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【结 构 式】

【药物名称】NT-702, NM-702

【化学名称】4-Bromo-6-[3-(4-chlorophenyl)propoxy]-5-(pyridin-3-ylmethylamino)pyridazin-3(2H)-one hydrochloride

【CA登记号】139145-27-0 (free base), 139145-89-4 (fumarate salt (2:1)), 139145-87-2 (maleate salt (1:1)), 139145-84-9 (monoHCl)

【 分 子 式 】C19H19BrCl2N4O2

【 分 子 量 】486.19888

【开发单位】Nissan Chemical (Originator), Catalyst Pharmaceutical (Licensee), Taisho (Codevelopment)

【药理作用】Antiplatelet Therapy, Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Treatment of Peripheral Obstructive Vascular Disease, Phosphodiesterase III Inhibitors, Phosphodiesterase V (PDE5A) Inhibitors, Thromboxane Synthase Inhibitors

合成路线1

The title compound was prepared by condensation of the dibromopyridiazinone (I) with 3-picolylamine (II), followed by conversion to the corresponding hydrochloride salt

1 Tanikawa, K.; Saito, A.; Matsumoto, T.; Sakoda, R.; Tsuruzoe, N.; Shikada, K.-I. (Nissan Chemical Industry, Ltd.); Pyridazinone deriv.. EP 0482208; JP 1992507543; US 5202323; US 5314883; US 5318968; WO 9116314 .
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) 60514 4,5-dibromo-6-[3-(4-chlorophenyl)propoxy]-3(2H)-pyridazinone C13H11Br2ClN2O2 详情 详情
(II) 18371 methyl (3S,4R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate 21085-72-3 C13H17BrO9 详情 详情

合成路线2

An improved procedure, amenable to the industrial synthesis of the precursor (I) was further developed. Heck coupling of p-chloroiodobenzene (III) with allyl alcohol (IV) in the presence of tetramethylammonium chloride and a catalytic amount of palladium acetate provided 3-(p-chlorophenyl)propanal (V) along with minor amounts of its branched isomer (VI). Further reduction of this mixture with NaBH4 led to the respective alcohols (VII) and (VIII). Only the desired alcohol (VII) underwent bromination to the desired bromide (IX) in the presence of PBr3 in hot toluene, whereas the branched alcohol (VIII) was dehydrohalogenated to olefin (X). Subsequent alkylation of pyridazinedione (XI) with the above reaction mixture afforded the pure intermediate

1 Matsumoto, H.; Kamikawaji, M.; Horiuchi, T. (Nissan Chemical Industry, Ltd.); Processes for the preparation of (p-chlorophenyl)propanol derivs.. EP 1138660; WO 0035843 .
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) 60514 4,5-dibromo-6-[3-(4-chlorophenyl)propoxy]-3(2H)-pyridazinone C13H11Br2ClN2O2 详情 详情
(III) 19395 1-chloro-4-iodobenzene 637-87-6 C6H4ClI 详情 详情
(IV) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(V) 60515 3-(4-chlorophenyl)propanal C9H9ClO 详情 详情
(VI) 60516 2-(4-chlorophenyl)propanal C9H9ClO 详情 详情
(VII) 60517 3-(4-chlorophenyl)-1-propanol C9H11ClO 详情 详情
(VIII) 60518 2-(4-chlorophenyl)-1-propanol C9H11ClO 详情 详情
(IX) 60520 1-(3-bromopropyl)-4-chlorobenzene C9H10BrCl 详情 详情
(X) 60519 1-chloro-4-isopropenylbenzene C9H9Cl 详情 详情
(XI) 63949 4,5-dibromo-1,2-dihydro-3,6-pyridazinedione C4H2Br2N2O2 详情 详情
Extended Information