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【结 构 式】 
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【分子编号】13017 【品名】Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile 【CA登记号】123-06-8 |
【 分 子 式 】C6H6N2O 【 分 子 量 】122.12652 【元素组成】C 59.01% H 4.95% N 22.94% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(II)Two related routes for the synthesis of pemirolast potassium have been reported: 1) The condensation of 2-amino-3-methylpyridine (I) with ethoxymethylenemalonodinitrile (II) gives the monocyclic intermediate (III), which is in tautomeric equilibrium with the pyridopyrimidine derivative (IV). The reaction of (IV) with aluminum azide (AlCl3.NaN3) in refluxing THF yields 4-imino-9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine (V). Finally, this compound is first hydrolyzed with 1N HCl and then treated with KOH. 2) Compound (IV) can be converted to the final product by a one-pot reaction: (VI) is treated first with NaN3 in refluxing acetic acid, then hydrolyzed with HCl and finally treated with KOH.
| 【1】 Sumino, M.; Ishihara, M.; Sano, A.; Yoshihara, J.; Nawa, H.; A facile and practical synthesis of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one. Chem Pharm Bull 1995, 43, 4, 683. |
| 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) | 13016 | 3-Methyl-2-pyridinylamine; 3-Methyl-2-pyridinamine; 2-Amino-3-picoline; 2-Amino-3-methylpyridine | 1603-40-3 | C6H8N2 | 详情 | 详情 |
| (II) | 13017 | Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile | 123-06-8 | C6H6N2O | 详情 | 详情 |
| (III) | 13018 | 2-[[(3-Methyl-2-pyridinyl)amino]methylene]malononitrile | C10H8N4 | 详情 | 详情 | |
| (IV) | 13019 | 4-Imino-9-methyl-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile | C10H8N4 | 详情 | 详情 | |
| (V) | 13020 | 9-Methyl-3-(1H-1,2,3,4-tetraazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-imine | C10H9N7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)Cyclization of ethoxymethylenemalonodinitrile (XVII) with hydrazine gives 5-aminopyrazole-4-carbonitrile (XVIII), which is further cyclized with acetamide (X) in refluxing AcOH to yield the 3-cyanopyrazolo[1,5-a]pyrimidine derivative (XIX). Finally, this compound is condensed with 2-bromothiophene (XX) by means of Mg.
| 【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739. |
| 【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 59947 | N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide | C14H18N2O2 | 详情 | 详情 | |
| (XVII) | 13017 | Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile | 123-06-8 | C6H6N2O | 详情 | 详情 |
| (XVIII) | 57051 | 5-Amino-4-pyrazolecarbonitrile | C4H4N4 | 详情 | 详情 | |
| (XIX) | 62965 | N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide | C16H13N5O | 详情 | 详情 | |
| (XX) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation between 3-(4-methoxyphenyl)propyl hydrazine (I) and (ethoxymethylene)malononitrile (II) afforded the pyrazole (III), which was transformed to the corresponding imidate (IV) by refluxing in triethyl orthoformate. Reaction of imidate (IV) with 2-furoic acid hydrazide (V) provided the pyrazolopyrimidine intermediate (VI), which was thermally cyclized in diphenyl ether to the tricyclic derivative (VII). Hydrolysis of (VII) with HCl induced the pyrimidine ring opening to furnish (VIII). This was finally converted into the title compound by treatment with cyanamide in N-methylpyrrolidone.
| 【1】 Moresco, R.M.; Simonelli, P.; Todde, S.; et al.; Design, radiosynthesis, and biodistribution of a new potent and selective ligand for in vivo imaging of the adenosine A2A receptor system using positron emission tomography. J Med Chem 2000, 43, 23, 4359. |
| 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) | 47277 | 1-[3-(4-methoxyphenyl)propyl]hydrazine; 4-(3-hydrazinopropyl)phenyl methyl ether | C10H16N2O | 详情 | 详情 | |
| (II) | 13017 | Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile | 123-06-8 | C6H6N2O | 详情 | 详情 |
| (III) | 47278 | 5-amino-1-[3-(4-methoxyphenyl)propyl]-1H-pyrazole-4-carbonitrile | C14H16N4O | 详情 | 详情 | |
| (IV) | 47279 | ethyl 4-cyano-1-[3-(4-methoxyphenyl)propyl]-1H-pyrazol-5-yliminoformate | C17H20N4O2 | 详情 | 详情 | |
| (V) | 41402 | 2-furohydrazide | 3326-71-4 | C5H6N2O2 | 详情 | 详情 |
| (VI) | 47280 | N-[4-imino-1-[3-(4-methoxyphenyl)propyl]-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl]-2-furamide | C20H20N6O3 | 详情 | 详情 | |
| (VII) | 47281 | 2-(2-furyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine; 4-[3-[2-(2-furyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl]propyl]phenyl methyl ether | C20H18N6O2 | 详情 | 详情 | |
| (VIII) | 47282 | 4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-[3-(4-methoxyphenyl)propyl]-1H-pyrazol-5-amine; 4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-[3-(4-methoxyphenyl)propyl]-1H-pyrazol-5-ylamine | C19H20N6O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of guanidine nitrate (I) with (ethoxymethylene)malononitrile (II) in the presence of NaOEt yields 2,4-diaminopyrimidine-5-carbonitrile (III). Reduction of nitrile (III) by means of Raney nickel in formic acid leads to aldehyde (IV), which is further reduced to alcohol (V) by means of NaBH4. Treatment of alcohol (V) with HBr in AcOH gives the bromide (VI), which is condensed with pyridine in DMF to form the crystalline pyridinium salt (VII). Finally, displacement of compound (VII) with the tetrahydroisoquinoline (VIII), followed by resolution by chiral HPLC, furnishes the title compound.
| 【1】 Gerber, P.; Wyss, P.C.; Hartman, P.G.; Hubschwerlen, C.; Locher, H.; Marty, H.-P.; Stahl, M.; Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003, 46, 12, 2304. |
| 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) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (II) | 13017 | Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile | 123-06-8 | C6H6N2O | 详情 | 详情 |
| (III) | 64871 | 2,4-diamino-5-pyrimidinecarbonitrile | C5H5N5 | 详情 | 详情 | |
| (IV) | 26525 | 2,4-diamino-5-pyrimidinecarbaldehyde | C5H6N4O | 详情 | 详情 | |
| (V) | 64872 | (2,4-diamino-5-pyrimidinyl)methanol | C5H8N4O | 详情 | 详情 | |
| (VI) | 64873 | 5-(bromomethyl)-2,4-pyrimidinediamine | C5H7BrN4 | 详情 | 详情 | |
| (VII) | 64874 | 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide | C10H12BrN5 | 详情 | 详情 | |
| (VIII) | 64875 | methyl 9-methyl-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinolin-4-yl ether; 9-methyl-4-(methyloxy)-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinoline | C12H15NO3 | 详情 | 详情 |