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【结 构 式】 
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【分子编号】53669 【品名】(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 【CA登记号】n/a |
【 分 子 式 】C55H79N7O10 【 分 子 量 】998.27344 【元素组成】C 66.17% H 7.98% N 9.82% O 16.03% |
合成路线1
该中间体在本合成路线中的序号：(XI)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 |
合成路线2
该中间体在本合成路线中的序号：(XI)To the peptide resin (XI) was coupled N-Boc-trans-4-hydroxy-L-proline (XII) to produce resin (XIII). Simultaneous removal of the N-terminal and side-chain protecting groups of (XIII) with trifluoroacetic acid in CH2Cl2 furnished the deprotected peptide resin (XIV). Acylation of (XIV) with the mono-fluorenylmethyl ester of glutaric acid (XV) produced amide (XVI). The desired peptide (XVII) was then liberated from the resin (XVI) employing HF in the presence of anisole.
| 【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 |
|---|---|---|---|---|---|---|
| (XVI),(XVII) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 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 |
| (XII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (XIII) | 53670 | (3S,6S,9S,12S,15S,18S)-1-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]-6,15-bis(tert-butoxymethyl)-9-cyclohexyl-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-12-[3-oxo-3-(tritylamino)propyl]-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C65H94N8O14 | 详情 | 详情 |
| (XIV) | 53671 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-6,15-bis(hydroxymethyl)-1-[(2S,4R)-4-hydroxypyrrolidinyl]-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C33H56N8O12 | 详情 | 详情 |
| (XV) | 53680 | 5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoic acid | n/a | C19H18O4 | 详情 | 详情 |