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【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
      (2R,6S,9S,11R,12S,14aS,15S,20S,23S,25aS)-12-(2-Aminoethylamino)-20-[3-amino-1(R)-hydroxypropyl]-23-[1(S),2(S)-dihydroxy-2-(4-hydroxyphenyl)ethyl]-9-(10,12-dimethyltetradecanamido)-2,11,15-trihydroxy-6-[1(R)-hydroxyethyl]perhydrodipyrrolo[2,1-c:2',1'-l][1,4,7,10,13,16]hexaazacycloheneicosine-5,8,14,19,22,25-hexaone diacetate
      1-[(4R,5S)-5-(2-Aminoethylamino)-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[3(R)-hydroxy-L-ornithine]-pneumocandin B0 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
Extended Information