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【结 构 式】 
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【分子编号】38394 【品名】5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether 【CA登记号】 |
【 分 子 式 】C5H5IN2O 【 分 子 量 】236.01205 【元素组成】C 25.45% H 2.14% I 53.77% N 11.87% O 6.78% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |