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【结 构 式】 
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【分子编号】18930 【品名】2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline 【CA登记号】 |
【 分 子 式 】C17H14Cl2N2O 【 分 子 量 】333.21644 【元素组成】C 61.28% H 4.23% Cl 21.28% N 8.41% O 4.8% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 2-methylquinolin-8-ol (I) with 2,6-dichloro-3-nitrobenzyl chloride (II) by means of NaH in DMF gives the corresponding benzyl ether (III), which is reduced with Fe and HCl in methanol/water to the aniline (IV). The acylation of (IV) with 2-phthalimidoacetyl chloride (V) by means of DMAP and pyridine yields the amide (VI), which is methylated at the amidic nitrogen with NaH and methyl iodide in DMF to the N-methylanilide (VII). Elimination of the phthalimido group of (VII) with hydrazine in refluxing ethanol affords the glycine anilide (VIII), which is acylated with the acrylic acid (IX) by means of 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide (DECD) and HOBT in DMF. The intermediate substituted acrylic acid (IX) has been obtained by reaction of 6-acetamidopyridine-3-carbaldehyde (X) with malonic acid and pyridine in refluxing ethanol.
| 【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 . |
| 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) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (II) | 18928 | 1,3-dichloro-2-(chloromethyl)-4-nitrobenzene | C7H4Cl3NO2 | 详情 | 详情 | |
| (III) | 18929 | 2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline | C17H12Cl2N2O3 | 详情 | 详情 | |
| (IV) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (V) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (VI) | 18932 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide | C27H19Cl2N3O4 | 详情 | 详情 | |
| (VII) | 18599 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide | C28H21Cl2N3O4 | 详情 | 详情 | |
| (VIII) | 18600 | 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide | C20H19Cl2N3O2 | 详情 | 详情 | |
| (IX) | 19304 | (E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid | C10H10N2O3 | 详情 | 详情 | |
| (X) | 26413 | N-(5-formyl-2-pyridinyl)acetamide | C8H8N2O2 | 详情 | 详情 | |
| (XI) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Benzyl alcohol (I) was treated with mesyl chloride and triethylamine in CH2Cl2 at 0 C, and the resulting mesylate (II) was subsequently coupled with 2-methyl-8-hydroxyquinoline (III) in the presence of NaH to afford ether (IV). Reduction of the nitro group of (IV) with hydrazine in the presence of FeCl3 and carbon gave aniline (V). Pyrrole (VII) was then obtained by heating (V) with 2,5-dimethoxy tetrahydrofuran (VI) in AcOH. Further reaction of (VII) with chlorosulfonylisocyanate (VIII) at low temperature provided the 2-cyanopyrrole (IX). The cyano group of (IX) was reduced with LiAlH4 to give amine (X). This was finally condensed with pyridinylacrylic acid (XI) using EDC and HOBt to yield the target amide, which was isolated as the dihydrochloride salt.
| 【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation. J Med Chem 1998, 41, 23, 4587. |
| 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) | 18590 | (2,6-dichloro-3-nitrophenyl)methanol | C7H5Cl2NO3 | 详情 | 详情 | |
| (II) | 19295 | 2,6-dichloro-3-nitrobenzyl methanesulfonate | C8H7Cl2NO5S | 详情 | 详情 | |
| (III) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (IV) | 18926 | (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid | C11H11NO3 | 详情 | 详情 | |
| (V) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (VI) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (VII) | 19300 | 2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl 2-methyl-8-quinolinyl ether; 8-[[2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl]oxy]-2-methylquinoline | C21H16Cl2N2O | 详情 | 详情 | |
| (VIII) | 14010 | ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H20ClN5O2S | 详情 | 详情 | |
| (IX) | 19302 | 1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrole-2-carbonitrile | C22H15Cl2N3O | 详情 | 详情 | |
| (X) | 19303 | [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methanamine; [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methylamine | C22H19Cl2N3O | 详情 | 详情 | |
| (XI) | 19304 | (E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid | C10H10N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The target FR-165649 has been obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as coupling agents. The two intermediates (V) and (XIII) have been obtained as follows: 1) Wittig reaction of 4-formylbenzoic acid (I) and methyl (triphenylphosphoranylidene)acetate (II) in THF gave methyl 4-carboxycinnamate (III), which was converted into amide (IV) by reaction with methylamine hydrochloride in the presence of EDC and HOBt. Further hydrolysis of the ester group with NaOH provided 4-(methylcarbamoyl)cinnamic acid (V). 2) The alkylation of 8-hydroxy-2-methylquinoline (VI) with benzylic chloride (VII) in the presence of NaH and a catalytic amount of tetrabutylammonium iodide in DMF afforded ether (VIII). Subsequent reduction of the nitro group with iron powder and HCl in refluxing aqueous methanol gave amine (IX), which was coupled with phthalimidoacetyl chloride (X) in the presence of DMAP in a mixture of N-methylpyrrolidone and pyridine to yield amide (XI). Then, alkylation at the amide N with CH3I and NaH provided (XII), and further hydrazinolysis of the phthalimido group yielded the primary amine (XIII). Finally, the target amide was obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as the coupling reagents.
| 【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 . |
| 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) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (II) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (III) | 18924 | 4-[(E)-3-methoxy-3-oxo-1-propenyl]benzoic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 18925 | methyl (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoate | C12H13NO3 | 详情 | 详情 | |
| (V) | 18926 | (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid | C11H11NO3 | 详情 | 详情 | |
| (VI) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (VII) | 18928 | 1,3-dichloro-2-(chloromethyl)-4-nitrobenzene | C7H4Cl3NO2 | 详情 | 详情 | |
| (VIII) | 18929 | 2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline | C17H12Cl2N2O3 | 详情 | 详情 | |
| (IX) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (X) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (XI) | 18932 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide | C27H19Cl2N3O4 | 详情 | 详情 | |
| (XII) | 18599 | N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide | C28H21Cl2N3O4 | 详情 | 详情 | |
| (XIII) | 18600 | 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide | C20H19Cl2N3O2 | 详情 | 详情 |