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With iron; ammonium chloride; In ethanol; water; at 90℃; for 1h;
To a stirred solution of 567 tert-butyl 4-(2-cyano-4-nitrophenyl)piperazine-1-carboxylate (2.0 g, 6.021 mmol, 1.0 eq) in 6 EtOH (30 mL) was added Fe(0) (1.0 g, 18.064 mmol, 3 eq) and a solution of 67 NH4Cl (644 mg, 12.042 mmol, 2 eq) in 7 water (30 mL) at rt. The resulting mixture was heated at 90 C. for 1 hr. The progress of reaction was monitored by LCMS. The reaction mixture was filtered through celite the residue was washed with EtOH (50 mL). The filtrate was concentrated and the residue was dissolved in 19 EtOAc (100 mL), washed with water (2×100 mL), dried over Na2SO4, and concentrated to afford the desired compound, 570 tert-butyl 4-(4-amino-2-cyanophenyl)piperazine-1-carboxylate (1.77 g, 88.5%). (0598) LCMS: 303.2 [M+1]+
With ammonium chloride; zinc; In methanol; for 3h;
4-(2-Cyano-4-nitro-phenyl)-piperazine-l -carboxylic acid tert-butyl ester (587 mg, 1.77 mmol) was dissolved in methanol (50 mL) and to this solution was added ammonium chloride (945 mg, 17.66 mmol) and zinc (1155 mg, 17.66 mmol). The mixture was <n="65"/>magnetically stirred for 3 hr and the mixture was filtered through a pad of celite. The solids were rinsed with methanol and the combined filtrate was concentrated to a yellow solid. This crude intermediate was dissolved in ethyl acetate (400 mL) and the resulting solution was washed with water (400 mL) and brine (200 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to give 4-(4-amino-2-cyano- phenyl)-piperazine-l-carboxylic acid tert-butyl ester that was used in the next step without further purification.
2-phenyl-5-(trifluoromethyl)oxazole-4-carboxylic acid[ No CAS ]
[ 288251-85-4 ]
[ 1085841-86-6 ]
Yield
Reaction Conditions
Operation in experiment
25%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20 - 50℃; for 90h;
Crude 4-(4-amino-2-cyano-phenyl)-piperazine-l-carboxylic acid tert-butyl ester from above was dissolved in methylene chloride (10 mL) and to the resulting solution was added 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (454 mg), triethylamine(247 muL) and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI,337 mg). The reaction mixture was stirred at room temperature for 3 hr. Another portion of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.5 eq) was added. The reaction mixture was stirred at 500C for 3 hr and at room temperature for 3.5 days.The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography afforded 4- {2-cyano-4-[(2-phenyl-5-trifluoromethyl-oxazole-4- carbonyl)-amino]-phenyl}-piperazine-l-carboxylic acid tert-butyl ester (240 mg, 25 % yield) as a yellow solid. LCMS calcd for C27H26F3N5O4 (m/e) 541, obsd 542 (M+H).
3-(2,6-dichlorophenyl)-7-methylsulfanyl-2H-pyrimido[5,4-e][1,3]oxazin-4-one[ No CAS ]
tert-butyl 4-(2-cyano-4-((3-(2,6-dichlorophenyl)-4-oxo-3,4-dihydro-2H-pyrimido[5,4-e][1,3]oxazin-7-yl)amino)phenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.68%
To a stirred solution of 21 3-(2,6-dichlorophenyl)-7-(methylthio)-2,3-dihydro-4H-pyrimido[5,4-e][1,3]oxazin-4-one (300 mg, 0.8767 mmol, 1.0 eq) in (10.0 mL) of 24 toluene was added 25 m-CPBA (376 mg, 2.1917 mmol, 2.5 eq) and allowed to stir at rt for 30 min followed by addition of 570 <strong>[288251-85-4]tert-butyl 4-(4-amino-2-cyanophenyl)piperazine-1-carboxylate</strong> (265 mg, 0.8767 mmol, 1 eq) and 27 DIPEA (452 mg, 3.506 mmol, 4.0 eq) and allowed to stir at rt for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, concentrated and purified by flash chromatography (elution 0-35% 19 EtOAc in 20 Hexane) to afford the desired compound, 573 tert-butyl 4-(2-cyano-4-((3-(2,6-dichlorophenyl)-4-oxo-3,4-dihydro-2H-pyrimido[5,4-e][1,3]oxazin-7-yl)amino)phenyl)piperazine-1-carboxylate (150 mg, 28.68%) as an off white solid. (0600) LCMS: 596.2 [M+1]+
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