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【结 构 式】 
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【分子编号】38094 【品名】3-aminopropanenitrile 【CA登记号】151-18-8 |
【 分 子 式 】C3H6N2 【 分 子 量 】70.09412 【元素组成】C 51.41% H 8.63% N 39.97% |
合成路线1
该中间体在本合成路线中的序号：(XV)Acid hydrolysis of the acetamido group of (V) gave amino acid (XI), which was further esterified with HCl in MeOH. The resulting amino ester (XII) was then protected as the tert-butyl carbamate (XIII) and the methyl ester was hydrolyzed to carboxylic acid (XIV) by means of LiOH. Coupling of (XIV) with 3-aminopropionitrile (XV) using BOP reagent provided the N-cyanoethyl amide (XVI). Elaboration of the tetrazole ring (XVII) was carried out by treatment of (XVI) with trimethylsilyl azide, diisopropyl azodicarboxylate and triphenyl phosphine. The Boc group of (XVII) was then deprotected by treatment with formic acid. The resulting amine (XVIII) was condensed with formaldehyde, followed by reaction of the intermediate trimeric hexahydrotriazine with diphenyl phosphite to furnish alpha-aminophosphonate (XIX). Basic cleavage of the cyanoethyl group of (XIX) produced the N-dealkylated tetrazole (XX). Finally, basic hydrolysis of phosphonate ester groups of (XX) gave rise to the title compound.
| 【1】 Blanchard, L.; De Lombaert, S.; Stamford, L.B.; et al.; Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action. J Med Chem 2000, 43, 3, 488. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 38084 | (2S)-2-(acetamido)-3-dibenzo[b,d]furan-3-ylpropionic acid | C17H15NO4 | 详情 | 详情 | |
| (XI) | 38090 | (2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropionic acid | C15H13NO3 | 详情 | 详情 | |
| (XII) | 38091 | methyl (2S)-2-amino-3-dibenzo[b,d]furan-3-ylpropanoate | C16H15NO3 | 详情 | 详情 | |
| (XIII) | 38092 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropanoate | C21H23NO5 | 详情 | 详情 | |
| (XIV) | 38093 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-dibenzo[b,d]furan-3-ylpropionic acid | C20H21NO5 | 详情 | 详情 | |
| (XV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (XVI) | 38095 | tert-butyl (1S)-2-[(2-cyanoethyl)amino]-1-(dibenzo[b,d]furan-3-ylmethyl)-2-oxoethylcarbamate | C23H25N3O4 | 详情 | 详情 | |
| (XVII) | 38096 | tert-butyl (1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethylcarbamate | C23H24N6O3 | 详情 | 详情 | |
| (XVIII) | 38097 | 3-[5-[(1S)-1-amino-2-dibenzo[b,d]furan-3-ylethyl]-1H-1,2,3,4-tetraazol-1-yl]propanenitrile | C18H16N6O | 详情 | 详情 | |
| (XIX) | 38098 | diphenyl ([(1S)-1-[1-(2-cyanoethyl)-1H-1,2,3,4-tetraazol-5-yl]-2-dibenzo[b,d]furan-3-ylethyl]amino)methylphosphonate | C31H27N6O4P | 详情 | 详情 | |
| (XX) | 38099 | diphenyl [[(1S)-2-dibenzo[b,d]furan-3-yl-1-(1H-1,2,3,4-tetraazol-5-yl)ethyl]amino]methylphosphonate | C28H24N5O4P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of 4-(tert-butoxycarbonylamino)-1-methyl-1H-pyrrole-2-carboxylic acid (I) with 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (II) by means of DCC, HOBT and TEA in hot DMF gives the dimeric amide (III), which is hydrolyzed with NaOH in hot methanol/water to yield the carboxylic acid (IV). The condensation of (IV) with methyl ester (II) by means of HBTU and TEA in hot DMF affords the trimeric diamide (V), which is hydrolyzed with NaOH in methanol/water to provide the carboxylic acid (VI). The deprotection of the carbamate group of (VI) with HCl in ethyl acetate gives the trimeric amino acid (VII), which is condensed with 4,5-dichloroisothiazole-3-carboxylic acid (VIII) by means of HBTU and DIEA in DMF to yield the tetrameric carboxylic acid (IX). The condensation of (IX) with 3-aminopropionitrile (X) by means of HBTU and TEA in DMF affords the corresponding tetrameric tetraamide (XI), which is treated with gaseous HCl in methanol to provide the iminoester (XII). Finally, this compound is treated with NH3 in methanol to furnish the target carboxamidine.
