* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
To a solution of POCl3(10.42 mL 122 mmol) and DIEA (33 mL 189 mmol) stirred under N2at 20 was added ethyl 4 6-dimethyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate (2.4 g 12.23 mmol) slowly. The reaction mixture was stirred at 80 for 2 hr. Then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over Na2SO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 Rf 0.7) were combined and concentrated to yield yellow oil of ethyl 2-chloro-4 6-dimethylpyrimidine-5-carboxylate (1.6 g 7.45 mmol 60.9yield) 1HNMR(400 MHz CDCl3) δ4.43 (q J 6.8 Hz 2H) 2.54 (s 6H) 1.40 (t J 7.1 Hz 3H) ES-LCMS m/z 215.1 (M+H) .
30%
at 105℃; for 3 h;
3. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate Into a 100-mL round-bottom flask, was placed a solution of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (300 mg, 1.53 mmol, 1.00 equiv) in phosphoroyl trichloride (10 mL), N,N-Diethylaniline (0.1 mL, 0.10 equiv). The resulting solution was stirred for 3 hours at 105° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 100 mg (30percent) of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate as a yellow solid. m/z: 214.85[MH+], tR=0.842 min (1.90 minute run).
Reference：
[1] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 213; 214
[2] Patent: US2018/99940, 2018, A1, . Location in patent: Paragraph 0563
[3] European Journal of Medicinal Chemistry, 2012, vol. 52, p. 82 - 97
[4] European Journal of Medicinal Chemistry, 2015, vol. 100, # 1, p. 1 - 9
[5] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 266 - 273
2
[ 168130-75-4 ]
[ 108381-23-3 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With N-benzyl-N,N,N-triethylammonium chloride; <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In acetonitrile for 5 h; reflux Stage #2: With sodium hydrogencarbonate In water; acetonitrile
Step 2. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate, 6b Phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 6a (1.47 g, 7.5 mmol), benzyltriethylammonium chloride (1.71 g, 7.5 mmol) and N,N-dimethylaniline (1.82 g, 15 mmol) in acetonitrile (30 ml). The mixture was reflux for 5 hours. The mixture was poured into ice water and neutralized with NaHCO3. The solution was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, concentrated and chromatographed to obtain 6b, (1.02 g, 4.75 mmol, 63percent).
39%
at 110℃; for 2 h;
To a solution of POCI3 (106ml) and DIEA (65ml) was added 4,6-dimethyl-2-hydroxy-pyrimi- dine-5-carboxylic acid ethyl ester (21.9mg, 111.6mmol). The mixture was heated to 110°C for 2h. Excess POCI3 and DIEA were removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (1.21) and treated with decolorizing carbon. After filtration, the solution was washed with IN NaOH, water and brine. The organic layer was dried over Na2S04. filtered and concentrated. The crude residue was purified by flash chromatography with a 0-30percent EtOAc in hexane gradient to afford the desired product (9.33g, 39percent yield).
39%
at 110℃; for 2 h;
Preparation of 2-Chloro-4,6-dimethyl-pyrimidine-5-carboxylic acid ethyl ester To a solution of POCl3 (106 ml) and DIEA (65 ml) was added 4,6-dimethyl-2-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (21.9 mg, 111.6 mmol). The mixture was heated to 110° C. for 2 h. Excess POCl3 and DIEA were removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (1.21) and treated with decolorizing carbon. After filtration, the solution was washed with 1N NaOH, water and brine. The organic layer was dried over Na2SO4. filtered and concentrated. The crude residue was purified by flash chromatography with a 0-30percent EtOAc in hexane gradient to afford the desired product (9.33 g, 39percent yield).
6.1
Step 1. Synthesis of ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate. 6a A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to -20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%).
Step 2. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate, 6b Phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 6a (1.47 g, 7.5 mmol), benzyltriethylammonium chloride (1.71 g, 7.5 mmol) and N,N-dimethylaniline (1.82 g, 15 mmol) in acetonitrile (30 ml). The mixture was reflux for 5 hours. The mixture was poured into ice water and neutralized with NaHCO3. The solution was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, concentrated and chromatographed to obtain 6b, (1.02 g, 4.75 mmol, 63%).
39%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 110℃; for 2.0h;
To a solution of POCI3 (106ml) and DIEA (65ml) was added 4,6-dimethyl-2-hydroxy-pyrimi- dine-5-carboxylic acid ethyl ester (21.9mg, 111.6mmol). The mixture was heated to 110C for 2h. Excess POCI3 and DIEA were removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (1.21) and treated with decolorizing carbon. After filtration, the solution was washed with IN NaOH, water and brine. The organic layer was dried over Na2S04. filtered and concentrated. The crude residue was purified by flash chromatography with a 0-30% EtOAc in hexane gradient to afford the desired product (9.33g, 39% yield).
39%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 110℃; for 2.0h;
Preparation of 2-Chloro-4,6-dimethyl-pyrimidine-5-carboxylic acid ethyl ester To a solution of POCl3 (106 ml) and DIEA (65 ml) was added 4,6-dimethyl-2-hydroxy-pyrimidine-5-carboxylic acid ethyl ester (21.9 mg, 111.6 mmol). The mixture was heated to 110 C. for 2 h. Excess POCl3 and DIEA were removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (1.21) and treated with decolorizing carbon. After filtration, the solution was washed with 1N NaOH, water and brine. The organic layer was dried over Na2SO4. filtered and concentrated. The crude residue was purified by flash chromatography with a 0-30% EtOAc in hexane gradient to afford the desired product (9.33 g, 39% yield).
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 80℃; for 2.0h;Inert atmosphere;
To a solution of POCl3(10.42 mL 122 mmol) and DIEA (33 mL 189 mmol) stirred under N2at 20 was added ethyl 4 6-dimethyl-2-oxo-1 2-dihydropyrimidine-5-carboxylate (2.4 g 12.23 mmol) slowly. The reaction mixture was stirred at 80 for 2 hr. Then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over Na2SO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 101) . All fractions found to contain product by TLC (PE/EA 101 Rf 0.7) were combined and concentrated to yield yellow oil of ethyl 2-chloro-4 6-dimethylpyrimidine-5-carboxylate (1.6 g 7.45 mmol 60.9yield) 1HNMR(400 MHz CDCl3) delta4.43 (q J 6.8 Hz 2H) 2.54 (s 6H) 1.40 (t J 7.1 Hz 3H) ES-LCMS m/z 215.1 (M+H) .
30%
With N,N-diethylaniline; trichlorophosphate; at 105℃; for 3.0h;
3. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate Into a 100-mL round-bottom flask, was placed a solution of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (300 mg, 1.53 mmol, 1.00 equiv) in phosphoroyl trichloride (10 mL), N,N-Diethylaniline (0.1 mL, 0.10 equiv). The resulting solution was stirred for 3 hours at 105 C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 100 mg (30%) of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate as a yellow solid. m/z: 214.85[MH+], tR=0.842 min (1.90 minute run).
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