|
【结 构 式】 
|
【分子编号】39294 【品名】6-Nitroindole; 6-Nnitro-1H-indole 【CA登记号】4769-96-4 |
【 分 子 式 】C8H6N2O2 【 分 子 量 】162.14792 【元素组成】C 59.26% H 3.73% N 17.28% O 19.73% |
合成路线1
该中间体在本合成路线中的序号：(VII)Protected 2,4-diaminobutyric acid (I) is coupled with benzylamine (A) in acetonitrile in the presence of DCC and HOBt to yield (II), which is Boc deprotected by means of TFA in CH2Cl2 and loaded onto 2-Cl-trityl-Cl resin to provide (III). Treatment of (III) with piperidine/DMF to remove the Fmoc group, followed by coupling with Fmoc-3,4-difluoro-L-phenylalanine (IV) with HBTU, HOBt in DMF in and DIEA affords (V). The Fmoc group of dipeptide (V) is removed with piperidine/DMF and reaction with (X) in the presence of 4-nitrophenylchloroformate and DIEA in DCM yields (VI). Amine (X) can be obtained by treatment of indole (VII) with bromo derivative (VIII) by means of Cs2CO3 in DMF to yield (IX) followed by reduction of the nitro moiety with FeCl3?H2O, charcoal powder and Me2NNH2 in refluxing MeOH. Finally, Mannich reaction of (VI) with pyrrolidine and formaldehyde in HOAc followed by resin cleavage with TFA in CH2Cl2 furnishes the target molecule.
| 【1】 Derian, C.K.; Andrade-Gordon, P.; Maryanoff, B.E.; et al.; Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proceedings of the National Academy of Sciences of the United States of America 1999, 96, 22, 12257. |
| 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) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (I) | 42257 | (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | 125238-99-5 | C24H28N2O6 | 详情 | 详情 |
| (II) | 42258 | 9H-fluoren-9-ylmethyl (1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propylcarbamate | C31H35N3O5 | 详情 | 详情 | |
| (III) | 42259 | 9H-fluoren-9-ylmethyl (1S)-3-amino-1-[(benzylamino)carbonyl]propylcarbamate | C26H27N3O3 | 详情 | 详情 | |
| (IV) | 42260 | (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H19F2NO4 | 详情 | 详情 | |
| (V) | 42261 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-3-amino-1-[(benzylamino)carbonyl]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate | C35H34F2N4O4 | 详情 | 详情 | |
| (VI) | 42262 | (2S)-4-amino-N-benzyl-2-[[(2S)-2-[([[1-(2,6-dichlorobenzyl)-1H-indol-6-yl]amino]carbonyl)amino]-3-(3,4-difluorophenyl)propanoyl]amino]butanamide | C36H34Cl2F2N6O3 | 详情 | 详情 | |
| (VII) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (VIII) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (IX) | 42263 | 1-(2,6-dichlorobenzyl)-6-nitro-1H-indole | C15H10Cl2N2O2 | 详情 | 详情 | |
| (X) | 42264 | 1-(2,6-dichlorobenzyl)-1H-indol-6-ylamine; 1-(2,6-dichlorobenzyl)-1H-indol-6-amine | C15H12Cl2N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)6-Nitroindole (I) was methylated using iodomethane and NaH and the resulting 1-methyl-6-nitroindole (II) was acylated with oxalyl chloride in dichloromethane to furnish the glyoxylyl chloride (III). Subsequent condensation of (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gave the bisindolylmaleic anhydride (V). This was finally converted into the target maleimide by heating with ammonia in aqueous DMF in a sealed vessel at 140 C.
| 【1】 Hill, C.H.; Wilkinson, S.E.; Hurst, S.A.; Lawton, G.; Keech, E.; Davis, P.D.; Nixon, J.S.; Turner, S.E.; Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35, 1, 177. |
| 【2】 Davis, P.D.; Hill, C.H.; Lawton, G. (F. Hoffmann-La Roche AG); Substd. pyrroles. AU 8929658; EP 0328026; JP 1989233281; US 5057614 . |
| 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) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 39295 | 1-methyl-6-nitro-1H-indole | C9H8N2O2 | 详情 | 详情 | |
| (III) | 39296 | 2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride | C11H7ClN2O4 | 详情 | 详情 | |
| (IV) | 39297 | 1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid | 1912-48-7 | C11H11NO2 | 详情 | 详情 |
| (V) | 39298 | 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione | C22H15N3O5 | 详情 | 详情 | |
| (VI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Treatment of 6-nitroindole (I) with aqueous NaNO2 and HCl affords 3-indazolecarboxaldehyde (II), which is then subjected to reductive amination with pyrrolidine (III) by means of NaBH(OAc)3 in dichloroethane/DMF in the presence of acetic acid to provide compound (IV). Alkylation of (IV) with 2,6-dichlorobenzyl bromide (V) by means of KOH in THF yields compound (VI), whose nitro group is reduced with dimethyl hydrazine (Me2NNH2), FeCl3 and charcoal in refluxing MeOH to furnish aminoindazole intermediate (VII). The synthesis of intermediate (XIII) is performed as follows: Coupling of protected diaminobutyric acid (VIII) with benzylamine (IX) by means of DCC and HOBt in acetonitrile, followed by Fmoc removal after treatment with diethylamine, gives derivative (X), which is then condensed with protected difluorophenylalanine (XI) by means of DIC and HOBt in acetonitrile to afford protected dipeptide (XII). Finally, intermediate (XIII) is obtained by Fmoc removal of (XII) by treatment with ethylamine. The desired product is finally obtained by condensation of intermediates (VII) and (XIII) by means of 4-nitrophenyl chloroformate and DIEA in dichloromethane, followed by Boc removal with TFA in dichloromethane.
