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【结 构 式】 
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【药物名称】9-Aminocamptothecin glucuronide, 9-ACG 【化学名称】1-O-[4-[N-[4(S)-Ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]carbamoyloxymethyl]phenyl]-beta-D-glucuronic acid 【CA登记号】246032-57-5, 246032-60-0 (K salt) 【 分 子 式 】C34H31N3O13 【 分 子 量 】689.63847 |
【开发单位】Academia Sinica (Originator) 【药理作用】Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC DRUGS, Camptothecins, DNA Topoisomerase I Inhibitors |
合成路线1
Treatment of (20S)-camptothecin (I) with HOAc and H2O2 followed by light irradiation in H2SO4 yields hydroxy derivative (II), which is then nitrated by means of HNO3 and H2SO4 to afford compound (III). Sulfonation of (III) by reaction with p-TsCl (IV) in the presence of Et3N and DMAP in CH2Cl2 provides sulfonate (V), which is then subjected to reduction by treatment with Pd(OAc)2, PPh3 and triethylammoniumformate (HCOOH·Et3N) to give 9-aminocamptothecin (VI). Reaction of (VI) with nitrophenyl chloroformate (VII) in dioxane, followed by treatment with intermediate (VIII) and DMAP in acetonitrile, provides (IX). Alternatively, (IX) can also be obtained by first treatment of (VI) with triphosgene followed by reaction with intermediate (VIII) in pyridine and chromatographic purification. Finally, (IX) is treated with potassium trimethyl silanate (KOSiMe3) for methyl ester cleavage and acidified with HCl.
| 【1】 Cabri, W.; et al.; A new high yield semisynthetic approach to (20S)-9-NH2-camptothecin based on a sequence of palladium-catalysed reductions. Tetrahedron Lett 1995, 36, 50, 9197. |
| 【2】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623. |
| 【3】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 44149 | bis(trichloromethyl) carbonate;Triphosgene | 32315-10-9 | C3Cl6O3 | 详情 | 详情 |
| (I) | 10816 | Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione | 7689-03-4 | C20H16N2O4 | 详情 | 详情 |
| (II) | 13340 | (4S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | 86639-52-3 | C20H16N2O5 | 详情 | 详情 |
| (III) | 43901 | (4S)-4-ethyl-4,9-dihydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H15N3O7 | 详情 | 详情 | |
| (IV) | 13975 | p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride | 98-59-9 | C7H7ClO2S | 详情 | 详情 |
| (V) | 43902 | (4S)-4-ethyl-4-hydroxy-10-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylbenzenesulfonate | C27H21N3O9S | 详情 | 详情 | |
| (VI) | 44148 | (4S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H17N3O4 | 详情 | 详情 | |
| (VII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (VIII) | 44150 | methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C14H18O8 | 详情 | 详情 | |
| (IX) | 44151 | methyl 6-(4-[[([[(4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]amino]carbonyl)oxy]methyl]phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate | C35H33N3O13 | 详情 | 详情 |
合成路线2
Intermediate (VIII) can be obtained as follows: Bromination of glucuronate derivative (X) by means of TiBr4 in CH2Cl2 followed by reaction with p-hydroxybenzaldehyde (XI) in acetonitrile in the presence of Ag2O affords derivative (XII), whose aldehyde moiety is then reduced by means of NaBH4 and silica gel in isopropanol/CHCl3 to provide benzyl alcohol (XIII). Finally, O-acetyl groups of (XIII) are cleaved by means of NaOMe in MeOH to furnish intermediate (VIII).
| 【1】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623. |
| 【2】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 44150 | methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C14H18O8 | 详情 | 详情 | |
| (X) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (XI) | 44154 | methyl 3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate | C15H20O11 | 详情 | 详情 | |
| (XII) | 44152 | methyl 3,4,5-tris(acetoxy)-6-(4-formylphenoxy)tetrahydro-2H-pyran-2-carboxylate | C20H22O11 | 详情 | 详情 | |
| (XIII) | 44153 | methyl 3,4,5-tris(acetoxy)-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C20H24O11 | 详情 | 详情 |
合成路线3
Treatment of glucuronic acid gamma-lactone (I) with sodium methoxide in methanol affords methyl glucuronate (II), which is further acylated by acetic anhydride to form the tetraacetate ester (III). Bromination of (III) with TiBr4, followed by coupling of the resultant bromide (IV) with p hydroxybenzaldehyde (V) in the presence of Ag2O yields the peracetylated glucuronide (VI). Aldehyde (VI) reduction employing NaBH4 in the presence of silica gel leads to the benzyl alcohol (VII). The acetate ester groups of (VII) are then removed with sodium methoxide in methanol to furnish (VIII).
| 【1】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623. |
| 【2】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 . |
| 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) | 18369 | (3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one | 32449-92-6 | C6H8O6 | 详情 | 详情 |
| (II) | 62238 | methyl (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate | C7H12O7 | 详情 | 详情 | |
| (III) | 17324 | methyl (2S,3R,4S,5R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate | 7355-18-2 | C15H20O11 | 详情 | 详情 |
| (IV) | 17580 | methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate | C13H17BrO9 | 详情 | 详情 | |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VI) | 62239 | methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-(4-formylphenoxy)tetrahydro-2H-pyran-2-carboxylate | C20H22O11 | 详情 | 详情 | |
| (VII) | 62240 | methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C20H24O11 | 详情 | 详情 | |
| (VIII) | 62241 | methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C14H18O8 | 详情 | 详情 |
合成路线4
10-Hydroxycamptothecin (IX) is nitrated with HNO3/H2SO4 and the resulting 9-nitro-10-hydroxycamptothecin (X) is treated with tosyl chloride to form the tosylate (XI). Palladium-catalyzed reduction of nitro tosylate (XI) gives rise to 9-aminocapmtothecin (XII). Amine (XII) is activated as the isocyanate (XIII) upon treatment with triphosgene (1) or alternatively as the aryl carbamate (XIV) employing p-nitrophenyl chloroformate. Coupling of either isocyanate (XIII) or carbamate (XIV) with p-hydroxybenzyl alcohol glucuronide (VIII) leads to adduct (XV). The methyl glucuronate ester (XV) is finally hydrolyzed to the target acid under anhydrous conditions by using potassium trimethylsilanolate.
| 【1】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623. |
| 【2】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 62241 | methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate | C14H18O8 | 详情 | 详情 | |
| (IX) | 13340 | (4S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | 86639-52-3 | C20H16N2O5 | 详情 | 详情 |
| (X) | 43901 | (4S)-4-ethyl-4,9-dihydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H15N3O7 | 详情 | 详情 | |
| (XI) | 43902 | (4S)-4-ethyl-4-hydroxy-10-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylbenzenesulfonate | C27H21N3O9S | 详情 | 详情 | |
| (XII) | 44148 | (4S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H17N3O4 | 详情 | 详情 | |
| (XIII) | 62243 | (4S)-4-ethyl-4-hydroxy-10-isocyanato-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C21H15N3O5 | 详情 | 详情 | |
| (XIV) | 62244 | 4-nitrophenyl (4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-ylcarbamate | C27H20N4O8 | 详情 | 详情 | |
| (XV) | 62245 | methyl (2S,3S,4S,5R)-6-(4-{[({[(4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]amino}carbonyl)oxy]methyl}phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate | C35H33N3O13 | 详情 | 详情 |