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Name Vinblastine sulfate;29060-LE;NSC-49842;Velbe;Velsar;Velban
Chemical Name Vincaleukoblastine sulfate
CAS 143-67-9
Related CAS 865-21-4 (free base)
Formula C46H60N4O13S
Structure
Formula Weight 909.0741
Stage 上市
Company Janssen (Originator), Lilly (Licensee)
Activity/Mechanism ONCOLYTIC DRUGS, Vinca Alkaloids
Syn. Route 17
Route 1
the indole alkaloid catharanthine (i) is treated with m-chloroperbenzoic acid to provide the n-oxide (ii). condensation of (ii) with the alkaloid vindoline (iii) under polonovski reaction conditions leads to the bis-indole adduct (iv), which is further reduced to the tetrahydropyridine compound (v). catalytic hydrogenation of tetrahydropyridine (v) furnishes (vi). this is then oxidized to the n-oxide (vii) (3).
List of intermediates No.
Reference 1:
    mangeney, p.; andriamialisoa, r.z.; langlois, n.; langlois, y.; potier, p.; preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from catharanthus spp. (apocynaceae). j am chem soc 1979, 101, 8, 2243.

Route 2
n-oxide (vii) is subjected to a new polonovski rearrangement, leading to enamine (viii). exposure of (viii) to thallium triacetate gives rise to the iminium salt (ix), which undergoes further reduction and acetate ester hydrolysis in the presence of nabh4 to yield the desired compound (3).
List of intermediates No.
Reference 1:
    mangeney, p.; andriamialisoa, r.z.; langlois, n.; langlois, y.; potier, p.; preparation of vinblastine, vincristine, and leurosidine, antitumor alkaloids from catharanthus spp. (apocynaceae). j am chem soc 1979, 101, 8, 2243.

Route 3
in a similar procedure, coupling of catharanthine-n-oxide (i) with vindoline (ii) under polonovski reaction conditions leads to the iminium salt (iii). this is subsequently converted into the desired enamine (iv) employing nadh as the reducing reagent. aeration of enamine (iv) in the presence of fecl3, followed by reductive work up leads to the title compound (4).
List of intermediates No.
Reference 1:
    kutney, j.p.; choi, l.s.l.; nakano, j.; tsukamoto, h.; mchugh, m.; boulet, c.a.; a highly efficient and commercially important synthesis of the antitumor catharantus alkaloids vinblastine and leurosidine from catharanthine and vindoline. heterocycles 1988, 27, 8, 1845.

Route 4
in an alternative synthesis, which does not utilize the alkaloid catharanthine, sharpless asymmetric epoxidation of 2-ethyl-2-propenol (i) in the presence of ( )-diethyl tartrate provides (r)-2-ethyl-2,3-epoxypropanol (ii). subsequent addition of allylmagnesium chloride (iii) to epoxide (ii) leads to diol (iv), which is further protected as the corresponding acetonide (v) with 2,2 dimethoxypropane and p-tsoh. ozonolysis of the terminal olefin (v) gives rise to aldehyde (vi). condensation of aldehyde (vi) with the indoloazapine (vii) furnishes the bridged azepine (viii) as a diastereomeric mixture. without isolation, this mixture of amines is n-alkylated with benzyl bromide, and the resultant ammonium salts (ix) are subjected to rearrangement in boiling meoh in the presence of et3n to provide an equimolecular mixture of the tetracyclic diastereoisomers (x) and (xi) (5).
List of intermediates No.
Reference 1:
    kuehne, m.e.; matson, p.a..; bornmann, w.g.; enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20-epi-vincovaline. j org chem 1991, 56, 2, 513.

Route 5
acidic hydrolysis of the mixture of diastereoisomeric acetonides (x) and (xi) leads to the respective diols, which are then separated by flash chromatography. after selective tosylation of the primary hydroxyl group of isomer (xii) with p-toluenesulfonic anhydride, the remaining tertiary hydroxyl is protected by silylation with trimethylsilyl triflate to furnish (xiii). chlorination of (xiii) with tert-butyl hypochlorite leads to (xiv), which is then coupled to vindoline (xv) in the presence of agbf4 to afford the bis-indolyl derivative (xvi) (5).
List of intermediates No.
Reference 1:
    kuehne, m.e.; matson, p.a..; bornmann, w.g.; enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20-epi-vincovaline. j org chem 1991, 56, 2, 513.

