【结 构 式】 |
【分子编号】40490 【品名】3-nitro-2,4-pyridinediol 【CA登记号】89282-12-2 |
【 分 子 式 】C5H4N2O4 【 分 子 量 】156.09784 【元素组成】C 38.47% H 2.58% N 17.95% O 41% |
合成路线1
该中间体在本合成路线中的序号:(XII)Reaction of 2-hydroxy-4-methoxypyridine-3-carbonitrile (X) with 85% phosphoric acid at 180 C gives 2,4-dihydroxypyridine (XI), which is nitrated with HNO3 in hot acetic acid to yield 2,4-dihydroxy-3-nitropyridine (XII). The reaction of (XII) with POCl3 in hot toluene affords 4-chloro-3-nitropyridin-2(1H)-one (XIII), which is condensed with the previously described amine (II) by means of DIEA in isopropanol to afford the aminopyridinol (XIV). Chlorination of (XIV) with POCl3 in toluene gives the previously described 4-amino-2-chloro-3-nitropyridine derivative (III), which is condensed with the described cyclopentanecarboxamide (IV) by means of K2CO3 in toluene, yielding the already known 2,4-diamino-3-nitropyridine (V). The reduction of (V) with ammonium formate over Pt/C or with Zn and ammonium acetate affords the described 2,3,4-triaminopyridine (VI), which is treated with HCl in THF in order to eliminate the acetonide group, providing the deprotected triaminopyridine derivative (XV). Finally, this compound is cyclized with formamidine (VII), triethyl orthoformate (XVI) or dimethylformamide dimethylacetal (XVII) in a suitable solvent.
【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
【2】 Reilly, L.W.; Vanasse, B.J.; Garcia, H.; Shah, H.C.; Leon, P.; O'Brien, M.K.; Walther, F.L.; Powner, T.H.; Tsuei, C.T.; Thompson, M.D. (Aventis Pharmaceuticals, Inc.); Preparation of [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]N-ethyl-2,3-dihydroxycyclopentanecarboxamide. WO 9825921 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(III) | 23849 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amine; 2-chloro-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine | C13H13Cl2N3O2S | 详情 | 详情 | |
(IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
(V) | 23851 | (3aR,4S,6R,6aS)-6-[[4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H32ClN5O5S | 详情 | 详情 | |
(VI) | 23848 | (2R)-1-(3-chloro-2-thienyl)-2-butanamine; (1R)-1-[(3-chloro-2-thienyl)methyl]propylamine | C8H12ClNS | 详情 | 详情 | |
(VI) | 23852 | (3aR,4S,6R,6aS)-6-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H34ClN5O3S | 详情 | 详情 | |
(VII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
(X) | 40489 | 2-hydroxy-4-methoxynicotinonitrile | C7H6N2O2 | 详情 | 详情 | |
(XI) | 34269 | 2,4-pyridinediol | 626-03-9 | C5H5NO2 | 详情 | 详情 |
(XII) | 40490 | 3-nitro-2,4-pyridinediol | 89282-12-2 | C5H4N2O4 | 详情 | 详情 |
(XIII) | 40491 | 4-chloro-3-nitro-2(1H)-pyridinone | C5H3ClN2O3 | 详情 | 详情 | |
(XIV) | 40492 | 4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinol | C13H14ClN3O3S | 详情 | 详情 | |
(XV) | 40493 | (1S,2R,3S,4R)-4-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide | C21H30ClN5O3S | 详情 | 详情 | |
(XVI) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
(XVII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)Nitration of 2,4-dihydroxypyridine (I) affords the 3-nitro derivative (II). Selective chlorination of the 4-hydroxy group of (II) is accomplished by treatment of the cycloheptylamine salt of (II) with POCl3 to furnish 4-chloro-2-hydroxy-3-nitropyridine (III). The 2-hydroxy group of (III) is then protected as the benzyl ether (IV) using benzyl bromide in the presence of silver carbonate. Suzuki coupling of protected chloropyridine (IV) with 2-chloro-4-(difluoromethoxy)phenylboronic acid (V) leads to the phenylpyridine derivative (VI). The O-benzyl group of (VI) is then removed with trifluoroacetic acid, and the resultant 2-hydroxypyridine (VII) is further chlorinated by means of POCl3, yielding (VIII). Displacement of the 2-chloro substituent of (VIII) with 1-cyclobutylethylamine (IX) in refluxing acetonitrile furnishes the 2-amino-3-nitropyridine (X). Subsequent nitro group reduction in (X) employing sodium dithionite and ammonium hydroxide leads to diamine (XI). This is finally cyclized to the desired imidazopyridine upon heating at reflux with propionic acid.
