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【结 构 式】

【分子编号】67891

【品名】methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

【CA登记号】 

【 分 子 式 】C20H17NO6

【 分 子 量 】367.35812

【元素组成】C 65.39% H 4.66% N 3.81% O 26.13%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXXII)

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
Extended Information