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【结 构 式】 
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【分子编号】11675 【品名】(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 【CA登记号】 |
【 分 子 式 】C27H29NO11 【 分 子 量 】543.5274 【元素组成】C 59.67% H 5.38% N 2.58% O 32.38% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be obtained by two related ways: 1) By reaction of adriamycin (I) with 2,3-dihydropyran (II) by means of p-toluenesulfonic acid as a catalyst in DMF. 2) The reaction of adriamycin (I) with 2,3-dihydropyran (II) under stronger conditions yields 14,4'-O-bistetrahydropyranyladriamycin (III), which is selectively hydrolyzed with aqueous 10% acetic acid.
| 【1】 Kinoshita, M.; Ishizuka, M.; Takeuchi, T.; Tatsuta, K.; Takahashi, Y.; Umezawa, H.; Naganawa, H.; Masuda, T.; Tetrahydropyranyl derivatives of daunomycin and adriamycin. J Antibiot 1979, 32, 10, 1082-85. |
| 【2】 Umezawa, H.; Takeuchi, T.; Naganawa, H.; Tatsuka, K. (Microbial Chemistry Research Foundation); Anthracycline derivatives, a process for their preparation and pharmaceutical compositions containing them. AT 369384B; CA 1136618; EP 0014853; ES 488209; US 4303785 . |
| 【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; THP-ADM. Drugs Fut 1983, 8, 7, 610. |
| 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) | 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 | |
| (II) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (III) | 31091 | (8S,10S)-10-[[(2R,4S,5S,6S)-4-amino-6-methyl-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-2-yl]oxy]-6,8,11-trihydroxy-1-methoxy-8-[2-(tetrahydro-2H-pyran-2-yloxy)acetyl]-7,8,9,10-tetrahydro-5,12-naphthacenedione | C37H45NO13 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)MRA-CN is a byproduct of the synthesis of 3'-deamino-3'-(4-morpholinyl)doxorubicin (III) by the reductive alkylation of doxorubicin (I) with 2,2'-oxybisacetaldehyde (II) and NaBH3CN (I). An iminium intermediate in this process evidenly undergoes nucleophilic attack by cyanide ion present in the reaction mixture, in competition with the normal attack by hydride. Unlike the expected morpholino derivative (III) (and most anthracyclines), MRA-CN is nonbasic. It remains in the organic layer (e.g., chloroform) when the morpholino derivative is extracted with dilute aqueous acid. MRA-CN is then recovered from the organic layer and purified by chromatography on silica gel using gradient elution with dichloromethane-methanol. Yields range from 15% to 40%. MRA-CN does not form an HCl salt.
| 【1】 Acton, E.M.; MRA-CN. Drugs Fut 1985, 10, 9, 750. |
| 【2】 Acton, E.M.; et al.; Intensely potent morpholinyl anthracyclines. J Med Chem 1984, 27, 5, 638-45. |
| 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) | 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 | |
| (II) | 23126 | 2-(2-oxoethoxy)acetaldehyde；2,2'-oxydiacetaldehyde | C4H6O3 | 详情 | 详情 | |
| (III) | 27364 | (8S,10S)-8-glycoloyl-6,8,11-trihydroxy-10-[[(4S,5S,6S)-5-hydroxy-6-methyl-4-(4-morpholinyl)tetrahydro-2H-pyran-2-yl]oxy]-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C31H35NO12 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The oxidative cleavage of methyl beta-L-arabinopyranoside (I) with sodium periodate in water gives the dialdehyde (II), which is then cyclized with daunorubicin by means of NaHCO3 and sodium cyanoborohydride in acetonitrile/water.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Nemorubicin. Drugs Fut 1997, 22, 12, 1239. |
| 【2】 Bargiotti, A.; Zini, P.; Penco, S.; Giuliani, F. (Pharmacia Corp.); Novel morpholino derivs. of daunorubicins and doxorubicins. BE 0904431; DE 3609052; GB 2172594; JP 1986221194; US 4672057 . |
| 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) | 11673 | (2S,3R,4S,5S)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol | C6H12O5 | 详情 | 详情 | |
| (II) | 11674 | (2S)-2-Methoxy-2-(2-oxoethoxy)ethanal | C5H8O4 | 详情 | 详情 | |
| (III) | 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 |
合成路线4
该中间体在本合成路线中的序号：(I)By condensation of doxorubicin hydrochloride (I) with L-leucine N-carboxyanhydride (II) in a buffered aqueous solution at pH 10.2.
