CN121494792B - A method for preparing 5-methoxy-4,6-dihydroxypyrimidine - Google Patents

A method for preparing 5-methoxy-4,6-dihydroxypyrimidine

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CN121494792B
CN121494792B CN202610046096.8A CN202610046096A CN121494792B CN 121494792 B CN121494792 B CN 121494792B CN 202610046096 A CN202610046096 A CN 202610046096A CN 121494792 B CN121494792 B CN 121494792B
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methoxy
sodium methoxide
stirring
dihydroxypyrimidine
finished
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CN121494792A (en
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吴青华
杨阳
赵肖泽
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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Guobang Pharmaceutical Group Co Ltd
Shandong Guobang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of 5-methoxy-4, 6-dihydroxypyrimidine, which relates to the technical field of 5-methoxy-4, 6-dihydroxypyrimidine production, and is characterized in that N, N-diethyl-2, 3-tetrafluoropropionamide is subjected to defluorination and methoxylation to obtain 2-methoxy-3- (diethylaminoformyl) methyl propionate, and the 2-methoxy-3- (diethylaminoformyl) methyl propionate is subjected to cyclization to obtain 5-methoxy-4, 6-dihydroxypyrimidine, so that the preparation method is simple in step, low in production cost and suitable for industrial production.

Description

Preparation method of 5-methoxy-4, 6-dihydroxypyrimidine
Technical Field
The invention relates to the technical field of 5-methoxy-4, 6-dihydroxypyrimidine production, in particular to a preparation method of 5-methoxy-4, 6-dihydroxypyrimidine.
Background
The chemical formula of the 5-methoxy-4, 6-dihydroxypyrimidine is C 5H6N2O3, the molecular weight is 142.11, and the CAS registry number is 5193-84-0. The material is a pale yellow solid, the melting point is 341-345 ℃, and the density is 1.3-1.5 g/cm < 3 >.
Chinese patent CN102432550A discloses a preparation method of sulfanilamide and an intermediate thereof, wherein methoxyacetic acid methyl ester and excessive diethyl oxalate are used for reacting in the presence of sodium ethoxide to generate 3-methoxy-2-oxo succinic acid methyl ethyl ester, and 3-methoxy-2-oxo succinic acid methyl ethyl ester is further decarbonylated to obtain 2-methoxy-malonic acid methyl ethyl ester, and the 2-methoxy-malonic acid methyl ethyl ester is continuously reacted with formamide in the presence of sodium methoxide to generate 5-methoxy-4, 6-dihydroxypyrimidine.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the preparation method of the 5-methoxy-4, 6-dihydroxypyrimidine, which has the advantages of simple steps and low production cost, and is suitable for industrial production.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for preparing 5-methoxy-4, 6-dihydroxypyrimidine, which comprises the following steps:
s1, defluorination and methoxylation:
Defluorinated and methoxylated N, N-diethyl-2, 3-tetrafluoropropionamide to obtain 2-methoxy-3- (diethylaminoformyl) methyl propionate;
s2, cyclization:
Cyclizing the methyl 2-methoxy-3- (diethylcarbamoyl) propionate to obtain 5-methoxy-4, 6-dihydroxypyrimidine.
Preferably, the catalyst in step S1 is sodium methoxide and the solvent is methanol, wherein sodium methoxide is added in the form of 30% wt sodium methoxide in methanol.
Preferably, the molar ratio of the N, N-diethyl-2, 3-tetrafluoropropionamide, sodium methoxide and methanol is 1:4.0-6.0:10-20.
Preferably, the reaction temperature in the step S1 is 80-100 ℃ and the reaction time is 5-10h.
Preferably, after the reaction in the step S1 is finished, cooling to room temperature, filtering the feed liquid, adding calcium hydroxide, stirring for 1-3h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain white liquid methyl 2-methoxy-3- (diethylcarbamoyl) propionate, wherein the mass ratio of the calcium hydroxide to the N, N-diethyl-2, 3-tetrafluoropropionamide is 0.5-0.6:1.
Preferably, the cyclizing reagent in step S2 is formamide and the catalyst is sodium methoxide, wherein sodium methoxide is added in the form of 30% by weight of sodium methoxide in methanol.
Preferably, the molar ratio of the methyl 2-methoxy-3- (diethylcarbamoyl) propionate, the formamide and the sodium methoxide is 1:3.0-6.0:3.0-5.0, wherein the sodium methoxide is added in the form of 30% wt of sodium methoxide methanol solution.
Preferably, the reaction temperature in step S2 is 70-100℃and the reaction time is 10-30 hours.
Preferably, the methanol is distilled under reduced pressure after the reaction in the step S2 is finished, purified water and hydrochloric acid are added to adjust the pH value of the feed liquid to 2-5 after the distillation is finished, and crude 5-methoxy-4, 6-dihydroxypyrimidine is obtained through suction filtration.
Preferably, the reduced pressure distillation condition is 50-70 ℃ and less than or equal to-0.085 Mpa, the residual feed liquid is cooled to 10 ℃ after the distillation is finished, then purified water and hydrochloric acid are added, and the filtration is carried out under the condition of 10 ℃ after stirring for 10 min.
Preferably, the mass ratio of the purified water to the sodium methoxide methanol solution is 0.6-0.9:1.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. The invention provides a method for preparing 5-methoxy-4, 6-dihydroxypyrimidine by taking N, N-diethyl-2, 3-tetrafluoropropionamide (florfenicol byproduct NDFPA) as a raw material, obtaining 2-methoxy-3- (diethylcarbamoyl) methyl propionate under the catalysis of sodium methoxide, and finally cyclizing under the catalysis and deprotonation of sodium methoxide by taking formamide as a nitrogen source. The method is innovative in that NDFPA is used as a raw material, waste value can be realized, raw material cost is reduced, and the method accords with the green chemistry principle. In addition, after the independent methoxylation step is omitted, the reaction flow is simplified, and the treatment burden of waste gas and waste liquid is obviously reduced.
2. The cyclized intermediate 1, 3-dicarbonyl compound is obtained through NDFPA, and the formamide can serve as a high-boiling-point polar solvent while providing a nitrogen source, and does not need to additionally add other solvents or auxiliary agents. The subsequent cyclization is carried out under the condition of sodium methoxide with a certain proportion by adjusting the feeding sequence to generate 5-methoxy-4, 6-dihydroxypyrimidine, and the formamide can be better preserved, and the reaction condition is more suitable for industrial production. In addition, the florfenicol byproduct NDFPA is recycled, so that the pressure of the subsequent three-waste treatment is reduced.
Drawings
FIG. 1 is a liquid chromatogram of methyl 2-methoxy-3- (diethylcarbamoyl) propionate in example 5 according to the present invention;
FIG. 2 is a liquid chromatogram of 5-methoxy-4, 6-dihydroxypyrimidine in example 5 of the invention.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 644.55g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 286.34g, stirring and reacting for 30min, setting a water bath kettle to 90 ℃, when the temperature of the feed liquid reaches 90 ℃, starting to keep the temperature, controlling the reaction temperature to keep at 80 ℃ for 5h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 90g of calcium hydroxide into the filtrate, stirring for 1h, filtering again after stirring is finished, concentrating the filtrate under reduced pressure to obtain 124.18g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product, wherein the reaction yield is 56.09%, and the crude product purity is 82.09%.
Adding 273.65g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 67.82g of formamide and 101.94g of methyl 2-methoxy-3- (diethylcarbamoyl) propionate into a four-port bottle, setting 80 ℃ in a water bath, controlling the reaction temperature to be kept at 80 ℃ for 20h, carrying out reduced pressure distillation on methanol at 60 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 164g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 2, carrying out suction filtration at 10 ℃ after stirring for 10min, thus obtaining 68.74g of crude product, the cyclization reaction yield is 81.04%, and the purity of the crude product is 84.09%.
Example 2
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 966.82g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 429.5g, stirring and reacting for 30min, setting 100 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 100 ℃, controlling the reaction temperature to keep at 80 ℃ for 10h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 108g of calcium hydroxide into the filtrate, stirring for 3h, filtering again after stirring is finished, concentrating the filtrate under reduced pressure to obtain 124.85g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product, and obtaining the product with the reaction yield of 57.11% and the purity of 83.13%.
Adding 464.38g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 138.10g of formamide and 103.79g of methyl 2-methoxy-3- (diethylcarbamoyl) propionate into a four-port bottle, setting 80 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 80 ℃ for 20h, carrying out reduced pressure distillation on methanol at 70 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 417.94g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 5, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 70.40g of crude product, wherein the cyclization reaction yield is 81.12%, and the purity of the crude product is 83.67%.
