Preparation method of 4, 6-dihydroxypyrimidine

Abstract

The invention discloses a preparation method of 4, 6-dihydroxypyrimidine, which comprises the following steps: (1) adding an alcoholic solution of an alkali metal alcohol compound into a reaction container, concentrating the solvent at normal pressure until the mass concentration of the alkali metal alcohol compound reaches 32-45%, dropwise adding a mixture of formamide and malonate, after dropwise adding is finished and a heat preservation reaction is finished, cooling to room temperature, filtering, washing, and drying to obtain 4, 6-dihydroxypyrimidine; performing reduced pressure distillation to recover the solvent; (2) water is added for dissolution, carbon dioxide gas is introduced for acidification reaction, the acidification temperature is controlled to be 20-40 DEG C, the reaction pressure is controlled to be 0.05-0.5 Mpa, and the pH value is controlled to be 3.5-7 after acidification; and (3) acidifying, crystallizing, centrifuging, washing, separating and drying to obtain the product. The catalyst is added to improve the selectivity of reaction materials and reduce the reaction activation energy, and the dispersant is added to improve the flowability and uniformity of the reaction materials, thereby being beneficial to improving the reaction effect. Carbon dioxide acidification is adopted, wastewater is not introduced by adding acid, the wastewater amount is reduced by about 30%, a byproduct sodium carbonate can be sold as a product, and the cost is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 4,6-dihydroxypyrimidine. Background Art

[0002] 4,6 - As a synthetic intermediate, dihydroxypyrimidine is mainly used in the production of sulfonamide drugs. It is also the main intermediate for the preparation of the fungicide myclobutanil, and has a large market demand.

[0003] At present, the industry has 4,6 - Dihydroxypyrimidine is generally produced by reacting dimethyl malonate with formamide and sodium methoxide. After the reaction is completed, part of the methanol is removed, and then water is added to dissolve it. After the impurities are removed by activated carbon, inorganic acid is added to acidify and precipitate 4,6 - Dihydroxypyrimidine, the precipitated solid is washed with water and dried to obtain the product.

[0004] The production process is divided into normal pressure method and pressure method. The normal pressure method has a long reaction cycle and low requirements for mass transfer and heat transfer of the reaction equipment; the pressure method has a short reaction cycle and has particularly high requirements for the mixing and stirring efficiency and heat exchange of the materials in the reaction process, and requires special pressure-resistant reaction equipment. At present, there are ways to increase the reaction yield by adding catalysts, such as:

[0005] CN 107868057 A discloses a catalyst that is a mixture of phosphorus oxychloride, triethylamine and pyrimidine, wherein phosphorus oxychloride: triethylamine: pyrimidine = 3:1:0.8. CN 114685378 A discloses a catalyst that is a quaternary ammonium base, and CN 113444050 B discloses the use of methyl formate, where methyl formate and byproduct ammonia can regenerate formamide and methanol under certain pressure conditions, thereby reducing the consumption of formamide raw materials; the reaction under pressure conditions inhibits the decomposition of formamide-related intermediates into ammonia, and promotes the forward amination reaction of methyl formate and byproduct ammonia to form raw formamide. CN 118239893 A discloses a catalyst that is ethylene glycol and / or propylene glycol.

[0006] In the acidification process, inorganic acids such as sulfuric acid, hydrochloric acid, phosphoric acid or organic acids such as formic acid and chloroacetic acid are generally used for acidification. The inorganic acid is diluted and then acidified for 4,6 - The sodium salt solution of dihydroxypyrimidine produces a lot of wastewater, and the cost of adding acids such as formic acid and chloroacetic acid to the reaction is high. How to reduce the production wastewater of 4,6-dihydroxypyrimidine and reduce production costs has become the research topic of our project. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides another method for preparing 4,6-dihydroxypyrimidine, which can reduce the generation of waste water, improve the yield and reduce the cost.

[0008] To achieve the above object, the present invention is implemented by the following technical scheme: A method for preparing 4,6-dihydroxypyrimidine, characterized in that it is prepared according to the following method:

[0009] (1) adding an alcohol solution of an alkali metal alcohol compound into a reaction vessel, concentrating the solvent under normal pressure to make the mass concentration of the alkali metal alcohol compound reach 32-45%, raising the temperature to 50-90° C., adding dropwise a mixture of formamide and malonate, and after the dropwise addition is completed, heat-insulating the reaction to complete, and then distilling under reduced pressure to recover the solvent;

[0010] (2) adding water to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, introducing carbon dioxide gas for acidification reaction, wherein the acidification temperature is controlled at 20-40° C., the reaction pressure is 0.05-0.5 MPa, and the pH after acidification is controlled at 3.5-7;

[0011] (3) After acidification, the product is crystallized, centrifuged, washed, separated and dried to obtain the product.

