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【结 构 式】 
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【药物名称】Pemirolast potassium, TWT-8152, DE-068, BMY-26517, TBX, Alamast, Alegysal, Pemilaston 【化学名称】9-Methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt 【CA登记号】100299-08-9, 69372-19-6 (free acid) 【 分 子 式 】C10H7KN6O 【 分 子 量 】266.30889 |
【开发单位】Bristol-Myers Squibb (Originator), Mitsubishi Pharma (Licensee), Santen (Licensee) 【药理作用】Antiallergic Ophthalmic Agents, Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, RESPIRATORY DRUGS, Mediator Release Inhibitors |
合成路线1
| 【1】 Xiang HL．Hu GY．Tan ZY，et al 2003．Synthesis of potassium pemirolast. 中国药物化学杂志，l3(6): 358～360 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （III) | 66581 | ethyl 4-(3-methylpyridin-2-yl)-2-(1H-tetrazol-5-yl)but-2-enoate | C13H15N5O2 | 详情 | 详情 | |
| (I) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 66580 | ethyl 2-(1H-tetrazol-5-yl)acetate;(1H-Tetrazol-5-yl)acetic acid ethyl ester;(2H-Tetrazol-5-yl)acetic acid ethylester;Ethyl 5-tetrazolylacetate;Ethyltetrazole-5-acetate | 13616-37-0 | C5H8N4O2 | 详情 | 详情 |
合成路线2
| 【1】 Peng DM. 2004．Study on the synthesis of pemirolast potassium. 湖南医科大学学报, 27: 60～62 |
| 【2】 Zou P．Xie MH，Luo SN，et aL 2002.Synthesis of pemirolast potassium. 中国医药工业杂志，33：215～216. |
合成路线3
| 【1】 Xu YG，Lei L，Zhang R．et aL 2003．Synthesis of pemirolast potassium. 中国医药工业杂志, 34: 315～316. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （III) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (I) | 66580 | ethyl 2-(1H-tetrazol-5-yl)acetate;(1H-Tetrazol-5-yl)acetic acid ethyl ester;(2H-Tetrazol-5-yl)acetic acid ethylester;Ethyl 5-tetrazolylacetate;Ethyltetrazole-5-acetate | 13616-37-0 | C5H8N4O2 | 详情 | 详情 |
| (II) | 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 |
合成路线4
| 【1】 Sano A. Ishihara M. 1998. A facile and convenient synthesis of 9-methyl-3-(1H-tetrazol-5-yl_-4H-pyrido[1,2-α] pyrimidin-4-one, Heterocycles, 48: 775-778 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （III) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (I) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (II) | 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 |
合成路线5
合成路线6
| 【1】 Amano M, Nakagawa Y. 1991. Preparation of pyrido[1,2-a] pyrimidine derivatives. JP 03074385. |
合成路线7
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 |