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【结 构 式】 
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【药物名称】FS-32 【化学名称】N,N-Dimethyl-N-[3-(5-methyl-3-phenyl-1H-indazol-1-yl)propyl]amine 【CA登记号】 【 分 子 式 】C19H23N3 【 分 子 量 】293.41526 |
【开发单位】National Tsing Hua University (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS |
合成路线1
Alkylation of N,N-dimethyl-1,3-propanediamine (II) with ethyl bromoacetate (I) afforded the diamino ester (III). Basic hydrolysis of (III) and subsequent nitrosation of the resulting diamino acid (IV) yielded the nitrosamine (V). Cyclization of (V) in hot acetic anhydride as the dehydrating agent gave rise to sydnone (VI). Lithiation of (VI), followed by condensation with aldehyde (VII), produced adduct (VIII) as an inseparable mixture of diastereomers. The hydroxyl group of (VIII) was then protected as the methyl ether (IX) by alkylation with iodomethane and NaH. The azomethyne intermediate, generated by ejection of CO2 from (IX) upon heating in xylene, underwent an intramolecular 1,3-dipolar cycloaddition with the olefin double bond to furnish the indazole derivative (X). Finally, the target compound was obtained by aromatization of (X) under acidic conditions in the presence of platinum catalyst.
| 【1】 Yeu, J.P.; et al.; An expedient synthesis of 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32) - An antidepressant. Synthesis 2001, 12, 1775. |
| 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) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (II) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (III) | 50245 | ethyl 2-[[3-(dimethylamino)propyl]amino]acetate | C9H20N2O2 | 详情 | 详情 | |
| (IV) | 50246 | 2-[[3-(dimethylamino)propyl]amino]acetic acid | C7H16N2O2 | 详情 | 详情 | |
| (V) | 50247 | C7H15N3O3 | 详情 | 详情 | ||
| (VI) | 50248 | 3-[3-(dimethylamino)propyl]-1,2,3-oxadiazol-3-ium-5-olate | C7H13N3O2 | 详情 | 详情 | |
| (VII) | 50249 | (E)-3-methyl-6-phenyl-5-hexenal | C13H16O | 详情 | 详情 | |
| (VIII) | 50250 | 3-[3-(dimethylamino)propyl]-4-[(E)-1-hydroxy-3-methyl-6-phenyl-5-hexenyl]-1,2,3-oxadiazol-3-ium-5-olate | C20H29N3O3 | 详情 | 详情 | |
| (IX) | 50251 | 3-[3-(dimethylamino)propyl]-4-[(E)-1-methoxy-3-methyl-6-phenyl-5-hexenyl]-1,2,3-oxadiazol-3-ium-5-olate | C21H31N3O3 | 详情 | 详情 | |
| (X) | 50252 | 3-(7-methoxy-5-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N,N-dimethyl-1-propanamine; N-[3-(7-methoxy-5-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)propyl]-N,N-dimethylamine | C20H29N3O | 详情 | 详情 |
合成路线2
It can be prepared in several different way (Scheme 31229302a): 1) The nitrosation of 2-[3-(dimethylamino)propylamino]-5-methylbenzophenone (I) with NaNO2 and HCl in chloroform gives the corresponding N-nitroso compound (II), which is cyclized by reaction with Zn in acetic acid. 2) By reaction of 1-(3-methylaminopropyl)-5-methyl-3-phenyl-1H-indazole (III) with formaldehyde and NaBH4 in methanol. 3) The reaction of 3-phenyl-5-methyl-1H-indazole (IV) with 1,3-dibromopropane (V) by means of NaH in DMF gives 1-(3-bromopropyl)-5-methyl-3-phenyl-1H-indazole (VI), which is then condensed with dimethylamine (VII). 4) By reaction of (IV) with 1-(dimethylamino)-3-bromopropane (VIII) by means of NaOH in a mixture of toluene and water.
| 【1】 Fujimura, Y.; et al. (Cubist Pharmaceuticals, Inc.); JP 76125281 . |
| 【2】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); DE 2503815; FR 2259601; GB 1489280; JP 75106958; JP 75145244; JP 75148335; JP 7663172; US 3994890 . |
| 【3】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7659861 . |
| 【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; FS-32. Drugs Fut 1979, 4, 8, 583. |
| 【5】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7714765 . |
| 【6】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7714766 . |
| 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) | 61119 | (2-{[3-(dimethylamino)propyl]amino}-5-methylphenyl)(phenyl)methanone | C19H24N2O | 详情 | 详情 | |
| (II) | 61120 | C19H23N3O2 | 详情 | 详情 | ||
| (III) | 61123 | N-methyl-3-(5-methyl-3-phenyl-1H-indazol-1-yl)-1-propanamine; N-methyl-N-[3-(5-methyl-3-phenyl-1H-indazol-1-yl)propyl]amine | C18H21N3 | 详情 | 详情 | |
| (IV) | 34172 | 5-methyl-3-phenyl-1H-indazole | C14H12N2 | 详情 | 详情 | |
| (V) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (VI) | 61121 | 1-(3-bromopropyl)-5-methyl-3-phenyl-1H-indazole | C17H17BrN2 | 详情 | 详情 | |
| (VII) | 19443 | N-methylmethanamine; N,N-dimethylamine | 124-40-3 | C2H7N | 详情 | 详情 |
| (VIII) | 61122 | 3-bromo-N,N-dimethyl-1-propanamine; N-(3-bromopropyl)-N,N-dimethylamine | C5H12BrN | 详情 | 详情 |