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【结 构 式】 
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【药物名称】Irinotecan hydrochloride, U-101440E(hydrate), NSC-616348, DQ-2805, CPT-11, Camptosar, Topotecin, Campto 【化学名称】[1,4'-Bipiperidine]-1'-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester hydrochloride 【CA登记号】100286-90-6, 97682-44-5 (free base) 【 分 子 式 】C33H39ClN4O6 【 分 子 量 】623.15498 |
【开发单位】Yakult Honsha (Originator), Almirall Prodesfarma (Licensee), Aventis Pharma (Licensee), Daiichi Pharmaceutical (Licensee), Pfizer (Licensee), National Cancer Institute (Codevelopment) 【药理作用】Brain Cancer Therapy, Colorectal Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Solid Tumors Therapy, Camptothecins, DNA Topoisomerase I Inhibitors |
合成路线1
A more complete synthesis for CPT-11 has been reported: The reaction of camptothecin (I) with propionaldehyde and FeSO4 in water gives 7-ethylcamptothecin (II), which is oxidized with H2O2 in hot acetic acid yielding 7-ethylcamptothecin 1-oxide (III). The isomerization of (III) with UV light (high-pressure Hg lamp) in dioxane-1 N H2SO4 affords 7-ethyl-10-hydroxycamptothecin (IV), which is treated with phosgene and triethylamine in dioxane to give the corresponding chlorocarbonyl derivative (V). Finally, this compound is condensed with 4-piperidinopiperidine (VI) by means of pyridine in dichloromethane.
| 【1】 Nokata, K.-I.; Furuta, T.; Yokokura, T.; Okajima, S.; Sawada, S.; Sugino, E.; Miyasaka, T.; Aiyama, R.; Yamaguchi, K.; Synthesis and antitumor activity of 20(S)-camptothecin derivatives: Carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull 1991, 39, 6, 1446-54. |
| 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) | 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) | 10817 | (4S)-4,11-Diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethylcamptothecin | C22H20N2O4 | 详情 | 详情 | |
| (III) | 10818 | (4S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-6-ium-6-olate; 7-Ethylcamptothecin 1-oxide | C22H20N2O5 | 详情 | 详情 | |
| (IV) | 10819 | (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | C22H20N2O5 | 详情 | 详情 | |
| (V) | 10820 | (4S)-9-[(Chlorocarbonyl)oxy]-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline | C23H19ClN2O6 | 详情 | 详情 | |
| (VI) | 10821 | 4-Piperidinopiperidine | 4897-50-1 | C10H20N2 | 详情 | 详情 |
合成路线2
A new asymmetric synthesis of irinotecan has been reported: The reaction of 2,6-dihydroxypyridine-4-carboxylic acid (I) with hot POCl3 and trimethylammonium chloride gives 2,6-dichloropyridine-4-carboxylic acid (II), which by a Grignard condensation with ethylmagnesium bromide in THF is converted into the propanone (III). The ketalization of (III) with ethylene glycol and trimethylsilyl chloride (TMS-Cl) affords the dioxolane (IV), which by reaction with sodium methoxide in refluxing methanol gives the monomethoxy-pyridine derivative (V). The carbonylation of (V) with butyllithium and DMF affords the pyridine-carbaldehyde (VI), which is reduced to the methanol (VII) with NaBH4. The protection of the hydroxy group of (VII) with benzyl bromide and potassium tert-butoxide in THF affords the benzyl ether (VIII), which is treated with CO, K2CO3, palladium acetate and 1,3-bis(diphenylphosphino)propane (DPPP) in propanol/DMF giving the propyl ester (IX). The treatment of (IX) with trifluoroacetic acid yields the propanone (X), which is treated with methyltriphenylphosphonium bromide and potassium bis(trimethylsilyl)amide (KHMDS) in DMF to afford the expected methylene derivative (XI). The oxidation of (XI) with OsO4 in tert-butanol gives the racemic diol (XII), which is submitted to optical resolution with PS-30 catalyst (Pseudomonas cepaica lipase over Celite 521) to give the corresponding (S)-enantiomer (XIII). The oxidation of (XIII) with NaOCl affords the 2(S)-hydroxybutyraldehyde (XIV), which is submitted to cyclization by debenzylation with H2 over Pd/C in methanol giving the cyclized diol (XV). The oxidation of (XV) with NaOCl in dichloromethane affords the hydroxylactone (XVI), which is treated with trimethylsilyl chloride and NaI to give the pyridone (XVII). A new cyclization of (XVII) with tert-butyl acrylate (XVIII) by means of Cs2CO3 in DMSO yield the tricyclic tert-butyl ester (XIX), which is decarboxylated with trifluoroacetic acid in refluxing toluene to afford the tricyclic trione (XX). The cyclization of (XX) with 2-amino-5-hydroxypropiophenone (XXI) by means of p-toluenesulfonic acid in hot toluene/acetic acid gives the camptothecin derivative (XXII), which is finally acylated with 4-(1-piperidyl)piperidine-1-carbonyl chloride (XXIII) in pyridine.