| 【1】 Burli, R.; et al.; HARP: A novel class of antibiotics. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1685. |
| 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) | 53510 | 4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | 77716-11-1 | C11H16N2O4 | 详情 | 详情 |
| (II) | 53511 | methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate | 180258-45-1 | C7H10N2O2 | 详情 | 详情 |
| (III) | 53512 | methyl 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate | n/a | C18H24N4O5 | 详情 | 详情 |
| (IV) | 53513 | 4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C17H22N4O5 | 详情 | 详情 |
| (V) | 53514 | methyl 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylate | n/a | C24H30N6O6 | 详情 | 详情 |
| (VI) | 53515 | 4-[({4-[({4-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrol-2-yl}carbonyl)amino]-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C23H28N6O6 | 详情 | 详情 |
| (VII) | 53516 | 4-{[(4-{[(4-amino-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C18H20N6O4 | 详情 | 详情 |
| (VIII) | 53517 | 4,5-Dichloroisothiazole-3-carboxylic acid | 131947-13-2 | C4HCl2NO2S | 详情 | 详情 |
| (IX) | 53518 | 4-{[(4-{[(4-{[(4,5-dichloro-3-isothiazolyl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrole-2-carboxylic acid | n/a | C22H19Cl2N7O5S | 详情 | 详情 |
| (X) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (XI) | 53519 | 4,5-dichloro-N-(5-{[(5-{[(5-{[(2-cyanoethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-3-isothiazolecarboxamide | n/a | C25H23Cl2N9O4S | 详情 | 详情 |
| (XII) | 53520 | methyl 3-{[(4-{[(4-{[(4-{[(4,5-dichloro-3-isothiazolyl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1-methyl-1H-pyrrol-2-yl)carbonyl]amino}propanimidoate | n/a | C26H27Cl2N9O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The hydrolysis of the 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (I) with NaOH in hot ethanol gives the carboxylic acid (II), which is treated with refluxing SOCl2 to yield the acyl chloride (III). The reaction of (III) with 3-aminopropionitrile (IV) in toluene affords the carboxamide (V), which is treated with propane-1,3-diamine (VI) and HCl in ethanol to provide the tetrahydropyrimidine derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the aminopyrrole (VIII), which is finally condensed with bis pentafluorophenyl terephthalate (XI) to afford the target terephthalamide. The activated ester bis pentafluorophenyl terephthalate (XI) has been obtained by esterification of terephthalic acid (IX) with pentafluorophenyl trifluoroacetate (X) by means of DIEA in DMF.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (II) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (III) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (IV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (V) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VI) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (VII) | 54023 | 1-isopentyl-4-nitro-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 54024 | 4-amino-1-isopentyl-N-[2-(1,4,5,6-tetrahydro-2-pyrimidinyl)ethyl]-1H-pyrrole-2-carboxamide | C16H27N5O | 详情 | 详情 | |
| (IX) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (X) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Alkylation of ethyl 4-nitropyrrole-2-carboxylate (I) with 3-methylbutyl bromide (II) in the presence of NaOMe affords the N-isoamyl pyrrole (III). Saponification of the ethyl ester group of (III), followed by treatment of the resultant carboxylic acid (IV) with SOCl2 provides acid chloride (V). This is subsequently coupled with 3-aminopropionitrile (VI) to yield the N-(2-cyanoethyl) amide (VII). Conversion of the cyano group of (VII) into the N-methyl amidine (VIII) is then accomplished under Pinner reaction conditions. Reduction of the nitro group of (VIII) by catalytic hydrogenation over Pd/C furnishes the intermediate aminopyrrole (IX).
