A kind of preparation method of mesosulfuron

Abstract

The invention discloses a method for preparing mesosulfuron, wherein pyrimidine amine and a phosgene compound are reacted to obtain isocyanate, and then the isocyanate is condensed with 5-methylsulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide to obtain mesosulfuron. The method of the invention has high yield, high purity of the obtained product, and few by-products are generated during the preparation process and are easy to recover.

Description

Technical Field

[0001] The invention relates to a method for preparing a herbicide, in particular to a method for preparing sulfonylurea herbicide mesosulfuron. Background Art

[0002] Mesosulfuron-methyl, also known as methyldisulfone, is a new sulfonylurea herbicide developed by Aventis (later acquired by Bayer) in 1993. It is a sulfonylurea acetolactate synthase (ALS) inhibitor and is mainly used for weeding in winter wheat fields. It can control annual broad-leaved weeds and some grass weeds, such as wild oats, coix seed, bluegrass, hard grass, alkali grass, multi-flowered ryegrass, lycium barbarum, brome, candle grass, knotweed, chrysanthemum, wheat crown, wheatgrass, shepherd's purse, sophora japonica, chickweed, and spontaneous rapeseed.

[0003] Mesosulfuron works as an ALS inhibitor, which is mainly absorbed by the stems and leaves of plants, and transmitted through the phloem and xylem. It inhibits the activity of acetolactate synthase in sensitive plants, thereby inhibiting the cell division of sensitive plants and causing the death of plants. Generally, the absorption of sensitive weeds reaches a peak 2 to 4 hours after application, and growth stops after 2 days. After 4 to 7 days, the leaves begin to turn yellow, followed by the appearance of dead spots, and die after 2 to 4 weeks.

[0004] There have been many patent documents and other documents reporting on the preparation process of mesosulfuron-methyl, among which the earlier and more influential patent documents include DE433297, US5648315, US2002062029, etc.

[0005] For example, industrial products p-toluic acid, p-toluonitrile, 4-halo-2-aminobenzoic acid and 6-nitrosaccharin are used as starting materials, and the key intermediate methyl disulfonamide is obtained after multiple steps of reaction, and then methyl disulfonamide is obtained by ester exchange reaction with pyrimidine aminophenyl ester; the final product methyl disulfonamide is obtained; the last step of ester exchange reaction is as follows:

[0006] .

[0007] The biggest drawback of the last step of the transesterification reaction is that a large amount of phenol is produced as a byproduct, about 190 kg of phenol is produced for every ton of product produced. Although these byproduct phenols can be recycled, it is quite difficult to recycle due to the properties of phenol itself. In addition, the residual phenol in the product makes the product particularly prone to reddening and deterioration, which has a great impact on the quality and storage of the product.

[0008] Chinese patent document CN104610167A (application number 201510026964.8) reported another synthesis method, which is to use the key intermediate methyl disulfonamide to react with ethyl chloroformate to obtain a carbamate intermediate, and then react with pyrimidine amine to obtain the product methyl disulfonamide. The reaction formula is as follows:

[0009] .

[0010] This method uses ethyl ester instead of phenyl ester to avoid the defect of by-product phenol, but the maximum purity of the obtained product is only 96%, which may be due to the long-term heating reflux and the high temperature leading to more impurities. Even if isopropyl ether is used for purification, it is difficult to completely remove the impurities.

[0011] Chinese patent document CN 113999178A (application number 202011553706.2) discloses a one-pot method for preparing mesosulfuron, wherein 5-aminomethyl-2-methoxycarbonylbenzenesulfonamide and methanesulfonyl chloride are subjected to a first mesylation reaction in an organic solvent in the presence of 1,8-diazabicycloundec-7-ene, and 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine is directly added to the untreated system after the first mesylation reaction to carry out a second condensation reaction.

[0012] Chinese patent document CN 113999178A (application number 202011553706.2) discloses a method for preparing methyl disulfone, in which the last step is to couple 2-methoxycarbonyl-5-methylsulfonylaminomethylbenzenesulfonamide (compound 5) with 4,6-dimethoxy-2-(phenoxycarbonyl)aminopyrimidine to obtain the target product methyl disulfone. Summary of the invention

[0013] The technical problem to be solved by the present invention is to provide a preparation method of mesosulfuron with high yield and high purity.

[0014] The technical solution for achieving the purpose of the present invention is a method for preparing mesosulfuron, which comprises reacting pyrimidineamine with a phosgene compound to obtain isocyanate, and then condensing the isocyanate with 5-methylsulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide to obtain mesosulfuron.

