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Preparation 1Methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate To a suspension of methyl 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1 g, 5.43 mmol) in POCl3 (10 mL) was added 10 drops of N,N-dimethylaniline. The reaction mixture was heated at 105° C. for 6 h until it became a clear solution. It was then cooled, concentrated under reduced pressure, poured over ice, and extracted with EtOAc. The organic extract was washed with water and brine, dried and concentrated under reduced pressure to give the title compound as greenish-yellow solid (940 mg, 78percent). [M+H] calc'd for C7H6Cl2N2O2, 222. found, 221, 223.
70.2%
at 110℃; for 2 h;
Synthesis of compound 1.5. A solution of 1.4 (12.1 g, 0.06576 mol, 1.00 equiv) in phosphorusoxychloride (120ml) was heated at 110 °C for 2 hrs. After completion, reaction mixture was concentrated under reduced pressure and residue was quenched in ice. The crude product was extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by flash column chromatography This resulted in pure compound 1.5 (10.2g, 70.20percent>). MS (ES): m/z 222.8 [M+H]+
59%
at 95℃; for 3 h;
c) Synthesis of 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester 4-Methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.64 g, 3.48 mmol) is dissolved in phosphoryl chloride (6.5 ml) and to it is added tributylamine (1.75 ml). The resulting mixture is heated at 95° C. for 3 h. Excess phosphoryl chloride is distilled of and ice-water is added to the reaction mixture and extracted with EtOAc (3*30 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), evaporated to dryness to get the crude product, which is purified by column chromatography (silica gel, 5percent EtOAc/hexane) affording 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (0.45 g, 2.04 mmol, 59percent).
59%
at 95℃; for 3 h;
4-Methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.64 g, 3.48 mmol) is dissolved in phosphoryl chloride (6.5 ml) and to it is added tributylamine (1.75 ml). The resulting mixture is heated at 95 °C for 3 h. Excess phosphoryl chloride is distilled of and ice-water is added to the reaction mixture and extracted with EtOAc (3 x 30 ml). The combined organic layers are washed with water (30 ml), brine (30ml), evaporated to dryness to get the crude product, which is purified by column chromatography (silica gel, 5percent /hexane) affording 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (0.45 g, 2.04 mmol, 59percent).
With trichlorophosphate;N,N-dimethyl-aniline; at 105℃; for 6.0h;
Preparation 1Methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate To a suspension of <strong>[869891-41-8]methyl 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate</strong> (1 g, 5.43 mmol) in POCl3 (10 mL) was added 10 drops of N,N-dimethylaniline. The reaction mixture was heated at 105 C. for 6 h until it became a clear solution. It was then cooled, concentrated under reduced pressure, poured over ice, and extracted with EtOAc. The organic extract was washed with water and brine, dried and concentrated under reduced pressure to give the title compound as greenish-yellow solid (940 mg, 78%). [M+H] calc'd for C7H6Cl2N2O2, 222. found, 221, 223.
70.2%
With trichlorophosphate; at 110℃; for 2.0h;
Synthesis of compound 1.5. A solution of 1.4 (12.1 g, 0.06576 mol, 1.00 equiv) in phosphorusoxychloride (120ml) was heated at 110 C for 2 hrs. After completion, reaction mixture was concentrated under reduced pressure and residue was quenched in ice. The crude product was extracted twice with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by flash column chromatography This resulted in pure compound 1.5 (10.2g, 70.20%>). MS (ES): m/z 222.8 [M+H]+
59%
With tributyl-amine; trichlorophosphate; at 95℃; for 3.0h;
c) Synthesis of 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester 4-Methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.64 g, 3.48 mmol) is dissolved in phosphoryl chloride (6.5 ml) and to it is added tributylamine (1.75 ml). The resulting mixture is heated at 95 C. for 3 h. Excess phosphoryl chloride is distilled of and ice-water is added to the reaction mixture and extracted with EtOAc (3*30 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), evaporated to dryness to get the crude product, which is purified by column chromatography (silica gel, 5% EtOAc/hexane) affording 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (0.45 g, 2.04 mmol, 59%).