| 【1】 Andrade-Gordon, P.; Zhang, H.-C.; Derian, C.K.; et al.; Discovery and optimization of a novel series of thrombin receptor (PAR-1) antagonists: Potent, selective peptide mimetics based on indole and indazole templates. J Med Chem 2001, 44, 7, 1021. |
| 【2】 Zhang, H.-C.; Pandey, A.; Scarborough, R.M.; Maryanoff, B.E. (COR Therapeutics, Inc.; Ortho-McNeil Pharmaceutical, Inc.); Novel indazole peptidomimetics as thrombin receptor antagonists. WO 0100656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 | |
| (I) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 48891 | 6-nitro-1H-indazole-3-carbaldehyde | C8H5N3O3 | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 48892 | 6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C12H14N4O2 | 详情 | 详情 | |
| (V) | 40793 | 2-(bromomethyl)-1,3-dichlorobenzene | 20443-98-5 | C7H5BrCl2 | 详情 | 详情 |
| (VI) | 48893 | 1-(2,6-dichlorobenzyl)-6-nitro-3-(1-pyrrolidinylmethyl)-1H-indazole | C19H18Cl2N4O2 | 详情 | 详情 | |
| (VII) | 48894 | 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-ylamine; 1-(2,6-dichlorobenzyl)-3-(1-pyrrolidinylmethyl)-1H-indazol-6-amine | C19H20Cl2N4 | 详情 | 详情 | |
| (VIII) | 42257 | (2S)-4-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid | 125238-99-5 | C24H28N2O6 | 详情 | 详情 |
| (IX) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (X) | 48895 | tert-butyl (3S)-3-amino-4-(benzylamino)-4-oxobutylcarbamate | C16H25N3O3 | 详情 | 详情 | |
| (XI) | 42260 | (2S)-3-(3,4-difluorophenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C24H19F2NO4 | 详情 | 详情 | |
| (XII) | 48896 | 9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-[(benzylamino)carbonyl]-3-[(tert-butoxycarbonyl)amino]propyl]amino)-1-(3,4-difluorobenzyl)-2-oxoethylcarbamate | C40H42F2N4O6 | 详情 | 详情 | |
| (XIII) | 48897 | tert-butyl (3S)-3-[[(2S)-2-amino-3-(3,4-difluorophenyl)propanoyl]amino]-4-(benzylamino)-4-oxobutylcarbamate | C25H32F2N4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Methylation of 6-nitroindole (I) using either iodomethane and NaH or dimethyl carbonate and Na2CO3 provides 1-methyl-6-nitroindole (II), which is subsequently acylated with oxalyl chloride in CH2Cl2 to furnish the glyoxylyl chloride (III). Condensation of chloride (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gives the bis(indolyl)maleic anhydride (V), which is then converted to the target maleimide derivative by heating with ammonia in aqueous DMF in a sealed vessel at 140 °C .
In a related procedure, quaternization of 3-(dimethylaminomethyl)-indole (VI) with butyl bromide, followed by amine displacement with NaCN yields 2-(3-indolyl)acetonitrile (VII), which is alkylated using dimethyl carbonate and K2CO3 in hot DMF to give the 1-methylindole derivative (VIII). Treatment of compound (VIII) with isopropanol and HCl (generated from acetyl chloride and i-PrOH) affords imidate (IX), which is finally condensed with the indoleglyoxylyl chloride (III) in the presence of DIEA, followed by treatment with H2SO4 .
| 【1】 Davis, P.D., Hill, C.H., Lawton, G. (F. Hoffmann-La Roche AG). Substituted pyrroles. AU 8929658, EP 0328026, JP 1989233281, US 5057614. |
| 【2】 Davis, P.D., Hill, C.H., Lawton, G. et al. Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35(1): 177-84. |
| 【3】 Jiang, X. (F. Hoffmann La Roche AG). Methylation of indole compounds using dimethyl carbonate. CA 2405937, EP 1276721, JP 2003531192, JP 2007254487, US 6326501, WO 2001081305. |
| 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) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 39295 | 1-methyl-6-nitro-1H-indole | C9H8N2O2 | 详情 | 详情 | |
| (III) | 39296 | 2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride | C11H7ClN2O4 | 详情 | 详情 | |
| (IV) | 39297 | 1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid | 1912-48-7 | C11H11NO2 | 详情 | 详情 |
| (V) | 39298 | 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione | C22H15N3O5 | 详情 | 详情 | |
| (VI) | 37568 | N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine | 87-52-5 | C11H14N2 | 详情 | 详情 |
| (VII) | 44291 | 3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile | 771-51-7 | C10H8N2 | 详情 | 详情 |
| (VIII) | 69305 | 1-Methylindole-3-acetonitrile;1-Methylindole-3-acetonitrile;N-Methylindole-3-acetonitrile;3-(Cyanomethyl)-1-methylindole;2-(1-methyl-1H-indol-3-yl)acetonitrile | 51584-17-9 | C11H10N2 | 详情 | 详情 |
| (IX) | 69306 | isopropyl 2-(1-methyl-1H-indol-3-yl)acetimidate hydrochloride | C14H18N2O.HCl | 详情 | 详情 |