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【结 构 式】 
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【分子编号】15637 【品名】ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydro-2-pyridinecarboxylate 【CA登记号】 |
【 分 子 式 】C10H10N2O3 【 分 子 量 】206.20108 【元素组成】C 58.25% H 4.89% N 13.59% O 23.28% |
合成路线1
该中间体在本合成路线中的序号：(III)9-Amino-20(RS)-camptothecin is obtained as follows: The cyclization of cyanoacetamide (I) with 2-ethoxy-4-oxo-2-pentenoic acid ethyl ester (II) by means of K2CO3 in hot DMF gives the intermediate pyridone (III), which without isolation is cyclized again with methyl acrylate (IV) in the same conditions affording the indolizinone (V). The treatment of (V) with concentrated HCl in refluxing acetic acid gives the indolizinedione (VI), which is treated with ethylene glycol and trimethylsilyl chloride in dichloromethane to yield the ethylene ketal (VII). The carboxylation of (VII) with diethyl carbonate and KH in refluxing toluene affords the acetic ester derivative (VIII), which is alkylated with ethyl iodide and potassium tert-butoxide in anhydrous DME to the corresponding butyric ester derivative (IX). The reductive acetylation of (IX) with H2 over RaNi in acetic anhydride gives the acetamide derivative (X), which is treated with NaNO2 in acetic acid to yield the corresponding N-nitroso compound (XI). Thermal degradation of (XI) in refluxing CCl4 affords the acetoxymethyl compound (XII), which is submitted to a oxidative cyclization with O2 in methanol/K2CO3 to give the tetracyclic ketal (XIII). Hydrolysis of the ketal group of (XIII) with 2N H2SO4 in hot DME yields the tricyclic triketone (XIV), which is further cyclized with 2-amino-6-nitrobenzaldehyde (XV) by heating at 160 C to afford 9-nitro-20(RS)-camptothecin (XVI). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol. The title product can also be obtained by direct cyclization of tricyclic triketone (XIV) with 2,6-diaminobenzaldehyde (XVII) in the same conditions.
| 【1】 Sinai, B.K.; Palmer, K.H.; McPhail, A.T.; Sim, G.A.; Topoisomerase inhibitors. A review of their therapeutic potential in cancer. Drugs 1995, 49, 11-19. |
| 【2】 Wall, M.E.; Wani, M. (Research Triangle Institute); Camptothecin analogs as potent inhibitors of colorectal cancer. EP 0497910; JP 1993508619; US 5106742; WO 9105556 . |
| 【3】 Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Research Triangle Institute); Synthesis of camptothecin and analogs thereof. WO 9003169 . |
| 【4】 Wall, M.E.; Wani, M.C.; Nicholas, A.W.; Manikumar, G. (Res. Triangle Inst.); Camptothecin and analogues thereof and pharmaceutical compsns and method using them. US 5122526 . |
| 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) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (II) | 15636 | ethyl (Z)-2-ethoxy-4-oxo-2-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) | 15640 | 7-methyl-1,5-dioxo-1,2,3,5-tetrahydro-6-indolizinecarbonitrile | C10H8N2O2 | 详情 | 详情 | |
| (VII) | 15641 | 7'-Methyl-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-6'-ylcarbonitrile | C12H12N2O3 | 详情 | 详情 | |
| (VIII) | 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 | |
| (IX) | 15643 | 2-[6'-Cyano-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester | C17H20N2O5 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 15645 | 2-[6'-(N-Nitrosoacetamidomethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester | C19H25N3O7 | 详情 | 详情 | |
| (XII) | 15646 | 2-[6'-(Acetoxymethyl)-5'-oxo-1',2',3',5'-tetrahydrospiro[1,3-dixolane-2,1'-indolizin]-7'-yl]butyric acid ethyl ester | C19H25NO7 | 详情 | 详情 | |
| (XIII) | 15647 | 4'-Ethyl-4'-hydroxy-3',4',6',7',8',10'-hexahydro-1'H-spiro[1,3-dioxole-2,6'-pyrano[3,4-f]indolizine]-3',10'-dione | C15H17NO6 | 详情 | 详情 | |
| (XIV) | 63309 | (?-beta-methoxydiisopinocamphenylborane | 85134-98-1 | C13H13NO5 | 详情 | 详情 |
| (XV) | 15649 | 2-amino-6-nitrobenzaldehyde | C7H6N2O3 | 详情 | 详情 | |
| (XVI) | 15650 | 4-ethyl-4-hydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione | C20H15N3O6 | 详情 | 详情 | |
| (XVII) | 15651 | 2,6-diaminobenzaldehyde | C7H8N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |