V-Echinocandin, Anidulafungin, VER-002, LY-303366, Ecalta, -Drug Synthesis Database

【结构式】

【药物名称】V-Echinocandin, Anidulafungin, VER-002, LY-303366, Ecalta

【化学名称】(11aS,25aS)-N-[9(S)-[1(S),2(S)-Dihydroxy-2-(4-hydroxyphenyl)ethyl]-1(S),13(R),22(R),23(R)-tetrahydroxy-6(S),17(S)-bis[1(R)-hydroxyethyl]-2(S)-methyl-5,8,11,16,19,25-hexaoxoperhydrodipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacycloheneicosin-20(S)-yl]-4''-pentyloxy-p-terphenyl-4-carboxamide
　　　　　　4(R),5(R)-Dihydroxy-N2-(4''-pentyloxy-p-terphenyl-4-ylcarbonyl)-L-ornithyl-L-threonyl-[4(R)-hydroxy]-L-prolyl-[4(S)-hydroxy-4-(4-hydroxyphenyl)]-L-threonyl-L-threonyl-[3(S)-hydroxy-4(S)-methyl]-L-proline C-1.6-N-5.1-cyclic peptide

【CA登记号】166663-25-8

【分子式】C₅₈H₇₃N₇O₁₇

【分子量】1140.26521

【开发单位】Lilly (Originator), Vicuron Pharmaceuticals (Licensee)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, 1,3-beta-Glucan Synthase Inhibitors, Echinocandins

合成路线1 合成路线2

合成路线1

By condensation of cyclopeptide (I) with 4''-(pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester (II) by means of dicyclohexylcarbodiimide (DCC) in DMF at room temperature.

参考文献中间体

【1】 Burkhardt, F.J.; Debono, M.; Nissen, J.S.; Turner, W.W. Jr. (Eli Lilly and Company); Cyclic peptide antifungal agents and process for preparation thereof. EP 0561639; JP 1994056892 .
【2】 Fromtling, R.A.; LY-303366. Drugs Fut 1994, 19, 4, 338.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	16118	(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-amino-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6,20-bis[(1R)-1-hydroxyethyl]-16-methylhexadecahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosine-5,8,14,19,22,25(9H,25aH)-hexone		C₃₄H₅₁N₇O₁₅	详情	详情
(II)	16119	4''-(Pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester		C₃₀H₂₅Cl₃O₃	详情	详情

合成路线2

A new synthesis of LY-303366 has been reported: The enzymatic hydrolysis of echinocandin B (I) with Actinoplanes utahensis provides the corresponding cyclic peptide (II), which is then reacylated with the active ester 4''-(pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester (III) in DMF. The active ester (III) is obtained as follows: 4-Bromo-4'-(pentyloxy)biphenyl (IV) is treated with sec-butyllithium and triisopropyl borate in THF/cyclohexane, yielding (after hydrolysis with HCl) 4'-(pentyloxy)biphenyl-4-boronic acid (V), which is condensed with methyl 4-iodobenzoate (VI) by means of palladium tetrakis(triphenylphosphine) and K2CO3 in refluxing toluene, giving 4''-(pentyloxy)-p-terphenyl-4-carboxylic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in refluxing dioxane containing 2N NaOH affords the corresponding free acid (VIII), which is finally converted to the active ester (III) by esterification with 2,4,5-trichlorophenol (IX) by means of dicyclohexylcarbodiimide (DCC) in DMF.

参考文献中间体

【1】 LaGrandeur, L.; Turner, W.W.; Debono, M.; et al.; Semisynthetic chemical modification of the antifungal lipopeptidechinocandin B (ECB): Structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem 1995, 38, 17, 3271.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	16120	(9Z,12Z)-N-[(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6,20-bis[(1R)-1-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-9,12-octadecadienamide		C₅₂H₈₁N₇O₁₆	详情	详情
(II)	16118	(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-amino-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6,20-bis[(1R)-1-hydroxyethyl]-16-methylhexadecahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosine-5,8,14,19,22,25(9H,25aH)-hexone		C₃₄H₅₁N₇O₁₅	详情	详情
(III)	16119	4''-(Pentyloxy)-p-terphenyl-4-carboxylic acid 2,4,5-trichlorophenyl ester		C₃₀H₂₅Cl₃O₃	详情	详情
(IV)	16121	4-bromo-4'-(pentyloxy)-1,1'-biphenyl; 4'-bromo[1,1'-biphenyl]-4-yl pentyl ether		C₁₇H₁₉BrO	详情	详情
(V)	16122	4'-(Pentyloxy)biphenyl-4-ylboronic acid		C₁₇H₂₁BO₄	详情	详情
(VI)	16123	methyl 4-iodobenzoate	619-44-3	C₈H₇IO₂	详情	详情
(VII)	16124	4''-Pentyloxy-p-terphenyl-4-carboxylic acid methyl ester		C₂₅H₂₆O₃	详情	详情
(VIII)	16125	4''-(Pentyloxy)-p-terphenyl-4-carboxylic acid		C₂₄H₂₄O₃	详情	详情
(IX)	16126	2,4,5-trichlorophenol	95-95-4	C₆H₃Cl₃O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)