【结 构 式】 |
【药物名称】Caspofungin acetate, MK-0991, MK-991, L-743872, Caspofungin MSD, Cancidas 【化学名称】(3S,6S,9S,11R,15S,18S,20R,21S,24S,25S)-21-(2-Aminoethylamino)-3-[3-amino-1(R)-hydroxypropyl]-6-[1(S),2(S)-dihydroxy-2-(4-hydroxyphenyl)ethyl]-18-(10,12-dimethyltetradecanamido)-11,20,25-trihydroxy-15-[1(R)-hydroxyethyl]-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0(9,13)]heptacosane-2,5,8,14,17,23-hexaone diacetate 【CA登记号】179463-17-3, 162808-62-0 (free base) 【 分 子 式 】C56H96N10O19 【 分 子 量 】1213.44512 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, 1,3-beta-Glucan Synthase Inhibitors, Echinocandins |
合成路线1
【1】 Bouffard FA.Zambias RA,Dropinski.JF,et aL 1994.Synthesis and antifungal activity of novel cationic poeumocandin B derivatives J Med Chem, 37: 222~225 |
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) | 47003 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H80N8O17 | 详情 | 详情 | |
(II) | 66161 | C50H80N8O15 | 详情 | 详情 | ||
(III) | 47005 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H82N8O16 | 详情 | 详情 | |
(IV) | 47007 | N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)sulfanyl]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C52H87N9O15S | 详情 | 详情 | |
(V) | 66162 | C52H87N9O15S | 详情 | 详情 | ||
(VI) | 66163 | C56H84N8O16S | 详情 | 详情 |
合成路线2
【1】 Leonard Jr WR, Belyk KW, Conlon DA, et al.2007. Synthesis of the antifungal β-1,3-glucad synthase.inhibitor CANCIDAS (caspofungin aeetate) from Imeumocandin Bo J Or{j{ Chem, 72: 2335~2343 |
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) | 47003 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H80N8O17 | 详情 | 详情 | |
(II) | 66163 | C56H84N8O16S | 详情 | 详情 | ||
(III) | 66164 | C62H88N8O15S2 | 详情 | 详情 | ||
(IV) | 47006 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxo-12-(phenylsulfanyl)tetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C56H86N8O15S | 详情 | 详情 |
合成路线3
【1】 Belyk KM, Bender DR, Black RM,et aL 1996.Process for:preparing certain are cyclohexapeptides,US 5552521 |
【2】 Balkovec JM, Black RM, Bouffard FA 1995. Aza cyclohexapeptide conacpounds. US 5378804 |
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) | 47003 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H80N8O17 | 详情 | 详情 | |
(II) | 47005 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H82N8O16 | 详情 | 详情 | |
(III) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
(IV) | 66163 | C56H84N8O16S | 详情 | 详情 | ||
(V) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
合成路线4
The reaction of cyclopeptide (I) with phenylboronic acid in THF gives the bis boronate (II), which is reduced at the carbamoyl group with BH3/S(Me)2 in THF and deprotected with HCl to afford the cyclopeptide (III). The reaction of (III) with thiophenol and TFA in acetonitrile affords the phenylsulfanyl derivative (IV), which is finally treated with ethylenediamine to afford the target compound. Alternatively, cyclopeptide (I) can be reduced directly to cyclopeptide (II) with BH3/S(Me)2 in THF.
【1】 Hugues, D.L.; Belyk, K.M.; Black, R.M.; Bender, D.R.; Leonard, W. (Merck & Co., Inc.); Process for preparing certain aza cyclohexapeptides. US 5552521 . |
【2】 Belyk, K.M.; Black, R.M.; Hugues, D.L.; Bender, D.R.; Leonard, W. (Merck & Co., Inc.); A process for preparing certain aza cyclohexapeptides. WO 9624613 . |
【3】 Leonard, W.; Belyk, K.M. (Merck & Co., Inc.); A process for preparing certain aza cyclohexapeptides. WO 9747645 . |
【4】 Leonard, W.; Belyk, K.M. (Merck & Co., Inc.); Process for preparing certain aza cyclohexapeptides. US 5936062 . |
【5】 Kaufman, M.J.; Hunke, W.A.; Neururkar, M.J. (Merck & Co., Inc.); Antifungal compsns.. US 6136783 . |
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) | 47003 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H80N8O17 | 详情 | 详情 | |
(II) | 47004 | N-[(3aR,5aS,6S,11S,14S,16aS,18R,22S,25S,26aR)-11-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-6,18-dihydroxy-22-[(1R)-1-hydroxyethyl]-14-[(4S,5R)-5-(4-hydroxyphenyl)-2-phenyl-1,3,2-dioxaborolan-4-yl]-5,10,13,16,21,24-hexaoxo-2-phenyltetracosahydro-10H-[1,3,2]dioxaborolo[4,5-t]dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-25-yl]-10,12-dimethyltetradecanamide | C62H86B2N8O17 | 详情 | 详情 | |
(III) | 47005 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H82N8O16 | 详情 | 详情 | |
(IV) | 47006 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxo-12-(phenylsulfanyl)tetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C56H86N8O15S | 详情 | 详情 |
合成路线5
The reaction of cyclopeptide (V) with 2-sulfanylethylamine (VI) by means of camphorsulfonic acid (CSA) in DMF gives the epi-2-aminoethylsulfanyl compound (VII), which is oxidized with oxone in acetonitrile/water, affording the sulfone (VIII). Finally, this compound is treated with ethylenediamine in DMF to afford the target compound.
【1】 Balkovec, J.M.; Bouffard, F.A.; Black, R.M. (Merck & Co., Inc.); Aza cyclohexapeptide cpds.. CA 2118757; EP 0620232; JP 1994321986; US 5378804; WO 9421677 . |
【2】 Balkovec, J.M.; Black, R.M.; Bouffard, F.A. (Merck & Co., Inc.); Aza cyclohexapeptide cpds.. US 5792746 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 47005 | N-[(2R,6S,9S,11R,12R,14aS,15S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C50H82N8O16 | 详情 | 详情 | |
(VI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
(VII) | 47007 | N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)sulfanyl]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C52H87N9O15S | 详情 | 详情 | |
(VIII) | 47008 | N-[(2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-[(2-aminoethyl)sulfonyl]-20-[(1R)-3-amino-1-hydroxypropyl]-23-[(1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-2,11,15-trihydroxy-6-[(1R)-1-hydroxyethyl]-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-9-yl]-10,12-dimethyltetradecanamide | C52H87N9O17S | 详情 | 详情 |