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【结 构 式】 
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【分子编号】30262 【品名】diethyl 2-(methylamino)-2-oxoethylphosphonate 【CA登记号】 |
【 分 子 式 】C7H16NO4P 【 分 子 量 】209.182142 【元素组成】C 40.19% H 7.71% N 6.7% O 30.59% P 14.81% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts acylation of benzene with 6-chloronicotinyl chloride (I) using AlCl3 afforded ketone (II). Subsequent displacement of the chlorine atom of (II) by means of ethanolic ammonia at 145 C in a pressure reactor led to the aminopyridine (III), which was converted to sulfonamide (IV) by means of tosyl chloride in pyridine. Alkylation of the pyridine N of (IV) with iodoacetamide gave (V), and further cyclization in the presence of trifluoroacetic anhydride produced the imidazopyridine (VI). Phosphonate (VIII) was prepared by treatment of triethyl phosphonoacetate (VII) with methylamine. Horner-Emmons condensation of this phosphonate with ketone (VI) yielded the E-propenamide (IX). Selective iodination of (IX) at position 3 using N-iodosuccinimide furnished iodide (X). This compound was first deprotonated with PhLi, then subjected to a halogen-metal exchange reaction with tert-butyllithium, and the resulting trianion was reacted with isopropyl isopropanethiolsulfonate to give sulfide (XI). Finally, smooth hydrolysis of the trifluoroacetamide group of (XI) employing MeOH-CH2Cl2 in the presence of silica gel provided the title compound.
| 【1】 Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B.A.; Vance, L.; 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity. J Med Chem 1999, 42, 1, 50. |
| 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) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 30257 | (6-chloro-3-pyridinyl)(phenyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (III) | 30258 | (6-amino-3-pyridinyl)(phenyl)methanone | C12H10N2O | 详情 | 详情 | |
| (IV) | 30259 | N-(5-benzoyl-2-pyridinyl)-4-methylbenzenesulfonamide | C19H16N2O3S | 详情 | 详情 | |
| (V) | 30260 | 2-(5-benzoyl-2-[[(4-methylphenyl)sulfonyl]imino]-1-pyridinyl)acetamide | C21H19N3O4S | 详情 | 详情 | |
| (VI) | 30261 | N-(6-benzoylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide | C16H10F3N3O2 | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 30262 | diethyl 2-(methylamino)-2-oxoethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (IX) | 30263 | (E)-N-methyl-3-phenyl-3-[2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-2-propenamide | C19H15F3N4O2 | 详情 | 详情 | |
| (X) | 30264 | (E)-3-[3-iodo-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide | C19H14F3IN4O2 | 详情 | 详情 | |
| (XI) | 30265 | (E)-3-[3-(isopropylsulfanyl)-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide | C22H21F3N4O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Ketone (III) was prepared by Friedel-Crafts acylation of benzene (II) with 6-chloronicotinyl chloride (I). Horner-Emmons reaction of (III) with diethyl (N-methylcarbamoylmethyl)phosphonate (IV) using potassium hexamethyl-disilazide produced a 3:1 mixture of E (V) and Z olefins (VI). The desired E isomer (V) was isolated by column chromatography and then treated with bromoketone (VII) to afford the betaine (VIII). Finally, the target imidazopyridine was obtained by condensation of (VIII) with cyanamide in the presence of K2CO3.
| 【1】 Alvarez-Builla, J.; Ezquerra, J.; Vega, J.A.; Vaquero, J.J.; Hamdouchi, C.; Heinz, B.A.; Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: The effect of acyl groups at 3-position. Bioorg Med Chem Lett 1999, 9, 10, 1391. |
| 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) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (III) | 30257 | (6-chloro-3-pyridinyl)(phenyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (IV) | 30262 | diethyl 2-(methylamino)-2-oxoethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (V) | 30807 | (E)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VI) | 30808 | (Z)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VII) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (VIII) | 30810 | 1-[2-Chloro-5-[2-(N-metylcarbamoyl)-1-phenylvinyl]pyridinium-1-yl]-3,3-dimethyl-2-oxo-1-butanide | C21H23ClN2O2 | 详情 | 详情 |