| 4.23 g (79%) |
With sodium hydroxide; triphenylphosphine; In tetrahydrofuran; MeOH-benzene; dichloromethane; water; ethyl acetate; N,N-dimethyl-formamide; |
Example 27 4-[1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-nitrobenzoic Acid To a stirred solution of <strong>[616-82-0]4-hydroxy-3-nitrobenzoic acid</strong> (3.00 g, 0.0164 mol) in MeOH-benzene (1:4, v/v) was added dropwise 2.0 M-hexane solution of TMSCHN2 (8.2 mL, 0.0164 mol) at room temp. After the resulting solution was stirred for 4 hr at room temp, the mixture was evaporated off in vacuo. The oily residue was chromatographed on silica-gel with CHCl3 as eluent to afford 4.23 g (79%) methyl 4-hydroxy-3-nitrobenzoate as a pale yellow crystalline material. To a stirred mixture of N-tert-butoxycarbonylprolinol (1.02 g, 5.07 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol), and Ph3P (1.46 g, 5.58 mmol) in THF (10ML) was added dropwise diisopropyl azodicarboxylate (DIAD) (95%) (1.16 mL, 5.58 mmol) at 0 C. The resulting mixture was heated under reflux for 46 hr. After cooling, the mixture was evaporated off in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and added THA (10 mL). After the solution was stirred for 0.5 hr at room temp, the solution was evaporated in vacuo. Water was added to the residue and washed with EtOAc. The aqueous layer was neutralized by the addition of sat. NaHCO3 and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated in vacuo to afford 0.698 g (49%) methyl 3-nitro-4-(2-pyrrolidinylmethoxy) benzoate as a gum. A mixture of methyl 3-nitro-4-(2-pyrrolidinylmethoxy)benzoate (0.668 g, 2.38 mmol), 3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetic acid (1.12 g, 3.57 mmol), 1-hydroxybenzo triazole (HOBt) (0.482 g, 3.57 mmol), 4-dimethylaminopyridine(DMAP) (43.6 mg, 0.357 mmol), and 1-ethyl-33dimethylaminopropyl)carbodiimide (EDC) (0.684 g, 3.57 mmol) in DMF (10 mL) was stirred for 15 hr at room temp. EtOAc was added to the mixture and washed successively with 1 N HCl, sat. NaHCO3, and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed on silica-gel with EtOH-CHCl3 (1:20, v/v) as eluent to afford 0.927 g (68%) methyl 4-[1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacethyl]-2-pyrrolidinylmethoxy]-3-nitrobenzoate as a yellow crystalline material. A mixture of methyl 4-[1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacethyl]-2-pyrrolidinylmethoxy]-3-3-nitrobenzoate (0.917 g, 1.59 mmol) in THF (10 mL) and 1 N NaOH (2.38 mL, 2.38 mmol) was heated under reflux for 2 hr. After cooling, the mixture was poured into ice water and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated in vacuo to afford 0.826 g (92%) 31 as a yellow crystalline solid. 1H-NMR (400 MHz, CDCl3) delta 1.91, 2.09 (11, 3H, each m), 2.28 (3H, s), 3.54-3.62 (4H, m), 3.64 (3H, s), 4.15, 4.59 (each 1H, each d, J=7.8 Hz), 4.46 (1H, m), 6.66, 7.22 (each 1H, each s), 6.72 (1H, d, J=8.3 Hz), 7.11-7.28 (4H, m), 7.46 (1H, d, J=7.8 Hz), 7.74 (1H, d, J=7.8 Hz), 7.85 (11 s), 8.17 (1H, dd, J=2.0, 8.8 Hz), 8.48 (1H, d, J=2.4 Hz); MS (FAB) m/z 563 (M++1). |
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