Preparation method of 4-amino-2, 6-dimethoxy pyrimidine

Abstract

The invention provides the preparation method of the 4-amino-2, 6-dimethoxy pyrimidine, trichloroisocyanuric acid is used as a solid chlorine source and an oxidizing agent, and the trichloroisocyanuric acid has the characteristics of low cost, safety, high efficiency, simplicity and convenience in chlorination reaction operation, strong oxidation performance, environmental friendliness and the like, so that the yield is improved, wastewater is greatly reduced, and the preparation method has great social and economic benefits.

Description

TECHNICAL FIELD

[0001] The present application relates to an organic synthesis method, in particular to a preparation method of 4-amino-2,6-dimethoxy pyrimidine. BACKGROUND

[0002] 4-amino-2,6-dimethoxy pyrimidine, CAS No. 3289-50-7, molecular formula: C6H9N3O2, is an important pharmaceutical intermediate, which can be used for synthesizing long-acting sulfonamide drug sulfadimoxazole. This drug is particularly effective for upper respiratory tract and urinary tract infections, and has extremely slight stimulation to the kidneys and low side effects. As an excellent long-acting sulfonamide drug, sulfadimoxazole can maintain a high concentration in the blood for a long time, so the frequency and dosage of administration can be greatly reduced.

[0003] The present inventors have summarized 9 routes of the existing synthesis process of 4-amino-2,6-dimethoxy pyrimidine through literature retrieval: Route 1 (early barbituric acid method): Disadvantages: poor selectivity, only 1 / 3 is the product, and the other 2 / 3 of the by-products are 2-amino-4,6-dichloropyrimidine, low yield, difficult to purify, and no production significance.

[0004] Route 2 (Pharmaceutical Industry, 1960, 15 (2)): Methyl cyanoacetate is condensed with urea, chlorinated by phosphorus oxychloride, and then reacted with sodium methoxide to obtain the product. This method needs to chlorinate two hydroxyl groups, which significantly increases the use amount of phosphorus oxychloride, and increases the safety hazard and environmental pollution problem, which is the literature viewpoint.

[0005] Route 3 (Chinese invention patent application No. CN201811268244.2, authorized announcement No. CN109293582, Jiangsu Tianhe Pharmaceutical Co., Ltd.): The product is obtained by using malononitrile as raw material, protonation etherification, nitrile group, Lewis acid catalyzed protonation ring closure. Malononitrile is added with a proportioning amount of methanol in a dry solvent, the temperature is controlled at 20-50 degrees, dry hydrogen chloride gas is introduced to generate 1,3-dimethoxypropylenediamine hydrochloride, then 1,3-dimethoxypropylenediamine hydrochloride is reacted with monocyanoamine under the conditions of pH 5-6 and reaction temperature 20-50 to generate 3-amino-3-methoxy-N-cyano-2-propylenediamine, the intermediate is dissolved in a solvent, dry hydrogen chloride gas is introduced under the protection of boron trifluoride to add and ring close to generate the product. This method avoids the problems of safety and environmental pollution caused by the use of phosphorus oxychloride, but the reaction conditions are harsh, dry hydrogen chloride gas needs to be introduced during the reaction, boron trifluoride protection is also required, amino nitrile is a toxic raw material, and there is also the problem of intramolecular reaction of itself, the steps are complex, and the process is difficult.

[0006] Route 4 (Chinese Invention Patent Application Publication No. CN113845482 A, Application No. 202010595659.1, Zhejiang Jiuzhou Pharmaceutical Co., Ltd.): The preparation method of the raw material 2-cyanoacetamidine hydrochloride is shown in Route 3. This route prepares the 2-chloro-4-amino-6-methoxymidazole intermediate through condensation reaction and ring closure reaction. With DMAP as catalyst, the intermediate product can be directly subjected to ring closure reaction without separation, to prepare 2-chloro-4-amino-6-methoxymidazole, and then one step methoxylation is performed to change the chlorine into methoxy group to obtain the product.

[0007] This process also needs to use boron trifluoride gas, which has a high risk coefficient.