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Dyatkina, N.; Hanson, E.; Liehr, S.; et al.; Synthesis, SAR and antimicrobial activity of pyrrole tetraamides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 62. |
| 【3】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 60988 | 1-methoxy-2,3-dihydro-1H-inden-2-yl methanesulfonate | C11H14O4S | 详情 | 详情 | |
| (II) | 46234 | 1-bromo-3-methylbutane | C5H11Br | 详情 | 详情 | |
| (III) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (IV) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (V) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (VI) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (VII) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VIII) | 60999 | N-[3-imino-3-(methylamino)propyl]-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C14H23N5O3 | 详情 | 详情 | |
| (IX) | 61000 | 4-amino-N-[3-imino-3-(methylamino)propyl]-1-isopentyl-1H-pyrrole-2-carboxamide | C14H25N5O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The hydrolysis of the 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (I) with NaOH in hot ethanol gives the carboxylic acid (II), which is treated with refluxing SOCl2 to yield the acyl chloride (III). The reaction of (III) with 3-aminopropionitrile (IV) in toluene affords the carboxamide (V), which is treated with ethylamine (VI) and HCl in ethanol to provide the N-ethylamidino derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the aminopyrrole (VIII), which is finally condensed with bis pentafluorophenyl terephthalate (XI) to afford the target terephthalamide. The activated ester bis pentafluorophenyl terephthalate (XI) has been obtained by esterification of terephthalic acid (IX) with pentafluorophenyl trifluoroacetate (X) by means of DIEA in DMF.
| 【1】 Roberts, C.D.; Keicher, J.D.; Dyatkina, N.B.; et al.; Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enteroccoci and methicillin resistant Staphylococcus aureus. J Med Chem 2002, 45, 4, 805. |
| 【2】 Nelson, P.H.; Muchowski, J.M.; Dyatkina, N.B.; Shi, D.-F.; Zhang, W.; Liehr, S.J.R.; Velligan, M.D.; Botyanszki, J.; Roberts, C.D.; Khorlin, A. (Genelabs Technologies, Inc.); Novel cpds. possessing antibacterial, antifungal or antitumor activity. WO 0200650 . |
| 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) | 54019 | ethyl 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylate | C12H18N2O4 | 详情 | 详情 | |
| (II) | 54020 | 1-isopentyl-4-nitro-1H-pyrrole-2-carboxylic acid | C10H14N2O4 | 详情 | 详情 | |
| (III) | 54021 | 1-isopentyl-4-nitro-1H-pyrrole-2-carbonyl chloride | C10H13ClN2O3 | 详情 | 详情 | |
| (IV) | 38094 | 3-aminopropanenitrile | 151-18-8 | C3H6N2 | 详情 | 详情 |
| (V) | 54022 | N-(2-cyanoethyl)-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C13H18N4O3 | 详情 | 详情 | |
| (VI) | 10928 | Ethanamine | 75-04-7 | C2H7N | 详情 | 详情 |
| (VII) | 54028 | N-[3-(ethylamino)-3-iminopropyl]-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide | C15H25N5O3 | 详情 | 详情 | |
| (VIII) | 54029 | 4-amino-N-[3-(ethylamino)-3-iminopropyl]-1-isopentyl-1H-pyrrole-2-carboxamide | C15H27N5O | 详情 | 详情 | |
| (IX) | 54025 | 1,4-Benzenedicarboxylic acid; Benzene-1,4-dicarboxylic acid; p-Benzenedicarboxylic acid; p-Phthalic acid; Terephthalic acid | 100-21-0 | C8H6O4 | 详情 | 详情 |
| (X) | 54026 | Trifluoroacetic acid pentafluorophenylester | 14533-84-7 | C8F8O2 | 详情 | 详情 |
| (XI) | 54027 | bis(2,3,4,5,6-pentafluorophenyl) terephthalate | C20H4F10O4 | 详情 | 详情 |