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【结 构 式】 
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【分子编号】19652 【品名】indoline 【CA登记号】496-15-1 |
【 分 子 式 】C8H9N 【 分 子 量 】119.1662 【元素组成】C 80.63% H 7.61% N 11.75% |
合成路线1
该中间体在本合成路线中的序号：(XLVI)The reaction of (XLII) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLIII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLIV). The rearrangement of (XLIV) with Ag2O in DMF/water affords the acetic acid derivative (XLV), which is condensed with indoline (XLVI) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (XLVII). The desilylation of (XLVII) with TFA/water in dichloromethane gives the secondary alcohol (XLVIII), which is oxidized with DMP in dichloromethane to yield the corresponding ketonic compound (XLIX). The dehydrogenation of the indoline group of (XLIX) with chloranil in refluxing toluene affords the corresponding indole derivative (L).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLII) | 35714 | C36H50O9Si | 详情 | 详情 | ||
| (XLIII) | 35715 | C39H56O9SSi | 详情 | 详情 | ||
| (XLIV) | 35716 | C37H50N2O8Si | 详情 | 详情 | ||
| (XLV) | 35717 | C37H52O9Si | 详情 | 详情 | ||
| (XLVI) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (XLVII) | 35718 | (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C45H59NO8Si | 详情 | 详情 | |
| (XLVIII) | 35719 | (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C39H45NO8 | 详情 | 详情 | |
| (XLIX) | 35720 | (9S,12S,13S,15R)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione | C39H43NO8 | 详情 | 详情 | |
| (L) | 35721 | (9S,12S,13S,15R)-15-[(E)-4-hexenoyl]-9-[2-(1H-indol-1-yl)-2-oxoethyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione | C39H41NO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(L)The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in CH2Cl2 to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677. |
| 【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLIV) | 35712 | C30H36O8 | 详情 | 详情 | ||
| (XLV) | 35713 | C36H50O8Si | 详情 | 详情 | ||
| (XLVI) | 35714 | C36H50O9Si | 详情 | 详情 | ||
| (XLVII) | 35715 | C39H56O9SSi | 详情 | 详情 | ||
| (XLVIII) | 35716 | C37H50N2O8Si | 详情 | 详情 | ||
| (XLIX) | 35717 | C37H52O9Si | 详情 | 详情 | ||
| (L) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (LI) | 35718 | (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C45H59NO8Si | 详情 | 详情 | |
| (LII) | 35719 | (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C39H45NO8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLVI)The reaction of (XLII) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLIII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLIV). The rearrangement of (XLIV) with Ag2O in DMF/water affords the acetic acid derivative (XLV), which is condensed with indoline (XLVI) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (XLVII). The desilylation of (XLVII) with TFA/water in dichloromethane gives the secondary alcohol (XLVIII), which is oxidized with DMP in dichloromethane to yield the corresponding ketonic compound (XLIX). The dehydrogenation of the indoline group of (XLIX) with chloranil in refluxing toluene affords the corresponding indole derivative (L).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLII) | 35714 | C36H50O9Si | 详情 | 详情 | ||
| (XLIII) | 35715 | C39H56O9SSi | 详情 | 详情 | ||
| (XLIV) | 35716 | C37H50N2O8Si | 详情 | 详情 | ||
| (XLV) | 35717 | C37H52O9Si | 详情 | 详情 | ||
| (XLVI) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (XLVII) | 35718 | (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C45H59NO8Si | 详情 | 详情 | |
| (XLVIII) | 35719 | (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C39H45NO8 | 详情 | 详情 | |
| (XLIX) | 35720 | (9S,12S,13S,15R)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione | C39H43NO8 | 详情 | 详情 | |
| (L) | 35721 | (9S,12S,13S,15R)-15-[(E)-4-hexenoyl]-9-[2-(1H-indol-1-yl)-2-oxoethyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6,18-trione | C39H41NO8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(L)The silylation at the remaining OH group of (XLIV) with TBDMS-OTf and lutidine in dichloromethane affords the silyl ether (XLV), which is oxidized at the aldehyde group with NaClO2 in tert-butanol/water giving the carboxylic acid (XLVI). The reaction of (XLVI) with methanesulfonyl chloride and Et3N in THF gives the mixed anhydride (XLVII), which is treated with diazomethane in ethyl ether/THF to yield the diazoketone (XLVIII). The rearrangement of (XLVIII) with Ag2O in DMF/water affords the acetic acid derivative (XLIX), which is condensed with indoline (L) by means of EDC and DMAP in dichloromethane to provide the acyl indoline (LI). The desilylation of (LI) with TFA/water in dichloromethane gives the secondary alcohol (LII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-225,917 and CP-263,114 - Part 2: Evolution of the final strategy. Angew Chem. Int Ed Engl 1999, 38, 11, 1677. |
| 【2】 Nicolaou, K.C.; et al.; The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, Phomoidrides B and A). Angew Chem. Int Ed Engl 2000, 39, 10, 1829. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLIV) | 35712 | C30H36O8 | 详情 | 详情 | ||
| (XLV) | 35713 | C36H50O8Si | 详情 | 详情 | ||
| (XLVI) | 35714 | C36H50O9Si | 详情 | 详情 | ||
| (XLVII) | 35715 | C39H56O9SSi | 详情 | 详情 | ||
| (XLVIII) | 35716 | C37H50N2O8Si | 详情 | 详情 | ||
| (XLIX) | 35717 | C37H52O9Si | 详情 | 详情 | ||
| (L) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (LI) | 35718 | (9S,12S,13S,15R,18R)-18-[[tert-butyl(dimethyl)silyl]oxy]-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C45H59NO8Si | 详情 | 详情 | |
| (LII) | 35719 | (9S,12S,13S,15R,18S)-9-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-15-[(E)-4-hexenoyl]-18-hydroxy-12-[(E)-6-octenyl]-5,16,17-trioxapentacyclo[7.7.2.0(1,10).0(2,13).0(3,7)]octadeca-3(7),10-diene-4,6-dione | C39H45NO8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The bromination of styrene (II) with N-bromosuccinimide in the presence of cyanamide (I) provided 2-bromo-1-phenylethylcyanamide (III). Further addition of MeOH to (III) in the presence of HCl, followed by Na2CO3-promoted cyclization, produced the methoxyimidazoline (IV). Acylation of indoline (V) with trifluoroacetic anhydride and pyridine gave amide (VI) and subsequent chlorosulfonation yielded sulfonyl cloride (VII). This acid chloride was coupled to imidazoline (IV) in the presence of NaHCO3 in aqueous acetone to furnish a mixture of sulfonyl imidazolines (VIII) and (IX). The major isomer (IX) was isolated by column chromatography, and then, hydrolysis with HCl in MeOH at r.t. provided imidazolidinone (X). The trifluoroacetamide group of (X) was further hydrolyzed by treatment with NaOH in aqueous MeOH to give (XI). Subsequent condensation of (XI) with 4-nitrobenzoyl chloride (XII) in the presence of pyridine yielded 4-nitrobenzamide (XIII), which was finally reduced to the aminobenzamide by hydrogenation using Raney-nickel as the catalyst.