[0008] Route 5 (Chinese Invention Patent Authorized Publication No. CN105646373 B, Application No. 201610089718.1, Binhai New Oriental Pharmaceutical Co., Ltd.): The patent method is as follows: adding urea and sodium methoxide methanol solution (sodium methoxide content 50%) into a container, adding methyl cyanoacetate dropwise, cyclizing under reflux, keeping warm for 3-7 hours, after keeping warm, controlling the temperature ≤80℃, evaporating methanol under normal pressure until no distillate, then evaporating methanol under negative pressure until the negative pressure ≤-0.09MPa and no distillate, obtaining 4-amino-2,6-dihydroxypyrimidine sodium salt. Adding anhydrous potassium carbonate and acetone to the 4-amino-2,6-dihydroxypyrimidine sodium salt obtained above, stirring and adding dimethyl sulfate dropwise, keeping warm under reflux for 5-15 hours. After keeping warm, controlling the temperature ≤70℃, evaporating acetone under normal pressure until no distillate, then evaporating acetone under negative pressure until the negative pressure in the container ≤-0.09MPa and no distillate. Adding water with the same weight as acetone, adjusting the pH to 7.0-9.0 with alkali, stirring thoroughly, cooling to 5-10℃ and filtering, washing with water and drying, obtaining the product, the yield is more than 80% and the content can reach 98.0%.

[0009] The present application saves the acidification and chlorination processes in the traditional process, and only needs two steps of cyclization and methylation to obtain the finished product. The 4-amino-2,6-dihydroxypyrimidine sodium salt generated in the process does not need to be separated and can directly participate in the next reaction, thereby avoiding ring opening hydrolysis. We have found that it is actually difficult to achieve this.

[0010] Route 6 (Chinese patent application publication No. CN108929278 A, application No. 201710388652.0, Jiangsu Tianhe Pharmaceutical Co., Ltd.): The patent means is similar to route 5, except that: in the first step of cyclization reaction, solid sodium methoxide and urea are added into a closed reactor under nitrogen protection, fully stirred (frame stirring) and mixed, methyl cyanoacetate is added dropwise, and after the dropwise addition is completed, the reaction is continued; after the reaction is completed, the generated methanol is evaporated under reduced pressure, and the solid material is discharged, obtaining 4-amino-2,6-dihydroxypyrimidine sodium salt. Then, methanol is added into the reactor, the above-mentioned sodium salt is added under stirring, and a methyl etherification reagent is added under stirring, controlling the temperature not to exceed 50℃, and after the addition is completed, keeping warm; after the reaction is completed, the temperature is reduced to 25-30℃, and the product is obtained after post-treatment.

[0011] The operation steps are as follows: a 500mL frame stirring reactor is evacuated with nitrogen three times to remove the air and water vapor inside, 108.04g of solid sodium methoxide and 120.12g of urea are added under nitrogen protection, stirring until mixed uniformly, then 198.18g of methyl cyanoacetate is added dropwise under nitrogen protection, keeping warm at 110℃ for 6h after the dropwise addition is completed, the reaction is completed, the generated methanol is evaporated under reduced pressure, and the solid is discharged, obtaining 338.55g of 4-amino-2,6-dihydroxypyrimidine sodium salt, the yield is 98.95%.

[0012] 1L reaction bottle is added with 400 g of methanol, 100 g of sodium salt of 4-amino-2, 6-dihydroxy pyrimidine, temperature control is not more than 50℃, 74.46 g of dimethyl sulfate is added dropwise, and after the dropwise addition is completed, the reaction is maintained at 65℃ for 10 h, the temperature is reduced to room temperature, filtration is performed, about 300 g of methanol is recovered from the filtrate, crystallization is performed by reducing the temperature, filtration is performed, the filter cake is washed with a small amount of methanol, filtration is performed, and drying is performed to obtain 86.15 g of 4-amino-2, 6-dimethoxy pyrimidine, with a yield of 95.04%.

[0013] Route 7 (China invention patent authorized publication No. CN110981816 B, application No. 201911379297.6, Tianhe Pharmaceutical Co., Ltd.): The patent obtains the product by subjecting 4, 6-dichloropyrimidine-5-carboxylic acid to ammonolysis reaction in ammonia water, chlorination, decarboxylation and methoxylation.