Route 6
reductive opening of (xvi) with kbh4 in acoh produces the indoloazonine system (xvii). intramolecular cyclization of the amino tosylate (xvii) in refluxing meoh leads to the quaternary salt (xviii). the n-benzyl group of (xviii) is then removed by hydrogenolysis over pd/c to give the silyl ether of vinblastine (xix). the trimethylsilyl group of (xix) is finally removed with tetrabutylammonium fluoride to furnish the target compound (5).
List of intermediates No.
Reference 1:
    kuehne, m.e.; matson, p.a..; bornmann, w.g.; enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20-epi-vincovaline. j org chem 1991, 56, 2, 513.

Route 7
in an improved method for the preparation of intermediate (xi), indolodiazepine (i) is condensed with the chiral ferrocenylethyl acetate (ii) to produce the n-alkylated compound (iii) as an inseparable mixture of diastereoisomers. subsequent condensation of (iii) with aldehyde (iv) and rearrangement in refluxing benzene gives rise to the tetracyclic compound (v) as a single diastereoisomer. acetolysis of (v) provides amine (vi) along with minor amounts of a partly epimerized compound, which can be removed by chromatography. then, alkylation of (vi) with benzyl bromide yields the key synthetic intermediate (xi) (6).
List of intermediates No.
Reference 1:
    kuehne, m.e.; bandarage, u.k.; an alternative enantioselective generation of intermediates in the total synthesis of vinblastine: enantioselection in secodine-type reactions induced by alpha-ferrocenylethyl n-substituents. j org chem 1996, 61, 3, 1175.

Route 8
in a nonoxidative coupling sytrategy, the required tetracyclic precursor (x) has been prepared by two methods. alkylation of thiolactam (i) with 2 (bromomethyl)-1-butene (ii) gives the thioiminium salt (iii), which undergoes thio-claisen rearrangement in the presence of dbu in thf to produce (iv) as a mixture of cis and trans isomers. after conversion of thiolactams (iv) into the corresponding lactams with m-chloroperoxybenzoic acid (mcpba), the desired isomer (v) is isolated employing preparative hplc. double bond dihydroxylation with n-methylmorpholine-n-oxide in the presence of a catalytic amount of oso4 leads to diol (vi) as a diastereomeric mixture. protection of diols (vi) with 1-methoxycyclohexene (vii) affords the corresponding mixture of cyclohexylidene ketals (viii). after conversion of (viii) to the respective thiolactams with lawessons reagent in hot toluene, separation of isomers employing preparative hplc furnishes thiolactam (ix). then, desulfuration of thiolactam (ix) by means of raney nickel gives rise to intermediate (x) (7).
List of intermediates No.
Reference 1:
    magnus, p.; mendoza, j.s.; stamford, a.; ladlow, m.; willis, p.; nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: solvent effect on the stereochemistry of the crucial c-15/c-18 bond. j am chem soc 1992, 114, 26, 10232.

Route 9
in an alternative, stereospecific synthesis of (x), sharpless asymmetric epoxidation of 2-ethyl-2-propen-1-ol (xi) in the presence of (-)-diethyl tartrate provides the (r)-epoxide (xii). ring opening of (xii) with sodium thiophenoxide produces diol (xiii), which is further protected with 1-methoxycyclohexene (vii), yielding ketal (xiv). sulfide (xiv) is then oxidized with mcpba to afford sulfoxide (xv) as a mixture of diastereoisomers. pummerer rearrangement of sulfoxides (xv) in boiling ac2o, followed by alkaline hydrolysis of the intermediate alpha-acetoxy sulfides furnishes aldehyde (xvi). then, aldol condensation of aldehyde (xvi) with thiolactam (i) employing stannous triflate and n-ethylpiperidine gives adduct (xvii). dehydration of alcohol (xvii) to the alpha,beta-unsaturated thiolactam (xviii) is accomplished by tosylation with p-toluenesulfonic anhydride, followed by tosylate elimination in the presence of dbu. desulfuration of thiolactam (xviii) with deactivated ra-ni leads to (xix). then, hydrogenation of olefin (xix) produces a mixture of epimers, from which the target isomer (x) can be isolated by column chromatography (7).
List of intermediates No.
Reference 1:
    magnus, p.; mendoza, j.s.; stamford, a.; ladlow, m.; willis, p.; nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: solvent effect on the stereochemistry of the crucial c-15/c-18 bond. j am chem soc 1992, 114, 26, 10232.

