【结 构 式】 |
【分子编号】30226 【品名】6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril 【CA登记号】 |
【 分 子 式 】C9H9NO2 【 分 子 量 】163.176 【元素组成】C 66.25% H 5.56% N 8.58% O 19.61% |
合成路线1
该中间体在本合成路线中的序号:(III)By reaction of N-[(4-chlorobutyl)carbonyl]cyclohexylamine (I) first with PCl5 and then with NH3 in benzene to give 1-cyclohexyl-5-(4-chlorobutyl)tetrazole (II), which is treated with 6-hydroxy-3,4-dihydrocarbostyril (III) and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) in ethanol. Alternatively, the condensation can be performed by means of either NaOH, KOH or KOH / K2CO3 in a great variety of solvents.
【1】 Nishi, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Tetrazolylalkoxycarbostyril derivatives and pharmaceutical compositions containing them. DE 2934747; FR 2434809; GB 2033893; JP 55035019; US 4277479 . |
【2】 Finkelstein, N.; Mendelovichi, M.; Pilarksi, G. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for preparing cilostazol. WO 0214283 . |
【3】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; OPC-13,013. Drugs Fut 1982, 7, 4, 264. |
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) | 31946 | N-[(4-chlorobutyl)carbonyl]cyclohexylamine; 5-chloro-N-cyclohexylpentanamide | 15862-18-6 | C11H20ClNO | 详情 | 详情 |
(II) | 31947 | 1-Cyclohexyl-5-(4-chlorobutyl)tetrazole; 5-(4-Chlorobutyl)-1-cyclohexyl-1H-1,2,3,4-tetraazole | 73963-42-5 | C11H19ClN4 | 详情 | 详情 |
(III) | 30226 | 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril | C9H9NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(III)The condensation of p-anisidine (IV) with 3-chloropropionyl chloride (V) by means of TEA in hot toluene, hot 2-butanone or DMF gives the corresponding amide (VI), which is then cyclized by means of AlCl3 in N,N-dimethylacetamide at 150-60 C and treated with NaBH4 in water to yield the desired 6-hydroxy-1,2,3,4-tetrahydroquinolin-2-one intermediate (III).
【1】 Mendelovici, M.; Nidam, T.; Pilarsky, G. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for preparing 6-hydroxy-3,4-dihydroquinolinone, cilostazol and N-(4-methoxyphenyl)-3-chloropropionamide. WO 0170697 . |
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) | 30226 | 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril | C9H9NO2 | 详情 | 详情 | |
(IV) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
(V) | 18936 | 3-chloropropanoyl chloride | 625-36-5 | C3H4Cl2O | 详情 | 详情 |
(VI) | 55445 | 3-chloro-N-(4-methoxyphenyl)propanamide | C10H12ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(A)The enantiomerically pure sulfoxide was prepared by a different route, starting from the alkylation of hydroxyquinolinone (A) with (S)-glycidyl tosylate (IV) to give the chiral epoxide (V). Ring opening with mercaptoimidazole (I) afforded the enantiomerically rich (R)-mercapto alcohol (VI), which after recrystallization from EtOH provided the pure (R)-isomer. Oxidation with m-chloroperbenzoic acid yielded a diastereomeric mixture of hydroxy sulfoxides (VII). After separation by column chromatography, the required (S)-sulfoxide was converted to mesylate (VIII), and finally reduced with lithium triethylborohydride to afford the target (S)-compound.
【1】 Nishi, T.; Chu, G.-N.; Okada, M.; Tamura, K.; Unemi, F.; Koga, Y.; Kido, M.; Igawa, T.; Ozeki, Y.; Uno, T.; Synthesis of 2(1H)-quinolinone derivatives and their inhibitory activity on the release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) from platelets. Chem Pharm Bull 1995, 43, 10, 1724. |
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) | 30226 | 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril | C9H9NO2 | 详情 | 详情 | |
(I) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
(IV) | 16740 | (2S)-(+)-Glycidyl tosylate; (2S)oxiranylmethyl 4-methylbenzenesulfonate | 70987-78-9 | C10H12O4S | 详情 | 详情 |
(V) | 30227 | 6-[(2S)oxiranylmethoxy]-3,4-dihydro-2(1H)-quinolinone | C12H13NO3 | 详情 | 详情 | |
(VI) | 30228 | 6-[((2R)-2-hydroxy-3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]propyl)oxy]-3,4-dihydro-2(1H)-quinolinone | C22H23N3O3S | 详情 | 详情 | |
(VII) | 30229 | 6-[((2R)-2-hydroxy-3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl)oxy]-3,4-dihydro-2(1H)-quinolinone | C22H23N3O4S | 详情 | 详情 | |
(VIII) | 30230 | (1R)-2-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-[[(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)oxy]methyl]ethyl methanesulfonate | C23H25N3O6S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(IV)
【1】 Nishi T,NakagawaI(.1981. Tetnuolylalkoxyc而otyril derivatives and pharmaceutical compositions containing them US 4277479 |
【2】 YamamotoA,FukuyamaN,et al.2004.Process for producing alostazoL W0 2004024716 |
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) | 31946 | N-[(4-chlorobutyl)carbonyl]cyclohexylamine; 5-chloro-N-cyclohexylpentanamide | 15862-18-6 | C11H20ClNO | 详情 | 详情 |
(II) | 66193 | (Z)-5-chloro-N-cyclohexylpentanimidoyl chloride | C11H19Cl2N | 详情 | 详情 | |
(III) | 31947 | 1-Cyclohexyl-5-(4-chlorobutyl)tetrazole; 5-(4-Chlorobutyl)-1-cyclohexyl-1H-1,2,3,4-tetraazole | 73963-42-5 | C11H19ClN4 | 详情 | 详情 |
(IV) | 30226 | 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril | C9H9NO2 | 详情 | 详情 |