CN121494792A - A method for preparing 5-methoxy-4,6-dihydroxypyrimidine - Google Patents
A method for preparing 5-methoxy-4,6-dihydroxypyrimidineInfo
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- CN121494792A CN121494792A CN202610046096.8A CN202610046096A CN121494792A CN 121494792 A CN121494792 A CN 121494792A CN 202610046096 A CN202610046096 A CN 202610046096A CN 121494792 A CN121494792 A CN 121494792A
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- methoxy
- sodium methoxide
- dihydroxypyrimidine
- preparing
- propionate
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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 ethyl 2-methoxy-3- (diethylaminoformyl) propionate, and the ethyl 2-methoxy-3- (diethylaminoformyl) 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
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 methylation:
defluorination and methoxylation are carried out on the N, N-diethyl-2, 3-tetrafluoropropionamide to obtain 2-methoxy-3- (diethylaminoformyl) ethyl propionate;
s2, cyclization:
cyclizing the ethyl 2-methoxy-3- (diethylaminoformyl) propionate to obtain the 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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 mol ratio of the ethyl 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 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- (diethylaminoformyl) ethyl 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 ethyl 2-methoxy-3- (diethylcarbamoyl) propionate according to example 5 of 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 crude product of ethyl 2-methoxy-3- (diethylcarbamoyl) propionate, wherein the reaction yield is 56.09%, and the purity of the crude product 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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 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, stirring for 10min, carrying out suction filtration at 10 ℃ to obtain 68.74g of crude product, carrying out cyclization reaction yield 81.04%, and carrying out purity 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 crude product of ethyl 2-methoxy-3- (diethylcarbamoyl) propionate, and obtaining the reaction yield 57.11% and the crude product with 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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 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 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 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 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 crude product of 2-methoxy-3- (diethylcarbamoyl) ethyl propionate, wherein the purity is 80.34% (sampling 0.1386g is constant to 25ml of 50% acetonitrile aqueous solution, the liquid phase peak area is 74534.9, and substituting a standard curve formula y=16663x+320.29 to obtain an external standard content 80.34%).
Adding 339.81g of sodium methoxide methanol solution (the mass fraction of sodium methoxide in the sodium methoxide methanol solution is 30% wt), 72.85g of formamide and 109.5g of ethyl 2-methoxy-3- (diethylaminoformyl) 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, obtaining 74.57g of crude product, carrying out cyclization reaction yield of 81.21 percent and crude product purity of 83.44 percent (sampling 0.0952g of purified water with constant volume of 100ml, measuring liquid phase peak area of 11226, substituting standard curve formula y=131×806.15, and obtaining external standard content of 83.44 percent).
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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 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 74.23g 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) propionate into a four-port 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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, stirring for 10min, carrying out suction filtration at 10 ℃ to obtain 74.57g of crude product, and carrying out cyclization reaction with the yield of 80.14% and the purity of the crude product of 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 76.37g of crude product, wherein the cyclization reaction yield is 78.09%, and the purity of the crude product is 78.34%.
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 crude product of the ethyl 2-methoxy-3- (diethyl carbamoyl) propionate.
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 ethyl 2-methoxy-3- (diethylaminoformyl) 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 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 (10)
1. A method for preparing 5-methoxy-4, 6-dihydroxypyrimidine, which is characterized by comprising the following steps:
S1, defluorination methylation:
defluorination and methoxylation are carried out on the N, N-diethyl-2, 3-tetrafluoropropionamide to obtain 2-methoxy-3- (diethylaminoformyl) ethyl propionate;
s2, cyclization:
cyclizing the ethyl 2-methoxy-3- (diethylaminoformyl) propionate to obtain the 5-methoxy-4, 6-dihydroxypyrimidine.
2. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine according to claim 1, wherein the catalyst in step S1 is sodium methoxide and the solvent is methanol.
3. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine according to claim 2, wherein the molar ratio of N, N-diethyl-2, 3-tetrafluoropropionamide, sodium methoxide and methanol is 1:4.0-6.0:10-20.
4. The process for preparing 5-methoxy-4, 6-dihydroxypyrimidine as claimed in claim 1, wherein the reaction temperature in step S1 is 80-100℃and the reaction time is 5-10h.
5. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine according to claim 1, wherein the reaction in the step S1 is completed, the temperature is reduced to room temperature, the feed liquid is filtered, calcium hydroxide is added and stirred for 1-3 hours, the stirring is completed, the filtration is carried out again, the filtrate is concentrated under reduced pressure to obtain white liquid ethyl 2-methoxy-3- (diethylcarbamoyl) propionate, and the mass ratio of the calcium hydroxide to the N, N-diethyl-2, 3-tetrafluoropropionamide is 0.5-0.6:1.
6. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine according to claim 1, wherein the cyclizing reagent in step S2 is formamide and the catalyst is sodium methoxide.
7. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine according to claim 6, wherein the molar ratio of ethyl 2-methoxy-3- (diethylcarbamoyl) propionate, formamide to sodium methoxide is 1:3.0-6.0:3.0-5.0.
8. The process for preparing 5-methoxy-4, 6-dihydroxypyrimidine as claimed in claim 1, wherein the reaction temperature in step S2 is from 70℃to 100℃and the reaction time is from 10 to 30 hours.
9. The method for preparing 5-methoxy-4, 6-dihydroxypyrimidine as claimed in claim 1, wherein the step S2 is carried out by distilling methanol under reduced pressure, adding purified water and hydrochloric acid to adjust pH of feed liquid to 2-5 after distillation, and vacuum filtering to obtain crude 5-methoxy-4, 6-dihydroxypyrimidine.
10. The process for preparing 5-methoxy-4, 6-dihydroxypyrimidine as claimed in claim 9, wherein the reduced pressure distillation conditions are 50-70 ℃ and less than or equal to-0.085 MPa, the residual liquid is cooled to 10 ℃ after the distillation is finished, then purified water and hydrochloric acid are added, and the mixture is stirred for 10min and subjected to suction filtration at 10 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0019811A1 (en) * | 1979-05-18 | 1980-12-10 | Ciba-Geigy Ag | Pyrimidine compounds, process for their preparation, pharmaceutical compositions containing them and their therapeutical use |
| JPS5785340A (en) * | 1980-11-13 | 1982-05-28 | Ihara Chem Ind Co Ltd | Production of alpha-fluoro-beta-(alkylketo) ester |
| US6248571B1 (en) * | 1995-08-31 | 2001-06-19 | Lonza Ag | Method of producing dihydroxypyrimidine derivatives |
| CN1539827A (en) * | 2003-10-31 | 2004-10-27 | 中国科学院上海有机化学研究所 | 6-Substituted-5-fluoro-4-hydroxypyrimidine compounds and their intermediates, synthesis methods and uses |
| JP2016183151A (en) * | 2015-03-25 | 2016-10-20 | 富士フイルム株式会社 | Diagnostic or therapeutic agent for diseases involving integrins |
| CN110267948A (en) * | 2016-12-09 | 2019-09-20 | 弗特克斯药品有限公司 | Modulators of Cystic Fibrosis Transmembrane Conductance Modulators, Pharmaceutical Compositions, Methods of Treatment and Methods of Making the Modulators |
| CN113444050A (en) * | 2021-08-30 | 2021-09-28 | 潍坊滨海石油化工有限公司 | Production method of 4, 6-dihydroxypyrimidine |
-
2026
- 2026-01-14 CN CN202610046096.8A patent/CN121494792A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0019811A1 (en) * | 1979-05-18 | 1980-12-10 | Ciba-Geigy Ag | Pyrimidine compounds, process for their preparation, pharmaceutical compositions containing them and their therapeutical use |
| JPS5785340A (en) * | 1980-11-13 | 1982-05-28 | Ihara Chem Ind Co Ltd | Production of alpha-fluoro-beta-(alkylketo) ester |
| US6248571B1 (en) * | 1995-08-31 | 2001-06-19 | Lonza Ag | Method of producing dihydroxypyrimidine derivatives |
| CN1539827A (en) * | 2003-10-31 | 2004-10-27 | 中国科学院上海有机化学研究所 | 6-Substituted-5-fluoro-4-hydroxypyrimidine compounds and their intermediates, synthesis methods and uses |
| JP2016183151A (en) * | 2015-03-25 | 2016-10-20 | 富士フイルム株式会社 | Diagnostic or therapeutic agent for diseases involving integrins |
| CN110267948A (en) * | 2016-12-09 | 2019-09-20 | 弗特克斯药品有限公司 | Modulators of Cystic Fibrosis Transmembrane Conductance Modulators, Pharmaceutical Compositions, Methods of Treatment and Methods of Making the Modulators |
| CN113444050A (en) * | 2021-08-30 | 2021-09-28 | 潍坊滨海石油化工有限公司 | Production method of 4, 6-dihydroxypyrimidine |
Non-Patent Citations (3)
| Title |
|---|
| YING ZHENG ET AL.: "F-Free Deoxyhydrotrifluoromethylation of #-Keto Esters with Ph3P+CF2CO2-: Synthesis of #-CF3-Substituted Esters", 《J. ORG. CHEM.》, 21 July 2020 (2020-07-21), pages 8 * |
| 崔龙等: "4, 6-二羟基嘧啶合成工艺条件的优化", 《精细石油化工》, vol. 28, no. 3, 31 May 2011 (2011-05-31), pages 18 - 20 * |
| 车琳等: "无过渡金属参与的偕二氟环丙烷双脱氟烷氧基化合成环丙酮缩酮(英文)", 《有机化学》, vol. 45, no. 6, 31 December 2025 (2025-12-31), pages 2222 - 2230 * |
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