Route 10
the tetracyclic intermediate (x) is coupled to vindoline (xx) upon treatment with p-nitrobenzyl chloroformate to furnish the bis-indole adduct (xxi) as a mixture of epimers at the carbomethoxy group. isolation of the desired isomer, followed by acidic ketal hydrolysis leads to diol (xxii). this is then oxidized to the alpha-hydroxy aldehyde (xxiii) with so3-pyridine in dmso. finally, hydrogenolysis of the p-nitrobenzyl carbamate, with concomitant intramolecular reductive amination of the aldehyde group produces the title bis-indole alkaloid
List of intermediates No.
Reference 1:
    magnus, p.; mendoza, j.s.; stamford, a.; ladlow, m.; willis, p.; nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: solvent effect on the stereochemistry of the crucial c-15/c-18 bond. j am chem soc 1992, 114, 26, 10232.

Route 11
a stereocontrolled total synthesis of vinblastine has been reported. 3-ethyl-5-phenyl-4-pentenal (i) is transformed into cyanohydrin (ii), which is further acetylated with ac2o in pyridine to furnish the racemic alpha-acetoxy nitrile (iii). enzymatic hydrolysis of cyanohydrin acetate (iii) leads to (s)-cyanohydrin (iv) as a mixture of diastereomers at the 4-ethyl group. ozonolysis of (iv) produces the cyclic hemiacetal (v), which is subsequently dehydrated to the dihydrofuran (vi) employing mesyl chloride and triethylamine. the cyano group of (vi) is then reduced to the primary amine (vii) with lialh4 in thf. acylation of amine (vii) with 2,4-dinitrobenzenesulfonyl chloride leads to the corresponding sulfonamide (viii) (8).
List of intermediates No.
Reference 1:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.

Route 12
treatment of 7-mesyloxyquinoline (ix) with thiophosgene, followed by reduction with nabh4 gives rise to isothiocyanate (x). after protection of the hydroxyl group of (x) as the tetrahydropyranyl ether (xi), nucleophilic addition of the anion of benzyl methyl malonate to the isothiocyanate group affords thioanilide (xii). the radical cyclization of (xii) in the presence of aibn and bu3snh furnishes indole (xii). after protection of indole (xiii) as the n-boc derivative (xiv), the benzyl ester group is removed by hydrogenolysis, producing the mono-methyl malonate (xv). decarboxylative mannich reaction of (xv) with formaldehyde and dimethylamine leads to the indolylacrylate (xvi). the tetrahydropyranyl group is then selectively removed by means of csa in meoh to provide tryptophol (xvii) (8, 9).
List of intermediates No.
Reference 1:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.
Reference 2:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.

Route 13
mitsunobu coupling between tryptophol (xvii) and sulfonamide (viii) yields the n-sulfonyl tryptamine derivative (xviii). hydration of the cyclic enol ether, with simultaneous boc group cleavage under acidic conditions affords lactol (xix). subsequent deprotection of the dinitrobenzenesulfonyl group of (xix) with piperidine in meoh proceeds with rearrangement of the deprotected amino lactol to the cyclic hydroxy enamine (xx). this, upon further heating, undergoes a diels-alder type reaction to afford the pentacyclic vindoline ring system (xxi). following a previously reported synthetic pathway for (xxi), regioselective elimination of the secondary alcohol function, followed by protective group exchange at the phenolic hydroxyl, and oxidation with benzeneseleninic anhydride leads to the c4-alcohol (xxii). further introduction of the c3-hydroxyl with m chloroperbenzoic acid, and reduction of the resultant imine with nabh3cn provides diol (xxiii). after reductive methylation of the indoline n of (xxiii) with hcho/nabh3cn, acetylation of the secondary hydroxyl group produces ( ) vindoline (xxiii) (8, 9).
List of intermediates No.
Reference 1:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.
Reference 2:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.