[0015] Furthermore, when pyrimidineamine reacts with phosgene compounds, the phosgene compounds are first dispersed in a solvent, cooled to 0-5°C, and then the pyrimidineamine solution is added dropwise, stirred for 20-60 minutes after the addition is complete, and an acid binding agent is added after the addition is complete, and stirred for 0.5-1h after the addition is complete to obtain isocyanate.

[0016] Preferably, the phosgene compound is phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate.

[0017] Preferably, the acid binding agent is one or a combination of more than one of trialkylamine, pyridine, alkylpyridine, N-methyltetrahydropyrrole, and N-methylpiperidine.

[0018] Preferably, the molar ratio of the acid binding agent to the pyrimidineamine is 3 to 5:1.

[0019] The molar ratio of the 5-methanesulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide to pyrimidineamine is 0.5-1.2:1.

[0020] The present invention has positive effects:

[0021] The invention firstly reacts pyrimidine amine with a phosgene compound to obtain an intermediate isocyanate with high activity, and then condenses the intermediate isocyanate with a sulfonamide to obtain the desired sulfonylurea product methyl disulfonyl; the by-products generated in the preparation process are easy to recover, thereby avoiding the problem of difficult recovery of phenol in the ester exchange reaction between methyl disulfonamide and pyrimidine aminophenyl ester; therefore, the invention has a high yield (more than 92%) and a high purity of the product (reaching 99%). BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the HPLC detection spectrum of mesosulfuron prepared in Example 1.

[0023] Figure 2 This is the HPLC detection spectrum of mesosulfuron prepared in Example 2.

[0024] Figure 3 This is the HPLC detection spectrum of mesosulfuron prepared in Example 3. DETAILED DESCRIPTION

[0025] The reaction principle of preparing mesosulfuron in the present invention is shown in the following formula:

[0026] .

[0027] (Example 1)

[0028] The preparation method of mesosulfuron of the present embodiment comprises the following steps:

[0029] ① Preparation of isocyanate.

[0030] Add 700g of dichloromethane and 35g of di(trichloromethyl)carbonate to a dry 1000mL reaction bottle, stir, and cool the solution to 0-5°C after the di(trichloromethyl)carbonate is dissolved. Add pyrimidineamine (compound III, 2-amino-4,6-dimethoxypyrimidine) solution (0.226 mol, 35g of pyrimidineamine is dissolved in 100g of dichloromethane) dropwise to the di(trichloromethyl)carbonate solution, stir for 20-60min (30min in this embodiment), then add 100g of acid-binding agent triethylamine dropwise, stir for 0.5-1h after addition, and obtain an isocyanate (compound IV) solution for standby use. The temperature is controlled below 50°C during the reaction.

[0031] In addition to the above-mentioned dichloromethane, other aprotic organic solvents may also be used as the solvent, for example, one of benzene, toluene, xylene, acetonitrile, chloroform, and dichloroethane.

[0032] Furthermore, the acid binding agent is one or a combination of trialkylamine, pyridine, alkylpyridine, N-methyltetrahydropyrrole, and N-methylpiperidine. In this embodiment, the acid binding agent is trialkylamine, specifically triethylamine.

[0033] ②Condensation reaction.

[0034] In another dry 3000mL reaction bottle, add 69g (0.215 mol) of 5-methanesulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide and 150g of dichloromethane, cool to 0-5°C, slowly add the isocyanate solution prepared in step ① under stirring, the reaction is exothermic, and the dropping rate of the isocyanate solution is controlled so that the temperature of the system does not exceed 30°C.

[0035] After the isocyanate solution was added, stirring was continued for 2 h, 1 L of water was added, stirring was thorough, and the organic phase was separated. The aqueous phase was acidified with 2 M hydrochloric acid, the precipitated solid was filtered, and dried to obtain 99 g of the target product as a milky white powdery solid with a yield of 92% and a purity of 99.1% as determined by HPLC (see HPLC detection spectrum). Figure 1 ).

[0036] Among them, HPLC detection instrument: Agilent Technologies 1260 Infinity.

[0037] Chromatographic column: BDS-5, column length: 250 mm, inner diameter: 4.6 mm, column temperature: 30 C, column pressure: 151 MPa, flow rate: 1.5 mL / min, detection wavelength: 254 nm, mobile phase: acetonitrile / water (pH = 3.0, phosphoric acid) = 40 / 60.

[0038] (Example 2)

[0039] The preparation method of mesosulfuron in this embodiment is the same as that in Example 1, except that:

[0040] Step ① When preparing isocyanate, add 700g of dichloromethane and 35g of trichloromethyl chloroformate into a dry 1000mL reaction bottle.

[0041] The above-mentioned diphosgene and triphosgene can also be replaced by phosgene.

[0042] Step ② After drying, 100 g of milky white powdery solid was obtained with a yield of 92% and a purity of 98.6% as determined by HPLC (see HPLC detection spectrum). Figure 2 ).

[0043] (Example 3)

[0044] The preparation method of mesosulfuron in this embodiment is the same as that in Example 1, except that:

[0045] Step ① When preparing isocyanate, add 700g toluene and 35g di(trichloromethyl)carbonate to a dry 1000mL reaction bottle, stir, and after the di(trichloromethyl)carbonate is dissolved, cool the solution to 0-5°C, add pyrimidineamine solution (0.226 mol, 35g pyrimidineamine is dispersed in 100g toluene to obtain a suspension) dropwise to the di(trichloromethyl)carbonate solution, stir for 30min after addition, then add 100g of acid binding agent triethylamine dropwise, stir for 1h after addition, and obtain an isocyanate solution for standby use.

[0046] The solvent in step ② is toluene.

[0047] Step ② After drying, a milky white powdery solid of 102 g was obtained with a yield of 93% and a purity of 98.2% as determined by HPLC (see HPLC detection spectrum). Figure 3 ).

[0048] (Example 4)

[0049] The preparation method of mesosulfuron in this embodiment is the same as that in Example 1, except that:

[0050] Step ① When preparing isocyanate, add 700g of acetonitrile and 35g of di(trichloromethyl)carbonate to a dry 1000mL reaction bottle, stir, and after the di(trichloromethyl)carbonate is dissolved, cool the solution to 0-5°C, dropwise add pyrimidineamine solution (0.226 mol, 35g of pyrimidineamine dissolved in 100g of acetonitrile) to the di(trichloromethyl)carbonate solution, stir for 30min after addition, then dropwise add 100g of acid binding agent triethylamine, stir for 1h after addition, and obtain an isocyanate solution for standby use.

[0051] The solvent in step ② is acetonitrile.

[0052] After drying in step ②, 91 g of a milky white powdery solid was obtained with a yield of 84% and a purity of 98% as determined by HPLC.

[0053] (Example 5)

[0054] The preparation method of mesosulfuron in this embodiment is the same as that in Example 1, except that:

[0055] Step ① When preparing isocyanate, the acid binding agent is diisopropylethylamine. After adding the pyrimidine amine solution and stirring for 30 minutes, 128 grams of diisopropylethylamine is added dropwise, and stirred for 1 hour after adding to obtain an isocyanate solution for standby use.

[0056] Step ② After drying, 104 g of a milky white powdery solid was obtained with a yield of 96% and a purity of 98.4% as determined by HPLC.

[0057] (Comparative Example 1)

[0058] A -20 ℃ deep-freezing condenser was installed in a 500 mL dry reaction bottle, and 300 mL dry xylene, 40 g 5-methylsulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide, 35 g di(trichloromethyl)carbonate and 10 g n-butyl isocyanate were added to the reaction bottle, and the temperature was slowly raised, and the temperature was kept at 80-90 ℃ for 1 hour, and 130-140 ℃ for 2 hours. The whole process was turbid and no dissolution was observed. After cooling to room temperature, filtering and drying, 38 g of milky white solid was obtained, which was detected by HPLC as unreacted raw material 5-methylsulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide.

Claims

1. A method for preparing mesosulfuron, characterized in that: First, pyrimidine amine is reacted with a phosgene compound to obtain isocyanate, and then the isocyanate is condensed with 5-methylsulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide to obtain methyl disulfonyl; The pyrimidine amine is 2-amino-4,6-dimethoxypyrimidine; the phosgene compound is phosgene, trichloromethyl chloroformate or bis(trichloromethyl) carbonate; When pyrimidine amine reacts with a phosgene compound, the phosgene compound is first dispersed in a solvent, the solvent is dichloromethane, cooled to 0-5°C, then the pyrimidine amine solution is added dropwise, stirred for 20-60 minutes after the addition, and then an acid binding agent is added, stirred for 0.5-1h after the addition, to obtain an isocyanate, and the temperature is controlled to be lower than 50°C during the reaction; the acid binding agent is triethylamine or diisopropylethylamine, and the molar ratio of the acid binding agent to the pyrimidine amine is 3-5:1; When isocyanate reacts with 5-methanesulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide, 5-methanesulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide and a solvent are added to a reaction bottle, wherein the solvent is dichloromethane, and the reaction is cooled to 0-5°C; pyrimidineamine and a phosgene compound are slowly added under stirring to react to obtain an isocyanate solution, the reaction is exothermic, and the dropping speed of the isocyanate solution is controlled so that the temperature of the system does not exceed 30°C; the molar ratio of 5-methanesulfonylaminomethyl-2-methoxycarbonylbenzenesulfonamide to pyrimidineamine is 0.5-1.2:1.

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