| 【1】 Jung, S.-H.; Lee, H.S.; Song, J.S.; Kim, H.M.; Han, S.B.; Lee, C.W.; Lee, M.; Choi, D.R.; Lee, J.A.; Chung, Y.H.; Yoon, S.J.; Moon, E.Y.; Hwang, H.S.; Seong, S.K.; Lee, D.K.; Synthesis and antitumor activity of 4-phenyl-1-arylsulfonyl imidazolidinones. Bioorg Med Chem Lett 1998, 8, 12, 1547. |
| 【2】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 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) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (II) | 19649 | 1-vinylbenzene | 100-42-5 | C8H8 | 详情 | 详情 |
| (III) | 19650 | 2-bromo-1-phenylethylcyanamide | C9H9BrN2 | 详情 | 详情 | |
| (IV) | 19651 | methyl 5-phenyl-4,5-dihydro-1H-imidazol-2-yl ether; 2-methoxy-5-phenyl-4,5-dihydro-1H-imidazole | C10H12N2O | 详情 | 详情 | |
| (V) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (VI) | 19653 | 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone | C10H8F3NO | 详情 | 详情 | |
| (VII) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (VIII) | 19655 | 2,2,2-trifluoro-1-[5-[(2-methoxy-5-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (IX) | 19656 | 2,2,2-trifluoro-1-[5-[(2-methoxy-4-phenyl-4,5-dihydro-1H-imidazol-1-yl)sulfonyl]-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C20H18F3N3O4S | 详情 | 详情 | |
| (X) | 19657 | 4-phenyl-1-[[1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-2-imidazolidinone | C19H16F3N3O4S | 详情 | 详情 | |
| (XI) | 19658 | 1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (XII) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (XIII) | 19660 | 1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Protection of indoline (I) using trifluoroacetic anhydride provided N-trifluoroacetylindoline (II), which was sulfonated with chlorosulfonic acid to give sulfonyl chloride (III). Further treatment with ammonia in CH2Cl2 produced sulfonamide (IV). Phenylglycinol (V) was condensed with phenyl chloroformate to afford carbamate (VI). Subsequent reaction of (VI) with metanesulfonyl chloride and triethylamine yielded mesylate (VII). The condensation of sulfonamide (IV) with mesylate (VII), with concomitant cyclization of carbamate group and trifluoroacetyl deprotection, furnished imidazolone (VIII). This was further condensed with 4-nitrobenzoyl chloride (IX), and the resulting 4-nitrobenzamide (X) was finally reduced to the target aminobenzamide by hydrogenation over Raney Nickel.
| 【1】 Yoon, S.J.; Chung, Y.H.; Lee, M.S.; Choi, D.R.; Lee, J.A.; Lee, H.S.; Yun, H.R.; Lee, D.K.; Moon, E.Y.; Hwang, H.S.; Choi, C.H.; Jung, S.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Arylsulfonylimidazolone derivs. as an antitumor agent. EP 1021437; JP 2000505096; US 5929103; WO 9807719 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 | |
| (I) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 19653 | 1-(2,3-dihydro-1H-indol-1-yl)-2,2,2-trifluoro-1-ethanone | C10H8F3NO | 详情 | 详情 | |
| (III) | 19654 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonyl chloride | C10H7ClF3NO3S | 详情 | 详情 | |
| (IV) | 19665 | 1-(2,2,2-trifluoroacetyl)-5-indolinesulfonamide | C10H9F3N2O3S | 详情 | 详情 | |
| (V) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (VI) | 19663 | phenyl (1S)-2-hydroxy-1-phenylethylcarbamate | C15H15NO3 | 详情 | 详情 | |
| (VII) | 19664 | (2S)-2-[(phenoxycarbonyl)amino]-2-phenylethyl methanesulfonate | C16H17NO5S | 详情 | 详情 | |
| (VIII) | 19666 | (4S)-1-(2,3-dihydro-1H-indol-5-ylsulfonyl)-4-phenyl-2-imidazolidinone | C17H17N3O3S | 详情 | 详情 | |
| (IX) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (X) | 19667 | (4S)-1-[[1-(4-nitrobenzoyl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]-4-phenyl-2-imidazolidinone | C24H20N4O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
| 【2】 Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal); Diazepino-indoles as phosphodiesterase IV inhibitors. EP 0828742; US 5972927; WO 9736905 . |
| 【1】 Burnouf, C.; Auclair, E.; Avenel, N.; et al.; Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors. J Med Chem 2000, 43, 25, 4850. |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 47455 | 2,3-dihydro-1H-indol-7-yl(phenyl)methanone | C15H13NO | 详情 | 详情 | |
| (IV) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (V) | 47456 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N2O | 详情 | 详情 | |
| (VI) | 47457 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C17H13N3O2 | 详情 | 详情 | |
| (VII) | 47458 | 3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (VIII) | 47459 | (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (IX) | 47460 | (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N4O3 | 详情 | 详情 | |
| (X) | 47461 | (3R)-3,9-diamino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H16N4O | 详情 | 详情 | |
| (XI) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of indoline (I) with formic acid in refluxing toluene gives N-formylindoline (II), which is treated with chlorosulfonic acid to yield 5-(chlorosulfonyl)indoline-1-carbaldehyde (III). The reaction of (III) with 3,4,5-trimethoxyaniline (IV) and pyridine in THF affords the sulfonamide (V), which is deformylated to sulfonamide (VI) with HCl in methanol. The reaction of indoline (VI) with salcomine and O2 in methanol provides the corresponding indole derivative (VII), which is finally methylated with methyl iodide and NaHMDS in THF to give the target 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.
