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【结 构 式】 
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【分子编号】33118 【品名】(2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid 【CA登记号】71989-33-8 |
【 分 子 式 】C22H25NO5 【 分 子 量 】383.44424 【元素组成】C 68.91% H 6.57% N 3.65% O 20.86% |
合成路线1
该中间体在本合成路线中的序号：(VI)The title compound was obtained by the solid-phase method using a peptide synthesizer. Starting from Fmoc-valine linked to Wang resin (I), cleavage of the Fmoc group with piperidine in DMF provided the deprotected valine-resin (II), which was then coupled with Fmoc-leucine (III) by means of 1-hydroxybenzotriazole and diisopropylcarbodiimide. The resulting dipeptide resin (IV) was deprotected with piperidine in DMF to give (V), and further coupling with protected serine (VI) yielded (VII). After Fmoc-deprotection, the tripeptide-resin (VIII) was coupled with phenyl isocyanate (IX), affording urea (X). Cleavage from the resin with simultaneous deprotection using trifluoroacetic acid furnished the tripeptide urea (XI). This was finally esterified by treatment with ethanolic HCl to provide the target ethyl ester.
| 【1】 Sawa, E.; et al.; Structural modification of Fas C-terminal tripeptide and its effects on the inhibitory activity of Fas/FAP-1 binding. J Med Chem 1999, 42, 17, 3289. |
| 【2】 Kataoka, S.; Nishitoba, T.; Takahashi, M.; Sawa, E.; Kamishohara, M. (Kirin Brewery Co., Ltd.); Novel peptide cpds. and medicinal compsns. thereof. JP 1999171896; WO 9711091 . |
| 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) | 19932 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
| (II) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (III) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (IV) | 33117 | (2S)-2-[((2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C26H32N2O5 | 详情 | 详情 | |
| (V) | 33123 | (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-3-methylbutyric acid | 35436-83-0 | C11H22N2O3 | 详情 | 详情 |
| (VI) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
| (VII) | 33119 | (5S,8S,11S)-5-(tert-butoxymethyl)-1-(9H-fluoren-9-yl)-8-isobutyl-11-isopropyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oic acid | C33H45N3O7 | 详情 | 详情 | |
| (VIII) | 33120 | (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C18H35N3O5 | 详情 | 详情 | |
| (IX) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (X) | 33121 | (2S)-2-[((2S)-2-[[(2S)-2-[(anilinocarbonyl)amino]-3-(tert-butoxy)propanoyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C25H40N4O6 | 详情 | 详情 | |
| (XI) | 33122 | (2S)-2-[[(2S)-2-([(2S)-2-[(anilinocarbonyl)amino]-3-hydroxypropanoyl]amino)-4-methylpentanoyl]amino]-3-methylbutyric acid | C21H32N4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The peptide moiety (XVII) was prepared by solid-phase synthesis in a peptide synthesizer starting from Boc-Leu-PAM resin (I). Removal of the Boc protecting group of (I) was effected by treatment with trifluoroacetic acid in CH2Cl2. To the deprotected Leu-resin (II) were sequentially incorporated the following amino acids: N-Fmoc-L-serine(O-t-Bu) (III), N-Fmoc-L-glutamine(Trt) (V), N-Fmoc-L-cyclohexylglycine (VII), again Fmoc-L-serine(O-t-Bu) (III), and N-Fmoc-L-alanine (X) using DCC and HOBt activation in N-methyl-2-pyrrolidinone, each followed by an Fmoc deprotection cycle with piperidine in DMF. The peptide resins (IV), (VI), (VIII), (IX) and (XI) were in turn obtained.
| 【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
| 【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
| 【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (III) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
| (IV) | 53663 | (2S)-2-{[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C13H26N2O4 | 详情 | 详情 |
| (V) | 53664 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxo-5-(tritylamino)pentanoic acid | n/a | C39H34N2O5 | 详情 | 详情 |
| (VI) | 53665 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C37H48N4O6 | 详情 | 详情 |
| (VII) | 53666 | (2S)-2-cyclohexyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoic acid | n/a | C23H25NO4 | 详情 | 详情 |
| (VIII) | 53667 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C45H61N5O7 | 详情 | 详情 |
| (IX) | 53668 | (2S,5S,8S,11S,14S)-14-amino-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C52H74N6O9 | 详情 | 详情 |
| (X) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |