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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 triethylamine In water at 50 - 60℃; for 21 h;
b) Synthesis of 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester A mixture of 3-amino-2-(ethoxycarbonyl-carbamoyl)-but-2-enoic acid methyl ester (0.71 g, 3.08 mmol) and triethylamine (30percent aqueous solution, 0.56 ml) is stirred at 50° C. for 18 h. Another portion of triethylamine (30percent aqueous solution, 0.14 ml) is added and the reaction mixture is further at 60° C. for 3 h. The reaction mixture is evaporated and then acidified with AcOH. The resulting solid is collected by filtration and dried under vacuum to get 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.33 g, 1.79 mmol, 58percent), which is directly used for the next step.
58%
With triethylamine In water at 50 - 60℃; for 21 h;
A mixture of 3-amino-2-(ethoxycarbonyl-carbamoyl)-but-2-enoic acid methyl ester (0.71 g, 3.08 mmol)and triethylamine (30 percent aqueous solution, 0.56 ml) is stirred at 50 °C for 18 h. Another portion of triethylamine (30 percent aqueous solution, 0.14 ml) is added and the reaction mixture is further at 60° for 3h. The reaction mixture is evaporated and then acidified with AcOH. The resulting solid is collected by filtration and dried under vacuum to get 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.33 g, 1.79 mmol, 58percent), which is directly used for the next step.
3-amino-2-ethoxycarbonylaminocarbonyl-but-2-enoic acid methyl ester[ No CAS ]
[ 869891-41-8 ]
Yield
Reaction Conditions
Operation in experiment
With trimethylamine; In water; at 50 - 60℃; for 21.0h;
A suspension of 3-amino-2-ethoxycarbonylaminocarbonyl-but-2-enoic acid methyl ester (59 g, 0.26 mol) in 25% aqueous trimethylamine (400 mL) is stirred at 50 C for 18 h. Another 100 mL of 25% aqueous trimethylamine is added and the reaction mixture is heated at 60 C for 3h to form a homogeneous yellow solution. The reaction mixture is evaporated at reduced pressure to remove most of the trimethylamine and then acidified with HOAc. The resulting white solid is collected by suction filtration and dried under vacuum at 60 C to afford the title compound. ¹H NMR (CDC13) No. = 3.92 (br s, 2H), 3.71 (s, 3H), 2.22 (s, 3H).
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 triethylamine; In water; at 50 - 60℃; for 21.0h;
b) Synthesis of 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester A mixture of 3-amino-2-(ethoxycarbonyl-carbamoyl)-but-2-enoic acid methyl ester (0.71 g, 3.08 mmol) and triethylamine (30% aqueous solution, 0.56 ml) is stirred at 50 C. for 18 h. Another portion of triethylamine (30% aqueous solution, 0.14 ml) is added and the reaction mixture is further at 60 C. for 3 h. The reaction mixture is evaporated and then acidified with AcOH. The resulting solid is collected by filtration and dried under vacuum to get 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.33 g, 1.79 mmol, 58%), which is directly used for the next step.
58%
With triethylamine; In water; at 50 - 60℃; for 21.0h;
A mixture of 3-amino-2-(ethoxycarbonyl-carbamoyl)-but-2-enoic acid methyl ester (0.71 g, 3.08 mmol)and triethylamine (30 % aqueous solution, 0.56 ml) is stirred at 50 C for 18 h. Another portion of triethylamine (30 % aqueous solution, 0.14 ml) is added and the reaction mixture is further at 60 for 3h. The reaction mixture is evaporated and then acidified with AcOH. The resulting solid is collected by filtration and dried under vacuum to get 4-methyl-2,6-dioxo-3H-pyrimidine-5-carboxylic acid methyl ester (0.33 g, 1.79 mmol, 58%), which is directly used for the next step.
Synthesis of compound 1.4 A solution of 1.3 (16 g, 0.06956 mol, 1.00 equiv) in 25% triethylamine (105 mL) was heated at 70 C until starting material was consumed. Subsequently, the reaction was stopped and the mixture was acidified with acetic acid. The solid white crystals were filtered off and dried under vacuum to provide pure compound 1.4 (12. lg, 94.53%>). MS (ES) m/z 185.21 [M+H]+.
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