Preparation method of 5-methoxy-4, 6-dihydroxypyrimidine

Abstract

The invention discloses a preparation method of 5-methoxy-4, 6-dihydroxypyrimidine, and relates to the technical field of production of 5-methoxy-4, 6-dihydroxypyrimidine. N, N-diethyl-2, 3, 3, 3-tetrafluoropropionamide is subjected to defluorination and methoxylation to obtain 2-methoxy-3-(diethylaminoformyl) ethyl propionate, and the 2-methoxy-3-(diethylaminoformyl) ethyl propionate is subjected to defluorination and methoxylation to obtain 2-methoxy-4, 6-dihydroxypyrimidine. According to the method, 2-methoxy-3-(diethylaminoformyl) ethyl propionate is cyclized to obtain the 5-methoxy-4, 6-dihydroxypyrimidine, the steps are simple, the production cost is low, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of 5-methoxy-4,6-dihydroxy pyrimidine production, in particular to a preparation method of 5-methoxy-4,6-dihydroxy pyrimidine. BACKGROUND

[0002] 5-methoxy-4,6-dihydroxy pyrimidine has a chemical formula of C5H6N2O3, a molecular weight of 142.11, and a CAS registration number of 5193-84-0. The substance is a light yellow solid, with a melting point of 341-345℃ and a density of 1.3-1.5g / cm3.

[0003] Chinese patent CN102432550A discloses a preparation method of a week sulfonamide and an intermediate thereof. In the method, methoxyacetic acid methyl ester is reacted with excess diethyl oxalate in the presence of sodium ethoxide to generate 3-methoxy-2-oxosuccinic acid methyl ester, and the 3-methoxy-2-oxosuccinic acid methyl ester is further decarboxylated to obtain 2-methoxy-malonic acid methyl ester, which is continuously reacted with formamide in the presence of sodium methoxide to generate 5-methoxy-4,6-dihydroxy pyrimidine. The method has many reaction steps, is not suitable for continuous production in industry, and has a high production cost. SUMMARY

[0004] The present application solves the technical problem of the prior art by providing a preparation method of 5-methoxy-4,6-dihydroxy pyrimidine, which has simple steps, a low production cost, and is suitable for industrial production.

[0005] To solve the above technical problems, the technical solution of the present application is as follows:

[0006] A preparation method of 5-methoxy-4,6-dihydroxy pyrimidine, comprising the following steps:

[0007] S1, defluoromethylation:

[0008] N,N-diethyl-2,3,3,3-tetrafluoropropionamide is defluoromethoxylated to obtain 2-methoxy-3-(diethylaminocarbonyl) ethyl propionate;

[0009] S2, cyclization:

[0010] 2-methoxy-3-(diethylaminocarbonyl) ethyl propionate is cyclized to obtain 5-methoxy-4,6-dihydroxy pyrimidine.

[0011] Preferably, in step S1, the catalyst is sodium methoxide, and the solvent is methanol, wherein the sodium methoxide is added in the form of a 30%wt sodium methoxide methanol solution.

[0012] Preferably, the molar ratio of N,N-diethyl-2,3,3,3-tetrafluoropropamide, sodium methoxide, and methanol is 1:4.0-6.0:10-20.

[0013] Preferably, the reaction temperature in step S1 is 80-100℃ and the reaction time is 5-10h.

[0014] Preferably, after the reaction in step S1 is completed, the temperature is lowered to room temperature, the liquid is filtered, calcium hydroxide is added and stirred for 1-3 hours, the mixture is filtered again after stirring, and the filtrate is concentrated under reduced pressure to obtain a white liquid ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, wherein the mass ratio of calcium hydroxide to N,N-diethyl-2,3,3,3-tetrafluoropropionamide is 0.5-0.6:1.

[0015] Preferably, in step S2, the cyclizing agent is formamide and the catalyst is sodium methoxide, wherein the sodium methoxide is added in the form of a 30% wt sodium methoxide methanol solution.

[0016] Preferably, the molar ratio of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, formamide, and sodium methoxide is 1:3.0-6.0:3.0-5.0, wherein the sodium methoxide is added in the form of a 30% wt sodium methoxide methanol solution.

[0017] Preferably, the reaction temperature in step S2 is 70℃-100℃, and the reaction time is 10-30h.

[0018] Preferably, after the reaction in step S2 is completed, methanol is distilled under reduced pressure. After distillation, purified water and hydrochloric acid are added to adjust the pH of the solution to 2-5, and the crude product 5-methoxy-4,6-dihydroxypyrimidine is obtained by filtration.

[0019] Preferably, the vacuum distillation conditions are 50-70℃ and ≤-0.085Mpa. After distillation, the remaining liquid is cooled to 10℃ and then purified water and hydrochloric acid are added. After stirring for 10 minutes, the mixture is filtered at 10℃.

[0020] Preferably, the mass ratio of purified water to sodium methoxide methanol solution is 0.6 to 0.9:1.

[0021] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0022] 1. This invention provides a method for using N,N-diethyl-2,3,3,3-tetrafluoropropionamide (NDFPA, a byproduct of florfenicol) as a raw material, obtaining ethyl 2-methoxy-3-(diethylcarbamoyl)propionate under the catalysis of sodium methoxide, and finally cyclizing it with formamide as a nitrogen source under the catalysis and deprotonation of sodium methoxide to obtain 5-methoxy-4,6-dihydroxypyrimidine. The innovation of this method lies in using NDFPA as a raw material, which enables waste value utilization, reduces raw material costs, and conforms to green chemistry principles. Furthermore, by eliminating the independent methoxylation step, the reaction process is simplified, and the burden of waste gas and waste liquid treatment is significantly reduced.

[0023] 2. This invention yields the cyclization intermediate 1,3-dicarbonyl compound via NDFPA. Formamide provides a nitrogen source and also acts as a high-boiling-point polar solvent, eliminating the need for additional solvents or additives. Subsequently, by adjusting the feeding sequence, cyclization is performed under specific sodium methoxide conditions to generate 5-methoxy-4,6-dihydroxypyrimidine. Formamide is also better preserved, and the reaction conditions are more suitable for industrial production. Furthermore, by utilizing the florfenicol byproduct NDFPA, the burden of subsequent waste treatment is reduced. Attached Figure Description

[0024] Figure 1 This is the liquid chromatogram of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate in Example 5 of the present invention;

[0025] Figure 2 This is a liquid chromatogram of 5-methoxy-4,6-dihydroxypyrimidine in Example 5 of the present invention. Detailed Implementation

[0026] The present invention will be further illustrated below with reference to the embodiments. Example 1

[0027] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 644.55 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 286.34 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 90 °C. When the temperature of the solution reached 90 °C, the temperature was kept at 80 °C for 5 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The solution was then filtered, and 90 g of calcium hydroxide was added to the filtrate and stirred for 1 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 124.18 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, with a reaction yield of 56.09% and a purity of 82.09%.

[0028] A mixture of 273.65 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 67.82 g of formamide, and 101.94 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 80℃, and the reaction temperature was maintained at 80℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 60℃ with a vacuum pump of -0.085 MPa. After distillation, 164 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 2. After stirring for 10 min, the solution was filtered at 10℃ to obtain 68.74 g of crude product. The cyclization reaction yield was 81.04%, and the purity of the crude product was 84.09%. Example 2

[0029] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 966.82 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 429.5 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 100 °C. When the temperature of the solution reached 100 °C, the temperature was kept at 80 °C for 10 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The solution was then filtered, and 108 g of calcium hydroxide was added to the filtrate and stirred for 3 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 124.85 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, with a reaction yield of 57.11% and a purity of 83.13%.

[0030] A mixture of 464.38 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 138.10 g of formamide, and 103.79 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 80℃, and the reaction temperature was maintained at 80℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 70℃ with a vacuum pump of -0.085 MPa. After distillation, 417.94 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 5. After stirring for 10 min, the solution was filtered at 10℃ to obtain 70.40 g of crude product. The cyclization reaction yield was 81.12%, and the purity of the crude product was 83.67%. Example 3

[0031] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0032] A mixture of 339.81 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 70℃, and the reaction temperature was maintained at 70℃ for 20 h. After the holding time, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 4. After stirring for 10 min, the solution was filtered at 10℃ to obtain 70.02 g of crude product. The cyclization reaction yield was 75.46%, and the purity of the crude product was 82.56%. Example 4

[0033] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0034] A mixture of 339.81 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 80℃, and the reaction temperature was maintained at 80℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 66.33 g of crude product. The cyclization reaction yield was 77.45%, and the purity of the crude product was 89.45%. Example 5

[0035] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the solution reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The solution was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the solution was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate with a purity of 80.34% (0.1386 g was taken and diluted to 25 ml). A 50% acetonitrile aqueous solution was used, and the measured peak area was 74534.9. Substituting this into the standard curve formula y=16663x+320.29, the external standard content was found to be 80.34%.

[0036] A mixed solution of sodium methoxide in methanol (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 hours. After the holding time, methanol was distilled under reduced pressure at 50℃ with a vacuum pump pressure of -0.085 MPa. The distillation was completed at 10℃. 275g of purified water was added at ℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 74.57g of crude product. The cyclization reaction yield was 81.21%, and the purity of the crude product was 83.44% (0.0952g of sample was taken and diluted to 100ml of purified water, and the peak area of ​​the liquid phase was measured to be 11226. Substituting this into the standard curve formula y=13118x+806.15, the external standard content was found to be 83.44%). Example 6

[0037] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0038] A mixed solution of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), formamide, and ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 100℃, and the reaction temperature was maintained at 100℃ for 20 hours. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 minutes, the solution was filtered at 10℃ to obtain 74.23 g of crude product. The cyclization reaction yield was 79.44%, and the purity of the crude product was 81.99%. Example 7

