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【结 构 式】 
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【药物名称】 【化学名称】(3bR,4aS)-6-[3-(2-Methoxy-5-pyrimidinyl)-2(E)-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylic acid methyl ester 【CA登记号】221549-90-2 【 分 子 式 】C22H20N4O5 【 分 子 量 】420.4285 |
【开发单位】Kyowa Hakko (Originator) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Oncolytic Drugs |
合成路线1
The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). Finally, the condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the target compound.
| 【1】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669. |
| 【2】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206. |
| 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) | 11191 | 2-Chloropyrimidine | 1722-12-9 | C4H3ClN2 | 详情 | 详情 |
| (II) | 38398 | methyl 2-pyrimidinyl ether; 2-methoxypyrimidine | C5H6N2O | 详情 | 详情 | |
| (III) | 38394 | 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether | C5H5IN2O | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 38395 | methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C9H10N2O3 | 详情 | 详情 | |
| (VI) | 38396 | (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid | C8H8N2O3 | 详情 | 详情 | |
| (VII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (VIII) | 38397 | 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate | C14H11N3O5 | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 |