| 【1】 Ashford, S.W.; Sih, J.C.; Gu, R.L.; Henegar, K.E.; Baughman, T.A.; Practical asymmetric synthesis of (S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of irinotecan and other camptothecin analogs. J Org Chem 1997, 62, 19, 6588. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 10822 | 2,6-Dihydroxyisonicotinic acid; Citrazinic acid | 99-11-6 | C6H5NO4 | 详情 | 详情 |
| (II) | 10823 | 2,6-Dichloroisonicotinic acid | 5398-44-7 | C6H3Cl2NO2 | 详情 | 详情 |
| (III) | 10824 | 1-(2,6-Dichloro-4-pyridinyl)-1-propanone | C8H7Cl2NO | 详情 | 详情 | |
| (IV) | 10825 | 2,6-Dichloro-4-(2-ethyl-1,3-dioxolan-2-yl)pyridine | C10H11Cl2NO2 | 详情 | 详情 | |
| (V) | 10826 | 2-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxypyridine; 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-pyridinyl methyl ether | C11H14ClNO3 | 详情 | 详情 | |
| (VI) | 10827 | 6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxynicotinaldehyde | C12H14ClNO4 | 详情 | 详情 | |
| (VII) | 10828 | [6-Chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methanol | C12H16ClNO4 | 详情 | 详情 | |
| (VIII) | 10829 | 3-[(Benzyloxy)methyl]-6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxypyridine; Benzyl [6-chloro-4-(2-ethyl-1,3-dioxolan-2-yl)-2-methoxy-3-pyridinyl]methyl ether | C19H22ClNO4 | 详情 | 详情 | |
| (IX) | 10830 | propyl 5-[(benzyloxy)methyl]-4-(2-ethyl-1,3-dioxolan-2-yl)-6-methoxy-2-pyridinecarboxylate | C23H29NO6 | 详情 | 详情 | |
| (X) | 10831 | propyl 5-[(benzyloxy)methyl]-6-methoxy-4-propionyl-2-pyridinecarboxylate | C21H25NO5 | 详情 | 详情 | |
| (XI) | 10832 | propyl 5-[(benzyloxy)methyl]-4-(1-ethylvinyl)-6-methoxy-2-pyridinecarboxylate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 10833 | propyl 5-[(benzyloxy)methyl]-4-[1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate | C22H29NO6 | 详情 | 详情 | |
| (XIII) | 10834 | propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-hydroxy-1-(hydroxymethyl)propyl]-6-methoxy-2-pyridinecarboxylate | C22H29NO6 | 详情 | 详情 | |
| (XIV) | 10835 | propyl 5-[(benzyloxy)methyl]-4-[(1S)-1-formyl-1-hydroxypropyl]-6-methoxy-2-pyridinecarboxylate | C22H27NO6 | 详情 | 详情 | |
| (XV) | 10836 | propyl (4S)-4-ethyl-3,4-dihydroxy-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C15H21NO6 | 详情 | 详情 | |
| (XVI) | 10837 | propyl (4S)-4-ethyl-4-hydroxy-8-methoxy-3-oxo-3,4-dihydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C15H19NO6 | 详情 | 详情 | |
| (XVII) | 10838 | propyl (4S)-4-ethyl-4-hydroxy-3,8-dioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-6-carboxylate | C14H17NO6 | 详情 | 详情 | |
| (XVIII) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XIX) | 10840 | tert-butyl (4S)-4-ethyl-4,6-dihydroxy-3,10-dioxo-3,4,8,10-tetrahydro-1H-pyrano[3,4-f]indolizine-7-carboxylate | C18H21NO7 | 详情 | 详情 | |
| (XX) | 10841 | (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione | C13H13NO5 | 详情 | 详情 | |
| (XXI) | 10842 | 1-(2-Amino-5-hydroxyphenyl)-1-propanone | C9H11NO2 | 详情 | 详情 | |
| (XXII) | 10819 | (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | C22H20N2O5 | 详情 | 详情 | |
| (XXIII) | 63047 | C11H19ClN2O | 详情 | 详情 |
合成路线3
The reaction of 7-ethyl-10-hydroxycamptothecin (I) with phosgene gives 7-ethyl-10-(chlorocarbonyloxy)camptothecin (II), which is then condensed with 4-(1-piperidyl)piperidine.
| 【1】 Miyasaka, T.; Mutai, M.; Nokata, K.; Sawada, S.; Sugino, E. (Yakult Honsha Co., Ltd.); New camptothecin derivs. and process for preparing same. EP 0137145; JP 1985019790 . |
| 【2】 Davis, P.D. (Angiogene Pharmaceuticals Ltd.); Benzimidazole vascular damaging agents. EP 1140078; WO 0041669 . |
| 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) | 10819 | (4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin | C22H20N2O5 | 详情 | 详情 | |
| (II) | 10820 | (4S)-9-[(Chlorocarbonyl)oxy]-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline | C23H19ClN2O6 | 详情 | 详情 | |
| (III) | 10821 | 4-Piperidinopiperidine | 4897-50-1 | C10H20N2 | 详情 | 详情 |