Route 14
4-ethylpent-4-enoic acid (xxiv) is coupled to (r)-4-benzyl-2-oxazolidinone (xxv) via its mixed anhydride with pivaloyl chloride, producing the n-acyl oxazolidinone (xxvi). diastereoselective cyanoethylation of (xxvi) with acrylonitrile leads to (xxvii). reduction of imide (xxvii) with nabh4, followed by protection of the resulting alcohol with t-butyldiphenylsilyl chloride furnishes the silyl ether (xxviii). the nitrile function of (xxviii) is then reduced by means of dibal to the aldehyde (xxix), which is further treated with hydroxylamine to yield the corresponding oxime (xxx). exposure of oxime (xxx) to naocl generates an intermediate nitrile oxide, which undergoes intramolecular 1,3-dipolar cycloaddition to the isoxazoline (xxxi). subsequent reductive cleavage of the isoxazoline (xxxi) n-o bond with zn/acoh leads to compound (xxxii). cyclohexanone (xxxii) is then converted to lactone (xxxiii) under baeyer-villiger conditions. further methanolysis of lactone (xxxiii) gives rise to the open-chain dihydroxyester (xxxiv). sequential protection of the primary hydroxyl group with triethylchlorosilane and the tertiary hydroxyl with trimethylchlorosilane furnishes the fully silylated triol (xxxv) (8). the lithium enolate of ester (xxxv) is then condensed with isothiocyanate (xxxvi) to produce thioanilide (xxxvii) (8, 9).
List of intermediates No.
(3as,4r,8r,8as)-4,8-dibenzyl-2,2-dimethylhexahydro-6h-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one (xxvi)
Reference 1:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.
Reference 2:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.

Route 15
radical cyclization of thioanilide (xxxvii) gives rise to indole (xxxviii), which is further protected as the n-boc derivative (xxxix) employing boc2o. the fully protected tr (xxxix) is then treated with 95% acoh to furnish triol (xl). upon treatment of triol (xl) with tosyl chloride and triethylamine in the presence of dibutyltin oxide, tosylation occurs selectively at the primary alcohol of the 1,2-diol moiety. the resulting tosylate (xli) is further cyclized to epoxide (xlii) in the presence of nahco3 in hot dmf. the remaining primary alcohol of (xliii) is then coupled to p-nitrobenzenesulfonamide (xliii) under mitsunobu conditions, producing (xliv). macrocyclization of the epoxy sulfonamide (xliv) upon heating with k2co3 in dmf yields the 11-membered ring compound (xlv) (8,9).
List of intermediates No.
Reference 1:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.
Reference 2:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.

Route 16
acid-catalyzed deprotection of the n-boc and o-silyl groups of (xlv) leads to (xlvi). the primary hydroxyl group of (xlvi) is then tosylated to afford (xlvii). subsequent esterification of the remaining tertiary hydroxyl with trifluoroacetic anhydride and pyridine yields trifluoroacetate (xlviii). chlorination of the indole nucleus of (xlviii) with t-butyl hypochlorite furnishes the chloroindolenine (xlix). thisi is then coupled to vindoline (xxiii) in the presence of trifluoroacetic acid to form the bis-indole adduct (l) (8,9).
List of intermediates No.
Reference 1:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.
Reference 2:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.

Route 17
the trifluoroacetate ester group of (l) is deprotected by treatment with triethylamine in meoh to give (li). subsequent deprotection of the n-sulfonyl group with mercaptoethanol and dbu liberates the secondary amine which finally undergoes cyclization to the title compound upon intramolecular displacement of the tosylate group (8, 9).
List of intermediates No.
Reference 1:
    schneider, c.; first de novo synthesis of the bisindole alkaloid vinblastine. angew chem. int ed 2002, 41, 22, 4217.
Reference 2:
    yokoshima, s.; ueda, t.; kobayashi, s.; sato, a.; kuboyama, t.; tokuyama, h.; fukuyama, t.; stereocontrolled total synthesis of (+)-vinblastine. j am chem soc 2002, 124, 10, 2137.

 
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