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【结 构 式】 
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【分子编号】68904 【品名】methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate 【CA登记号】 |
【 分 子 式 】C18H18N4O2S 【 分 子 量 】354.433 【元素组成】C 61.00% H 5.12% N 15.81% O 9.03% S 9.05% |
合成路线1
该中间体在本合成路线中的序号：(V)Cyclization of 4-cyclopropyl-1-naphthyl isothiocyanate (I) with aminoguanidine hydrochloride (II) using DIEA in DMF yields the naphthyl-1,2,4-triazole-3-thiol (III), which is then alkylated with methyl chloroacetate (IV) by means of K2CO3 in DMF to give the (triazolylsulfanyl)acetate (V). Diazotization of the amine (V) with NaNO2 and Cl2CHCOOH in the presence of BnEt3NBr or BnEt3NCl in CHBr3 gives rise to the 5-bromotriazole derivative (VI), which is hydrolyzed with LiOH in THF/EtOH/H2O to produce lesinurad (VII) , and is finally treated with NaOH in EtOH .
Also, coupling of the thiol (III) with the 2-chloroacetamide derivative (VIII) by means of K2CO3 in DMF yields the amide (IX), which is then brominated with CHBr3 in the presence of NaNO2, Cl2CHCOOH and BnEt3NBr or BnEt3NCl to give the 5-bromotriazole derivative (X) .Finally, hydrolysis of amide (X) with NaOH in refluxing EtOH affords lesinurad (VII) .
| 【1】 Miner, J., Quart, B.D., Girardet, J.-L. (Ardea Biosciences, Inc.). Treatment of gout. WO 201116852. |
| 【2】 Quart, B.D., Girardet, J.-L., Gunic, E., Yeh, L.-T. (Ardea Biosciences, Inc.).Novel compounds and composition and methods of use. CA 2706858, CN 01918377, EP 2217577, JP 2011504935, KR 2010085195, US 2009197825, US 2011268801, WO 009070740. |
| 【3】 Zamansky, I., Galvin, G., Girardet, J.-L. (Ardea Biosciences, Inc.). Polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate, and uses thereof. WO 2011085009. |
| 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) | 68901 | 4-cyclopropyl-1-naphthyl isothiocyanate | 878671-95-5 | C14H11NS | 详情 | 详情 |
| (II) | 68902 | aminoguanidine hydrochloride;aminoguanidine monohydrochloride;Hydrazinecarboximidamide | 1937-19-5 | CH6N4.HCl | 详情 | 详情 |
| (III) | 68903 | 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol | C15H14N4S | 详情 | 详情 | |
| (IV) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (V) | 68904 | methyl 2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate | C18H18N4O2S | 详情 | 详情 | |
| (VI) | 68905 | methyl 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate | C18H16BrN3O2S | 详情 | 详情 | |
| (VII) | 68906 | 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid | C17H14BrN3O2S | 详情 | 详情 | |
| (VIII) | 68907 | 2-chloro-N-(2-chloro-4-sulfamoylphenyl)acetamide | C8H8Cl2N2O3S | 详情 | 详情 | |
| (IX) | 68908 | 2-((5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(2-chloro-4-sulfamoylphenyl)acetamide | C23H21ClN6O3S2 | 详情 | 详情 | |
| (X) | 68909 | 2-((5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)-N-(2-chloro-4-sulfamoylphenyl)acetamide | C23H19BrClN5O3S2 | 详情 | 详情 |