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【结 构 式】 
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【药物名称】E-4010 【化学名称】4-(3-Chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile hydrochloride 【CA登记号】178308-66-2, 178308-65-1 (free base) 【 分 子 式 】C22H23Cl2N5O2 【 分 子 量 】460.36691 |
【开发单位】Eisai (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, Phosphodiesterase V (PDE5A) Inhibitors |
合成路线1
The reaction of 4-aminophthalimide (I) with NaNO2/HCl and then with CuCl/KCN gives 4-cyanophthalimide (II), which is treated with hydrazone in ethanol, yielding 6-cyanophthalazine-2,3(1H,4H)-dione (III). The reaction of (III) with refluxing POCl3 affords 1,4-dichlorophthalazine-6-carbonitrile (IV), which is condensed with 3-chloro-4-methoxybenzylamine (V) by means of TEA in THF to provide the secondary amine (VI). Finally, this compound is condensed with 4-hydroxypiperidine (VII) by means of DIEA in N-methyl-2-pyrrolidone to furnish the target phthalazine.
| 【1】 Watanabe, N.; Kabasawa, Y.; Takase, Y.; Ozaki, F.; Ishibashi, K.; Miyazaki, K.; Matsukura, M.; Souda, S.; Miyake, K.; Ishihara, H.; Kodama, K.; Adachi, H. (Eisai Co., Ltd.); Fused pyridazine cpd.. EP 0722936; JP 1996225541; US 6218392; WO 9605176 . |
| 【2】 Takase, Y.; Adachi, H.; Watanabe, N.; et al.; 4-(3-Chloro-4-methoxybenzyl)aminophthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5. J Med Chem 2000, 43, 13, 2523. |
| 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) | 51974 | 5-amino-1H-isoindole-1,3(2H)-dione | C8H6N2O2 | 详情 | 详情 | |
| (II) | 51975 | 1,3-dioxo-5-isoindolinecarbonitrile | C9H4N2O2 | 详情 | 详情 | |
| (III) | 51976 | 1,4-dioxo-1,2,3,4-tetrahydro-6-phthalazinecarbonitrile | C9H5N3O2 | 详情 | 详情 | |
| (IV) | 51977 | 1,4-dichloro-6-phthalazinecarbonitrile | C9H3Cl2N3 | 详情 | 详情 | |
| (V) | 51978 | (3-chloro-4-methoxyphenyl)methanamine; 3-chloro-4-methoxybenzylamine | C8H10ClNO | 详情 | 详情 | |
| (VI) | 51979 | 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile | C17H12Cl2N4O | 详情 | 详情 | |
| (VII) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
合成路线2
The condensation of the commercially available (Amersham) 14C-labeled 1-chloro-4-(3-chloro-4-methoxybenzylamino)phthalazine-6-carbonitrile (I) with 4-hydroxypiperidine (II) by means of K2CO3 and N-methyl-2-pyrrolidinone at 170 C yields the target phthalazine derivative.
| 【1】 Watanabe, N.; et al.; Synthesis of 14C-labeled E4010. J Label Compd Radiopharm 2001, 44, 12, 843. |
| 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) | 51979 | 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile | C17H12Cl2N4O | 详情 | 详情 | |
| (I) | 51980 | 1-chloro-4-[(3-chloro-4-methoxybenzyl)amino]-6-phthalazinecarbonitrile | C17H12Cl2N4O | 详情 | 详情 | |
| (II) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |