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【结 构 式】 
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【分子编号】51011 【品名】(2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid 【CA登记号】 |
【 分 子 式 】C26H38N2O9 【 分 子 量 】522.5958 【元素组成】C 59.76% H 7.33% N 5.36% O 27.55% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Coupling between gamma-tert-butoxy glutamic acid (XI) and gamma-tert-butoxy-N-Cbz-glutamic acid succinimidyl ester (XII) produced the protected dipeptide (XIII). This was further coupled to the intermediate amine (X) to furnish the corresponding amide (XIV). After hydrogenolysis of the N-Cbz protecting group of (XIV), the resultant amine (XV) was acylated with tetraazacyclododecanetetraacetic acid tri-tert-butyl ester (XVI), yielding the amide adduct (XVII).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77. |
| 【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 52482 | methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate | C25H30N6O4 | 详情 | 详情 | |
| (XI) | 51009 | (2S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid | C9H17NO4 | 详情 | 详情 | |
| (XII) | 51010 | tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate | C21H26N2O8 | 详情 | 详情 | |
| (XIII) | 51011 | (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid | C26H38N2O9 | 详情 | 详情 | |
| (XIV) | 52486 | C51H66N8O12 | 详情 | 详情 | ||
| (XV) | 51014 | 2-[4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C28H52N4O8 | 详情 | 详情 | |
| (XVI) | 52483 | C43H60N8O10 | 详情 | 详情 | ||
| (XVII) | 52484 | C71H110N12O17 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Coupling of the succinimidyl ester of protected glutamic acid (XVI) with glutamic acid gamma-tert-butyl ester (XV) provided the protected dipeptide (XVII), which was then activated with tetrafluorophenol (XVIII) by means of EDC in DMF to yield the tetrafluorophenyl ester (XIX). Condensation of (XIX) with amine (XIV) produced amide (XX), whose N-benzyloxycarbonyl group was then removed by hydrogenolysis over Pd/C to yield amine (XXI).
| 【1】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 51008 | (2S)-2-[[(4-[4-[(2-aminoethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid | C31H41N9O7S | 详情 | 详情 | |
| (XV) | 51009 | (2S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid | C9H17NO4 | 详情 | 详情 | |
| (XVI) | 51010 | tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate | C21H26N2O8 | 详情 | 详情 | |
| (XVII) | 51011 | (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid | C26H38N2O9 | 详情 | 详情 | |
| (XVIII) | 49986 | 2,3,5,6-Tetrafluorophenol | 769-39-1 | C6H2F4O | 详情 | 详情 |
| (XIX) | 51012 | 5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate | C32H38F4N2O9 | 详情 | 详情 | |
| (XX) | 51013 | (2S)-2-([[4-([(10S,13S)-10,13-bis[3-(tert-butoxy)-3-oxopropyl]-4,9,12,15-tetraoxo-17-phenyl-16-oxa-5,8,11,14-tetraazaheptadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid | C57H77N11O15S | 详情 | 详情 | |
| (XXI) | 51021 | (2S)-2-([[4-([(10S,13S)-13-amino-10-[3-(tert-butoxy)-3-oxopropyl]-18,18-dimethyl-4,9,12,16-tetraoxo-17-oxa-5,8,11-triazanonadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid | C49H71N11O13S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)In a related procedure, intermediate (XII) was first deprotected by hydrogenolysis of the N-benzyloxycarbonyl group, yielding amine (XXV). Coupling of this amine with the dipeptide (XVII) furnished adduct (XXVI), which was again deprotected by hydrogenolysis, yielding (XXVII).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 51006 | methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propanoate | C59H63N9O9S | 详情 | 详情 | |
| (XVII) | 51011 | (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid | C26H38N2O9 | 详情 | 详情 | |
| (XXV) | 51017 | methyl (2S)-2-[[(4-[4-[(2-aminoethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propanoate | C51H57N9O7S | 详情 | 详情 | |
| (XXVI) | 51018 | tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxopentanoate | C77H93N11O15S | 详情 | 详情 | |
| (XXVII) | 51019 | tert-butyl (4S)-4-amino-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxopentanoate | C69H87N11O13S | 详情 | 详情 |