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【结 构 式】 
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【分子编号】12114 【品名】methyl 6-aminonicotinate 【CA登记号】 |
【 分 子 式 】C7H8N2O2 【 分 子 量 】152.1528 【元素组成】C 55.26% H 5.3% N 18.41% O 21.03% |
合成路线1
该中间体在本合成路线中的序号：(II)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：(VIa)Alkylation of pyrrole-2-carboxaldehyde (II) with 2-nitrobenzyl chloride (I) in the presence of NaH afforded the N-benzyl pyrrole (III). Subsequent reductive ring closure of (III) by hydrogenation over Pd/C produced the pyrrolobenzodiazepine (IV). Acid-catalyzed esterification of 6-aminonicotinic acid (V) with either methanol or ethanol provided the corresponding esters (VIa) or (VIb). Further coupling of (VIa) or (VIb) with two equivalents of 5-fluoro-2-methylbenzoyl chloride (VII) gave rise to imide (VIII). Simultaneous hydrolysis of ester function and one benzoyl group of (VIIIa-b) with NaOH furnished acid (IX), which was then converted to the corresponding acid chloride (X) employing either thionyl chloride or oxalyl chloride. Finally, coupling of acid chloride (X) with amine (IV) in the presence of Et3N yielded the target amide.
| 【1】 Albright, J.D.; Venkatesan, A.M.; Dusza, J.P.; Sum, F.W. (American Cyanamid Co.); Tricyclic benzazepine vasopressin antagonists. US 5700796; WO 9749708 . |
| 【2】 Burgoyne, D.L.; Shen, Y.; Langlands, J.M.; Rogers, C.; Chau, J.H.-L.; Piers, E.; Salari, H. (InflaZyme Pharmaceuticals Ltd.); 6,7-Oxygenated steroids and uses related thereto. US 6046185; WO 9802450 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 12114 | methyl 6-aminonicotinate | C7H8N2O2 | 详情 | 详情 | |
| (VIb) | 33794 | ethyl 6-aminonicotinate | C8H10N2O2 | 详情 | 详情 | |
| (VIIIa) | 33795 | methyl 6-[bis(5-fluoro-2-methylbenzoyl)amino]nicotinate | C23H18F2N2O4 | 详情 | 详情 | |
| (VIIIb) | 33814 | ethyl 6-[bis(5-fluoro-2-methylbenzoyl)amino]nicotinate | C24H20F2N2O4 | 详情 | 详情 | |
| (I) | 33792 | 1-(chloromethyl)-2-nitrobenzene | 612-23-7 | C7H6ClNO2 | 详情 | 详情 |
| (II) | 21081 | Pyrrole-2-carbaldehyde; 1H-pyrrole-2-carbaldehyde | 1003-29-8 | C5H5NO | 详情 | 详情 |
| (III) | 21083 | 1-(2-nitrobenzyl)-1H-pyrrole-2-carbaldehyde; N-(2-Nitrobenzyl)pyrrole-2-carboxaldehyde | 22162-51-2 | C12H10N2O3 | 详情 | 详情 |
| (IV) | 21084 | 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine | 22162-53-4 | C12H12N2 | 详情 | 详情 |
| (V) | 33793 | 6-aminonicotinic acid | 3167-49-5 | C6H6N2O2 | 详情 | 详情 |
| (VII) | 26677 | 5-fluoro-2-methylbenzoyl chloride | C8H6ClFO | 详情 | 详情 | |
| (IX) | 33796 | 6-[(5-fluoro-2-methylbenzoyl)amino]nicotinic acid | C14H11FN2O3 | 详情 | 详情 | |
| (X) | 33797 | 6-[(5-fluoro-2-methylbenzoyl)amino]nicotinoyl chloride | C14H10ClFN2O2 | 详情 | 详情 |