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【结 构 式】 
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【分子编号】18908 【品名】(2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid 【CA登记号】 |
【 分 子 式 】C36H47ClN2O8 【 分 子 量 】671.23056 【元素组成】C 64.42% H 7.06% Cl 5.28% N 4.17% O 19.07% |
合成路线1
该中间体在本合成路线中的序号：(XI)Title compound can be prepared either by bacterial fermentation or by chemical synthesis. Thus, the compund was isolated from cultures of Nostoc sp. GSV 224, growing in the presence of 2,2-dimethyl-b-alanine. After lyophilization and extraction with CH3CN-CH2Cl2, the extract was subjected to several chromatographic purifications to provide the pure compound. Alternatively, 2,2-dimethyl-b-alanine tert-butyl ester (I) was deprotected with trifluoroacetic acid, and the resulting carboxylic acid (II) was treated with di tert-butyl oxalate (III) in the presence of NaOH to afford carbamate (IV). Subsequent coupling with allyl (S)-2-hydroxy-4-methylpentanoate (V) using DCC and DMAP gave ester (VI). The allyl ester was then cleaved by treatment with Pd(Ph3P)4 and morpholine in THF at r.t., and the resulting acid (VII) was coupled with compound (VIII) in the presence of DCC and DMAP to afford (IX). After deprotection of the trichloroethyl ester group by treatment with Zn in AcOH and subsequent cleavage of the N-Boc group with trifluoroacetic acid, the resulting amino acid compound (XI) was cyclized using pentafluorophenyl diphenyl phosphinate (FDPP) to furnish (XII). Finally, epoxidation with meta-chloroperbenzoic acid provided a mixture of diastereomeric epoxides that were separated 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) | 18898 | tert-butyl 3-amino-2,2-dimethylpropanoate | C9H19NO2 | 详情 | 详情 | |
| (II) | 18899 | 2,2-dimethyl-beta-alanine | C5H11NO2 | 详情 | 详情 | |
| (III) | 18900 | tert-butyl 2-(tert-butoxy)-2-oxoacetate | C10H18O4 | 详情 | 详情 | |
| (IV) | 18901 | N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine | C10H19NO4 | 详情 | 详情 | |
| (V) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (VI) | 18903 | allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate | C19H33NO6 | 详情 | 详情 | |
| (VII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (VIII) | 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 | |
| (IX) | 18906 | 2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-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 | C43H56Cl4N2O10 | 详情 | 详情 | |
| (X) | 18907 | (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-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 | C41H55ClN2O10 | 详情 | 详情 | |
| (XI) | 18908 | (2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid | C36H47ClN2O8 | 详情 | 详情 | |
| (XII) | 18909 | (3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C36H45ClN2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Elimination of the trichloroethyl group of (XXV) with Zn in acetic acid gives the carboxyl free intermediate (XXVI), which is treated with TFA to yield intermediate (XXVII) with free amino and carboxy groups. The cyclization of (XXVII) with pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF affords the corresponding cyclic amide (XXVIII), which is finally epoxidated with MCPBA in dichloromethane, furnishing a diastereomeric mixture of epoxides that are separated by reverse phase chromatography.
| 【1】 WO 9640184 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXV) | 18906 | 2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-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 | C43H56Cl4N2O10 | 详情 | 详情 | |
| (XXVI) | 18907 | (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-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 | C41H55ClN2O10 | 详情 | 详情 | |
| (XXVII) | 18908 | (2R)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]-3-(3-chloro-4-methoxyphenyl)propionic acid | C36H47ClN2O8 | 详情 | 详情 | |
| (XXVIII) | 18909 | (3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C36H45ClN2O7 | 详情 | 详情 |