Example 3
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 70 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 70 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to be 4, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 70.02g of crude product, wherein the cyclization reaction yield is 75.46%, and the purity of the crude product is 82.56%.
Example 4
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-mouth bottle, setting 80 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 80 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 66.33g of crude product, wherein the cyclization reaction yield is 77.45%, and the purity of the crude product is 89.45%.
Example 5
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep 7h at 80 ℃, naturally cooling to room temperature after the temperature keeping, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring, concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethylcarbamoyl) methyl propionate crude product, and obtaining a purity 80.34% (sampling 0.1386g to 25ml of 50% acetonitrile aqueous solution, measuring the liquid phase peak area to be 74534.9, substituting a standard curve formula y=16663x+320.29 to obtain an external standard content 80.34%).
Adding 339.81g of a mixed solution of 109.5g of methyl 2-methoxy-3- (diethylaminoformyl) propionate, 72.85g of formamide, and 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight) into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of the feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, obtaining 74.57g of crude product, carrying out cyclization reaction yield of 81.21% and crude product purity of 83.44% (sampling 0.0952g of purified water to be 100ml, measuring liquid phase peak area 11226, and substituting into a standard curve formula y=131×806.15 to obtain external standard content of 83.44%).
Example 6
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 100 ℃ in a water bath kettle, controlling the reaction temperature to be 100 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 74.23g of crude product, wherein the cyclization reaction yield is 79.44%, and the purity of the crude product is 81.99%.
Example 7
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-mouth bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 10 hours, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 74.30g of crude product, wherein the cyclization reaction yield is 80.07%, and the purity of the crude product is 82.56%.
Example 8
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be at 90 ℃ for 30h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa in a vacuum pump, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 75.77g of crude product, wherein the cyclization reaction yield is 80.66%, and the purity of the crude product is 81.56%.
Example 9
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 97.13g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa in a vacuum pump, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 74.57g of crude product, wherein the cyclization reaction yield is 80.14%, and the purity of the crude product is 82.34%.
Example 10
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 121.42g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 71.70g of crude product, wherein the cyclization reaction yield is 79.34%, and the purity of the crude product is 84.78%.
Example 11
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 145.70g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 72.95g of crude product, wherein the cyclization reaction yield is 79.01%, and the purity of the crude product is 82.98%.
Example 12
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 320.39g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-port bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, stirring for 10min, carrying out suction filtration at 10 ℃ to obtain 71.12g of crude product, wherein the cyclization reaction yield is 79.84%, and the purity of the crude product is 86.01%.
Example 13
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 349.52g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-mouth bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, thus obtaining 76.37g of crude product, 78.09% of cyclization reaction yield and 78.34% of purity of the crude product.
Example 14
Adding 180g of N, N-diethyl-2, 3-tetrafluoropropionamide into a four-port bottle, wherein the mass of a sodium methoxide methanol solution is 725.12g (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), the mass of methanol is 573.43g, stirring and reacting for 30min, setting 80 ℃ in a water bath kettle, starting to keep the temperature when the temperature of the feed liquid reaches 80 ℃, controlling the reaction temperature to keep at 80 ℃ for 7h, naturally cooling to room temperature after the heat preservation is finished, filtering the feed liquid, adding 100g of calcium hydroxide into the filtrate, stirring for 2h, filtering again after stirring is finished, and concentrating the filtrate under reduced pressure to obtain 136.30g of a 2-methoxy-3- (diethyl carbamoyl) methyl propionate crude product.
Adding 291.27g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% by weight), 72.85g of formamide and 109.5g of methyl 2-methoxy-3- (diethyl carbamoyl) propionate into a four-mouth bottle, setting 90 ℃ in a water bath kettle, controlling the reaction temperature to be kept at 90 ℃ for 20h, carrying out reduced pressure distillation on methanol at 50 ℃ after the heat preservation is finished, carrying out vacuum degree of-0.085 MPa, adding 275g of purified water at 10 ℃ after the distillation is finished, adding hydrochloric acid to adjust the pH of feed liquid to 3, carrying out suction filtration at 10 ℃ after stirring for 10min, and obtaining 64.04g of crude product, wherein the cyclization reaction yield is 76.31%, and the purity of the crude product is 91.29%.
It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (4)

1.一种5-甲氧基-4,6-二羟基嘧啶的制备方法，其特征在于包括以下步骤：1. A method for preparing 5-methoxy-4,6-dihydroxypyrimidine, characterized by comprising the following steps: S1、脱氟甲氧基化：S1, Defluorination and methoxylation: N,N-二乙基-2,3,3,3-四氟丙酰胺经脱氟甲氧基化后得到2-甲氧基-3-(二乙氨基甲酰基)丙酸甲酯，其中催化剂为甲醇钠，溶剂为甲醇，N,N-二乙基-2,3,3,3-四氟丙酰胺、甲醇钠和甲醇的摩尔比为1：4.0～6.0：10～20；80-100℃下反应5-10h，结束后降温至室温，将料液进行过滤后加入氢氧化钙搅拌1-3h，搅拌结束再次进行过滤，滤液减压浓缩后得到白色液体2-甲氧基-3-(二乙氨基甲酰基)丙酸甲酯，其中氢氧化钙与N,N-二乙基-2,3,3,3-四氟丙酰胺的质量比为0.5～0.6：1；N,N-Diethyl-2,3,3,3-tetrafluoropropionamide was defluorinated and methoxylated to obtain methyl 2-methoxy-3-(diethylcarbamoyl)propionate. The catalyst was sodium methoxide, the solvent was methanol, and the molar ratio of N,N-diethyl-2,3,3,3-tetrafluoropropionamide, sodium methoxide, and methanol was 1:4.0–6.0:10–20. The reaction was carried out at 80–100 °C for 5–10 h. After the reaction, the temperature was lowered to room temperature, the solution was filtered, and calcium hydroxide was added and stirred for 1–3 h. After stirring, the solution was filtered again, and the filtrate was concentrated under reduced pressure to obtain a white liquid, methyl 2-methoxy-3-(diethylcarbamoyl)propionate, in which the mass ratio of calcium hydroxide to N,N-diethyl-2,3,3,3-tetrafluoropropionamide was 0.5–0.6:1. S2、环合：S2, cyclopeptide: 2-甲氧基-3-(二乙氨基甲酰基)丙酸甲酯经环化得到5-甲氧基-4,6-二羟基嘧啶，其中环化试剂为甲酰胺，催化剂为甲醇钠；反应结束后减压蒸馏甲醇，蒸馏结束后加入纯化水和盐酸调节料液pH为2-5，抽滤得到粗品5-甲氧基-4,6-二羟基嘧啶。2-Methoxy-3-(diethylcarbamoyl)propionate methyl ester was cyclized to give 5-methoxy-4,6-dihydroxypyrimidine, wherein the cyclizing agent was formamide and the catalyst was sodium methoxide. After the reaction was completed, methanol was distilled under reduced pressure. After distillation, purified water and hydrochloric acid were added to adjust the pH of the solution to 2-5. The crude product 5-methoxy-4,6-dihydroxypyrimidine was obtained by filtration. 2.如权利要求1所述的一种5-甲氧基-4,6-二羟基嘧啶的制备方法，其特征在于：2-甲氧基-3-(二乙氨基甲酰基)丙酸甲酯、甲酰胺和甲醇钠的摩尔比为1：3.0～6.0：3.0～5.0。2. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine according to claim 1, characterized in that: the molar ratio of methyl 2-methoxy-3-(diethylcarbamoyl)propionate, formamide and sodium methoxide is 1:3.0-6.0:3.0-5.0. 3.如权利要求1所述的一种5-甲氧基-4,6-二羟基嘧啶的制备方法，其特征在于：步骤S2中的反应温度为70℃-100℃，反应时间为10-30h。3. 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. 4.如权利要求1所述的一种5-甲氧基-4,6-二羟基嘧啶的制备方法，其特征在于：减压蒸馏条件为50-70℃、≤-0.085Mpa，蒸馏结束后剩余料液降温至10℃然后加入纯化水和盐酸，搅拌10min后在10℃条件下进行抽滤。4. The method for preparing 5-methoxy-4,6-dihydroxypyrimidine as described in claim 1, characterized in that: the vacuum distillation conditions are 50-70℃ and ≤-0.085Mpa, after the distillation is completed, the remaining liquid is cooled to 10℃ and then purified water and hydrochloric acid are added, stirred for 10 min and then filtered at 10℃.
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