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【结 构 式】 
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【分子编号】28994 【品名】7-amino[1,8]naphthyridin-2-ol 【CA登记号】 |
【 分 子 式 】C8H7N3O 【 分 子 量 】161.1632 【元素组成】C 59.62% H 4.38% N 26.07% O 9.93% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(I)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 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III), which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV). Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V), which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (±)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone). The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII). Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX), which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.
| 【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651. |
| 【2】 Bourzat, J.-D.; Cotrel, C.; Roussel, G.; Capet, M.; Labaudiniere, R.; Pitchen, P. (Aventis SA); Isoindolinone derivs.. AU 8781911; EP 0274930; FR 2607503; JP 1988154681; US 4960779 . |
| 【3】 David-Comte, M.-T.; Roussel, G. (Aventis Pharma SA); Novel 2-aminonaphthyridine deriv., its preparation and its use. EP 0522969; FR 2678931 . |
| 【4】 David-Comte, M.-T. (Aventis Pharma SA); Dextrorotatory isomer of a deriv. of 2-amino naphthyridine and its preparation. EP 0522971; FR 2678933 . |
| 【5】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of a dextrorotatory isomer of an isoindolinone deriv.. EP 0522972; FR 2678934 . |
| 【6】 David-Comte, M.-T. (Aventis Pharma SA); Process for the preparation of the optical isomers of 2-aminonaphthyridine derivs.. EP 0522970; FR 2678932 . |
| 【7】 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 . |
| 【8】 (Aventis Pharma SA); Novel isoindoline derivs., their preparation and compsns. containing them. FR 2229400 . |
| 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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 47675 | 2-(7-hydroxy[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione | C16H9N3O3 | 详情 | 详情 | |
| (IV) | 47676 | 2-(7-chloro[1,8]naphthyridin-2-yl)-1H-isoindole-1,3(2H)-dione | C16H8ClN3O2 | 详情 | 详情 | |
| (V) | 11334 | 2-(7-Chloro[1,8]naphthyridin-2-yl)-3-hydroxy-1-isoindolinone | C16H10ClN3O2 | 详情 | 详情 | |
| (VI) | 47677 | 2-Methyl-5-Hexanone; 5-Methyl-2-hexanone; 5-Methyl-2-oxohexane; iso-Amyl methyl ketone; Isopentyl methyl ketone; Methyl isoamyl ketone | 110-12-3 | C7H14O | 详情 | 详情 |
| (VII) | 47678 | 2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone | C23H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 47679 | (rac)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid | C23H24ClN3O3 | 详情 | 详情 | |
| (IX) | 47680 | (+)-2-[1-[(7-chloro[1,8]naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl]benzoic acid | C23H24ClN3O3 | 详情 | 详情 |