[0014] Disadvantages: the raw material 4, 6-dichloropyrimidine-5-carboxylic acid is relatively high in price, the reaction steps are long and the cost is high, and chlorine gas is used, which has certain safety risks.

[0015] Route 8 (China invention patent application No. 202111475568.5, application publication No. CN114014815A, Zhejiang University of Science and Technology): Step 1) cyclization reaction: adding o-methyl isourea sulfate (CAS: 29427-58-5) and methyl cyanoacetate into a reaction container, stirring uniformly, heating and cyclization reaction under solvent-free conditions, cooling to room temperature after the reaction is completed, precipitating solid, filtering, and drying to obtain 4-amino-2-methoxy-6-hydroxy pyrimidine; 2) chlorination reaction: adding phosphorus oxychloride into the product obtained in 1), heating and chlorination reaction, recovering excess phosphorus oxychloride under reduced pressure after the reaction is completed, slowly adding the remaining product into ice water, adding a pH adjuster to adjust to a certain pH value, precipitating solid, filtering, and drying to obtain 4-amino-2-methoxy-6-chloropyrimidine; 3) methoxylation reaction: adding 4-amino-2-methoxy-6-chloropyrimidine obtained in 2) into a reaction container, mixing with methanol, continuously adding sodium methoxide, refluxing and heating for methoxylation reaction, evaporating methanol after the reaction is completed, stirring with ice water, filtering and drying to obtain the product.

[0016] Route 9 (China invention patent application No. 201810999839, application publication No. CN109232441A, Nanjing University of Technology): The route takes o-methyl isourea salt and cyanoacetate as raw materials, and is subjected to condensation, methylation, and then self-cyclization to generate 4-amino-2,6-dimethoxy pyrimidine. The method skips the chlorination step, avoids the use of phosphorus oxychloride, and reduces wastewater. The patent reports that the yield of the third step is 86% (calculated based on methyl cyanoacetate).

[0017] In the published granted patents or documents, the toxicity and danger of the reagents participating in the reaction are generally large, and the environmental protection pressure of the wastewater produced in the production is large, so it is very meaningful to research a new green and environmental protection process path. SUMMARY

[0018] To solve the above problems, the application provides a preparation method of 4-amino-2,6-dimethoxy pyrimidine, which takes trichloroisocyanuric acid (TCCA) as a solid chlorine source and an oxidant. The TCCA is cheap, safe, efficient, easy to operate in chlorination reaction, has strong oxidation performance, and is environment-friendly. The yield is improved and the wastewater is greatly reduced, which has great social and economic benefits.

[0019] To achieve the purpose of the application, the following technical solutions are adopted: A preparation method of 4-amino-2,6-dimethoxy pyrimidine, comprising the following steps: (1) In a t-butyl alcohol-sodium t-butoxide system, urea and methyl cyanoacetate are reacted in a reaction kettle. After the reaction is completed, t-butyl alcohol is recovered by normal pressure distillation, and then vacuum distillation is performed. After 4-amino-2,6-dihydroxy pyrimidine sodium salt is obtained, hydrochloric acid solution is used to adjust the pH value to 4-5, and then centrifugal drying is performed to obtain 4-amino-2,6-dihydroxy pyrimidine; (2) In the presence of ethylene glycol monomethyl ether, 4-amino-2,6-dihydroxy pyrimidine, trichloroisocyanuric acid and potassium iodide are added to the reaction kettle and reacted at 80-90 DEG C. After the reaction is completed, ethylene glycol monomethyl ether is recovered by vacuum distillation. The distillation residue is quenched, centrifuged, and then 4-amino-2,6-dichloropyrimidine is obtained; (3) In the presence of methanol, 4-amino-2,6-dichloropyrimidine and a base are added to the reaction kettle and reacted. After the reaction is completed, the solid in the reaction liquid is filtered off, the filtrate is collected, the pH value is adjusted to 6-8 with hydrochloric acid, and the crude product is collected; .

