【结 构 式】 |
【分子编号】29016 【品名】N-(4-aminophenyl)acetamide 【CA登记号】122-80-5 |
【 分 子 式 】C8H10N2O 【 分 子 量 】150.18028 【元素组成】C 63.98% H 6.71% N 18.65% O 10.65% |
合成路线1
该中间体在本合成路线中的序号:(I)OPC-8212 is obtained through the piperazine ring formation method from bis(beta-bromoethyl)amine hydrobromide and 6-amino-3,4-dihydro-2(1H)-quinolinone (V) to give (VI). (V) is synthesized using the ring closure reaction of p-acetylamino-beta-ethoxyacryloanilide (II). p-Acetylaminoaniline (I) is converted to (II) by treatment with beta-ethoxyacryloyl chloride and afterwards cyclized in the presence of sulfuric acid to give 6-acetylamino-2-(1H)-quinolinone (III). Hydrogenation of (III) over 10% palladium on charcoal gives 6-acetylamino-3,4-dihydro-2(1H)-quinolinone (IV). Hydrolysis of (IV) gives 6-amino-3,4-dihydro-2(1H)-quinolinone (V). OPC-8212 is obtained by adding 3,4-dimethoxybenzyl chloride (VII) to (VI).
【1】 Nakagawa, K.; Osumi, T.; Shimizu, T.; Niimi, K.; Physicochemical properties and stabilities of a new positive inotropic agent, OPC 8212. Arzneim-Forsch Drug Res 1984, 34, 3A, 334-341. |
【2】 Yo, E.; Ogawa, H.; Yamashita, S.; Tominaga, M.; Nakagawa, K.; Yabuuchi, Y.; Studies on positive inotropic agents. I. Synthesis of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone and related compounds. Chem Pharm Bull 1984, 32, 6, 2100. |
【3】 Mannhold, R.; OPC-8212. Drugs Fut 1985, 10, 1, 28. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 20616 | (E)-3-ethoxy-2-propenoyl chloride | 99471-66-6 | C5H7ClO2 | 详情 | 详情 |
(B) | 29020 | 2-bromo-N-(2-bromoethyl)-1-ethanamine | C4H9Br2N | 详情 | 详情 | |
(I) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
(II) | 29017 | (E)-N-[4-(acetamido)phenyl]-3-ethoxy-2-propenamide | C13H16N2O3 | 详情 | 详情 | |
(III) | 29018 | N-(2-oxo-1,2-dihydro-6-quinolinyl)acetamide | C11H10N2O2 | 详情 | 详情 | |
(IV) | 29019 | N-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)acetamide | C11H12N2O2 | 详情 | 详情 | |
(V) | 29022 | 6-amino-3,4-dihydro-2(1H)-quinolinone | C9H10N2O | 详情 | 详情 | |
(VI) | 29021 | 6-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinone | C13H17N3O | 详情 | 详情 | |
(VII) | 13438 | 3,4-Dimethoxybenzoyl chloride | 3535-37-3 | C9H9ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(II)Catalytic hydrogenation of 4-nitroacetanilide (I) afforded aniline (II), which was condensed with N,N-dimethylformamide azine to produce the triazolyl derivative (III). Acid hydrolysis of the acetamido group gave rise to amine (IV). Then, diazotization, followed by stannous chloride reduction of the diazonium salt, furnished the intermediate hydrazine (V).
【1】 Matassa, V.G.; Pengilley, R.R.; Russell, M.G.N.; et al.; 3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT1D receptor agonists. J Med Chem 1999, 42, 24, 4981. |
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
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) | 36535 | N-(4-nitrophenyl)acetamide | 104-04-1 | C8H8N2O3 | 详情 | 详情 |
(II) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
(III) | 36536 | N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide | 154594-15-7 | C10H10N4O | 详情 | 详情 |
(IV) | 36537 | 4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline | C8H8N4 | 详情 | 详情 | |
(V) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)Hydrogenation of p-nitroacetanilide (I) over Pd/C afforded p-aminoacetanilide (II), which was converted to triazolylacetanilide (III) upon treatment with N,N-dimethylformamide azine and p-toluenesulfonic acid. Acid hydrolysis of the acetamide (III) provided triazolylaniline (IV). Subsequent diazotization of (IV), followed by SnCl2 reduction of the diazonium salt furnished hydrazine (V). Fischer indole synthesis employing (V) and dihydropyran (VI) gave rise to the indolylpropanol (VII), which was converted to the intermediate mesylate (VIII) using CH3SO2Cl and Et3N.
