【结 构 式】 |
【药物名称】R-278995, CRA-0450 【化学名称】1-[8-(2,4-Dichlorophenyl)-2-methylquinolin-4-yl]-1,2,3,6-tetrahydropyridine-4-carboxamide benzenesulfonate 【CA登记号】388122-48-3 (free base) 【 分 子 式 】C28H25Cl2N3O4S 【 分 子 量 】570.49915 |
【开发单位】Johnson & Johnson (Originator), Taisho (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, CRF1 Antagonists |
合成路线1
Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III). This is condensed with ethyl acetoacetate (IV) to produce enamine (V), which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI). Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII). Finally, displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound
【1】 Nakazato, A.; et al.; Chemical modification of 4-carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine, CRA0316, for discovery CRH1 receptor antagonists. Drugs Fut 2002, 27, Suppl. A. |
【2】 Kennis, L.; Kumagai, T.; Nakazato, A.; et al.; Synthesis, SAR and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinoquinoline derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 258. |
【3】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 . |
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) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
(II) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |
(III) | 60295 | 2',4'-dichloro[1,1'-biphenyl]-2-amine; 2',4'-dichloro[1,1'-biphenyl]-2-ylamine | C12H9Cl2N | 详情 | 详情 | |
(IV) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(V) | 60296 | ethyl 3-[(2',4'-dichloro[1,1'-biphenyl]-2-yl)amino]-2-butenoate | C18H17Cl2NO2 | 详情 | 详情 | |
(VI) | 60297 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol | C16H11Cl2NO | 详情 | 详情 | |
(VII) | 60298 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl trifluoromethanesulfonate | C17H10Cl2F3NO3S | 详情 | 详情 | |
(VIII) | 60299 | 1,2,3,6-tetrahydro-4-pyridinecarboxamide | C6H10N2O | 详情 | 详情 |
合成路线2
Alternatively, hydroxyquinoline (I) is chlorinated in refluxing POCl3 to provide chloroquinoline (II). Substitution of (II) with 4-piperidone ethylene ketal (III) in boiling DMF furnishes the piperidinyl quinoline derivative (IV), which is further hydrolyzed to piperidone (V) under acidic conditions. Addition of cyanide to piperidone (V) gives rise to cyanohydrin (VI), and subsequent dehydration by means of POCl3/pyridine affords the unsaturated nitrile (VII). Finally, partial hydrolysis of nitrile (VII) with HCl in formic acid leads to the target amide compound
【1】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 . |
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) | 60297 | 8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol | C16H11Cl2NO | 详情 | 详情 | |
(II) | 60301 | 4-chloro-8-(2,4-dichlorophenyl)-2-methylquinoline | C16H10Cl3N | 详情 | 详情 | |
(III) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
(IV) | 60302 | 8-(2,4-dichlorophenyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylquinoline | C23H22Cl2N2O2 | 详情 | 详情 | |
(V) | 60303 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-piperidinone | C21H18Cl2N2O | 详情 | 详情 | |
(VI) | 60304 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-4-hydroxy-4-piperidinecarbonitrile | C22H19Cl2N3O | 详情 | 详情 | |
(VII) | 60305 | 1-[8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl]-1,2,3,6-tetrahydro-4-pyridinecarbonitrile | C22H17Cl2N3 | 详情 | 详情 |
合成路线3
In a related synthetic strategy, 8-bromo-4-hydroxy-2-methylquinoline (I) is converted to aryl triflate (II) by using N-phenyl trifluoromethanesulfonimide and NaH. Displacement of the triflate group of (II) with 1,2,3,6-tetrahydropyridine-4-carboxamide (III) gives the tetrahydropyridyl quinoline (IV). The bromoquinoline (IV) is finally subjected to Suzuki coupling with 2,4-dichlorophenylboronic acid (V) to produce the title compound
【1】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 . |
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) | 60306 | 8-bromo-2-methyl-4-quinolinol | C10H8BrNO | 详情 | 详情 | |
(II) | 60307 | 8-bromo-2-methyl-4-quinolinyl trifluoromethanesulfonate | C11H7BrF3NO3S | 详情 | 详情 | |
(III) | 60299 | 1,2,3,6-tetrahydro-4-pyridinecarboxamide | C6H10N2O | 详情 | 详情 | |
(IV) | 60308 | 1-(8-bromo-2-methyl-4-quinolinyl)-1,2,3,6-tetrahydro-4-pyridinecarboxamide | C16H16BrN3O | 详情 | 详情 | |
(V) | 48912 | 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid | 68716-47-2 | C6H5BCl2O2 | 详情 | 详情 |