|
【结 构 式】 
|
【分子编号】12117 【品名】Nitroethane; 1-Nitroethane 【CA登记号】79-24-3 |
【 分 子 式 】C2H5NO2 【 分 子 量 】75.06724 【元素组成】C 32% H 6.71% N 18.66% O 42.63% |
合成路线1
该中间体在本合成路线中的序号：(V)Three related new synthetic routes for E-1020 have been reported: 1) The cyclization of 2-bromoacetaldehyde diethylacetal (I) with 2-aminopyridine-5-carboxylic acid methyl ester (II) by means of HCl in hot water gives imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (III), which is reduced with dibutylaluminum hydride in dichloromethane to the corresponding aldehyde (IV). The condensation of (IV) with nitroethane (V) by means of butylamine in refluxing ethanol affords 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (VI), which is treated with Fe-FeCl2-HCl in hot ethanol-water to give 1-(imidazo[1,2-a]pyridyl-6-yl)-2-propanone (VII). The condensation of (VII) with dimethylformamide dimethylacetal (VIII) in hot DMF yields 4-(dimethylamino)-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one (IX), which is finally cyclized with cyanacetamide (X) by means of sodium methoxide in hot DMF. 2) The cyclization of acetal (I) with 2-amino-5-bromopyridine (XI) as before gives 6-bromoimidazo[1,2-a]pyridine (XII), which is condensed with potassium acetylacetonate (XIII) by means of KI and Cu2I2 in hot DMF yielding the adduct (XIV). The cleavage of (XIV) with NaOH and then with HCl gives the propanone (VII), already obtained. 3) The condensation of the bromo derivative (XII) with 3-chloro-2-methylpropene (XV) by means of ethylmagnesium bromide in hot THF gives 6-isobutenylimidazo[1,2-a]pyridine (XVI), which is ozonolyzed with O3 in methanol-water-HCl to yield the propanone (VII), already obtained.
| 【1】 Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.; Ogawa, T.; Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives. Chem Pharm Bull 1991, 39, 6, 1556-67. |
| 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) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (II) | 12114 | methyl 6-aminonicotinate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 12115 | methyl imidazo[1,2-a]pyridine-6-carboxylate | C9H8N2O2 | 详情 | 详情 | |
| (IV) | 12116 | Imidazo[1,2-a]pyridine-6-carbaldehyde | C8H6N2O | 详情 | 详情 | |
| (V) | 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 |
| (VI) | 12118 | 6-[(E)-2-Nitro-1-propenyl]imidazo[1,2-a]pyridine | C10H9N3O2 | 详情 | 详情 | |
| (VII) | 12119 | 1-Imidazo[1,2-a]pyridin-6-ylacetone | C10H10N2O | 详情 | 详情 | |
| (VIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (IX) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (X) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (XI) | 12123 | 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine | 1072-97-5 | C5H5BrN2 | 详情 | 详情 |
| (XII) | 12124 | 6-Bromoimidazo[1,2-a]pyridine | 6188-23-4 | C7H5BrN2 | 详情 | 详情 |
| (XIII) | 12125 | [2-Methoxy-1-(methoxycarbonyl)-2-oxoethyl]potassium | C5H7KO4 | 详情 | 详情 | |
| (XIV) | 12126 | 3-Imidazo[1,2-a]pyridin-6-yl-2,4-pentanedione | C12H12N2O2 | 详情 | 详情 | |
| (XV) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (XVI) | 12128 | 6-(2-Methyl-2-propenyl)imidazo[1,2-a]pyridine | C11H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)2) The condensation of imidazo[1,2-a]pyridine-6-carboxaldehyde (VIII) with nitroethane (IX) by means of butylamine in refluxing ethanol gives 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (X), which is treated with FeCl2 and concentrated HCl in refluxing ethanol to afford propanone (IV), already obtained.
| 【1】 Miyake, K.; Ohhara, H.; Suda, S.; Toshiaki, O.; Yamanaka, M. (Eisai Co., Ltd.); 5-(6-Imidazo[1,2-a]pyridyl)pyridine derivs.. EP 0199127; ES 8706146; ES 8708230; ES 8708231; ES 8801654; ES 8801655; JP 1986218589; US 4751227 . |
| 【2】 Prous, J.; Castaner, J.; E-1020. Drugs Fut 1988, 13, 6, 514. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12119 | 1-Imidazo[1,2-a]pyridin-6-ylacetone | C10H10N2O | 详情 | 详情 | |
| (V) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VI) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (VII) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (VIII) | 12116 | Imidazo[1,2-a]pyridine-6-carbaldehyde | C8H6N2O | 详情 | 详情 | |
| (IX) | 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 |
| (X) | 12118 | 6-[(E)-2-Nitro-1-propenyl]imidazo[1,2-a]pyridine | C10H9N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Reaction of 3-fluoroaniline (I) with formic acid gave formanilide (II), which was reduced by means of LiAlH4 to afford 3-fluoro-N-methylaniline (III). Further alkylation of (III) with benzyl chloride provided the tertiary amine (IV). Vilsmeier-Haack formylation of (IV) with POCl3 and DMF yielded aldehyde (V), which was condensed with nitroethane in the presence of ammonium acetate to give the 2-nitropropene derivative (VI). After reduction of (VI) to the amine (VII) with LiAlH4, condensation with chloroacetyl chloride afforded chloracetamide (VIII). Subsequent displacement of the chlorine of (VIII) with dibenzylamine yielded the tertiary amine (IX). Finally, hydrogenolytic debenzylation of (IX) in the presence of Pd/C furnished the title compound.
| 【1】 Larsson, L.-G.; Florvall, L.; Ross, S.B.; Fagervall, I.; Prodrugs of neuron-selective monoamine oxidase inhibitors: Amino acid derivatives of 1-(4-aminophenyl)-2-aminopropanes. Eur J Med Chem 1999, 34, 2, 137. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 | |
| 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 | |
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 29575 | 3-fluorophenylformamide | C7H6FNO | 详情 | 详情 | |
| (III) | 20700 | 3-fluoro-N-methylaniline; N-(3-fluorophenyl)-N-methylamine | C7H8FN | 详情 | 详情 | |
| (IV) | 29576 | N-benzyl-3-fluoro-N-methylaniline; N-benzyl-N-(3-fluorophenyl)-N-methylamine | C14H14FN | 详情 | 详情 | |
| (V) | 29577 | 4-[benzyl(methyl)amino]-2-fluorobenzaldehyde | C15H14FNO | 详情 | 详情 | |
| (VI) | 29578 | N-benzyl-N-[3-fluoro-4-[(E)-2-nitro-1-propenyl]phenyl]-N-methylamine; N-benzyl-3-fluoro-N-methyl-4-[(E)-2-nitro-1-propenyl]aniline | C17H17FN2O2 | 详情 | 详情 | |
| (VII) | 29579 | N-[4-(2-aminopropyl)-3-fluorophenyl]-N-benzyl-N-methylamine; 4-(2-aminopropyl)-N-benzyl-3-fluoro-N-methylaniline | C17H21FN2 | 详情 | 详情 | |
| (VIII) | 29580 | N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-chloroacetamide | C19H22ClFN2O | 详情 | 详情 | |
| (IX) | 29581 | N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-(dibenzylamino)acetamide | C33H36FN3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)Vilsmeier-Haack formylation of 6-chloro-5-fluoroindole (I) with dimethylformamide (XIII) by means of POCl3 gives 6-chloro-5-fluoroindole-3-carbaldehyde (XIV), which by Henry reaction with nitroethane (XV) in the presence of NH4OAc yields 6-chloro-5-fluoro-3-(2-nitroprop-1-enyl)indole (XVI). Reduction of the unsaturated nitro compound (XVI) by means of LiAlH4 in refluxing THF provides the trypt amine derivative (XVII), which is then subjected to Pictet-Spengler cyclization with 5-chloroisatin (XII) by means of p-TsOH in EtOH at 110 °C to afford spiro racemate (XVIII). Finally, chiral chromatography of racemate (XVIII) affords the desired (1R,3S)-enantiomer .
| 【1】 Ang, S.H., Krastel, P., Leong, S.Y., Tan, L.J., Wong, W.L.J., Yeung, B.K.S., Zou, B. (Novartis AG). Spiro-indole derivatives for the treatment of parasitic diseases. CN 102015711; EP 2722333; KR 2010135320; EP 2285808;JP 2011518852; US 8399453; US 2011275613; WO 2009132921; US 2009275560; US 8053442. |
| 【2】 Yeung, B.K., Zou, B., Rottmann, M. et al. Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 2010, 53(14): 5155-64. |
| 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) | 30025 | 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole | 122509-72-2 | C8H5ClFN | 详情 | 详情 |
| (XII) | 14099 | 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin | 17630-76-1 | C8H4ClNO2 | 详情 | 详情 |
| (XIII) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (XIV) | 67561 | 6-chloro-5-fluoroindole-3-carbaldehyde | C9H5ClFNO | 详情 | 详情 | |
| (XV) | 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 |
| (XVI) | 67562 | (Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole | C11H8ClFN2O2 | 详情 | 详情 | |
| (XVII) | 67563 | 1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine | C11H12ClFN2 | 详情 | 详情 | |
| (XVIII) | 67564 | 5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one | C19H14Cl2FN3O | 详情 | 详情 |