【结 构 式】 |
【分子编号】29766 【品名】butanol; n-butanol; 1-butanol 【CA登记号】71-36-3 |
【 分 子 式 】C4H10O 【 分 子 量 】74.1228 【元素组成】C 64.82% H 13.6% O 21.58% |
合成路线1
该中间体在本合成路线中的序号:(VI)1) By condensation of phenol (I) with 1-n-butoxy-2,3-epoxypropane (VII) in presence of potassium hydroxide. 2) By condensation of phenol (I) with 1-chloro-2,3-epoxypropane (II) followed either by addition of n-butanol (VI) in presence of a Lewis acid or in presence of a base (IV).
【1】 Hoffmann, H.; et al.; Procedimiento de fabricacion de sustancias medicinalmente activas y metodo de preparacion de medicamentos de accion coleretica. ES 402799; FR 2134389; GB 1393451; US 3839587 . |
【2】 Janiak, P. St.; Febuprol. Drugs Fut 1978, 3, 3, 191. |
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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
(II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
(III) | 33456 | 1-chloro-3-phenoxy-2-propanol | C9H11ClO2 | 详情 | 详情 | |
(IV) | 33457 | sodium 1-butanolate; Sodium butoxide; Sodium n-butoxide | 2372-45-4 | C4H9NaO | 详情 | 详情 |
(V) | 23932 | 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether | 122-60-1 | C9H10O2 | 详情 | 详情 |
(VI) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
(VII) | 33458 | 2-(butoxymethyl)oxirane; butyl 2-oxiranylmethyl ether | 2426-08-6 | C7H14O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(A)3-(4-Hydroxypiperidino)-6-(2-chlorophenyl)pyridazine (CM-40907) is synthesized from 3-chloro-6-(2-chlorophenyl)pyridazine (I) in boiling 1-butanol (A) with an excess of 4-hydroxypiperidine (II).
【1】 Chambon, J.P.; Brodin, R.; Biziere, K.; Hallot, A.; Roncucci, R.; Brochard, J.; Heaulme, M.; CM 40907: A structurally novel anticonvulsant in mice, rats and baboons. J Pharmacol Exp Ther 1985, 233, 3, 836-844. |
【2】 Loscher, W.; CM-40907. Drugs Fut 1985, 10, 11, 903. |
合成路线3
该中间体在本合成路线中的序号:(B)Alternatively, (+)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into butyl ester derivative (XXII) by treatment with refluxing butanol (B). Resolution of the racemic mixture (XXII) by treatment with Lipase PL in vinyl acetate followed by chromatographic separation provides alcohol (-)-(XXIII) and acetoxy (+)-(XXIV). Hydrolysis of (+)-(XXIV) with hot H2SO4/EtOH gives alcohol (+)-(XXV), which is then condensed with 1-methylpiperazine (XVI) in DMF to yield derivative (+)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (+)-(XVII). Alternatively, (+)-(XXV) can be obtained by conversion of (XXI) into octyl ester (XXVII) by means of refluxing octanol (A), followed by its enantiomer enzymatic resolution with Liposyme IM in vinyl acetate and chromatographic separation to afford (-)-(XXVIII) and (+)-(XXIX). Finally, hydrolysis of (+)-(XXIX) with hot H2SO4/EtOH yields (+)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
(A) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
(B) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
(X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
(XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
(XVII) | 42961 | ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 | |
(XVIII) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
(XIX) | 42962 | ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H19F2NO6S | 详情 | 详情 | |
(XX) | 42963 | ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H18ClF2NO6S | 详情 | 详情 | |
(XXI) | 42964 | ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H13F2NO5S | 详情 | 详情 | |
(XXII) | 42965 | butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
(XXIII) | 42966 | butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
(XXIV) | 42967 | butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C18H17F2NO5S | 详情 | 详情 | |
(XXV) | 42968 | ethyl (1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H11F2NO4S | 详情 | 详情 | |
(XXVI) | 42969 | ethyl (1R)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H22FN3O4S | 详情 | 详情 | |
(XXVII) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
(XXVIII) | 42972 | octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C23H27F2NO5S | 详情 | 详情 | |
(XXIX) | 42973 | octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(B)Alternatively, (-)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into octyl ester derivative (XXII) by treatment with refluxing octanol (A). Resolution of the racemic mixture (XXII) by treatment with Liposyme IM in vinyl acetate followed by chromatographic separation provides alcohol (+)-(XXIII) and acetoxy (-)-(XXIV). Hydrolysis of (-)-(XXIV) with hot H2SO4/EtOH gives alcohol (-)-(XXV), which then reacts with 1-methylpiperazine (XVI) in DMF to yield derivative (-)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (-)-(XVII). Alternatively, (-)-(XXV) can be obtained by conversion of (XXI) into butyl ester (XXVII) by means of refluxing butanol (B), followed by its enantiomer enzymatic resolution with Lipase PL in vinyl acetate and chromatographic separation to afford (+)-(XXVIII) and (-)-(XXIX). Finally, hydrolysis of (-)-(XXIX) with hot H2SO4/EtOH yields (-)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
(A) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
(B) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
(X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
(XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
(XVII) | 42975 | ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 | |
(XVIII) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
(XIX) | 42962 | ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H19F2NO6S | 详情 | 详情 | |
(XX) | 42963 | ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H18ClF2NO6S | 详情 | 详情 | |
(XXI) | 42964 | ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H13F2NO5S | 详情 | 详情 | |
(XXII) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
(XXIII) | 42973 | octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
(XXIV) | 42972 | octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C23H27F2NO5S | 详情 | 详情 | |
(XXV) | 42976 | ethyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H11F2NO4S | 详情 | 详情 | |
(XXVI) | 42977 | ethyl (1S)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H22FN3O4S | 详情 | 详情 | |
(XXVII) | 42965 | butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
(XXVIII) | 42967 | butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C18H17F2NO5S | 详情 | 详情 | |
(XXIX) | 42966 | butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 |