine in Catharanthus present, quite a number of ways of preparation have been proposed by chemists. Thus FR-A-2296418 describes the synthesis of vincristine by coupling Catha-ranthine and vindoline. Other laboratories have achieved the transformation of vinblastine vincristine oxidation under controlled conditions, very strict.
- FR-A-2210393 and US-A-3899493 perform the oxidation by chromic acid at -30, -90 ° C in a mixture of acetic acid-acetone or chloroform-acetic acid at -55 ° C.
- In U.S. 4,375,432, chromic compound is also used in acid medium at -65 ° C, -50 ° C in a medium based solvent THF. In addition, EP-A-37289 boasts an oxidation mixture ferrous salt, hydrogen peroxide, perchlorate in acetonitrile. ZA-A-82 08939 discloses a method with chromic acid and an ether-chloroform.
- HU-A-23638 offers diterbutylchromate in pelargonic acid, and finally EP-A-117861 gets vinblastinel transformation vincristine oxidant potassium permanganate in acetic acid medium. It is clear that these dimeric alkaloids are a valuable material because of their low levels in vegetable raw materials, and therefore the processes of synthesis or semi-synthesis performance are of extreme interest.
- Vincristine is used in cancer chemotherapy, particularly for the treatment of certain acute leukemias.
- This alkaloid is obtained mainly by extraction from leaves of Catharanthus Ro-seus (U.S. Patent No. 3,205,220) where it is accompanied by other alkaloids bis-Indo-holic, especially vinblastine.Vinblastine (I, R = CH 3), however, is present at a concentration much higher than that of vincristine and is therefore a precursor of choice for the semisynthesis of the latter.
- Several processes of vincristine from vinblastine were disclosed. We note in particular patents or patent applications include:
- a) Belgian Patent 739,337 (Gedeon Richter) which describes a method for the oxidation of vinblastine vincristine in a mixture chromic acid, acetic acid and acetone.
- b) Belgian Patent 823560 (Gedeon Richter) the oxidation is performed with oxygen in the presence of formic acid and of a catalyst based on platinum at room temperature.
- c) European Patent Application 18231 (Gedeon Richter): is carried out by oxidation with chromic acid or an alkali metal dichromate in the presence of acetic anhydride and, optionally, of ethanol and an organic solvent immis target with water.
- d) European Patent Application 37289 (Eli Lil-ly): the oxidation is effected by the perchlorate of iron (II) in the presence of hydrogen peroxide and acetonitrile.
- In addition, the European patent application 37. 290 discloses a process for the oxidation of vinblastine base with Na 2 Cr 2 O 7 in the presence of sulfuric acid in tetrahydrofuran. This reaction led to -50 ° C, is achieved with a yield of 80-92% calculated for each estimation.
- Observed yields or purity of the products obtained characterizing the processes described above are, however, significant disadvantages.
- Frequently a secondary product formed is N-demethyl vinblastine need then reformulate for vincristine.
- EP 0117861 B1
- The process of the present invention produces a simple vincristine, in quantity and purity requiring little or no additional purification by recrystallization or chromatography.
- The reagent used is oxidation permanganate ion dissolved in toluene or dichloromethane as solvent. An alternative consists in immobilizing the resin on a permanganate anion, for example a polymer such as polystyrene comprising ammonium groups. Solubilization can be achieved by the action of a complexing agent crown ether ("crown-ether") of potassium permanganate.
- The permanganate anion can also be solubilized by preparing an ammonium salt or quaternary phosphonium corresponding which is soluble in methylene chloride or toluene. For this purpose, it is preferable to use potassium permanganate benzyltriethylammonium.
- Obtaining from vincristine vinblastine using a permanganate salt is unexpected since the potassium permanganate used in some acetone oxide derivatives of vinblastine at the portion of the molecule velbanamine (Kutney, Balsevich and Worth, Heterocycles, 11, 69, 1978). The N-methyl group of the vindoline part intact.
- The formation of N-CHO indoline skeleton on a bis-indole group vinblastine using a permanganate salt has never been reported.
- According to one embodiment of the method of the present invention, vinblastine, preferably in the form of sulphate, is treated in the presence of an organic acid such as acetic acid, with an excess of potassium permanganate dissolved in dichloromethane or toluene in the presence of "18-crown-6" or ether derivatives dibenzo-or di-cyclohexylcorrespondants. The reaction is conducted at a temperature between -40 ° C and -75 ° C and is preferably followed by thin layer chromatography. The reaction time generally ranges from 5 minutes to 3 hours.
- Potassium permanganate is preferably dissolved in dichloromethane and the oxidation reaction is then carried out at -70 ° C.
- The solubility of potassium permanganate is indeed substantially increased in the presence of a macrocyclic polyether as the "18-crown-6" ether (1, 4, 7, 10, 13, 16-hexaoxacy-clooctadécane) or derivative dibenzo - or corresponding dicyclohexyl-hexyl.
- The reaction mixture is then treated simultaneously by a mild reducing and alkaline. For this purpose, use is preferably an aqueous solution of bisulfite, disulfite or sodium metabisulfite and ammonia.
- The organic phase was separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases were concentrated in vacuo to give a residue containing 80-85% of base vincristine, a 90-95% yield.
- Alternatively, you can proceed with the extraction of the reaction mixture after reduction without conducting a simultaneous alkalinization. The acidic aqueous solution was then extracted with dichloromethane. This route is a novel process for purification of vincristine formed in the reaction medium.
- According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblastine by reacting a quaternary ammonium permanganate. The ammonium cation is preferably benzyltriethylammonium group or benzyl trimethyl ammonium (see eg Angew. Chem., Intern. Ed. 13, 170, 1974). The reaction is carried out in 2 to 6 hours at -60 ° C in an inert solvent wherein the ammonium salt is soluble, and an acid, preferably an organic acid of low molecular weight. A mixture of dichloromethane and glacial acetic acid can be used. After treatment with a mild reducing agent in aqueous medium, the resulting acidic solution is extracted with dichloromethane, and the organic phase is made alkaline by washing with a basic aqueous solution and concentrated. Vincristine solvate is isolated with a yield higher than 90%.
- The latest variant of the method of the invention is particularly advantageous in terms of economic and technical.
- Purification or separation may be effected by crystallization and chromatography using techniques well known this from the crude product of the reaction. The product can also be lyophilized.
- In most cases, vincristine thus obtained can be converted directly into an addition salt with an organic or inorganic acid, preferably pharmaceutically acceptable. This salt is preferably a sulfate that may arise in a more or less solvated or hydrated.
- We can also prepare vincristine dissolved in a physiologically acceptable solvent and ready to be injected.
- In particular, vincristine sulfate is obtained by addition of H 2 S0 4 to a solution of vincristine gross or recrystallized from ethanol, dissolved in a mixture of methylene chloride and anhydrous ethanol, partial removal in vacuo chloride methylene and crystallization.
- Vincristine sulfate thus obtained has a purity sufficient for use as a medicament, particularly in the form of injectable solutions.
The Madagascar Periwinkle
Vinblastine and Vincristine
Stereocontrolled total synthesis of (+)-vincristine