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With triethylamine; In dichloromethane; |
Step D Preparation of Methyl 3-(t-butyloxycarbonyl)aminomethyl benzoate To a solution of the product from Step C (1.14 g) in methylene chloride (50 mL) was added triethylamine (2.90 mL) and di-tert-butyl dicarbonate (1.67 g) and the mixture was stirred 16 h. The solution was partitioned with water and methylene chloride. The methylene chloride layer was washed with saturated sodium hydrogen carbonate, 2% potassium hydrogen sulfate and saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to yield 1.71 g of the crude product. Chromotography on silica gel with hexane/ethyl acetate 9/1 yielded the title compound. 1 H-NMR (300 MHz, CDCl3)delta7.95 (1H, s), 7.93 (1H, d, J=8 Hz), 7.49 (1H, d, J=8 Hz), 7.41 (1H, t, J=8 Hz), 4.90 (1H, b), 4.37 (2H, d, J=6 Hz), 3.92 (3H, s), 1.45 (9H, s). |
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In dichloromethane; at 0 - 20℃; for 72h; |
Methyl 3-methylbenzoate (1.00 g) was dissolved in carbon tetrachloride (10 ml). N-Bromosuccinic imide (1.22 g) and 2,2-azobisisobutyronitrile (catalytic amount) were added to the resulting solution. The resulting mixture was heated under reflux for 1 hour under exposure to a mercury lamp. After the insoluble matter was filtered off, a residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate = 20:1) on a silica gel column, whereby a colorless oil (1.34 g) was obtained. The colorless oil thus obtained (0.62 g) was dissolved in N,N-dimethylformamide (10 ml). Sodium azide (0.38 g) was added and the resulting mixture was stirred at room temperature for 20 hours. After the reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (15 ml). Triphenylphosphine (0.75 g) was added to the resulting solution, followed by stirring for 5 hours at an external temperature of about 50C. About 28% aqueous ammonia (7 ml) was added and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, followed by extraction with ether. The extract was acidified with dilute hydrochloric acid. To the aqueous layer thus separated, a dilute aqueous solution of sodium hydroxide was added to make it alkaline, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in dichloromethane (7 ml). Under ice cooling, di-tert-butyl dicarbonate (0.45 g) was added and the resulting mixture was stirred at room temperature for 3 days. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography (hexane:ethyl acetate = 5:1) on a silica gel column, whereby the title compound (0.29 g, 35%) was obtained.1H-NMR(CDCl3) delta: 1.46(9H,s), 3.91(3H,s), 4.36(2H,d,J=5.9Hz), 4.97(1H, br), 7.40(1H, t, J=7.8Hz), 7.49(1H, d, J=7.8Hz), 7.90-8.00(2H, m). MS (FAB)m/z: 266(M+H)+. |
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