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【结 构 式】 
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【分子编号】53673 【品名】(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 【CA登记号】n/a |
【 分 子 式 】C52H72N8O15 【 分 子 量 】1049.1886 【元素组成】C 59.53% H 6.92% N 10.68% O 22.87% |
合成路线1
该中间体在本合成路线中的序号：(XVI),(XVII)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 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Coupling of peptide (XVII) to the amino group of doxorubicin (XVIII) using DPPA yielded amide (XIX). Alternatively, EDC in the presence of HOAt can be used as the coupling reagent. The fluorenylmethyl ester of (XIX) was finally removed by treatment with piperidine in DMF to produce the title compound.
| 【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 . |
| 【4】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
| 【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 |
|---|---|---|---|---|---|---|
| (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 |
| (XVIII) | 11675 | (8S,10S)-10-[[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C27H29NO11 | 详情 | 详情 | |
| (XIX) | 53674 | 9H-fluoren-9-ylmethyl 5-{(2S,4R)-2-[(3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-18-{[((2S,3S,4S,6R)-6-{[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy}-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl}-6,15-bis(hydroxymethyl)-3,20-dimethyl-4,7,10,13,16-pentaoxo-2,5,8,11,14,17-hexaazahenicos-1-anoyl]-4-hydroxypyrrolidinyl}-5-oxopentanoate | n/a | C79H99N9O25 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)Coupling between N-Boc-L-serine (XXIX) and L-leucine benzyl ester (XXX) furnished the Boc-dipeptide (XXXI), which was deprotected by means of a solution of HCl in isopropyl acetate. The resultant seryl-leucine benzyl ester (XXXII) was condensed with N-Boc-L-glutamine (XXXIII) to afford (XXXIV), which after N-Boc deprotection yielded tripeptide ester (XXXV). Further coupling of (XXXV) with N-Boc-L-cyclohexylglycine (XXXVI), followed by acidic deprotection, gave tetrapeptide (XXXVII). This was finally acylated with the glutaryl tripeptide (XXVIII) to provide the desired peptide intermediate (XVII).
| 【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 |
| (XXVIII) | 53682 | (2S)-2-({(2S)-2-[({(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}carbonyl)amino]propanoyl}amino)-3-hydroxypropanoic acid | n/a | C30H35N3O9 | 详情 | 详情 |
| (XXIX) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (XXX) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (XXXI) | 53672 | benzyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C21H32N2O6 | 详情 | 详情 |
| (XXXII) | 53683 | benzyl (2S)-2-{[(2S)-2-amino-3-hydroxypropanoyl]amino}-4-methylpentanoate | n/a | C16H24N2O4 | 详情 | 详情 |
| (XXXIII) | 31820 | (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13726-85-7 | C10H18N2O5 | 详情 | 详情 |
| (XXXIV) | 53684 | benzyl (6S,9S,12S)-6-(3-amino-3-oxopropyl)-9-(hydroxymethyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate | n/a | C26H40N4O8 | 详情 | 详情 |
| (XXXV) | 53685 | benzyl (2S)-2-[((2S)-2-{[(2S)-2,5-diamino-5-oxopentanoyl]amino}-3-hydroxypropanoyl)amino]-4-methylpentanoate | n/a | C21H32N4O6 | 详情 | 详情 |
| (XXXVI) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
| (XXXVII) | 53686 | benzyl (2S)-2-({(2S)-2-[((2S)-5-amino-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxopentanoyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C29H45N5O7 | 详情 | 详情 |