A sulfamethoxaline intermediate compound, its preparation method and application

Abstract

The present invention belongs to the technical field of agricultural herbicides and relates to a thiopyralid intermediate compound, a preparation method and an application thereof. The thiopyralid intermediate compound is shown in structural formula (I) and is a stable compound that can be conveniently crystallized, separated, purified, stored and transported. The three-step reaction for preparing the thiopyralid intermediate compound (I) has a stable yield and mild reaction conditions, thereby improving the safety of the process. In addition, in the reaction of synthesizing thiopyralid (II) from the intermediate compound (I) of the present invention, the reaction conditions of the diazotization hydrolysis and salt formation steps are mild, and the yield can reach more than 90%.

Description

Technical Field

[0001] The present invention belongs to the technical field of agricultural herbicides, and in particular relates to a sulfamethoxam intermediate compound, a preparation method and an application thereof. Background Art

[0002] Pyrisulfuron (II), chemically known as 2-chloro-6-(4,6-dimethoxypyrimidin-2-mercapto)benzoic acid sodium salt, was developed by Kumihiko Chemical Co., Ltd. of Japan and jointly developed by Shirahara Co., Ltd. and DuPont of the United States. It was launched in 1994 as a cotton field herbicide for controlling annual and perennial broadleaf weeds and barnyard grass in cotton fields at an application rate of 35-105g / ha. Pyrisulfuron is an acetolactate synthase (ALS) inhibitor that achieves its weed control effect by inhibiting amino acid biosynthesis.

[0003]

[0004] Literature reports that there are two main methods for synthesizing sulfamethoxazole (II).

[0005] Method 1: CN1028171C reports the use of 2-amino-6-chlorobenzoic acid (IV) as a raw material, which is first diazotized and then reacted with 2-mercapto-4,6-dimethoxypyrimidine to obtain compound (III). Compound (III) is converted to its sodium salt to yield pyrifossulfuron (II). This route yields only 23% over two steps to produce compound (III). The diazotization reaction is a hazardous chemical process and produces a large amount of waste gas, wastewater, and inorganic salts, resulting in serious pollution.

[0006]

[0007] Method 2: Journal of Labelled Compounds and Radiopharmaceuticals, 49(4), 339-343; 2006. It was reported that 2-mercapto-6-chlorobenzoic acid (V) was used as a raw material, and 2-methylsulfonyl-4,6-dimethoxypyrimidine was reacted in the presence of sodium carbonate to obtain pyrimidine sulfide (II) with a yield of 70%. There are many synthetic methods for the raw material (V) used in this route, such as the literature J.Med.Chem. 2023, 66, 1522-1542. It was reported that compound (IV) was used as a raw material, and after aminodiazotization, it was reacted with potassium thioacetate and then hydrolyzed to obtain (V); Patent CN103360288B reported that 2,6-dichlorobenzonitrile was used as a raw material, and (V) was obtained by thiolation and high-temperature hydrolysis (150°C). Compound (V) is an aromatic thiol compound, which is easily oxidized to disulfide, making it difficult to separate, purify, store and use, bringing difficulties to actual production operations.

[0008]

[0009] In summary, the first method for synthesizing pyrimidine sulfide suffers from the disadvantages of using a hazardous diazotization chemical process, resulting in low yields and high levels of waste. The intermediate (V) in the second method is unstable and cannot be isolated and purified. Furthermore, currently reported methods for synthesizing intermediate (V) either use diazotization or high-temperature reactions, both of which have safety drawbacks. Therefore, existing pyrimidine sulfide synthesis processes fail to meet economic, safety, and environmental requirements. Summary of the Invention

[0010] In view of the deficiencies in the above-mentioned prior art, the present invention provides a sulfamethoxam intermediate compound, a preparation method and application thereof. The specific technical solutions are as follows:

[0011] The first object of the present invention is to provide a sulfamethoxam intermediate compound, the structural formula of which is shown in (I):

[0012] The sulfamethoxazole intermediate compound (I) provided by the present invention, namely 2-chloro-6-[(4,6-dimethoxypyrimidin-2-yl)thio]-benzamide, is a stable compound and can be conveniently separated by crystallization, purified, stored and transported.

