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【结 构 式】 
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【分子编号】67882 【品名】methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate 【CA登记号】 |
【 分 子 式 】C18H15NO4 【 分 子 量 】309.32144 【元素组成】C 69.89% H 4.89% N 4.53% O 20.69% |
合成路线1
该中间体在本合成路线中的序号：(XX)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 |
合成路线2
该中间体在本合成路线中的序号：(XX)Condensation of 5-bromophthalide (XXIII) with phenol (XIII) by means of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (XXIV), which is submitted to lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene to yield 2-(chloro-methyl)-4-phenoxybenzoyl chloride (XXV). Esterification of acid chloride (XXV) with MeOH at 50 °C provides the methyl ester (XXVI), which is then condensed with methyl N-tosylglycinate (XXVII) in the presence of K2CO3 and NaI in DMF at 50 °C to afford the N-substituted amino ester (XXVIII). Cyclization of diester (XXVIII) with NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXIX), which is submitted to Mannich reaction with bis(dimethylamino)methane (XXX) by means of AcOH at 57 °C to provide the 1-(dimethylaminomethyl)isoquinoline derivative (XXXI). Treatment of compound (XXXI) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXXII). Hydrogenolysis of benzylic acetate (XXXII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XX), which is finally condensed with glycine (II) by means of NaOMe in MeOH at 110 °C .
| 【1】 Thompson, M.D., Park, J.M., Arend, M.P. (FibroGen, Inc.). Process for making isoquinoline compounds. CN 103435546; WO 2014014834. |
| 【2】 Witschi, C., Park, J.M., Thompson, M.D., Martinelli, M.J., Yeowell, D.A.,Arend, M.P. (FibroGen, Inc.). Crystalline forms of a prolyl hydroxylase inhibitor. WO 2014014835, US 2014024675. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (XIII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XX) | 67882 | methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate | C18H15NO4 | 详情 | 详情 | |
| (XXIII) | 33229 | 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one | 64169-34-2 | C8H5BrO2 | 详情 | 详情 |
| (XXIV) | 67885 | 5-phenoxyphthalide | 57830-14-5 | C14H10O3 | 详情 | 详情 |
| (XXV) | 67886 | 2-(chloromethyl)-4-phenoxybenzoyl chloride | C14H10Cl2O2 | 详情 | 详情 | |
| (XXVI) | 67887 | methyl 2-(chloromethyl)-4-phenoxybenzoate | C15H13ClO3 | 详情 | 详情 | |
| (XXVII) | 57744 | methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate | 2645-02-5 | C10H13NO4S | 详情 | 详情 |
| (XXVIII) | 67888 | methyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-4-phenoxybenzoate | C25H25NO7S | 详情 | 详情 | |
| (XXIX) | 67889 | methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C17H13NO4 | 详情 | 详情 | |
| (XXX) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (XXXI) | 67890 | methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C20H20N2O4 | 详情 | 详情 | |
| (XXXII) | 67891 | methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate | C20H17NO6 | 详情 | 详情 |