| 【1】 Baurain, R.; Trouet, A. (Medgenix Group); Novel doxorubicin derivs., process for their preparation and pharmaceutical compsns. BE 0869485; DE 2930637 . |
| 【2】 Prous, J.; Castaner, J.; Leurubicin. Drugs Fut 1993, 18, 2, 116. |
| 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) | 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 | |
| (II) | 14815 | (4S)-4-isobutyl-1,3-oxazolane-2,5-dione | 3190-70-3 | C7H11NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of doxorubicin (I) with Fmoc-beta-alanyl-L-leucyl-L-alanyl-L-leucine (II) by means of HATU and DIEA in DMF gives the protected adduct (III), which is treated with piperidine in DMF to yield the deprotected adduct (IV). Finally, this compound is condensed with succinic anhydride (V) in the same solvent and treated with NaOH or NaHCO3 to afford the target sodium salt.
| 【1】 Fernandez, A.-M.; et al.; N-Succinyl-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin: An extracellularly tumor-activated prodrug devoid of intravenous acute toxicity. J Med Chem 2001, 44, 22, 3750. |
| 【2】 Lobl, T.J.; Trouet, A.; Fernandez, A.-M.; Nieder, M.H.; Yarranton, G.T.; Gangwar, S.; Viski, P.; Lewis, E.; Dubois, V. (Beckman Coulter, Inc.); Prodrug cpds. and process for preparation thereof. WO 0033888 . |
| 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) | 49366 | (9S,12S,15S)-1-(9H-fluoren-9-yl)-9,15-diisobutyl-12-methyl-3,7,10,13-tetraoxo-2-oxa-4,8,11,14-tetraazahexadecan-16-oic acid | C33H44N4O7 | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 49367 | 9H-fluoren-9-ylmethyl 3-([(1S)-1-[([(1S)-2-[((1S)-1-[[((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]-3-methylbutyl)amino]-1-methyl-2-oxoethyl]amino)carbonyl]-3-methylbutyl]amino)-3-oxopropylcarbamate | C60H71N5O17 | 详情 | 详情 | |
| (IV) | 49368 | (2S)-2-[(3-aminopropanoyl)amino]-N-[(1S)-2-[((1S)-1-[[((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]-3-methylbutyl)amino]-1-methyl-2-oxoethyl]-4-methylpentanamide | C45H61N5O15 | 详情 | 详情 | |
| (V) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Adriamycin hydrochloride (I) was converted to the tosylhydrazone (II) upon treatment with p-toluenesulfonylhydrazide in methanol. Subsequent reduction of the hydrazone functionality of (II) by means of sodium cyanoborohydride in the presence of p-toluenesulfonic acid furnished the title deoxygenated Adriamycin.
| 【1】 Smith, T.H.; et al.; Adriamycin analogues. 2. Synthesis of 13-deoxyanthracyclines. J Med Chem 1978, 21, 3, 280. |
| 【2】 Olson, R.D.; Zhang, X.; Walsh, G.M. (Gem Pharmaceuticals, Inc.); 13-Deoxyanthracycline derivs. and processes for preparing them. EP 1011687; JP 2001515040; WO 9908687 . |
| 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) | 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 | |
| (II) | 51162 | N'-[(Z)-1-((2S,4S)-4-[[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl)-2-hydroxyethylidene]-4-methylbenzenesulfonohydrazide | C34H37N3O12S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)Coupling of 4-aminobenzyl alcohol (I) with diallyl L-glutamylisocyanate (II) produced the urea derivative (III). Subsequent activation of the benzylic alcohol group with 4-nitrophenyl chloroformate (IV) afforded carbonate (V). This was then condensed with doxorubicin (VI) to furnish the corresponding carbamate (VII). Finally, palladium-catalyzed cleavage of the allyl esters of (VII) yielded the title compound.