【1】 Arvanitis, A.G.; Rescinito, J.T.; Arnold, C.R.; Wilde, R.G.; Cain, G.A.; Sun, J.H.; Yan, J.-S.; Teleha, C.A.; Fitzgerald, L.W.; McElroy, J.; Zaczek, R.; Hartig, P.R.; Grossman, S.; Arneric, S.P.; Gilligan, P.J.; Olson, R.E.; Robertson, D.W.; Imidazo[4,5-b]pyridines as corticotropin releasing factor receptor ligands. Bioorg Med Chem Lett 2003, 13, 1, 125. |
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) | 34269 | 2,4-pyridinediol | 626-03-9 | C5H5NO2 | 详情 | 详情 |
(II) | 40490 | 3-nitro-2,4-pyridinediol | 89282-12-2 | C5H4N2O4 | 详情 | 详情 |
(III) | 63238 | 4-chloro-3-nitro-2-pyridinol | C5H3ClN2O3 | 详情 | 详情 | |
(IV) | 65004 | 02-(benzyloxy)-4-chloro-3-nitropyridine; benzyl 4-chloro-3-nitro-2-pyridinyl ether | C12H9ClN2O3 | 详情 | 详情 | |
(V) | 65003 | 2-chloro-4-(difluoromethoxy)phenylboronic acid | C7H6BClF2O3 | 详情 | 详情 | |
(VI) | 65002 | 2-(benzyloxy)-4-[2-chloro-4-(difluoromethoxy)phenyl]-3-nitropyridine; benzyl 4-[2-chloro-4-(difluoromethoxy)phenyl]-3-nitro-2-pyridinyl ether | C19H13ClF2N2O4 | 详情 | 详情 | |
(VII) | 65005 | 4-[2-chloro-4-(difluoromethoxy)phenyl]-3-nitro-2-pyridinol | C12H7ClF2N2O4 | 详情 | 详情 | |
(VIII) | 65006 | 2-chloro-4-[2-chloro-4-(difluoromethoxy)phenyl]-3-nitropyridine; 3-chloro-4-(2-chloro-3-nitro-4-pyridinyl)phenyl difluoromethyl ether | C12H6Cl2F2N2O3 | 详情 | 详情 | |
(IX) | 65007 | 1-cyclobutyl-1-ethanamine; 1-cyclobutylethylamine | C6H13N | 详情 | 详情 | |
(X) | 65008 | 4-[2-chloro-4-(difluoromethoxy)phenyl]-N-(1-cyclobutylethyl)-3-nitro-2-pyridinamine; N-{4-[2-chloro-4-(difluoromethoxy)phenyl]-3-nitro-2-pyridinyl}-N-(1-cyclobutylethyl)amine | C18H18ClF2N3O3 | 详情 | 详情 | |
(XI) | 65009 | 4-[2-chloro-4-(difluoromethoxy)phenyl]-N~2~-(1-cyclobutylethyl)-2,3-pyridinediamine; N-{3-amino-4-[2-chloro-4-(difluoromethoxy)phenyl]-2-pyridinyl}-N-(1-cyclobutylethyl)amine | C18H20ClF2N3O | 详情 | 详情 |