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【结 构 式】 
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【分子编号】10841 【品名】(4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione 【CA登记号】 |
【 分 子 式 】C13H13NO5 【 分 子 量 】263.24996 【元素组成】C 59.31% H 4.98% N 5.32% O 30.39% |
合成路线1
该中间体在本合成路线中的序号：(XX)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2
该中间体在本合成路线中的序号：(VII)Benzodioxan-6-amine (I) was protected as the corresponding acetanilide (II), which was subsequently subjected to Friedel-Crafts condensation with chloroacetyl chloride (III) in the presence of ZnCl2, yielding the chloro ketone (IV). Acidic hydrolysis of the acetamide function of (IV) provided amino ketone (V). Alternatively, intermediate (V) was prepared by direct acylation of aniline (I) employing chloroacetonitrile (VI) in the presence of BCl3. The 7-(chloromethyl)camptothecin derivative (VIII) was synthesized through a Friedlander condensation between amino ketone (V) and the known keto lactone (VII). Finally, displacement of the chloride of (VIII) with N-methylpiperazine (IX) gave rise to the title piperazinylmethyl camptothecin.
| 【1】 Luzzio, M.J.; et al.; Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995, 38, 3, 395. |
| 【2】 Luzzio, M.J.; Besterman, J.M.; Evans, M.G.; Myers, P.L. (GlaxoSmithKline plc); Water soluble camptothecin derivs.. EP 0540099; JP 1993222048; JP 2000109475; US 5559235 . |
| 【3】 Sternbach, D.D.; Lackey, K. (GlaxoSmithKline Inc.); Preparation of water soluble camptothecin derivs.. US 5342947 . |
| 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) | 54867 | 1,4-Benzodioxan-6-amine; 3,4-Ethylenedioxyaniline; 6-Amino-1,4-benzodioxane | 22013-33-8 | C8H9NO2 | 详情 | 详情 |
| (II) | 54868 | N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide | C10H11NO3 | 详情 | 详情 | |
| (III) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (IV) | 54869 | N-[7-(2-chloroacetyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetamide | C12H12ClNO4 | 详情 | 详情 | |
| (V) | 54870 | 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone | C10H10ClNO3 | 详情 | 详情 | |
| (VI) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (VII) | 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 | |
| (VIII) | 54871 | (8S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3-dihydro-11H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione | C23H19ClN2O6 | 详情 | 详情 | |
| (IX) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)The pyranoindolizine acetal (XVIII) was hydrolyzed to the trione (XIX) in 90% trifluoroacetic acid. Condensation of (XIX) with amino ketone (XVII) in refluxing toluene produced the hexacyclic compound (XX) as a diastereomeric mixture. The title compound was then obtained by acidic hydrolysis of the trifluoroacetamido group, followed by isolation of the desired isomer by preparative HPLC. The synthesis of the title compound was also reported by condensation of trione (XIX) with the acetamido tetralone (XXI). The resultant hexacyclic acetamide (XXII) was subsequently hydrolyzed with methanesulfonic acid, and the diastereomeric mixture of mesylate salts was finally separated by fractional crystallization.
| 【1】 Chilman-Blair, K.; Mealy, N.E.; Castaner, J.; Bayes, M.; Exatecan Mesilate. Drugs Fut 2004, 29, 1, 9. |
| 【2】 Terasawa, H.; Ejima, A.; Ohsuki, S.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Hexacyclic cpd.. EP 0495432; JP 1993059061; US 5834476; US 6407115 . |
| 【3】 Kamihara, S.; Kanai, K.; Noguchi, S.; Terasawa, H.; Kitaoka, H. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Campthothecin deriv. with antitumour activity. CA 2173671; EP 0737686; JP 1996337584 . |
| 【4】 Terasawa, H.; Sato, K.; Mitsui, I. (Daiichi Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.); Antitumor agents. JP 1994087746 . |
| 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) | 52774 | N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)-2,2,2-trifluoroacetamide | C13H12F4N2O2 | 详情 | 详情 | |
| (XVIII) | 52775 | C15H17NO6 | 详情 | 详情 | ||
| (XIX) | 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 | |
| (XX) | 52777 | N-[(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]-2,2,2-trifluoroacetamide | C26H21F4N3O5 | 详情 | 详情 | |
| (XXI) | 52776 | N-(8-amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide | C13H15FN2O2 | 详情 | 详情 | |
| (XXII) | 52778 | N-[(9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]acetamide | C26H24FN3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II), which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III). The reaction of (III) with methyl acrylate (A) gives compound (IV), which is sequentially submitted to decarboxylation, ketalization and treatment with diethylcarbonate, giving the functionalized tetrahydroindolizine (V). Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI), which is reacted with sodium nitrite, refluxed in CCl4, hydrolyzed and acidified to give the tricyclic compound (VII). The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII). Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL, K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX). The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X). Finally, Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.
