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【结 构 式】 
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【分子编号】67880 【品名】methyl 4-hydroxy-1-oxo-7-phenoxy-1,2-dihydroisoquinoline-3-carboxylate 【CA登记号】 |
【 分 子 式 】C17H13NO5 【 分 子 量 】311.29396 【元素组成】C 65.59% H 4.21% N 4.5% O 25.7% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Condensation of 4-nitro-ortho-phthalonitrile (XII) with phenol (XIII) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (XIV) , which by hydrolysis with NaOH or KOH in refluxing MeOH yields 4-phenoxyphthalic acid (I) . Dehydration of dicarboxylic acid (I) using Ac2O and AcOH at reflux provides the phthalic anhydride (XV), which is then condensed with methyl 2-isocyanoacetate (XVI) using DBU in THF to generate the oxazole derivative (XVII). Rearrangement of intermediate (XVII) with HCl in MeOH at 60 °C leads to the isoquinoline derivative (XVIII), which is partially chlorinated by means of POCl3 at 70 °C to afford the 1-chloro-isoquinoline derivative (XIX). Substitution of chlorine in intermediate (XIX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (XX), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (IX). Coupling of carboxylic acid (IX) with methyl glycinate hydrochloride (XXI) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields the methyl ester (XXII), which is finally hydrolyzed with aqueous NaOH in THF .
| 【1】 Arend, M.P., Flippin, L.A., Du, X., Ho, W.-B., Turtle, E.D., Guenzler-Pukall, V. (FibroGen, Inc.). Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin. WO 2004108681. |
| 【2】 Kang, X., Long, W., Zhang, J., Hu, Y., Wang, Y. (Zhejiang Beta Pharma, Inc.). Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof. EP 2734504; CN 104024227; WO 2013013609. |
| 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) | 67865 | 4-phenoxyphthalic acid | C14H10O5 | 详情 | 详情 | |
| (IX) | 67872 | 4-(benzyloxy)-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid | C21H21NO4 | 详情 | 详情 | |
| (XII) | 67875 | 4-nitro-ortho-phthalonitrile | 31643-49-9 | C8H3N3O2 | 详情 | 详情 |
| (XIII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XIV) | 67876 | 4-phenoxy-ortho-phthalonitrile | 38791-62-7 | C14H8N2O | 详情 | 详情 |
| (XV) | 67878 | 5-phenoxyisobenzofuran-1,3-dione | C14H8O4 | 详情 | 详情 | |
| (XVI) | 67877 | methyl 2-isocyanoacetate | 39687-95-1 | C4H5NO2 | 详情 | 详情 |
| (XVII) | 67879 | 2-(4-(methoxycarbonyl)oxazol-5-yl)-5-phenoxybenzoic acid | C18H13NO6 | 详情 | 详情 | |
| (XVIII) | 67880 | methyl 4-hydroxy-1-oxo-7-phenoxy-1,2-dihydroisoquinoline-3-carboxylate | C17H13NO5 | 详情 | 详情 | |
| (XIX) | 67881 | methyl 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C17H12ClNO4 | 详情 | 详情 | |
| (XX) | 67882 | methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate | C18H15NO4 | 详情 | 详情 | |
| (XXI) | 67884 | methyl glycinate hydrochloride | 5680-79-5 | C3H7NO2.HCl | 详情 | 详情 |
| (XXII) | 67883 | methyl 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetate | C20H18N2O5 | 详情 | 详情 |