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【结 构 式】 
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【分子编号】19890 【品名】allyl (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoate 【CA登记号】 |
【 分 子 式 】C18H31NO6 【 分 子 量 】357.44728 【元素组成】C 60.48% H 8.74% N 3.92% O 26.86% |
合成路线1
该中间体在本合成路线中的序号：(III)Condensation of (R)-3-(tert-butoxycarbonylamino)butyric acid (II) with hydroxyester (I) using DCC and DMAP provided compound (III). Removal of the allyl group of (III) ester was then effected by treatment with Pd(PPh3)4 and N-methylmorpholine (NMM) to afford acid (IV). Subsequent coupling of (IV) with alcohol (V) in the presence of DCC and DMAP yielded the corresponding ester (VI). After deprotection of the trichloroethyl ester with Zn in AcOH, and subsequent deprotection of the N-tert--butoxycarbonyl group with trifluoroacetic acid, the resulting amino acid compound (VIII) was cyclized by treatment with FDPP in the presence of diisopropylethylamine to provide lactam (IX). Finally, epoxidation of the styrene olefin with m-chloroperbenzoic acid in CH2Cl2 furnished a mixture of diastereoisomeric epoxides, from which the title compound was isolated by reverse-phase HPLC.
| 【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69. |
| 【2】 Moore, R.E.; Patel, V.F.; Ray, J.E.; Toth, J.E. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0850057; JP 2000501067; WO 9707798; WO 9708334 . |
| 【3】 Shih, C. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0869786; JP 2000502351; WO 9723211 . |
| 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) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (II) | 19889 | (3R)-3-[(tert-butoxycarbonyl)amino]butyric acid | C9H17NO4 | 详情 | 详情 | |
| (III) | 19890 | allyl (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoate | C18H31NO6 | 详情 | 详情 | |
| (IV) | 19891 | (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoic acid | C15H27NO6 | 详情 | 详情 | |
| (V) | 18905 | 2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate | C27H29Cl4NO5 | 详情 | 详情 | |
| (VI) | 19893 | 2,2,2-trichloroethyl (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate | C42H54Cl4N2O10 | 详情 | 详情 | |
| (VII) | 19894 | (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid | C40H53ClN2O10 | 详情 | 详情 | |
| (VIII) | 19895 | (2R)-2-([(2E,5S,6R,7E)-5-[((2S)-2-[[(3R)-3-aminobutanoyl]oxy]-4-methylpentanoyl)oxy]-6-methyl-8-phenyl-2,7-octadienoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C35H45ClN2O8 | 详情 | 详情 | |
| (IX) | 19896 | (3S,7R,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-7-methyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C35H43ClN2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of (R)-3-(tert-butoxycarbonylamino)butyric acid (II) with hydroxyester (I) using DCC and DMAP provided compound (III). Removal of the allyl group of (III) was then effected by treatment with Pd(PPh3)4 and N-methylmorpholine (NMM) to afford acid (IV). Subsequent coupling of (IV) with alcohol (V) in the presence of DCC and DMAP yielded the corresponding ester (VI). After deprotection of the trichloroethyl ester with Zn in AcOH group (VII), and subsequent deprotection of the N-tert-butoxycarbonyl group with trifluoroacetic acid, the resulting amino acid compound (VIII) was cyclized by treatment with FDPP in the presence of diisopropylethylamine to provide lactam (IX). Finally, epoxidation of the styrene olefin with m-chloroperbenzoic acid in CH2Cl2 furnished a mixture of diastereoisomeric epoxides, from which the title compound was isolated by reverse-phase HPLC.
| 【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69. |
| 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) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (II) | 19889 | (3R)-3-[(tert-butoxycarbonyl)amino]butyric acid | C9H17NO4 | 详情 | 详情 | |
| (IV) | 19890 | allyl (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoate | C18H31NO6 | 详情 | 详情 | |
| (V) | 19891 | (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoic acid | C15H27NO6 | 详情 | 详情 | |
| (VII) | 19893 | 2,2,2-trichloroethyl (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate | C42H54Cl4N2O10 | 详情 | 详情 | |
| (VIII) | 19894 | (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid | C40H53ClN2O10 | 详情 | 详情 | |
| (IX) | 19895 | (2R)-2-([(2E,5S,6R,7E)-5-[((2S)-2-[[(3R)-3-aminobutanoyl]oxy]-4-methylpentanoyl)oxy]-6-methyl-8-phenyl-2,7-octadienoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C35H45ClN2O8 | 详情 | 详情 | |
| (X) | 19896 | (3S,7R,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-7-methyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C35H43ClN2O7 | 详情 | 详情 |