【1】 Stanton, J.A.; Showell, G.A.; Neduvelil, J.G.; Bourrain, S.; Beer, M.S.; MacLeod, A.M.; 4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: Selective h5-HT1D agonists for the treatment of migraine. Bioorg Med Chem Lett 1999, 9, 23, 3369. |
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
40722 | N'-[(E)-(dimethylamino)methylidene]-N,N-dimethylhydrazonoformamide | C6H14N4 | 详情 | 详情 | ||
(I) | 36535 | N-(4-nitrophenyl)acetamide | 104-04-1 | C8H8N2O3 | 详情 | 详情 |
(II) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
(III) | 36536 | N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide | 154594-15-7 | C10H10N4O | 详情 | 详情 |
(IV) | 36537 | 4-(4H-1,2,4-triazol-4-yl)phenylamine; 4-(4H-1,2,4-triazol-4-yl)aniline | C8H8N4 | 详情 | 详情 | |
(V) | 25647 | 4-(4-hydrazinophenyl)-4H-1,2,4-triazole | C8H9N5 | 详情 | 详情 | |
(VI) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
(VII) | 36538 | 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]-1-propanol | C13H14N4O | 详情 | 详情 | |
(VIII) | 36539 | 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate | C14H16N4O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(VI)Bromination of methyl toluate (I) with N-bromosuccinimide and benzoyl peroxide (Bz2O2) in refluxing CCl4 gives alpha-bromo-o-toluate (II), which is coupled with phenolic derivative (III) by means of K2CO3 in DMF to provide phenoxy derivative (IV). Saponification of the methyl ester group of (IV) by treatment with KOH in refluxing EtOH affords carboxylic acid (V), which is then converted into the desired compound via the corresponding acid chloride obtained by reaction with oxalyl chloride in CHCl3, followed by coupling with 4,6-diamino-2-methylquinoline (XII) by means of pyridine. Quinoline (XII) can be obtained as follows: Condensation of 4-aminoacetanilide (VII) with methyl acetoacetate (VIII) by heating in MeOH affords crotonate (IX), which is then subjected to cyclization in refluxing Dowtherm A to provide hydroxy quinoline (X). Methylation of (X) with dimethyl sulfate in refluxing toluene gives methoxy quinoline (XI), whose methoxy group is converted into an amino group with ammonium acetate and whose acetyl group is finally removed by hydrolysis with HCl.
【1】 Kitao, Y.; Shinkai, H.; Ito, T.; Uchida, I.; Yamada, H.; Iida, T.; 4-Aminoquinolones: Novel nociceptin antagonists with analgesics activity. J Med Chem 2000, 43, 24, 4667. |
【2】 Shinkai, H.; Yamada, H.; to, T. (Japan Tobacco Inc.); Amide derivs. and nociceptin antagonists. EP 1072263; JP 1999335355; WO 9948492 . |
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) | 49024 | 2-Methyl Methylbenzoate; 2-Methylbenzoic acid methyl ester; Methyl o-toluate; o-Toluic acid methyl ester | 89-71-4 | C9H10O2 | 详情 | 详情 |
(II) | 28575 | methyl 2-(bromomethyl)benzoate | C9H9BrO2 | 详情 | 详情 | |
(III) | 49025 | p-Ethylphenol; 4-Ethylphenol | 123-07-9 | C8H10O | 详情 | 详情 |
(IV) | 49026 | methyl 2-[(4-ethylphenoxy)methyl]benzoate | C17H18O3 | 详情 | 详情 | |
(V) | 49027 | 2-[(4-ethylphenoxy)methyl]benzoic acid | C16H16O3 | 详情 | 详情 | |
(VI) | 29016 | N-(4-aminophenyl)acetamide | 122-80-5 | C8H10N2O | 详情 | 详情 |
(VII) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
(VIII) | 49028 | methyl (Z)-3-[4-(acetamido)anilino]-2-butenoate | C13H16N2O3 | 详情 | 详情 | |
(IX) | 49029 | N-(4-hydroxy-2-methyl-6-quinolinyl)acetamide | C12H12N2O2 | 详情 | 详情 | |
(X) | 49030 | N-(4-methoxy-2-methyl-6-quinolinyl)acetamide | C13H14N2O2 | 详情 | 详情 | |
(XI) | 49031 | 4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine | C10H11N3 | 详情 | 详情 |