[0020] Further, in the step (1), the temperature of the reaction kettle is 80-85 DEG C, and reflux occurs, and the reaction is carried out under the reflux condition, and the tert-butyl alcohol is recovered by normal pressure distillation, and then negative pressure distillation is carried out until the negative pressure is less than or equal to-0.09 MPa, and no distillate is obtained, and then 4-amino-2, 6-dihydroxypyrimidine sodium salt is obtained, water is added to the reaction kettle, hydrochloric acid is added dropwise to adjust pH=4-5, the temperature of the hydrochloric acid is controlled at 30-40 DEG C, and after the pH value is adjusted, the system is cooled to 5-10 DEG C, and then the product is obtained by centrifugation after stirring and drying.

[0021] Further, in the step (2), the molar ratio of 4-amino-2, 6-dihydroxypyrimidine, trichloroisocyanuric acid and potassium iodide is 1:1:0.2. Further, in the step (2), the temperature of the reaction kettle is 80-90 DEG C, and direct negative pressure distillation is carried out until the negative pressure is less than or equal to-0.09 MPa, and basically no liquid drops, and the ethylene glycol monomethyl ether is recovered, and after the distillation is completed, the vacuum and steam valves are closed, the water is added to the quenching kettle, and the temperature is cooled to 5-10 DEG C, and then the distillation residue is slowly dropped into the quenching kettle under stirring, and the temperature during the dropping is kept at 5-10 DEG C, and after the dropping is completed, the temperature is increased to 25-35 DEG C under stirring, and then the product is obtained by centrifugation after stirring, water washing and drying at 70-90 DEG C.

[0022] Further, in the step (3), the temperature of the reaction kettle is 60-65 DEG C, and after the reaction is completed, the solid in the reaction liquid is filtered off, the filtrate is collected and cooled to 5-10 DEG C, and the pH value is adjusted to 6-8 by using hydrochloric acid, and then the crude product is collected.

[0023] Further, in the step (3), the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide.

[0024] Further, after the step (3) is completed, the crude product is refined, and water, acetonitrile, the crude product and activated carbon are added to the reaction kettle, and then the activated carbon is filtered off after heating and stirring at 80 DEG C, and then the final product is obtained by centrifugation after the obtained filtrate is gradually cooled to 0-5 DEG C and crystallization.

[0025] The preparation method of the 4-amino-2, 6-dimethoxypyrimidine has the following beneficial effects: (1) The tert-butyl alcohol-tert-butyl alcohol sodium system is used, compared with the traditional methanol-methanol sodium or ethanol-ethanol sodium system, the solution preparation is more moderate, and the reaction time is shortened from the original 6-10 h to the present 2 h, and the reaction yield is increased from the original 80% to more than 95%.

[0026] (2) In the chlorination step, the traditional method needs to use excessive phosphorus oxychloride as chlorination reagent and solvent. Phosphorus oxychloride is easy to explode when it meets water, which has great safety hazards, and it is easy to produce a large amount of strong acid, salt and phosphorus-containing wastewater (about 40-50 tons of wastewater per ton of product), which has great environmental pressure. As a solid chlorine source and oxidant, trichloroisocyanuric acid (TCCA) has the characteristics of low cost, safety, high efficiency, simple operation of chlorination reaction, strong oxidation performance and environmental friendliness, so that the yield of the conversion of hydroxyl in 4-amino-2, 6-dihydroxypyrimidine to chlorine is increased from 60-75% to 85-92%.

[0027] (3) In the chlorination reaction, iodide ion is a good nucleophile and also a good leaving group, so a small amount of potassium iodide is added to the reaction solution, so that the hydroxyl group in 4-amino-2, 6-dihydroxypyrimidine is easily attacked by iodide ion and lost to form 4-amino-2, 6-iodopyrimidine, and iodine is easily attacked by chloride ion and lost to further form 4-amino-2, 6-dichloropyrimidine, so the reaction rate can be accelerated.

[0028] (4) Because 4-amino-2, 5-dihydroxypyrimidine has poor solubility and is insoluble in most solvents, ethylene glycol monomethyl ether has a polar group hydroxyl and an ether bond that does not have too high a boiling point, and after heating, the raw material can be dissolved, which is conducive to the reaction.

[0029] (5) In the workup process, the product is obtained by adjusting the pH to obtain a crude product, and then the product is refined by recrystallization, the yield is as high as 90% or more, the purity is more than 99.5%, and the maximum single impurity is less than 0.1%. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the liquid chromatogram of the product 4-amino-2, 6-dimethoxypyrimidine of Example 3 of the present application. DETAILED DESCRIPTION

[0031] The embodiments of the present application will be specifically described by examples, and those skilled in the art should understand that these examples are exemplary and do not constitute a limitation on the scope of protection of the present application.

[0032] Example 1 Preparation of 4-amino-2, 6-dihydroxypyrimidine: ​Into a 3000L reactor, 310L of t-butyl alcohol was added, and 160Kg of sodium t-butyl alcohol was added under stirring, and the temperature was controlled to be no more than 60°C, and stirring was continued until complete dissolution, to prepare a 40% sodium t-butyl alcohol-t-butyl alcohol solution. After complete dissolution, 100Kg of urea was added, and 150Kg of methyl cyanoacetate was added dropwise under stirring. The temperature of the reactor was increased to 80-85°C to produce reflux, and reflux was maintained for 2h, and t-butyl alcohol was recovered by normal pressure distillation, and then negative pressure distillation was performed until the negative pressure was no more than -0.09MPa, and no distillate was obtained, to obtain 4-amino-2,6-dihydroxypyrimidine sodium salt. Into the reactor, 600L of water was added, and 15% hydrochloric acid was added dropwise to adjust the pH to 4-5, and the temperature of the hydrochloric acid was controlled to be 30-40°C. After the pH was adjusted, the system was cooled to 5-10°C, and stirring was maintained for 30min, and then the product was discharged and centrifuged, and was dried at 70-90°C to obtain 190Kg of the first product 4-amino-2,6-dihydroxypyrimidine, with a yield of 98.7%.

[0033] Example 2 Preparation of 4-amino-2,6-dichloropyrimidine: Into a 3000L reactor, 1000L of ethylene glycol monomethyl ether was added, and 250Kg of the first product 4-amino-2,6-dihydroxypyrimidine, 457.1Kg (1eq) of TCCA (trichloroisocyanuric acid), and 65.3Kg (0.2eq) of potassium iodide were sequentially added under stirring at room temperature (25-30°C), and heating and stirring were continued at 40-50°C for 5h, and the reaction was completed. Post-treatment: the temperature of the reactor was 80-90°C, and the ethylene glycol monomethyl ether was recovered by distillation under reduced pressure until the negative pressure was no more than -0.09MPa, and no liquid was dropped, and after the distillation was completed, the vacuum and steam valves were closed, and the water bypass was closed. Into a quenching kettle, 1200L of water was added, and was cooled to 5-10°C, and the distillation residue was slowly added dropwise into the quenching kettle under stirring until the addition was completed, and the temperature during the addition was controlled to be 5-10°C, and after the addition was completed, the temperature was increased to 25-35°C, and stirring was continued for 2h, and then centrifugation was performed, and the product was washed with water and was discharged. Drying was performed at 70-90°C to obtain 292Kg of 4-amino-2,6-dichloropyrimidine, with a yield of 90.5%.

[0034] Example 3 Preparation of 4-amino-2,6-dimethoxypyrimidine: Into a 3000L reactor, 1300L of methanol was added, cooled to 15-25°C, and then 250Kg of the product from Step 2, 4-amino-2,6-dichloropyrimidine, and 463.3Kg of potassium carbonate (2.2eq) were added portionwise with stirring. The reaction was heated to reflux at 65°C for 6-8h. After the reaction was completed, the solids in the reaction liquid were filtered off, the filtrate was collected, and cooled to 5-10°C. The pH was adjusted to 6-8 with hydrochloric acid, and the crude product was collected. Purification: Into a 3000L reactor, 1200L of water and 400L of acetonitrile were added, and then 200Kg of the crude wet product and 10Kg of activated carbon were added. After stirring at 80°C for 1h, the activated carbon was filtered off hot. The filtrate was gradually cooled to 0-5°C for 1h, and then the product was discharged and centrifuged to obtain 213Kg of the final product, with a yield of 90%, a purity of 99.5%, and a maximum single impurity of less than 0.1%. Figure 1 .