[0012] The reaction formula is:

[0013]

[0014] In the above scheme: in step (1), a catalyst and a dispersant are also added to the alkali metal alcohol compound solution, and the catalyst is at least one of cyclohexane-18-crown-6, 18-crown-6, dibenzo-18-crown-6, cyclodextrin, benzo-15-crown-5, 15-crown-5, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monopalmitate.

[0015] In the above scheme: in step (1), the dispersant is at least one of sodium pyrophosphate, sodium hexametaphosphate, sodium polyacrylate, sodium polymethacrylate, styrene maleic anhydride copolymer, alkylphenol polyoxyethylene ether, polyoxyethylene castor oil, sorbitol alkylate, sodium alkylaryl sulfonate, maleic acid acrylic acid copolymer, ethylene bis stearamide, stearic acid monoglyceride, tristearate glyceride, polyvinyl pyrrolidone, and fatty alcohol polyoxyethylene ether. Adding a catalyst improves the selectivity of the reaction materials, reduces the reaction activation energy, and thus improves the yield of the reaction. Adding a dispersant makes the local raw material ratio in the reactor more uniform, avoids the occurrence of intense heat release in the local reaction caused by an imbalance in the proportion of the reaction materials, and improves the reaction yield and effect.

[0016] In the above scheme: the alkali metal alcohol is compounded into one of sodium methoxide and sodium ethoxide, the alcohol is methanol or ethanol; the molar ratio of the malonic ester: alkali metal alcohol: formamide is 1:2-2.5:3-3.5.

[0017] In the above scheme: the amount of catalyst added is 0.05%-1% of the mass of the malonate.

[0018] In the above scheme: the mass of the dispersant is 0.01%-0.5% of the mass of the malonate.

[0019] In the above scheme: when the solvent is recovered by vacuum distillation, the temperature is controlled below 80° C. The heat preservation reaction time is 0.5-2h.

[0020] The present invention has the following beneficial effects:

[0021] (1) Adding a catalyst to the alkali metal alcohol compound solution improves the selectivity of the reaction materials, reduces the reaction activation energy, and thus increases the reaction yield.

[0022] (2) Adding a dispersant to the alkali metal alcohol compound solution improves the fluidity and uniformity of the reaction materials, which is beneficial to improving the reaction effect.

[0023] (3) The present invention adopts carbon dioxide acidification, which will not introduce wastewater due to acid addition. The amount of wastewater per ton of product is reduced by 30%-40% compared with the current acidification with sulfuric acid or hydrochloric acid (the amount of wastewater is about 10-15 tons / ton of product), and the by-product sodium carbonate can be sold as a product, thereby reducing costs. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with embodiments.

[0025] Example 1

[0026] Sodium methoxide methanol solution, 0.32g 18-crown ether-6 and 0.25g polyvinyl pyrrolidone were added to the reaction bottle, and methanol was concentrated at normal pressure to make the concentration of sodium methoxide reach 33%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135g dimethyl malonate and 94g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1h. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0027] Add 460g of water to make the 4,6 - Dihydroxypyrimidine sodium salt was dissolved, carbon dioxide gas was introduced, the acidification temperature was controlled at 20-40°C, the reaction pressure was 0.4Mpa, and the pH after acidification was 3.9.

[0028] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed with water, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.2% and a yield of 96.5%.

[0029] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0030] Example 2

[0031] Sodium methoxide methanol solution, 0.81 g of polyoxyethylene sorbitan monostearate and 0.41 g of sodium hexametaphosphate were added to the reaction flask, and methanol was concentrated at normal pressure to make the concentration of sodium methoxide reach 39%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2:3.5. 135 g of dimethyl malonate and 92 g of formamide were weighed and stirred to mix. The temperature was raised to 90°C, and the formamide and malonate mixture were added dropwise. After the addition was completed, the mixture was kept warm for 0.5 h. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0032] Add 500g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved and carbon dioxide gas was introduced for acidification. The acidification temperature was controlled at 20-40°C, the reaction pressure was 0.4Mpa, and the pH after acidification was 3.7.

[0033] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.0% and a yield of 98.1%.

[0034] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0035] Example 3

[0036] Sodium ethoxide ethanol solution, 0.27g benzo-15-crown ether-5 and 0.35g stearic acid monoglyceride are added to the reaction bottle, and ethanol is concentrated at normal pressure to make the concentration of sodium ethoxide reach 36%. The molar ratio of dimethyl malonate: formamide: sodium ethoxide is 1:2.12:3.05. 162g diethyl malonate and 97g formamide are weighed and stirred to mix. The temperature is raised to 50°C, and the formamide and malonate mixture are added dropwise. After the addition is completed, the temperature is kept warm for 2h. The kettle temperature is controlled below 80°C under vacuum conditions, and ethanol is recovered by reduced pressure distillation.

[0037] Add 480g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved, and carbon dioxide gas was introduced for acidification. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.5 MPa, and the pH after acidification was 6.2.

[0038] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 98.8% and a yield of 97.6%.

[0039] The mother liquor is first distilled to recover ethanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0040] Example 4

[0041] Sodium ethoxide ethanol solution, 1.6 g cyclohexane-18-crown ether-6, and 0.8 g tristearin were added to the reaction flask, and ethanol was concentrated under normal pressure to make the sodium ethoxide concentration reach 38%. The molar ratio of dimethyl malonate: formamide: sodium ethoxide was 1:2.5:3.5. 162 g diethyl malonate and 115 g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the formamide and malonate mixture were added dropwise. After the addition was completed, the temperature was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and ethanol was recovered by reduced pressure distillation.

[0042] Add 480g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved, and carbon dioxide gas was introduced for acidification. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 3.9.

[0043] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.2% and a yield of 98.5%.

[0044] The mother liquor is first distilled to recover ethanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0045] Example 5

[0046] Sodium methoxide methanol solution, 0.0675 g of dibenzo-18-crown ether-6 and 0.675 g of sodium pyrophosphate were added to the reaction flask, and methanol was concentrated at normal pressure to make the concentration of sodium methoxide reach 33%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g of dimethyl malonate and 94 g of formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0047] Add 440g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 4.8.

[0048] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.4% and a yield of 97.2%.

[0049] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0050] Example 6

[0051] Sodium methoxide methanol solution, 0.43g cyclodextrin, and 0.0135g styrene maleic anhydride copolymer are added to a reaction bottle, and methanol is concentrated at normal pressure to make the sodium methoxide concentration reach 33%. The molar ratio of dimethyl malonate: formamide: sodium methoxide is 1:2.05:3.1. 135g dimethyl malonate and 94g formamide are weighed and stirred to mix. The temperature is raised to 60°C, and the mixture of formamide and dimethyl malonate is added dropwise. After the addition is completed, the reaction is kept warm for 1h. The kettle temperature is controlled below 80°C under vacuum conditions, and the methanol is recovered by reduced pressure distillation.

[0052] Add 480g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.3 MPa, and the pH after acidification was 5.2.

[0053] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.2% and a yield of 96.5%.

[0054] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0055] Example 7

[0056] Sodium methoxide methanol solution, 1.0 g of polyoxyethylene sorbitan monolaurate and 0.02 g of maleic acid acrylic acid copolymer were added to a reaction flask, and methanol was concentrated at normal pressure to make the sodium methoxide concentration reach 45%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.2:3.1. 135 g of dimethyl malonate and 101 g of formamide were weighed and stirred to mix. The temperature was raised to 70°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0057] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 4.6.

[0058] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99% and a yield of 98.5%.

[0059] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0060] Example 8

[0061] Sodium methoxide methanol solution, 0.4 g of polyoxyethylene sorbitan monopalmitate and 0.32 g of ethylene bisstearamide were added to a reaction bottle, and methanol was concentrated under normal pressure to make the concentration of sodium methoxide reach 32%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g of dimethyl malonate and 94 g of formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0062] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 6.5.

[0063] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.3% and a yield of 97.5%.

[0064] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0065] Example 9

[0066] Sodium methoxide methanol solution, 0.6g 15-crown ether-5 and 0.35g polyoxyethylene castor oil were added to the reaction bottle, and methanol was concentrated under normal pressure to make the sodium methoxide concentration reach 35%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135g dimethyl malonate and 94g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1h. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0067] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.05 MPa, and the pH after acidification was 6.5.

[0068] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.3% and a yield of 94.8%.

