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【结 构 式】

【分子编号】38399

【品名】methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate

【CA登记号】

【 分 子 式 】C22H20N4O5

【 分 子 量 】420.42476

【元素组成】C 62.85% H 4.79% N 13.33% O 19.03%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.

1 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.
2 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.
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
(XI) 38399 methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C22H20N4O5 详情 详情
(XII) 38400 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate C22H21BrN4O5 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 38401 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C29H24BrN5O9 详情 详情
(XV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
Extended Information