Green synthesis method of 4, 6-dimethoxy-2-methylthio pyrimidine

Abstract

The invention discloses a green synthesis method of 4, 6-dimethoxy-2-(methylthio) pyrimidine, which comprises the following steps of: synthesizing 4, 6-dimethoxy-2-(methylthio) pyrimidine; according to the method, 4, 6-dihydroxypyrimidine-2-sodium sulfide is taken as a raw material, low-toxicity and harmless dimethyl carbonate is taken as a methylation reagent, lewis acid is added to serve as a catalyst, a reaction is performed in a phase transfer catalyst, and a 4, 6-dimethoxy-2-methylthio pyrimidine solid is prepared. The synthesis method disclosed by the invention has the advantages of cheap raw materials, simple synthesis method and high yield, toxic and harmful reagents in a fractional step method are avoided, the used phase transfer catalyst can be recycled and reused, and the synthesis method is suitable for commercial production.

Description

Technical Field

[0001] The present invention relates to the field of fine chemical technologies, and particularly to a green one-step synthesis method of 4,6-dimethoxy-2-methylthiopyrimidine, which is an important intermediate for pharmaceuticals and pesticides.

Background Art

[0002] 4,6-Dimethoxy-2-methylthiopyrimidine is an important intermediate for fine chemicals and can be used in the production of pyrimidine herbicides such as pyrithiobac-sodium, bispyribac-sodium, and propyl-oxadiazon, and also in the synthesis of intermediates for drugs such as ET A -R antagonists (antihypertensive drugs), amoxapine (antidepressant drugs), etc. Currently, the developed syntheses of 4,6-dimethoxy-2-methylthiopyrimidine include a three-step synthesis method and a one-step synthesis method.

[0003] The three-step method uses 4,6-dihydroxypyrimidine-2-sodium sulfide as a raw material and synthesizes 4,6-dimethoxy-2-methylthiopyrimidine through methylation, chlorination, and methoxylation (CN105026376A[P].2015), which is also the most common production method at home and abroad currently. For the first step of methylation, dimethyl sulfate (Tian Shengjun. Synthesis of 2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid and related intermediates [D]. Shandong University, 2003.), methyl iodide (U.S.Patent 4,199,583[P].1980-4-22.), methyl bromide (U.S.Patent 5,097,030[P].1992-3-17), etc. are commonly used. However, when methyl iodide is used with acetone or methanol as a solvent, the yield is less than 65%. When methyl bromide is used as a methylation reagent, the yield is 91%, but methyl bromide is a gas, highly toxic, and prone to explosion at room temperature. Currently, the commonly used dimethyl sulfate reaction has a yield of 98%, but dimethyl sulfate decomposes into sulfuric acid and methanol when encountering water and is accompanied by intense heat release, posing a safety hazard in industry. For the second step of chlorination reagent (CN112552244A), phosphorus trichloride and phosphorus oxychloride are generally used, and the yield is 92%. Both are toxic chemicals and will cause a large amount of acidic phosphorus-containing wastewater. In addition, the product after chlorination is sensitizing and can cause damage to operators. For the third step of methoxylation reagent, Williamson ether synthesis (CN101747283B) is generally used, and the yield is 97%. The overall yield of the three-step reaction is currently between 70% and 80%, but the three-step method is dangerous to operate and all require highly toxic and harmful chemicals, and the post-treatment is quite troublesome.

[0004] There have also been explorations on the method of directly synthesizing 4,6-dimethoxy-2-methylthiopyrimidine in one step. Guo Feng used dimethyl sulfate as the methylation reagent to directly synthesize 4,6-dimethoxy-2-methylthiopyrimidine under the action of a phase transfer catalyst and ultrasonic waves, with a yield of 53% ("Simple Synthesis of 2-Methylsulfonyl-4,6-dimethoxypyrimidine" [J]. Chemical Bulletin, 2005(11): 876-877). Using chloromethane, etc. as the methylation reagent, N,N-dimethylformamide as the solvent, and potassium carbonate as the catalyst and acid-binding agent, 4,6-dimethoxy-2-methylthiopyrimidine was obtained in one step, with a yield of 53.1% (Guan J, Hu H, Wang B, et al. Facile and green synthesis of 4,6-dimethoxy-2-methylsulfonylpyrimidine - using chloromethane as methylating agent [J]. Journal of the Chinese Institute of Engineers, 2021, 44(1): 72-76.). Chloromethane is in a gaseous state, inconvenient to operate, and highly toxic. However, the yields in the above examples are not high, and highly toxic chemicals such as dimethyl sulfate and chloromethane are still used.

Summary of the Invention

[0005] In order to overcome the disadvantages existing in the above-mentioned prior art, the present invention provides a method for directly synthesizing 4,6-dimethoxy-2-methylthiopyrimidine in one step using low-toxic and harmless dimethyl carbonate.

[0006] The present invention is achieved through the following technical solutions:

[0007] The synthesis route is as follows:

[0008]

[0009] Among them, M = Na or K;

[0010] Specific steps: 1) Stir 4,6-dihydroxypyrimidine-2-sodium sulfide shown in formula I and an alkali in an aqueous solution until clear to obtain the salt shown in formula II, remove water, and dry; 2) Add the salt shown in formula II, a phase transfer catalyst, a catalyst, and dimethyl carbonate to an autoclave, stir and heat up. After the reaction is completed, filter by suction, distill to remove dimethyl carbonate to obtain a crude product, acidify the crude product to adjust the pH to 7-8, and filter to obtain 4,6-dimethoxy-2-methylthiopyrimidine shown in formula III.

[0011] The phase transfer catalyst is one or more of polyethylene glycol-400, tetrabutylammonium bromide, tetrabutylammonium chloride, sodium dodecyl sulfate, and cetyltrimethylammonium bromide.

[0012] In step 2), the catalyst is one or more of zinc trifluoromethanesulfonate, cesium carbonate, and zinc chloride.

[0013] In step 2), the molar ratio of the salt shown in formula II to dimethyl carbonate is 1:10 to 20.

[0014] In step 2), the reaction pressure is 1.5 to 3.0 MPa, and the reaction temperature is 120 to 200 °C.

[0015] In step 1), the base is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, and potassium carbonate.

[0016] Compared with the existing synthesis methods, the present invention has the following advantages:

[0017] (1) The reaction methylation reagent is dimethyl carbonate, which is low-toxic and harmless, avoiding the generation of sulfur-containing waste gas and waste liquid.

[0018] (2) The reaction is a one-step synthesis, avoiding the generation of toxic intermediate products and simplifying the reaction route.

[0019] (3) The reaction reduces the use of catalysts. The phase transfer catalyst can be recycled and reused, effectively reducing the generation of solid waste and waste water.

Description of the Drawings

[0020] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of the 4,6-dimethoxy-2-methylthio-pyrimidine product.

Specific Embodiments

[0021] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0022] Example 1:

[0023] 4,6-Dihydroxypyrimidine-2-sodium sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain 4,6-diphenolate-2-sodium sulfide pyrimidine, and then the solvent was removed and dried. 4.2 g (0.02 mol) of 4,6-diphenolate-2-sodium sulfide pyrimidine, 6.4 g of cetyltrimethylammonium chloride, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The temperature was raised to 130 °C under stirring, the pressure in the autoclave was 1.5 MPa, and the reaction time was 14 to 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered, the pH of the filtrate was adjusted to 7 to 8, and 2.72 g of a yellowish-white solid was obtained by filtration, with a yield of 73.2% and a purity of 98%. The filtrate was recycled.

[0024] Example 2:

[0025] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of potassium hydroxide were stirred in an aqueous solution until clear to obtain potassium 4,6-dihydroxypyrimidine-2-sulfide. Then the solvent was removed and dried. 5.2 g (0.02 mol) of potassium 4,6-dihydroxypyrimidine-2-sulfide, 6.4 g of cetyltrimethylammonium chloride, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 150 °C with stirring, the pressure inside the autoclave was 2.2 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.93 g of a yellowish-white solid was obtained by filtration, with a yield of 78.6% and a purity of 97.6%. The filtrate was recycled for reuse.

