Pyrazole herbicide intermediate and preparation method thereof

Abstract

The invention discloses a pyrazole herbicide intermediate and a preparation method thereof. Wherein the compound (4) is prepared by cyclization of the compound (3). The compound (3) is synthesized by reacting a compound (2) with methanol under an acidic condition, and the compound (2) is synthesized by reacting a compound (1) with methylhydrazine. The synthesis method of the compound (4) is simple, convenient, safe, green, environment-friendly, high in conversion rate and low in cost. Structures of compounds (1), (2), (3) and (4) are as follows: # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of pesticide synthesis, and in particular to a pyrazole herbicide intermediate and a preparation method thereof. Background Art

[0002] Benpyrazone is a common herbicide with good effects. It belongs to the class of hydroxyphenylpyruvate dioxidase (HPPD) inhibitors and has a good control effect on weeds resistant to glyphosate, triazines, acetolactate synthase (ALS) inhibitors and acetyl-CoA carboxylase inhibitors. The chemical structure of Benpyrazone is as follows:

[0003] 1-Methyl-5-hydroxypyrazole is an important intermediate for preparing benzathine. The prior art discloses a variety of methods for preparing 1-methyl-5-hydroxypyrazole, among which CN105218449, IN201611027903, WO2017075910, WO2009069044, and CN111440160 disclose methods for preparing 1-methyl-5-hydroxypyrazole as follows:

[0004]

[0005] The existing method uses diethyl malonate or the like and triethyl orthoformate or methyl ester, acetic anhydride to react, and then with methyl hydrazine ring closure, hydrolysis and decarboxylation to obtain the intermediate 1-methyl-5-hydroxypyrazole of fenpyrazone. However, the method has poor selectivity in the ring closure step with methyl hydrazine, resulting in the final production of a large amount of isomers of 1-methyl-4-hydroxypyrazole, with low yield, and the acetic anhydride and its by-products in the process are highly corrosive and difficult to recover, and the amount of triethyl orthoformate (or methyl ester) used is large and the price is relatively expensive, which is not conducive to large-scale industrial production.

[0006] In addition, the prior art WO2009069044 reports the following reaction formula for preparing 1-methyl-5-hydroxypyrazole:

[0007]

[0008] That is, 1-methyl-5-hydroxypyrazole is prepared by cyclizing methyl 3-methoxyacrylate with methyl hydrazine in methanol as solvent. However, the raw material methyl 3-methoxyacrylate is difficult to buy on the market and is expensive, which is not conducive to industrial production. At the same time, a large number of isomer products will be generated in this route, which reduces the yield of the target product and further increases the synthesis cost of 1-methyl-5-hydroxypyrazole.

[0009] Finding a suitable preparation method for 1-methyl-5-hydroxypyrazole and reducing its synthesis cost can also reduce the production cost of fenpyrazone, which is more conducive to its promotion and application in agriculture. Summary of the invention

[0010] The purpose of the present invention is to provide a preparation method of compound ④ (1-methyl-5-hydroxypyrazole) to reduce its production cost in view of the defect of high synthesis cost of 1-methyl-5-hydroxypyrazole in the prior art. The present invention uses common and cheap chemicals to replace expensive and corrosive chemicals, provides a simple, safe, environmentally friendly and low-cost synthesis route, is suitable for large-scale industrial production, and greatly reduces the production cost of compound ④.

[0011] Specifically, the present invention provides a method for preparing compound ④, comprising the following steps: in a solvent, compound ③ undergoes a ring-closing reaction in the presence of a base to prepare compound ④;

[0012] Its synthetic route is as follows:

[0013]

[0014] Preferably, the preparation of compound ③ comprises the following steps: compound ② reacts with methanol in the presence of an acid to generate compound ③; the synthesis route is as follows:

[0015]

[0016] Preferably, the preparation method of compound ② comprises the following steps: compound ① reacts with methylhydrazine to generate compound ②;

[0017] Its synthetic route is as follows:

[0018]

[0019] Particularly preferably, the present invention provides intermediate compound ② and compound ③,

[0020]

[0021] Further, compound ① is prepared by the following steps: cyanoacetic acid is reacted with N,N-dimethylformamide dimethyl acetal to prepare compound ①. Specific reference is made to document CN115551511A.

[0022] Beneficial effects of the present invention

[0023] 1. The present invention synthesizes compound ④ (1-methyl-5-hydroxypyrazole) from compound ③ with high yield and purity, and the cost of synthesizing 1-methyl-5-hydroxypyrazole is low.

[0024] 2. Compound ① is synthesized from raw materials with lower cost, compound ② is synthesized with high yield from compound ① and methylhydrazine, and compound ③ is synthesized from intermediate compound ②. The process is simple as a whole, and the cost is optimized, thus overcoming the defects that the raw material 3-methoxymethyl acrylate is difficult to buy on the market, is expensive, and is not conducive to industrial production.

[0025] 3. The process route of the present invention has low raw material cost, and the preparation method is simpler, safer and more environmentally friendly. The cost advantage of preparing compound ④ is obvious. Even if compound ① is used as raw material, the cost of compound ④ (1-methyl-5-hydroxypyrazole) per ton is only RMB 100,000 per ton. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0027] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0028] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0029] One general aspect of the present invention provides a method for preparing a pyrazole herbicide intermediate compound ④, which comprises the following steps: in a solvent, compound ③ undergoes a ring-closing reaction in the presence of a base to prepare compound ④;

[0030] Its synthetic route is as follows:

[0031]

[0032] The base is selected from an inorganic base or an organic base, wherein the inorganic base is one or more of potassium carbonate, sodium hydroxide and sodium carbonate, preferably one of potassium carbonate and sodium hydroxide, and particularly preferably potassium carbonate; the organic base is one of sodium methoxide, sodium ethoxide, N,N-diisopropylethylamine, pyridine, sodium formate, sodium acetate, potassium acetate and N,N-dimethylaniline, preferably one of sodium methoxide and sodium acetate;

[0033] The solvent is selected from at least one of methanol, ethanol, toluene, tetrahydrofuran, cyclohexane, ethylene dichloride, DMF and 1,2-butylene oxide, preferably at least one of methanol, ethanol and DMF, more preferably methanol.

[0034] Preferably, the molar ratio of compound ③ to the base is 1:(0.9-1.5), preferably 1:(1-1.2); the temperature of the ring-closure reaction is 10-140°C, preferably 30°C-80°C.

[0035] In the above preparation method, the preparation of compound ③ comprises the following steps: compound ② reacts with methanol in the presence of an acid to generate compound ③; its synthesis route is as follows:

[0036]

[0037] This route has high reaction yield and purity, and overcomes the defect of excessive isomer products in the prior art.

[0038] In the above preparation route, the acid is selected from an inorganic acid or an organic acid, the inorganic acid is one of sulfuric acid, hydrochloric acid, and phosphoric acid, preferably at least one of sulfuric acid and hydrochloric acid; the organic acid is one of p-toluenesulfonic acid, trifluoroacetic acid, and acetic acid. The molar ratio of compound ② to methanol is 1:(2-10), preferably 1:(3-8); the reaction temperature is 10-80°C, preferably 30°C-70°C.

[0039] In the above preparation method, the preparation method of compound ② comprises the following steps: compound ① reacts with methylhydrazine to generate compound ②;

[0040] Its synthetic route is as follows:

[0041]

[0042] The reaction temperature is -15 to 100°C, preferably -10 to 60°C. The reaction of compound ① with methylhydrazine is carried out in the presence of an organic solvent; the organic solvent is selected from at least one or more of methanol, ethylene dichloride, toluene, tetrahydrofuran, dichloromethane, ethanol, propylene oxide, cyclohexane, and N,N-dimethylformamide, preferably at least one or more of methanol, cyclohexane, ethylene dichloride, and toluene. The molar ratio of compound ① to methylhydrazine is 1:(1.05-1.5), preferably 1:(1.1-1.2).