[0069] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0070] Example 10

[0071] Sodium methoxide methanol solution, 0.6 g 15-crown ether-5 and 0.43 g sodium polyacrylate were added to the reaction flask, and methanol was concentrated at normal pressure to make the sodium methoxide concentration reach 35%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g dimethyl malonate and 99 g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0072] 480 g of water was added to dissolve the sodium 4,6-dihydroxypyrimidine generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.2 MPa, and the pH after acidification was 4.2.

[0073] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99% and a yield of 95.2%.

[0074] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0075] Embodiment 11

[0076] Sodium methoxide methanol solution, 0.6 g 15-crown ether-5 and 0.43 g sodium polymethacrylate were added to the reaction flask, and methanol was concentrated at normal pressure to make the concentration of sodium methoxide reach 36%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g dimethyl malonate and 94 g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0077] Add 480g of water to make the 4,6 - The sodium salt of dihydroxypyrimidine was dissolved, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.2 MPa, and the pH after acidification was 3.9.

[0078] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.2% and a yield of 96.2%.

[0079] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0080] Example 12

[0081] Sodium methoxide methanol solution, 0.23g cyclohexane-18-crown ether-6, and 0.76g alkylphenol polyoxyethylene ether are added to the reaction bottle, and methanol is concentrated at normal pressure to make the concentration of sodium methoxide reach 37%. The molar ratio of dimethyl malonate: formamide: sodium methoxide is 1:2.05:3.1. 135g dimethyl malonate and 94g formamide are weighed and stirred to mix. The temperature is raised to 60°C, and the mixture of formamide and dimethyl malonate is added dropwise. After the addition is completed, the reaction is kept warm for 1h. The kettle temperature is controlled below 80°C under vacuum conditions, and the methanol is recovered by reduced pressure distillation.

[0082] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 5.3.

[0083] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.2% and a yield of 96.3%.

[0084] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0085] Embodiment 13

[0086] Sodium methoxide methanol solution, 0.36 g cyclohexane-18-crown ether-6, and 0.82 g sodium alkyl aryl sulfonate were added to the reaction flask, and methanol was concentrated at normal pressure to make the sodium methoxide concentration reach 39%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g dimethyl malonate and 94 g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and dimethyl malonate was added dropwise. After the addition was completed, the reaction was kept warm for 1 hour. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0087] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 5.6.

[0088] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.1% and a yield of 96.9%.

[0089] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0090] Embodiment 14

[0091] Sodium methoxide methanol solution, 0.95g cyclohexane-18-crown ether-6, and 0.06g fatty alcohol polyoxyethylene ether are added to the reaction bottle, and methanol is concentrated at normal pressure to make the concentration of sodium methoxide reach 39%. The molar ratio of dimethyl malonate: formamide: sodium methoxide is 1:2.05:3.1. 135g dimethyl malonate and 94g formamide are weighed and stirred to mix. The temperature is raised to 60°C, and the mixture of formamide and dimethyl malonate is added dropwise. After the addition is completed, the reaction is kept warm for 1h. The kettle temperature is controlled below 80°C under vacuum conditions, and the methanol is recovered by reduced pressure distillation.

[0092] 480 g of water was added to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 4.6.

[0093] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 99.3% and a yield of 97.9%.

[0094] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0095] Comparative Example 1

[0096] Add sodium methoxide methanol solution into the reaction flask, concentrate methanol at normal pressure to make the sodium methoxide concentration reach 33%, the molar ratio of dimethyl malonate: formamide: sodium methoxide is 1:2.05:3.1, weigh 135g of dimethyl malonate and 94g of formamide, stir and mix, heat to 60℃, add formamide and malonate mixture dropwise, keep warm for 1h, control the kettle temperature below 70℃ under vacuum condition, and recover methanol by distillation.

[0097] Add 460g of water to make the 4,6 - Dihydroxypyrimidine sodium salt is dissolved, carbon dioxide gas is introduced, the acidification temperature is controlled at 20-40°C, the reaction pressure is 0.4Mpa, and the pH after acidification is 4.5.

[0098] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 98.3% and a yield of 77.6%.

[0099] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0100] Comparative Example 2

[0101] Sodium methoxide methanol solution and 0.57g 18-crown ether-6 were added to the reaction flask, and methanol was concentrated at normal pressure to make the sodium methoxide concentration reach 35%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135g dimethyl malonate and 101g formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the formamide and malonate mixture were added dropwise. After the addition was completed, the temperature was kept warm for 1h. The kettle temperature was controlled below 80°C under vacuum conditions, and methanol was recovered by distillation.

