• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【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
Extended Information