[0043] The present invention also discloses compound ② and compound ③,

[0044]

[0045] The present invention also discloses that compound ② and compound ③ are used to prepare compound ④ (1-methyl-5-hydroxypyrazole), which overcomes the defects of high raw material cost and low production yield in the prior art, improves the yield of compound ④ (1-methyl-5-hydroxypyrazole), has a simpler production process and lowers production cost.

[0046] Furthermore, in the above preparation method, compound ① is prepared by the following steps:

[0047]

[0048] First, cyanoacetic acid is dissolved in dichloromethane, and N,N-dimethylformamide dimethyl acetal is added dropwise under stirring, and the reaction is maintained at 30-35° C. for 12 hours. The reaction of cyanoacetic acid is completed by detecting the completion of the reaction under GC conditions.

[0049] The present invention will be described in detail below by way of examples. The raw materials in the following examples are purchased from the market or obtained by self-production.

[0050] In the following examples, the amounts of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0051] In the following examples, the conversion rate and selectivity of the reaction were calculated by the following formula:

[0052] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%;

[0053] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%.

[0054] The conversion rate and yield in the following examples are calculated based on the results of HPLC detection, and the purity is the purity detected by HPLC.

[0055] Example 1 Preparation of Compound ①

[0056]

[0057] In a 500ml four-necked bottle equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel, add 1mol of cyanoacetic acid and 200g of dichloromethane, and when the temperature rises to 30-35°C, begin to dropwise add 1mol of N,N-dimethylformamide dimethyl acetal, and after the dropwise addition is completed, keep the temperature at 30-35°C for 12 hours, desolvate the dichloromethane under reduced pressure, and obtain compound ①. After testing and calculation, the purity of the obtained compound ① is 95%, the weight is 94g, and the yield is 93%.

[0058] The NMR characterization data of compound ① are as follows:

[0059] 1 HNMR (500MHz, CDCl3) δ6.93(d,1H),3.68(d,1H),2.89(s,6H).

[0060] Example 2 Synthesis of Compound ②

[0061]

[0062] In a 500ml four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel, add 94g (95% 0.93mol) of compound ① and 200g of methanol. Stir and cool to -10°C. Add 112g (42% 1.023mol) of methylhydrazine solution dropwise. Keep the reaction warm for 3 hours. Remove the solvent under reduced pressure to obtain compound ② with a weight of 89g, a purity of 96%, and a yield of 95.7%.

[0063] The NMR characterization data of compound ② are as follows:

[0064] 1 H NMR (500MHz, DMSO-d6) δ6.80(d,1H),4.26(d,1H),2.47(s,3H),2.07(s,1H),1.91(s,1H).

[0065] Example 3 Synthesis of Compound ②

[0066] The method of Example 2 was followed, except that the reaction solvent was 200 g of cyclohexane. The obtained compound ② weighed 89 g, had a purity of 96%, and a yield of 94.7%.

[0067] Example 4 Synthesis of Compound ②

[0068] The method of Example 2 was followed, except that the reaction solvent was 200 g of dichloroethane. The obtained compound ② weighed 88.9 g, had a purity of 96.4%, and a yield of 95%.

[0069] Example 5 Synthesis of Compound ②

[0070] The method of Example 2 was followed, except that the reaction solvent was 200 g of toluene. The obtained compound ② weighed 90 g, had a purity of 95.3%, and a yield of 95.1%.

[0071] Example 6 Synthesis of Compound ②

[0072] The method of Example 2 was followed, except that the reaction solvent was 200 g of N,N-dimethylformamide. The obtained compound ② weighed 88 g, had a purity of 95%, and a yield of 92.6%.

[0073] Example Investigate the effect of reaction temperature on the synthesis of compound ②

[0074] The method of Example 2 was followed, except that the reaction temperatures were -15°C, 0°C, 20°C, 40°C, 60°C, and 70°C, respectively. The reaction results were as follows:

[0075] Table 1 Effect of reaction temperature on the synthesis of compound ②

[0076] Example No. Reaction temperature Yield of compound ② Compound ②Purity 7 -15℃ 92.6％ 93.2％ 8 0℃ 95.8％ 96.2％ 9 20℃ 95.9％ 96.4％ 10 40℃ 96.2％ 96.7％ 11 60℃ 96.1％ 96.5％ 12 70℃ 91.7％ 94％

[0077] Example 13-16 Influence of the molar ratio of compound ① to methylhydrazine on the synthesis of compound ②

[0078] The method of Example 2 was followed, except that the molar ratios of compound ① to methylhydrazine were 1:1.05, 1:1.15, 1:1.2, and 1:1.3, respectively. The reaction results were as follows:

[0079] Table 2 Effect of the molar ratio of compound ① to methylhydrazine on the synthesis of compound ②

[0080]

[0081] Example 17 Synthesis of compound ③.

[0082]

[0083] In a 500ml four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel, add compound ②89g (97% 0.89mol), add anhydrous methanol 85.4g (2.67mol) and 1g sulfuric acid, stir and heat to 30°C to react for 6 hours. After the reaction is completed, remove the methanol under reduced pressure to obtain compound ③ with a weight of 115.7g, a purity of 95%, and a yield of 95%.

[0084] The NMR characterization data of compound ③ are as follows:

[0085] 1H NMR (500MHz, DMSO-d6) δ7.23(d,1H),4.79(d,1H),3.78(s,3H),2.47(s,3H),2.38(s,1H),2.10(s,1H).

[0086] Embodiment 18:

[0087] The method of Example 17 was followed, except that the reaction acid was 1 g of hydrochloric acid.

[0088] The weight of compound ③ obtained was 116 g, the purity was 95%, and the yield was 95.2%.

[0089] Embodiment 19:

[0090] The method of Example 17 was followed, except that 1 g of p-toluenesulfonic acid was used as the reaction acid.

[0091] The weight of compound ③ obtained was 114 g, the purity was 93%, and the yield was 91.6%.

[0092] Example Investigate the effect of reaction temperature on the synthesis of compound ③

[0093] The method of Example 17 was followed, except that the reaction temperatures were 10°C, 20°C, 50°C, 70°C, and 80°C, respectively. The reaction results are as follows:

[0094] Table 3 Effect of reaction temperature on the synthesis of compound ③

[0095] Example No. Reaction temperature Yield of compound ③ Compound ③ Purity 20 10℃ 93％ 92％ 21 20℃ 93.7％ 93.8％ 22 50℃ 95.5％ 95.9％ 23 70℃ 95.3％ 95.8％ 24 80℃ 93.2％ 92.5％

[0096] Example Investigate the effect of the molar ratio of compound ② to methanol on the synthesis of compound ③

[0097] The method of Example 17 was followed, except that the molar ratio of compound ② to methanol was 1:2, 1:3, 1:5, 1:8, and 1:10, respectively. The reaction results are as follows:

[0098] Table 4 Effect of the molar ratio of compound ② to methanol on the synthesis of compound ③

[0099]

[0100]

[0101] Example 30 Synthesis of compound ④.

[0102]

[0103] In a 1000ml four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and a dropping funnel, add compound ②115.7g (95% 0.845mol), add 200g anhydrous methanol, add 116.6g (0.845mol) of potassium carbonate, stir and heat to 30°C and keep stirring for 8 hours, remove the methanol under reduced pressure, add ethyl acetate 200g and 200g water to the reaction flask, add hydrochloric acid dropwise to adjust the aqueous phase to pH = 6-7, stir for 20 minutes, let stand and separate to obtain an ethyl acetate layer, remove the ethyl acetate under reduced pressure to obtain compound ④ weighing 82g, with a purity of 97% and a yield of 96%.

[0104] The NMR characterization data of compound ④ are as follows:

[0105] 1H NMR (500MHz, CDCl3) δ10.72(br,1H),7.27(d,1H),6.38(d,1H),3.61(s,3H).

[0106] Example 31 Synthesis of Compound ④:

[0107] The method of Example 30 was followed, except that the reaction solvent was 200 g of anhydrous ethanol.

[0108] The weight of compound ④ obtained was 81.5 g, the purity was 96%, and the yield was 94.5%.

[0109] Example 32 Synthesis of Compound ④:

[0110] The method of Example 30 was followed, except that the reaction solvent was 200 g DMF.

[0111] The weight of compound ④ obtained was 81 g, the purity was 95%, and the yield was 92.9%.

[0112] Example 33 Synthesis of Compound ④:

[0113] The method of Example 30 was followed, except that the reaction base was 45.6 g (0.845 mol) of sodium methoxide.

[0114] The weight of compound ④ obtained was 82 g, the purity was 96%, and the yield was 95%.

[0115] Example 34 Synthesis of Compound ④:

[0116] The method of Example 30 was followed, except that the reaction base was 57.4 g (0.845 mol) of sodium ethoxide.

[0117] The weight of compound ④ obtained was 81.3 g, the purity was 94.6%, and the yield was 92.9%.

[0118] Example The effect of reaction temperature on the synthesis of compound ④ was investigated by following the method of Example 30, except that the reaction temperatures were 10°C, 40°C, 60°C, and 70°C, respectively. The reaction results are as follows:

[0119] Table 5 Effect of reaction temperature on the synthesis of compound ④

[0120] Example No. Reaction temperature Yield of compound ④ Compound ④ Purity 35 10℃ 92.91％ 94.33％ 36 40℃ 96.52％ 97.64％ 37 60℃ 96.69％ 97.88％ 38 70℃ 96.61％ 97.82％

[0121] Example Investigate the effect of the molar ratio of compound ③ to base on the synthesis of compound ④

[0122] The method of Example 30 was followed, except that the molar ratios of compound ③ to the base were 1:0.9, 1:1.2, 1:1.3, and 1:1.5, respectively. The reaction results were as follows:

[0123] Table 6 Effect of the molar ratio of compound ③ to base on the synthesis of compound ④

[0124]

[0125] Comparative Example 1

[0126] According to the process route shown below in the prior art, a benzopyrazole herbicide intermediate having a structure shown in the formula is produced.

[0127]

[0128] The method specifically includes:

[0129] In a 500ml four-necked bottle equipped with a mechanical stirrer, a thermometer, and a condenser, add 0.1mol of diethyl malonate compound, 0.3mol of acetic anhydride, and 0.24mol of triethyl orthoformate, heat to 125℃ and reflux for 2 hours, then reduce the reflux temperature to 100-105℃, and control the diethyl malonate content to be less than 1% in the gas chromatography. Vacuum off the acetic acid mixture to 110℃, cool to 10℃ and add 50g of anhydrous methanol. Stir and control the reaction temperature to 10-15℃, add 0.12mol of methylhydrazine dropwise, add for 2h, react for 4 hours at 20-30℃, remove methanol under reduced pressure, add 30g of butanol and 20g of 70% sulfuric acid, heat to 90℃ and react for 7 hours, remove the water in the system, cool and filter to obtain the target product.

[0130] After testing and calculation, the purity of the phenylpyrazole herbicide intermediate with the structure shown in the obtained product is 83%, and the yield is 51%. In addition, it can be seen from the process of the process that the isomer 1-methyl-4-hydroxypyrazole is produced, which affects the yield, and acetic anhydride is used in the process, which will produce a large amount of acetic acid by-products. The acetic acid by-products are difficult to handle, so the process is not easy to produce in an environmentally friendly manner.