[0102] 460 g of water was added to dissolve the sodium 4,6-dihydroxypyrimidine generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 4.2.

[0103] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 98.7% and a yield of 88.3%.

[0104] The mother liquor is first distilled to recover methanol and formic acid, and then concentrated to recover sodium carbonate. The desalted mother liquor is decolorized and applied to subsequent acidification and crystallization, and the mother liquor is applied multiple times for wastewater treatment.

[0105] Comparative Example 3

[0106] Sodium methoxide methanol solution and 0.57 g of polyvinyl pyrrolidone were added to the reaction flask, and methanol was concentrated at normal pressure to make the concentration of sodium methoxide reach 36%. The molar ratio of dimethyl malonate: formamide: sodium methoxide was 1:2.05:3.1. 135 g of dimethyl malonate and 94 g of formamide were weighed and stirred to mix. The temperature was raised to 60°C, and the mixture of formamide and malonate was added dropwise. After the addition was completed, the mixture was kept warm for 0.5 h. The kettle temperature was controlled below 80°C under vacuum conditions, and the methanol was recovered by reduced pressure distillation.

[0107] 460 g of water was added to dissolve the sodium 4,6-dihydroxypyrimidine generated by the reaction, and carbon dioxide gas was introduced. The acidification temperature was controlled at 20-40° C., the reaction pressure was 0.4 MPa, and the pH after acidification was 4.3.

[0108] After acidification, the mixture was crystallized for 3 hours, centrifuged, washed, the product was separated, and dried to obtain light yellow 4,6-dihydroxypyrimidine with a product content of 98.8% and a yield of 83.2%.

[0109] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 4,6-dihydroxypyrimidine, characterized in that: Prepare as follows: (1) adding an alcohol solution of an alkali metal alcohol compound into a reaction vessel, concentrating the solvent under normal pressure to make the mass concentration of the alkali metal alcohol compound reach 32-45%, raising the temperature to 50-90° C., adding dropwise a mixture of formamide and malonate, and after the dropwise addition is completed, heat-insulating the reaction to complete, and then distilling under reduced pressure to recover the solvent; (2) adding water to dissolve the 4,6-dihydroxypyrimidine sodium salt generated by the reaction, introducing carbon dioxide gas for acidification reaction, wherein the acidification temperature is controlled at 20-40° C., the reaction pressure is 0.05-0.5 MPa, and the pH after acidification is controlled at 3.5-7; (3) After acidification, the product is crystallized, centrifuged, washed, separated and dried to obtain the product.

2. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: In step (1), a catalyst and a dispersant are also added to the alkali metal alcohol compound solution, and the catalyst is at least one of cyclohexane-18-crown-6, 18-crown-6, dibenzo-18-crown-6, cyclodextrin, benzo-15-crown-5, 15-crown-5, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monopalmitate.

3. The method for preparing 4,6-dihydroxypyrimidine according to claim 2, characterized in that: The dispersant is at least one of sodium pyrophosphate, sodium hexametaphosphate, sodium polyacrylate, sodium polymethacrylate, styrene maleic anhydride copolymer, alkylphenol polyoxyethylene ether, polyoxyethylene castor oil, sorbitol alkylate, sodium alkyl aryl sulfonate, maleic acid acrylic acid copolymer, ethylene bisstearamide, stearic acid monoglyceride, tristearic acid glyceride, polyvinyl pyrrolidone, and fatty alcohol polyoxyethylene ether.

4. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, 2 or 3, characterized in that: The alkali metal alcohol is compounded into one of sodium methoxide and sodium ethoxide, the alcohol is methanol or ethanol; the molar ratio of the malonic acid ester: alkali metal alcohol: formamide is 1:2-2.5:3-3.

5.

5. The method for preparing 4,6-dihydroxypyrimidine according to claim 4, characterized in that: The added amount of the catalyst is 0.05%-1% of the mass of the malonic ester.

6. The method for preparing 4,6-dihydroxypyrimidine according to claim 5, characterized in that: The mass of the dispersant is 0.01%-0.5% of the mass of the malonic ester.

7. The method for preparing 4,6-dihydroxypyrimidine according to claim 6, characterized in that: When the solvent is recovered by reduced pressure distillation, the temperature is controlled below 80°C.

8. The method for preparing 4,6-dihydroxypyrimidine according to claim 1, characterized in that: The heat preservation reaction time of step (1) is 0.5-2h.

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