[0039] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0040] A mixed solution of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 10 h. After the holding time, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 74.30 g of crude product. The cyclization reaction yield was 80.07%, and the purity of the crude product was 82.56%. Example 8

[0041] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0042] A mixture of 339.81 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 30 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 75.77 g of crude product. The cyclization reaction yield was 80.66%, and the purity of the crude product was 81.56%. Example 9

[0043] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0044] A mixed solution of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 97.13 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After the distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 74.57 g of crude product. The cyclization reaction yield was 80.14%, and the purity of the crude product was 82.34%. Example 10

[0045] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0046] A mixture of 339.81 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 121.42 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 71.70 g of crude product. The cyclization reaction yield was 79.34%, and the purity of the crude product was 84.78%. Example 11

[0047] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0048] A mixture of 339.81 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 145.70 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 72.95 g of crude product. The cyclization reaction yield was 79.01%, and the purity of the crude product was 82.98%. Example 12

[0049] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0050] A mixture of 320.39 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 h. After the holding time, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 71.12 g of crude product. The cyclization reaction yield was 79.84%, and the purity of the crude product was 86.01%. Example 13

[0051] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0052] A mixture of 349.52 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90℃, and the reaction temperature was maintained at 90℃ for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50℃ with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10℃, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10℃ to obtain 76.37 g of crude product. The cyclization reaction yield was 78.09%, and the purity of the crude product was 78.34%. Example 14

[0053] 180 g of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, 725.12 g of sodium methoxide methanol solution (sodium methoxide in the methanol solution has a mass fraction of 30% wt), and 573.43 g of methanol were added to a four-necked flask. The mixture was stirred for 30 min, and a water bath was set to 80 °C. When the temperature of the liquid reached 80 °C, the temperature was kept at 80 °C for 7 h. After the temperature was kept at 80 °C, the mixture was allowed to cool naturally to room temperature. The liquid was then filtered, and 100 g of calcium hydroxide was added to the filtrate and stirred for 2 h. After stirring, the mixture was filtered again. The filtrate was concentrated under reduced pressure to obtain 136.30 g of crude ethyl 2-methoxy-3-(diethylcarbamoyl)propionate.

[0054] A mixture of 291.27 g of sodium methoxide methanol solution (sodium methoxide mass fraction of 30% wt), 72.85 g of formamide, and 109.5 g of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was added to a four-necked flask. The water bath was set to 90 °C, and the reaction temperature was maintained at 90 °C for 20 h. After the maintenance, methanol was distilled under reduced pressure at 50 °C with a vacuum pump of -0.085 MPa. After distillation, 275 g of purified water was added at 10 °C, and hydrochloric acid was added to adjust the pH of the solution to 3. After stirring for 10 min, the solution was filtered at 10 °C to obtain 64.04 g of crude product. The cyclization reaction yield was 76.31%, and the purity of the crude product was 91.29%.

[0055] It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing 5-methoxy-4,6-dihydroxypyrimidine, characterized in that... Includes the following steps: S1, Defluorination methylation: N,N-Diethyl-2,3,3,3-tetrafluoropropionamide was defluorinated and methoxylated to give ethyl 2-methoxy-3-(diethylcarbamoyl)propionate; S2, cyclic closure: Ethyl 2-methoxy-3-(diethylcarbamoyl)propionate was cyclized to give 5-methoxy-4,6-dihydroxypyrimidine.

2. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: In step S1, the catalyst is sodium methoxide and the solvent is methanol.

3. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 2, characterized in that: The molar ratio of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, sodium methoxide, and methanol is 1:4.0–6.0:10–20.

4. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: In step S1, the reaction temperature is 80-100℃ and the reaction time is 5-10h.

5. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: After the reaction in step S1 is completed, the temperature is lowered to room temperature. The solution is filtered and calcium hydroxide is added and stirred for 1-3 hours. After stirring, the solution is filtered again. The filtrate is concentrated under reduced pressure to obtain a white liquid, ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, wherein the mass ratio of calcium hydroxide to N,N-diethyl-2,3,3,3-tetrafluoropropionamide is 0.5-0.6:

1.

6. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: In step S2, the cyclizing agent is formamide and the catalyst is sodium methoxide.

7. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 6, characterized in that: The molar ratio of ethyl 2-methoxy-3-(diethylcarbamoyl)propionate, formamide, and sodium methoxide is 1:3.0–6.0:3.0–5.

0.

8. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: The reaction temperature in step S2 is 70℃-100℃, and the reaction time is 10-30h.

9. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: After the reaction in step S2 is completed, methanol is distilled under reduced pressure. After distillation, purified water and hydrochloric acid are added to adjust the pH of the solution to 2-5. The crude product 5-methoxy-4,6-dihydroxypyrimidine is obtained by filtration.

10. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 9, characterized in that: The vacuum distillation conditions are 50-70℃ and ≤-0.085Mpa. After distillation, the remaining liquid is cooled to 10℃ and then purified water and hydrochloric acid are added. After stirring for 10 minutes, the mixture is filtered at 10℃.

Images