[0131] Comparative Example 2

[0132] According to the process route shown below in the prior art, a benzopyrazole herbicide intermediate having a structure shown in the formula is produced.

[0133]

[0134] The method specifically includes:

[0135] In a 250ml four-necked bottle equipped with a mechanical stirrer, a thermometer, and a condenser, methyl 3-methoxyacrylate (0.2mol), 30g methanol, and methyl hydrazine (0.2mol) were added in sequence. The mixture was stirred and heated to 90°C for 18 hours. When the methyl 3-methoxyacrylate content was less than 0.1%, the reaction was complete. The reaction solution was concentrated to obtain the target product compound ④.

[0136] After testing and calculation, the purity of the phenylpyrazole herbicide intermediate with the structure shown in the obtained product is 86% and the yield is 68%. And from the process of this process, it can be seen that the isomer 1-methyl-4-hydroxypyrazole is produced, which affects the yield, and the raw material 3-methoxy methyl acrylate is currently expensive in the market (the market price is as high as more than 100,000 yuan per ton, and the production cost of compound ④ produced by this route is as high as more than 300,000 yuan per ton), which is not conducive to large-scale industrial production.

[0137] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing compound ④, characterized in that: The method comprises the following steps: compound ③ is subjected to a ring-closing reaction in the presence of a base in a solvent to prepare compound ④; Its synthetic route is as follows:

2. The preparation method according to claim 1, characterized in that: The base is selected from an inorganic base or an organic base. The inorganic base is preferably one of potassium carbonate, sodium hydroxide, sodium carbonate and sodium carbonate, and particularly preferably one of potassium carbonate and sodium hydroxide. The organic base is preferably one of sodium methoxide, sodium ethoxide, N,N-diisopropylethylamine, pyridine, sodium formate, sodium acetate, potassium acetate and N,N-dimethylaniline. The solvent is selected from at least one of methanol, ethanol, toluene, tetrahydrofuran, cyclohexane, ethylene dichloride, DMF and 1,2-butylene oxide, preferably at least one of methanol, ethanol and DMF.

3. The preparation method according to claim 1 or 2, characterized in that The molar ratio of compound ③ to the base is 1:(0.9-1.5), preferably 1:(1-1.2); the temperature of the ring-closure reaction is 10-140°C, preferably 30°C-80°C.

4. The preparation method according to any one of claims 1 to 3, characterized in that The preparation of the compound ③ comprises the following steps: compound ② reacts with methanol in the presence of an acid to generate compound ③; the synthesis route is as follows:

5. The preparation method according to claim 4, characterized in that: The acid is an inorganic acid or an organic acid.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the compound ② to methanol is 1:(2-10), preferably 1:(3-8); the reaction temperature is 10-80°C, preferably 30°C-70°C.

7. The preparation method according to claim 6, characterized in that: The preparation method of compound ② comprises the following steps: compound ① reacts with methylhydrazine to generate compound ②; Its synthetic route is as follows:

8. The preparation method according to claim 7, characterized in that: The reaction temperature is -15°C to 100°C, preferably -10°C to 60°C.

9. The preparation method according to claim 7 or 8, characterized in that: The reaction of compound ① with methylhydrazine is carried out in the presence of an organic solvent; the organic solvent is selected from at least one or more of methanol, ethylene dichloride, toluene, tetrahydrofuran, dichloromethane, ethanol, propylene oxide, cyclohexane, and N,N-dimethylformamide, preferably at least one or more of methanol, cyclohexane, ethylene dichloride, and toluene.

10. The preparation method according to claim 9, characterized in that: The molar ratio of compound ① to methylhydrazine is 1:(1.05-1.5), preferably 1:(1.1-1.2).

11. Compound ②, 12. Compound ③,

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