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With tin(II) chloride dihdyrate In ethyl acetate at 70℃; for 5 h; Sealed tube
A suspension of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv) and stannous chloride dihydrate (3.38 g, 14.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a 50-mL sealed tube was stirred for 5 hours at 70° C. The resulting solution was diluted with 50 mL of water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with 3*100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64percent) as a light yellow solid. LC-MS (ES, m/z): 236 [M+H]+.
64%
With tin(II) chloride dihdyrate In ethyl acetate at 70℃; for 5 h; Sealed tube
A suspension of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv)and stannous chloride dihydrate (3.38 g, i4.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a50-mL sealed tube was stirred for 5 hours at 70 °C. The resulting solution was diluted with 50 mLof water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with3x 100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64percent) as a light yellow solid. LC-MS (ES, mlz): 236 [M+H].
With palladium on activated charcoal; hydrogen; magnesium oxide; In tetrahydrofuran; for 7.0h;
4) 15 g of ethyl 2,4-dichloro-5-nitro-6-pyrimidinecarboxylic acid, 10 g of palladium on carbon, 5 g of magnesium oxide,Add 150 ml of THF, hydrogenate for 7 hours, filter, and apply with palladium and carbon recovery.The filtrate was evaporated to dryness to obtain a crude product. Column chromatography5.5 g of ethyl 2-chloro-5-amino-6-pyrimidinecarboxylic acid was obtained, more than 98%,The yield was 48%.
With hydrogen; magnesium oxide;5%-palladium/activated carbon; In 1,4-dioxane; at 20.0℃; under 2812.78 Torr; for 5.0h;
The product from step 2 (2.64 g) was HYDROGENATED at room temperature at a pressure of 3.75 bar hydrogen gas for 5 hours, in dioxane (180 ml) and in the presence of magnesium oxide (1.96 g) and 5% palladium on carbon (2.44 g). The reaction mixture was filtered through celite, washed with dioxane, ethyl acetate, and methanol. The solvents were combined and evaporated and the reaction mixture was purified by column chromatography on silica gel (40-60) eluting with ethyl acetate to give 5-amino-2-chloro-pyrimidine-4- carboxylic acid ethyl ester as a yellow solid (1. 38 g). IH NMR (CDCL3) 8 ppm : 1.45 (t, 3H), 4.5 (q, 2H), 5.75 (bs, 2H), 8.3 (s, LH).
With tin(II) chloride dihdyrate; In ethyl acetate; at 70.0℃; for 5.0h;Sealed tube;
A suspension of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv) and stannous chloride dihydrate (3.38 g, 14.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a 50-mL sealed tube was stirred for 5 hours at 70 C. The resulting solution was diluted with 50 mL of water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with 3*100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64%) as a light yellow solid. LC-MS (ES, m/z): 236 [M+H]+.
64%
With tin(II) chloride dihdyrate; In ethyl acetate; at 70.0℃; for 5.0h;Sealed tube;
A suspension of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv)and stannous chloride dihydrate (3.38 g, i4.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a50-mL sealed tube was stirred for 5 hours at 70 C. The resulting solution was diluted with 50 mLof water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with3x 100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64%) as a light yellow solid. LC-MS (ES, mlz): 236 [M+H].
ethyl 6-((2S,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)-2-chloro-5-nitropyrimidine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -60℃; for 1h;
28.1 Step 1: Synthesis of compound 28-3
To a cooled (-60 ) solution of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (6.21 g, 23.4 mmol, 1.0 eq. ) in anhydrous THF (40 mL) was added dropwise a solution of tert-butyl (3S, 5S) -3, 5-dimethylpiperazine-1-carboxylate (5.00 g, 23.4 mmol, 1.0 eq. ) and DIEA (4.52 g, 35.0 mmol, 1.5 eq. ) in anhydrous THF (30 mL) . The mixture was stirred at -60 for 1 h. TLC showed the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography eluting with Pet. ether /EtOAc (2: 1, v/v) to obtain ethyl 6- ( (2S, 6S) -4- (tert-butoxycarbonyl) -2, 6-dimethylpiperazin-1-yl) -2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 85%yield, 28-3)
85%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -60℃; for 1h;
28.1 Step 1: Synthesis of compound 28-3
To a cooled (-60 ) solution of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (6.21 g, 23.4 mmol, 1.0 eq. ) in anhydrous THF (40 mL) was added dropwise a solution of tert-butyl (3S, 5S) -3, 5-dimethylpiperazine-1-carboxylate (5.00 g, 23.4 mmol, 1.0 eq. ) and DIEA (4.52 g, 35.0 mmol, 1.5 eq. ) in anhydrous THF (30 mL) . The mixture was stirred at -60 for 1 h. TLC showed the reaction was completed. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography eluting with Pet. ether /EtOAc (2: 1, v/v) to obtain ethyl 6- ( (2S, 6S) -4- (tert-butoxycarbonyl) -2, 6-dimethylpiperazin-1-yl) -2-chloro-5-nitropyrimidine-4-carboxylate (8.80 g, 85%yield, 28-3)
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