|
【结 构 式】 
|
【分子编号】60299 【品名】1,2,3,6-tetrahydro-4-pyridinecarboxamide 【CA登记号】 |
【 分 子 式 】C6H10N2O 【 分 子 量 】126.15828 【元素组成】C 57.12% H 7.99% N 22.21% O 12.68% |
合成路线1
该中间体在本合成路线中的序号：(VI)The preparation of the intermediate 1,2,3,6-tetrahydropyridine-4-carboxamide (VI) is illustrated in Scheme 1. Demethylation of tetrahydropyridine (I) with ethyl chloroformate in refluxing benzene affords carbamate (II), which is further hydrolyzed to the aminoacid (III) upon heating with concentrated HBr. Subsequent protection of (III) by means of di-t-butyl dicarbonate leads to N-Boc tetrahydropyridine-4-carboxylic acid (IV). Coupling of acid (IV) with ammonia in the presence of EDC/HOBt provides amide (V). The N-Boc protecting group of (V) is then removed with trifluoroacetic acid in CHCl3, yielding tetrahydropyridine (VI)
| 【1】 Tomisawa, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Carbamoyl tetrahydropyridine derivs.. EP 1176146 . |
| 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) | 43676 | methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate | C10H16N2O6 | 详情 | 详情 | |
| (II) | 43674 | diethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate | C11H17NO4 | 详情 | 详情 | |
| (III) | 62072 | 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid | C6H9NO2 | 详情 | 详情 | |
| (IV) | 62073 | 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-pyridinecarboxylic acid | C11H17NO4 | 详情 | 详情 | |
| (V) | 62074 | tert-butyl 4-(aminocarbonyl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H18N2O3 | 详情 | 详情 | |
| (VI) | 60299 | 1,2,3,6-tetrahydro-4-pyridinecarboxamide | C6H10N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Condensation of 2,6-dibromo-4-(trifluoromethyl)aniline (VII) with acetoin (VIII), followed by heating the intermediate imine (IX) with malononitrile at 180 C gives rise to the N-aryl pyrrole (X). Acylation of aminopyrrole (X) with Ac2O provides acetamide (XI), which undergoes ring closure to the pyrrolopyrimidine (XII) in hot phosphoric acid. Chlorination of (XII) employing POCl3 furnishes aryl chloride (XIII). This is finally condensed with tetrahydropyridine (VI) to produce the title compound
| 【1】 Oshida, Y.; Kumagai, T.; Okubo, T.; Chaki, S.; Okuyama, S.; Nakazato, A.; Synthesis, SARs and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinopyrrolopyrimidine derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 259. |
| 【2】 Okubo, T.; et al.; 4- or 5-Carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine derivative as a CRH1 receptor antagonist. Drugs Fut 2002, 27, Suppl. A. |
| 【3】 Tomisawa, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Carbamoyl tetrahydropyridine derivs.. EP 1176146 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 60299 | 1,2,3,6-tetrahydro-4-pyridinecarboxamide | C6H10N2O | 详情 | 详情 | |
| (VII) | 62075 | 2,6-dibromo-4-(trifluoromethyl)phenylamine; 2,6-dibromo-4-(trifluoromethyl)aniline; 4-Amino-3,5-dibromobenzotrifluoride; 2,6-Dibromo-4-trifluoromethylaniline | 72678-19-4 | C7H4Br2F3N | 详情 | 详情 |
| (VIII) | 62081 | acetoin; 2-Butanone, 3-hydroxy-, (+-)-; 3-hydroxy-2-butanone; Acetyl methyl carbinol; 2-butanol-3-one; 3-Hydroxybutan-2-one; Dimethylketol; (R)-Acetoin; (R)-2-Acetoin; (R)-Dimethylketol; 2-acetoin; 2,3-Butanolone; Gamma-hydroxy-beta-oxobutane; ACETOIN, NATURAL; Acetoin, 85% Aqueous Soln.; Acetylmethylcarbinol, 85% Aqueous Soln.; 3-Hydroxy-2-Butanone, 85% Aqueous Soln.; Acetyl methyl carbinol, 85 wt. % solutionin water; Acetyl-methylcarbinol; Acetyl methyl carbinol pract.,; Methylacetylcarbinol; Acetylmethylcarbinol; (ACETOIN) | 513-86-0 | C4H8O2 | 详情 | 详情 |
| (IX) | 62076 | 3-{[2,6-dibromo-4-(trifluoromethyl)phenyl]imino}-2-butanol | C11H10Br2F3NO | 详情 | 详情 | |
| (X) | 62077 | 2-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4,5-dimethyl-1H-pyrrole-3-carbonitrile | C14H10Br2F3N3 | 详情 | 详情 | |
| (XI) | 62078 | N-{3-cyano-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4,5-dimethyl-1H-pyrrol-2-yl}acetamide | C16H12Br2F3N3O | 详情 | 详情 | |
| (XII) | 62079 | 7-[2,6-dibromo-4-(trifluoromethyl)phenyl]-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol | C16H12Br2F3N3O | 详情 | 详情 | |
| (XIII) | 62080 | 4-chloro-7-[2,6-dibromo-4-(trifluoromethyl)phenyl]-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine | C16H11Br2ClF3N3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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4
该中间体在本合成路线中的序号：(III)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 |