| 【1】 Hong, C.I.; Kim, J.K.; Ahn, S.K.; CKD-602. Drugs Fut 2000, 25, 12, 1243. |
| 【2】 Kim, J.M.; Jew, S.; Kim, M.G.; Kim, H.-J.; Hah, J.M.; Ok, K.; Cho, Y.; Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation. Tetrahedron Asymmetry 1995, 6, 6, 1245. |
| 【3】 Jew, S.-S.; Kim, H.-J.; Kim, M.G.; et al.; Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues. Bioorg Med Chem Lett 1996, 6, 7, 845. |
| 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) | 42500 | ethyl 2,4-dioxopentanoate | 615-79-2 | C7H10O4 | 详情 | 详情 |
| (II) | 42501 | ethyl (Z)-4-ethoxy-2-oxo-3-pentenoate | C9H14O4 | 详情 | 详情 | |
| (III) | 15637 | ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate | C10H10N2O3 | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 15639 | methyl 6-cyano-1-hydroxy-7-methyl-5-oxo-3,5-dihydro-2-indolizinecarboxylate | C12H10N2O4 | 详情 | 详情 | |
| (VI) | 15642 | 2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]acetic acid ethyl ester | C15H16N2O5 | 详情 | 详情 | |
| (VII) | 15644 | 2-[6'-(Acetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester | C19H26N2O6 | 详情 | 详情 | |
| (VIII) | 42502 | C15H17NO5 | 详情 | 详情 | ||
| (IX) | 42503 | C15H17NO4 | 详情 | 详情 | ||
| (X) | 42504 | C15H19NO6 | 详情 | 详情 | ||
| (XI) | 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 | |
| (XII) | 42505 | benzyl 3-(2-aminophenyl)-3-oxopropyl(isopropyl)carbamate | C20H24N2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)This compound can be obtained in two different ways: 1) By direct nitration of camptothecin (I) with nitric acid in sulfuric acid. 2) By direct nitration of camptothecin (I) with different inorganic nitrates (or mixtures of inorganic nitrates) in sulfuric acid. 3) The reaction of 2,6-dinitrobenzaldehyde (II) with ethylene glycol (III) and p-toluenesulfonic acid in refluxing toluene gives the corresponding ethylene ketal (IV), which is reduced with sodium sulfide in refluxing ehanol/water yielding 2-amino-6-nitrobenzaldehyde ethylene ketal (V). The hydrolysis of (V) with aqueous sulfuric acid affords 2-amino-6-nitrobenzaldehyde (VI), which is finally cyclized with the tricyclic ketone (VII) in refluxing acetic acid (the same cyclization can be performed with the ketal (V) and the ketone (VII).