| 【1】 Friedlos, F.; Spooner, R.; Marais, R.; Springer, C.J.; Martin, J.; Niculescu-Duvaz, I.; Niculescu-Duvaz, D.; Self-immolative anthracycline prodrugs for suicide gene therapy. J Med Chem 1999, 42, 13, 2485. |
| 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) | 34430 | (4-aminophenyl)methanol | 623-04-1 | C7H9NO | 详情 | 详情 |
| (II) | 34431 | diallyl (2S)-2-isocyanatopentanedioate | C12H15NO5 | 详情 | 详情 | |
| (III) | 34432 | diallyl (2S)-2-([[4-(hydroxymethyl)anilino]carbonyl]amino)pentanedioate | C19H24N2O6 | 详情 | 详情 | |
| (IV) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (V) | 34433 | diallyl (2S)-2-([[4-([[(4-nitrophenoxy)carbonyl]oxy]methyl)anilino]carbonyl]amino)pentanedioate | C26H27N3O10 | 详情 | 详情 | |
| (VI) | 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 | |
| (VII) | 34434 | C47H51N3O18 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The title hydrazone was prepared by condensation of doxorubicin hydrochloride (I) with 4-maleimidophenylacetic acid hydrazide trifluoroacetate salt (II) in methanol.
| 【1】 Kratz, F.; Schumacher, P.; Beyer, U.; Zahn, H.; Unger, C.; Kruger, M.; Synthesis and stability of four maleimide derivatives of the anticancer drug doxorubicin for the preparation of cemoinmunoconjugates. Chem Pharm Bull 1997, 45, 2, 399-401. |
| 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) | 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 | |
| (II) | 42233 | 2-[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl]acetohydrazide | C12H11N3O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XVIII)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10
该中间体在本合成路线中的序号：(VII)6-Aminocaproic acid (I) is condensed with maleic anhydride (II) in refluxing AcOH to provide maleimidocaproic acid (III). After activation of acid (III) as the corresponding mixed anhydride with isobutyl chloroformate, coupling with tert-butyl carbazate (IV) affords the N-Boc hydrazide (V). Subsequent acidic cleavage of the Boc group of (V) furnishes hydrazide (VI). Finally, hydrazide (VI) is condensed with doxorubicin (VII) to produce the title hydrazone conjugate.
| 【1】 Willner, D.; Trail, P.A.; Hofstead, S.J.; King, H.D.; Lasch, S.J.; Braslawsky, G.R.; Greenfield, R.S.; Kaneko, T.; Firestone, R.A.; (6-Maleimidocaproyl)hydrazone of doxorubicin - A new derivative for the preparation of immunoconjugates of doxorubicin. Bioconjugate Chem 1993, 4, 6, 521. |
| 【2】 Willner, D.; Trail, P.A.; King, D.H.; Hofstead, S.J.; Greenfield, R.S.; Braslawsky, G.R. (Bristol-Myers Squibb Co.); Thioether conjugates. EP 0554708; JP 1994025012; US 5622929 . |
| 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) | 41170 | 6-aminohexanoic acid | 60-32-2 | C6H13NO2 | 详情 | 详情 |
| (II) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (III) | 63203 | 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid | C10H13NO4 | 详情 | 详情 | |
| (IV) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (V) | 63204 | tert-butyl 2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-1-hydrazinecarboxylate | C15H23N3O5 | 详情 | 详情 | |
| (VI) | 63205 | 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide | C10H15N3O3 | 详情 | 详情 | |
| (VII) | 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 |