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【结 构 式】

【分子编号】53357

【品名】2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide

【CA登记号】n/a

【 分 子 式 】C33H47N5O8Si

【 分 子 量 】669.85058

【元素组成】C 59.17% H 7.07% N 10.46% O 19.11% Si 4.19%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XXI)

The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).

1 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 53353 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C48H57N5O13 详情 详情
(XVIII) 53354 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C57H77N5O13Si 详情 详情
(XIX) 53355 (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid n/a C53H69N5O13Si 详情 详情
(XX) 53356 benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate n/a C48H59N5O10Si 详情 详情
(XXI) 53357 2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide n/a C33H47N5O8Si 详情 详情
(XXII) 46950 3-methyl-2-oxopentanoic acid C6H10O3 详情 详情
(XXIII) 53358 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C39H55N5O10Si 详情 详情
(XXIV) 53359 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C30H35N5O10 详情 详情
(XXV) 53360 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C54H91N5O10Si4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXI)

The selective protection of the primary OH group of (XVII) with Tips-Cl and imidazole yields the silyl ether (XVIII), which is treated with TFA in dichloromethane to afford the carboxylic acid (XIX). The macrolactamization of (XIX) by means of EDC, HOAt and DIEA in DMF/dichloromethane provides the macrolactam (XX), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to furnish the aminophenol (XXI). The condensation of (XXI) with racemic 3-methyl-2-oxopentanoic acid (XXII) by means of EDC and HOAt in DMF/dichloromethane gives the amide (XXIII) as a diastereomeric mixture. The desilylation of (XXIII) by means of HF and pyridine gives the tetrahydroxy compound (XXIV), which is fully resilylated with Tes-OTf and lutidine in dichloromethane to yield the tetra-silyl ether (XXV).

1 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 53353 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1,3-dihydroxypropyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C48H57N5O13 详情 详情
(XVIII) 53354 tert-butyl (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoate n/a C57H77N5O13Si 详情 详情
(XIX) 53355 (2S)-4-amino-2-[((2S)-3-[4-(benzyloxy)-3-((3S)-3-{(1R,2R)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[(triisopropylsilyl)oxy]propyl}-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-7-yl)phenyl]-2-{[(benzyloxy)carbonyl]amino}propanoyl)amino]-4-oxobutanoic acid n/a C53H69N5O13Si 详情 详情
(XX) 53356 benzyl (10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-23-(benzyloxy)-10,11-dihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-ylcarbamate n/a C48H59N5O10Si 详情 详情
(XXI) 53357 2-[(10S,11R,12R,15S,18S)-18-amino-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-15-yl]acetamide n/a C33H47N5O8Si 详情 详情
(XXII) 46950 3-methyl-2-oxopentanoic acid C6H10O3 详情 详情
(XXIII) 53358 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-9,14,17-trioxo-12-{[(triisopropylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C39H55N5O10Si 详情 详情
(XXIV) 53359 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-10,11,23-trihydroxy-12-(hydroxymethyl)-9,14,17-trioxo-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C30H35N5O10 详情 详情
(XXV) 53360 N-[(10S,11R,12R,15S,18S)-15-(2-amino-2-oxoethyl)-9,14,17-trioxo-10,11,23-tris[(triethylsilyl)oxy]-12-{[(triethylsilyl)oxy]methyl}-8,13,16-triazatetracyclo[18.3.1.0~2,7~.0~6,10~]tetracosa-1(24),2,4,6,20,22-hexaen-18-yl]-3-methyl-2-oxopentanamide n/a C54H91N5O10Si4 详情 详情
Extended Information