[0035] 1 H NMR (400 MHz, DMSO-d6): δ 6.61 (s, 2H, NH2), 5.35 (s, 1H, CH), 3.71 (d, 6H, OCH3) ppm; 13 C NMR (100 MHz, DMSO-d6): δ 172.5, 172.3, 170.8, 84.7, 56.8, 56.8 ppm.

Claims

1. A process for the preparation of 4-amino-2,6-dimethoxy-pyrimidine, characterized in that, Comprising the following steps: (1) In the presence of t-butyl alcohol-sodium t-butyl alcohol system, urea and methyl cyanoacetate are reacted in a reaction kettle, after the reaction, t-butyl alcohol is recovered by normal pressure distillation, then vacuum distillation is performed, 4-amino-2, 6-dihydroxypyrimidine sodium salt is obtained, then the pH value is adjusted to 4-5 by hydrochloric acid solution, and then centrifugal drying is performed to obtain 4-amino-2, 6-dihydroxypyrimidine; (2) In the presence of ethylene glycol monomethyl ether, 4-amino-2, 6-dihydroxypyrimidine, trichloroisocyanuric acid and potassium iodide are added into a reaction kettle and reacted at 80-90℃, after the reaction, ethylene glycol monomethyl ether is recovered by vacuum distillation, the obtained distillation residue is quenched, and after centrifugation, 4-amino-2, 6-dichloropyrimidine is obtained; (3) In the presence of methanol, 4-amino-2, 6-dichloropyrimidine and a base are added into a reaction kettle and reacted, after the reaction, the solid in the reaction liquid is filtered off, the filtrate is collected, the pH value is adjusted to 6-8 by hydrochloric acid, and the crude product is collected. 。 2. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, In the step (1), the temperature of the reaction kettle is 80-85℃, reflux occurs, and the reaction is kept under reflux, t-butyl alcohol is recovered by normal pressure distillation, then vacuum distillation is performed, until the vacuum is less than or equal to-0.09MPa, and there is no distillate, 4-amino-2, 6-dihydroxypyrimidine sodium salt is obtained, water is added into the reaction kettle, hydrochloric acid is added dropwise to adjust the pH value to 4-5, the temperature of adding hydrochloric acid is controlled at 30-40℃, after the pH value is adjusted, the system is cooled to 5-10℃, and then the product is obtained by centrifugation and drying after keeping stirring.

3. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, In the step (2), the molar ratio of 4-amino-2, 6-dihydroxypyrimidine, trichloroisocyanuric acid and potassium iodide is 1:1:0.

2.

4. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, In the step (2), the temperature of the reaction kettle is 80-90℃, vacuum distillation is directly performed until the vacuum is less than or equal to-0.09MPa, and basically no liquid is dropped, ethylene glycol monomethyl ether is recovered, after the distillation is completed, the vacuum and steam valves are closed, the water is added into the quenching kettle, and cooled to 5-10℃, the distillation residue is slowly dropped into the quenching kettle under stirring, the dropping temperature is kept at 5-10℃ during the quenching process, after the dropping is completed, the temperature is increased to 25-35℃ under stirring, and then the product is obtained by centrifugation, water washing, discharging and drying after continuous stirring.

5. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, In the step (3), the temperature of the reaction kettle is 60-65℃, after the reaction, the solid in the reaction liquid is filtered off, the filtrate is collected and cooled to 5-10℃, the pH value is adjusted to 6-8 by hydrochloric acid, and the crude product is collected.

6. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, In the step (3), the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide.

7. The process for the preparation of 4-amino-2,6-dimethoxypyrimidine according to claim 1, characterized in that, After the step (3) is completed, the crude product is refined, including adding water, acetonitrile, the crude product and activated carbon into the reaction kettle, heating and stirring at 80℃ for 1h, then filtering off the activated carbon, gradually cooling the obtained filtrate to 0-5℃, crystallizing for 1h, and then discharging and centrifuging to obtain the final product.

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