59%
With tributyl-amine; trichlorophosphate; at 95℃; for 3.0h;
4-Methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.64 g, 3.48 mmol) is dissolved in phosphoryl chloride (6.5 ml) and to it is added tributylamine (1.75 ml). The resulting mixture is heated at 95 C for 3 h. Excess phosphoryl chloride is distilled of and ice-water is added to the reaction mixture and extracted with EtOAc (3 x 30 ml). The combined organic layers are washed with water (30 ml), brine (30ml), evaporated to dryness to get the crude product, which is purified by column chromatography (silica gel, 5% /hexane) affording 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (0.45 g, 2.04 mmol, 59%).
With tributyl-amine; In trichlorophosphate; at 95℃; for 3.0h;
To a suspension of <strong>[869891-41-8]5-carboxy-6-methyluracil methyl ester</strong> (25.6 g, 139 mmol) in phosphorous oxychloride (250 mL) is added slowly with magnetic stirring tri-n-butylamine (70 mL). The reaction mixture is heated at 95 C for 3 h. The reaction mixture is cooled to room temperature, evaporated at reduced pressure and poured onto ice. The resulting residue is transferred to a separatory funnel and extracted with EtOAc (100 mL x 3). The combined organic layers are washed with water (50 mL x 3) and brine (50 mL), dried over magnesium sulfate, filtered through a plug of silica gel and evaporated at reduced pressure to obtain a dark brown residue. Purification by chromatography on silica gel (1:4 EtOAc/hexanes) affords the title compound. 'H NMR (CDCI3) No. = 4.00 (s, 3H), 2.59 (s, 3H).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 4h;
Synthesis of compound 1.6. To a solution of 1.5 (2.37 g, 0.01072 mol, 1.00 equiv), in acetonitrile (35 mL) was added diisopropylethylamine ( 3.81mL, 0.02144 mol, 2.0 equiv) and tert-butyl 2-(4-aminophenyl)acetate (2.0 g, .009648 mol, 0.9 equiv). The mixture was heated at 100 C for 4 hours. After completion, reaction mixture was concentrated under reduced pressure and triturated with water to obtain solids. The precipitate was collected and dried under reduced pressure to yield pure compound 1.6 (2.45g, 58.3%). MS (ES): m/z 392.14 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 1.5h;
Synthesis of compound 6.1. To a solution of 1.5 (5.0 g, 22.6mmol, 1.0 equiv), in acetonitrile (40 mL) was added diisopropylethylamine (12mL, 67.8mmol, 3.0 equiv) and tert- butyl 2-(4-aminophenyl) acetate (4.68 g, 22.6mmol, 1.0 equiv). The reaction mixture was heated to 100 C for 1.5 hours. After completion, the reaction was stopped and the solvent removed. The crude material was triturated with water to furnish compound 6.1 (8.5g, 95%). MS (ES): m/z 192.14 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 1.0h;
To a 100 ml flask were added methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (309 mg, 1.4 mmol), <strong>[1190380-49-4]1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-amine</strong> (234 mg, 1.4 mmol), 10 ml of acetonitrile and DIPEA (0.54 g, 4.18 mmol). The reaction mixture was stirred at 40 C. for 1 h, acetonitrile was evaporated under reduced pressure and then 30 ml of EtOAc was added. The mixture was washed with 60 ml of water and 30 ml of brine. The organic phase was dired and concentrated to give 405 mg of intermediate 7a as a grey solid. MS m/z (ESI): 352.1[M+H]+.
With N-ethyl-N,N-diisopropylamine In acetonitrile at 40℃; for 2h;
9a Preparation of Intermediate 9a
A solution of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (500 mg, 2.3 mmol), 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (350 mg, 2.3 mmol) and DIPEA (890 mg, 6.9 mmol) in acetonitrile (10 mL) was heated to 40° C. and stirred for 2 h. Water and ethyl acetate were added to the reaction solution and extracted. The organic phase was combined, concentrated and then purified by combiflash to give 400 mg of compound 9a. MS m/z (ESI): 340[M+H]+.
With potassium carbonate; In dimethyl sulfoxide; at 20.0℃; for 16.0h;
methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (110 mg, 0.5 mmol) and 4-(2-methoxy-ethoxy)-phenol (84 mg, 0.5 mmol) were dissolved in 3 ml of DMSO, and potassium carbonate (138 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, and extracted with ethyl acetate (2×20 ml). The organic phases were combined, washed with water (2×30 ml) and saturated saline (30 ml) successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a crude product which was purified by Combi-flash column chromatography [PE:EA=100:070:30] to give compound G-12-1 (160 mg, 55.6%). M+=353.0[M+1]+.
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