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【结 构 式】 
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【分子编号】28998 【品名】6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one 【CA登记号】 |
【 分 子 式 】C14H10ClN3O2S2 【 分 子 量 】351.83712 【元素组成】C 47.79% H 2.86% Cl 10.08% N 11.94% O 9.09% S 18.23% |
合成路线1
该中间体在本合成路线中的序号：(V)The cyclization of 5,6-dihydro-1,4-dithiine-2,3-dicarboxylic acid anhydride (I) with 2-amino-7-hydroxy-1,8-naphthyridine (II) by means of acetic acid in refluxing diphenyl-diphenyl ether gives 6-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole-5,7-dione (III), which is treated with POCl3 in hot DMF to yield 6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole-5,7-dione (IV). The reduction of (IV) with NaBH4 in methanol affords 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrol-7-one (V), which is finally condensed with 1-chlorocarbonyl-4-methylpiperazine (VI) by means of NaH in DMF.
| 【1】 Jeanmart, C.; Leger, A.; Messer, M.N. (Aventis Pharma SA); 1,4-Dithiimo[2,3-c]pyrrole derivatives. CA 989841; DE 2360362; FR 2208651; FR 2209129; FR 2258182; GB 1397060; JP 7493392; NL 7316162; US 3948917; US 3966931; ZA 7309139 . |
| 【2】 Castaner, J.; Serradell, M.N.; Souto, M.E.; Suriclone. Drugs Fut 1984, 9, 3, 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) | 30369 | 2,3-dihydro[1,4]dithiino[2,3-c]furan-5,7-dione | C6H4O3S2 | 详情 | 详情 | |
| (II) | 28994 | 7-amino[1,8]naphthyridin-2-ol | C8H7N3O | 详情 | 详情 | |
| (III) | 28996 | 6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H9N3O3S2 | 详情 | 详情 | |
| (IV) | 28997 | 6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H8ClN3O2S2 | 详情 | 详情 | |
| (V) | 28998 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one | C14H10ClN3O2S2 | 详情 | 详情 | |
| (VI) | 30370 | 4-methyl-1-piperazinecarbonyl chloride | C6H11ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III), which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV). Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V), which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII), which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride. The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII), which is then condensed with phosgene in anhydrous toluene.
| 【1】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 . |
| 【2】 Serradell, M.N.; Castaner, J.; Suproclone. Drugs Fut 1985, 10, 1, 45. |
| 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) | 28994 | 7-amino[1,8]naphthyridin-2-ol | C8H7N3O | 详情 | 详情 | |
| (II) | 28995 | 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C6H5NO2S2 | 详情 | 详情 | |
| (III) | 28996 | 6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H9N3O3S2 | 详情 | 详情 | |
| (IV) | 28997 | 6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione | C14H8ClN3O2S2 | 详情 | 详情 | |
| (V) | 28998 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one | C14H10ClN3O2S2 | 详情 | 详情 | |
| (VI) | 28999 | tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate | C10H17ClN2O3 | 详情 | 详情 | |
| (VII) | 29000 | 1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate | C24H26ClN5O5S2 | 详情 | 详情 | |
| (VIII) | 29001 | 6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 1-piperazinecarboxylate | C19H18ClN5O3S2 | 详情 | 详情 | |
| (IX) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (X) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (XI) | 29002 | 2-[(azidocarbonyl)oxy]-2-methylpropane | C5H9N3O2 | 详情 | 详情 | |
| (XII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |