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【结 构 式】 
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【分子编号】12121 【品名】(Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one 【CA登记号】 |
【 分 子 式 】C13H15N3O 【 分 子 量 】229.28172 【元素组成】C 68.1% H 6.59% N 18.33% O 6.98% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(VI)1) The condensation of 6-bromoimidazo[1,2-a]-pyridine (I) with 2-(chloromethyl)propene (II) by means of Mg and ethyl bromide in THF gives 6-(2-methyl-2-propenyl)imidazo[1,2-a]pyridine (III), which is ozonolyzed with O3 yielding 1-(imidazo[1,2-a]-pyridin-6-yl)-2-propanone (IV). The condensation of (IV) with dimethylformamide dimethylketal (V) in hot DMF affords 4-(dimethylamino)-3-(imidazo[1,2-a]-pyridin-6-yl)-3-buten-2-one (IV), which is finally cyclized with 2-cyanoacetamide (VII) by means of sodium methoxide in hot DMF.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 12124 | 6-Bromoimidazo[1,2-a]pyridine | 6188-23-4 | C7H5BrN2 | 详情 | 详情 |
| (II) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (III) | 12128 | 6-(2-Methyl-2-propenyl)imidazo[1,2-a]pyridine | C11H12N2 | 详情 | 详情 | |
| (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 |
合成路线3
该中间体在本合成路线中的序号：(VI)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4
该中间体在本合成路线中的序号：(VI)In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.
| 【1】 Lisowski, V.; et al.; Design, synthesis and antiproliferative activity of tripentones: A new series of antitubulin agents. Bioorg Med Chem Lett 2001, 11, 16, 2205. |
| 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) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 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 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XI) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (XIII) | 23823 | 5-[4-hydroxy-2-(3-hydroxybutyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid | C20H32O5 | 详情 | 详情 | |
| (XIV) | 52232 | benzyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(benzyloxy)-4-(chloromethyl)-1-methoxybenzene | C15H15ClO2 | 详情 | 详情 | |
| (XV) | 52233 | (3-Benzyloxy-4-methoxyphenyl)acetonitrile | C16H15NO2 | 详情 | 详情 | |
| (XVI) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XVII) | 52235 | (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyanoethenyl benzenesulfonate | C23H19NO5S | 详情 | 详情 | |
| (XVIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XIX) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XX) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXI) | 52239 | 3-[3-(benzyloxy)-4-methoxyphenyl]-8H-thieno[2,3-b]pyrrolizin-8-one | C23H17NO3S | 详情 | 详情 |