[0026] Example 3:

[0027] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of potassium hydroxide were stirred in an aqueous solution until clear to obtain potassium 4,6-dihydroxypyrimidine-2-sulfide. Then the solvent was removed and dried. 5.2 g (0.02 mol) of potassium 4,6-dihydroxypyrimidine-2-sulfide, 6.4 g of cetyltrimethylammonium chloride, 4 mg of potassium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 150 °C with stirring, the pressure inside the autoclave was 2.2 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.14 g of a yellowish-white solid was obtained by filtration, with a yield of 57.3% and a purity of 94.6%. The filtrate was recycled for reuse.

[0028] Example 4:

[0029] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain sodium 4,6-dihydroxypyrimidine-2-sulfide. Then the solvent was removed and dried. 4.2 g (0.02 mol) of sodium 4,6-dihydroxypyrimidine-2-sulfide, 6.4 g of cetyltrimethylammonium chloride, 4 mg of zinc trifluoromethanesulfonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 150 °C with stirring, the pressure inside the autoclave was 2.3 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.42 g of a yellowish-white solid was obtained by filtration, with a yield of 64.9% and a purity of 96.2%. The filtrate was recycled for reuse.

[0030] Example 5:

[0031] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine. Then the solvent was removed and dried. 4.2 g (0.02 mol) of sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine, 6.4 g of cetyltrimethylammonium chloride, 4 mg of zinc chloride, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 140 °C with stirring, the pressure inside the autoclave was 2.4 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.31 g of a yellowish-white solid was obtained by filtration, with a yield of 61.8% and a purity of 94.7%. The filtrate was recycled and reused.

[0032] Example 6:

[0033] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine. Then the solvent was removed and dried. 4.2 g (0.02 mol) of sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine, 6.5 g of tetrabutylammonium bromide, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 140 °C with stirring, the pressure inside the autoclave was 2.4 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.47 g of a yellowish-white solid was obtained by filtration, with a yield of 65.6% and a purity of 95.7%. The filtrate was recycled and reused.

[0034] Example 7:

[0035] Sodium 4,6-dihydroxypyrimidine-2-sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine. Then the solvent was removed and dried. 4.2 g (0.02 mol) of sodium 4,6-dihydroxyphenolate-2-sulfopyrimidine, 8 g of polyethylene glycol-400, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave. After sealing, the temperature was raised to 140 °C with stirring, the pressure inside the autoclave was 2.4 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain a crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.04 g of a yellowish-white solid was obtained by filtration, with a yield of 54.7% and a purity of 94.0%. The filtrate was recycled and reused.

[0036] Example 8:

[0037] 4,6-Dihydroxypyrimidine-2-sodium sulfide and an equimolar amount of sodium hydroxide were stirred in an aqueous solution until clear to obtain 4,6-diphenolate-2-sodium thiopyrimidine. Then the solvent was removed and dried. 4.2 g (0.02 mol) of 4,6-diphenolate-2-sodium thiopyrimidine, 5.56 g of tetrabutylammonium chloride, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave, sealed, and then heated to 140 °C with stirring. The pressure inside the autoclave was 2.4 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain the crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 2.51 g of a yellowish-white solid was obtained by filtration, with a yield of 67.2% and a purity of 94.0%. The filtrate was recycled for use.

[0038] Comparative Example 1:

[0039] 4,6-Dihydroxypyrimidine-2-sodium sulfide and an equimolar amount of potassium hydroxide were stirred in an aqueous solution until clear to obtain 4,6-diphenolate-2-potassium thiopyrimidine. Then the solvent was removed and dried. 5.2 g (0.02 mol) of 4,6-diphenolate-2-potassium thiopyrimidine, 4 mg of cesium carbonate, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave, sealed, and then heated to 150 °C with stirring. The pressure inside the autoclave was 1.6 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain the crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 1.21 g of a yellowish-white solid was obtained by filtration, with a yield of 32.4% and a purity of 86.1%.