| 【2】 Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 . |
| 【1】 Li, Q.; Woods, K.W.; Steiner, A.; et al.; Synthesis and biological evaluation of biarylsulfonamides as tubulin polymerization inhibitors. Discovery of A-318315 and A-293620 as orally and intravenously active antimitotic agents. Proc Am Assoc Cancer Res 2002, 43, Abst 1313. |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 55546 | 1-Formylindoline | 2861-59-8 | C9H9NO | 详情 | 详情 |
| (III) | 55547 | 1-formyl-5-indolinesulfonyl chloride | C9H8ClNO3S | 详情 | 详情 | |
| (IV) | 31545 | 3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine | 24313-88-0 | C9H13NO3 | 详情 | 详情 |
| (V) | 55548 | 1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C18H20N2O6S | 详情 | 详情 | |
| (VI) | 55549 | N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C17H20N2O5S | 详情 | 详情 | |
| (VII) | 55550 | N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide | C17H18N2O5S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The reaction of indoline (I) with formic acid in refluxing toluene gives N-formylindoline (II), which is treated with chlorosulfonic acid to yield 5-(chlorosulfonyl)indoline-1-carbaldehyde (III). The reaction of (III) with 3,4,5-trimethoxyaniline (IV) and pyridine in THF affords the sulfonamide (V), which is deformylated to sulfonamide (VI) with HCl in methanol. The reaction of indoline (VI) with salcomine and O2 in methanol provides the corresponding indole derivative (VII), which is methylated with methyl iodide and NaHMDS in THF to give 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide (VIII). Finally, this compound is condensed with N,N-dimethylglycine (IX) by means of DCC and 4-(1-pyrrolidinyl)pyridine (pypyr) in dichloromethane.
| 【1】 Li, Q.; Woods, K.W.; Steiner, A.; et al.; Synthesis and biological evaluation of biarylsulfonamides as tubulin polymerization inhibitors. Discovery of A-318315 and A-293620 as orally and intravenously active antimitotic agents. Proc Am Assoc Cancer Res 2002, 43, Abst 1313. |
| 【2】 Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 . |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 55546 | 1-Formylindoline | 2861-59-8 | C9H9NO | 详情 | 详情 |
| (III) | 55547 | 1-formyl-5-indolinesulfonyl chloride | C9H8ClNO3S | 详情 | 详情 | |
| (IV) | 31545 | 3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine | 24313-88-0 | C9H13NO3 | 详情 | 详情 |
| (V) | 55548 | 1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C18H20N2O6S | 详情 | 详情 | |
| (VI) | 55549 | N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide | C17H20N2O5S | 详情 | 详情 | |
| (VII) | 55550 | N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide | C17H18N2O5S | 详情 | 详情 | |
| (VIII) | 55569 | 1-methyl-N-[3,4,5-tris(methyloxy)phenyl]-1H-indole-5-sulfonamide | C18H20N2O5S | 详情 | 详情 | |
| (IX) | 16765 | 2-(dimethylamino)acetic acid; N,N-Dimethylglycine | 1118-68-9 | C4H9NO2 | 详情 | 详情 |