| 【1】 Cao, Z.S.; et al.; Nitration of campothecin with various inorganic nitrate salts in concentrated sulfuric acid: A new preparation of anticancer drug 9-nitrocamptothecin. Synthesis 1998, 12, 1724. |
| 【2】 Sawada, S.; Matsuoka, S.-I.; Nokata, K.-I.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka, T.; Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins. Chem Pharm Bull 1991, 39, 12, 3183. |
| 【3】 Wani, M.C.; Nicholas, A.W.; Wall, M.E.; Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J Med Chem 1986, 29, 11, 2358. |
| 【4】 Leitner, P.; Tele, C.; Truesdale, A.; Nicholas, A.W.; Moore, L.; Besterman, J.M.; Manikumar, G.; Wani, M.C.; Wall, M.E.; Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs. J Med Chem 1993, 36, 18, 2689. |
| 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) | 39891 | 2,6-dinitrobenzaldehyde | 606-31-5 | C7H4N2O5 | 详情 | 详情 |
| (III) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (IV) | 39892 | 2-(2,6-dinitrophenyl)-1,3-dioxolane | C9H8N2O6 | 详情 | 详情 | |
| (V) | 39893 | 2-(1,3-dioxolan-2-yl)-3-nitrophenylamine; 2-(1,3-dioxolan-2-yl)-3-nitroaniline | C9H10N2O4 | 详情 | 详情 | |
| (VI) | 15649 | 2-amino-6-nitrobenzaldehyde | C7H6N2O3 | 详情 | 详情 | |
| (VII) | 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 |
合成路线6
该中间体在本合成路线中的序号：(XVII)Treatment of (XIII) with aqueous trifluoroacetic acid produced simultaneous ketal group hydrolysis and lactonization, yielding intermediate (XIV). Optionally, basic hydrolysis of the ester groups of (XIII) with LiOH produced the lithium carboxylate salt (XV). Lactonization of (XV) with HOAc in chloroform gave (XVI). The cyclic ketal group of (XVI) was then hydrolyzed with aqueous trifluoroacetic acid to produce the intermediate (XVII). Alternatively, (XVII) was also produced by simultaneous hydrolysis and cyclization of (XV) with aqueous trifluoroacetic acid or by basic hydrolysis of (XIV), followed by acidic treatment. Intermediate (XIX) was prepared by acetylation of (XVI) followed by acidic hydrolysis of the resulting ketal (XVIII).
| 【1】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 49943 | C44H48N2O11S | 详情 | 详情 | ||
| (XIV) | 49945 | (4S)-4-ethyl-3,6,10-trioxo-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indolizin-4-yl (3R)-2-([1,1'-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C35H30N2O8S | 详情 | 详情 | |
| (XV) | 49946 | C18H24LiNO7 | 详情 | 详情 | ||
| (XVI) | 49947 | C18H23NO6 | 详情 | 详情 | ||
| (XVII) | 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 | |
| (XVIII) | 49948 | C20H25NO7 | 详情 | 详情 | ||
| (XIX) | 49949 | (4S)-4-ethyl-3,6,10-trioxo-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indolizin-4-yl acetate | C15H15NO6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XVII)The title compound was prepared from aminopropiophenone (XXVII) by several procedures. Aldol condensation of (XXVII) with the intermediate pyranoindolizinetrione (XVII) with concomitant Friedlander quinoline synthesis under acidic conditions furnished the camptothecin derivative (XXVIII). Optionally, (XXVIII) was also obtained by condensation of (XXVII) with intermediate ketone (XIX), followed by basic hydrolysis of the resultant lactone-ester (XXIX) and subsequent relactonization under acidic conditions. Finally, acid cleavage of the N-Boc group of (XXVII) yielded the title compound.
| 【1】 Tsujihara, K.; Kawaguchi, T.; Okuno, S.; Yano, T. (Tanabe Seiyaku Co., Ltd.); Camptothecin derivs.. CA 2182244; EP 0757049; JP 1998072467; US 5837673 . |
| 【2】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 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) | 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 | |
| (XIX) | 49949 | (4S)-4-ethyl-3,6,10-trioxo-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indolizin-4-yl acetate | C15H15NO6 | 详情 | 详情 | |
| (XXVII) | 49954 | tert-butyl 3-(4-amino-3-propionylphenoxy)propylcarbamate | C17H26N2O4 | 详情 | 详情 | |
| (XXVIII) | 49955 | tert-butyl 3-[[(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-9-yl]oxy]propylcarbamate | C30H35N3O7 | 详情 | 详情 | |
| (XXIX) | 49956 | (4S)-9-[3-[(tert-butoxycarbonyl)amino]propoxy]-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl acetate | C32H37N3O8 | 详情 | 详情 |