[0040] Comparative Example 2:

[0041] 4,6-Dihydroxypyrimidine-2-sodium sulfide and an equimolar amount of potassium hydroxide were stirred in an aqueous solution until clear to obtain 4,6-diphenolate-2-potassium thiopyrimidine. Then the solvent was removed and dried. 5.2 g (0.02 mol) of 4,6-diphenolate-2-potassium thiopyrimidine, 6.4 g of cetyltrimethylammonium chloride, and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor inside the autoclave, sealed, and then heated to 150 °C with stirring. The pressure inside the autoclave was 2.2 MPa, and the reaction time was 14 - 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and the solvent was removed by distillation to obtain the crude product. The crude product was acidified and then filtered. The pH of the filtrate was adjusted to 7 - 8, and 0.925 g of a yellowish-white solid was obtained by filtration, with a yield of 24.8% and a purity of 92.3%.

[0042] Comparative Example 3:

[0043] 4,6-Dihydroxypyrimidine-2-sodium sulfide and an equimolar amount of potassium hydroxide were stirred in an aqueous solution until clear to obtain 4,6-dipotassium phenolate-2-potassium thiopyrimidine, and then the solvent was removed and dried. 5.2 g (0.02 mol) of 4,6-dipotassium phenolate-2-potassium thiopyrimidine and 27 g (0.3 mol) of dimethyl carbonate were added to a 100 mL autoclave. The autoclave was purged with nitrogen three times to remove oxygen and water vapor in the autoclave, sealed, and then heated to 150 °C with stirring. The pressure in the autoclave was 2.2 MPa, and the reaction time was 14 to 16 hours. After the reaction was completed, the reaction solution was filtered by suction, and almost no product was obtained after the solvent was removed by distillation.

[0044] The above are only the preferred embodiments of the present invention. For the present invention, they are merely illustrative and not restrictive; as understood by those of ordinary skill in the art, within the scope defined by the claims of the present invention, many changes, modifications, and even equivalent changes can be made to it, but all will fall within the protection scope of the present invention.

Claims

1. A green synthesis method of 4,6-dimethoxy-2-methylthiopyrimidine, characterized in that: The synthetic route is as follows: Wherein, M=Na or K; The specific steps are as follows: 1) stirring the sodium 4,6-dihydroxypyrimidine-2-sulfide shown in formula I and a base in an aqueous solution until it becomes clear to obtain the salt shown in formula II, removing water and drying; 2) adding the salt shown in formula II, a phase transfer catalyst, a catalyst, and dimethyl carbonate into an autoclave, stirring and heating, and after the reaction is completed, filtering and distilling to remove dimethyl carbonate to obtain a crude product, acidifying the crude product to adjust the pH to 7-8, and filtering to obtain 4,6-dimethoxy-2-methylthiopyrimidine shown in formula III.

2. The synthesis method according to claim 1, characterized in that The phase transfer catalyst is one or more of polyethylene glycol-400, tetrabutylammonium bromide, tetrabutylammonium chloride, sodium dodecyl sulfate, and hexadecyltrimethylammonium bromide.

3. The synthesis method according to claim 1, characterized in that In step 2), the catalyst is one or more of zinc trifluoromethanesulfonate, cesium carbonate, and zinc chloride.

4. The synthesis method according to claim 1, characterized in that In step 2), the molar ratio of the salt represented by formula II to dimethyl carbonate is 1:10-20.

5. The synthesis method according to claim 1, characterized in that In step 2), the reaction pressure is 1.5-3.0 MPa, and the reaction temperature is 120-200°C.

6. The synthesis method according to claim 1, characterized in that In step 1), the base is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate and potassium carbonate.

Images