[0013] The second object of the present invention is to provide a method for synthesizing the above-mentioned sulfamethoxazole intermediate compound, the reaction formula of which is as follows:

[0014]

[0015] (1) Using compound 2,6-dichlorobenzonitrile (VI) as a starting material, dissolving it in a solvent, and using a thiolation reagent to undergo sulfur substitution to obtain compound (VII);

[0016] (2) Hydrolysis of the cyano group of compound (VII) to obtain amide compound (VIII);

[0017] (3) Compound (VIII) reacts with compound (IX) having a leaving group R to obtain compound (I).

[0018] The starting material compound (VI) for synthesizing the thiosulfate intermediate (I) of the present invention is a cheap, readily available chemical product with a stable market supply. Due to the presence of electron-withdrawing functional groups, such as cyano and amide groups, adjacent to the thiol groups, the thiol groups of intermediates (VII) and (VIII) are not easily oxidized, allowing for stable separation and purification. The three-step reaction for preparing the thiosulfate intermediate compound (I) offers stable yields and mild reaction conditions, thereby enhancing process safety.

[0019] Furthermore, in the synthesis of compound (VII) in step (1), the thio reagent used is selected from sodium sulfide, sodium bisulfide, potassium ethyl xanthate, etc., preferably sodium sulfide; the solvent is selected from N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), etc., preferably DMF.

[0020] Furthermore, in the synthesis of compound (VIII) in step (2), the reagent used for hydrolysis is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, etc., preferably alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; the solvent used is selected from water, alcohol solvents such as ethanol, methanol, isopropanol, and mixtures of alcohol solvents and water, preferably water; the hydrolysis temperature is 50-100°C, preferably 80-100°C.

[0021] Furthermore, in the synthesis of compound (I) in step (3), the solvent used is selected from an alcohol solvent such as methanol, ethanol, isopropanol or a mixed solvent of an alcohol solvent and water, preferably a mixed solvent of ethanol, isopropanol and water; the reaction temperature is selected from 50-100°C, preferably 70-85°C; the leaving group R of compound (IX) is selected from methanesulfonyl, fluorine, chlorine, bromine, iodine, etc., preferably methanesulfonyl and chlorine, more preferably methanesulfonyl.

[0022] The third object of the present invention is to provide a use of the above-mentioned sulfamethoxam intermediate compound (I) in the synthesis of sulfamethoxam.

[0023] The reaction formula for synthesizing sulfamethoxazole (II) from the sulfamethoxazole intermediate compound (I) is as follows:

[0024]

[0025] 1) The amide bond of compound (Ⅰ) is diazotized and hydrolyzed with a diazotizing agent to obtain carboxyl compound (Ⅲ);

[0026] 2) Compound (III) is converted into sodium salt to obtain sulfhydryl ether (II).

[0027] In the reaction of synthesizing pyrimidinesulfonyl (II) using the intermediate compound (I) of the present invention, the reaction conditions of the diazotization hydrolysis and salt formation steps are mild, and the yield can reach more than 90%.

[0028] Furthermore, in the synthesis of compound (III) in step 1), the diazotization reagent used is selected from sodium nitrite / sulfuric acid, sodium nitrite / hydrochloric acid, tert-butyl nitroso, isoamyl nitrite, etc., preferably sodium nitrite / sulfuric acid, tert-butyl nitrite; when the diazotization reagent is sodium nitrite / sulfuric acid or hydrochloric acid, the solvent used is water; when the diazotization reagent is tert-butyl nitrite or isoamyl nitrite, the solvent used is acetic acid or a mixture of acetic acid and water.

[0029] Furthermore, in the synthesis of sulfamethoxazole (II) in step 2), the solvent used is water, a mixed solvent of toluene and water, or an alcohol solvent, such as methanol, ethanol, isopropanol, etc.; preferably, a mixed solvent of toluene and water.

[0030] The beneficial effects of the present invention are:

[0031] The pyrifos intermediate compound (I) provided by the present invention can avoid the shortcomings of low yield, serious three-waste pollution, and unstable intermediates in traditional processes when synthesizing pyrifos (II), and is more suitable for industrial production, thereby effectively reducing the production cost of the product and improving the quality controllability of the product.

[0032] The starting raw material compound (VI) for synthesizing the sulfhydryl intermediate compound (I) of the present invention is cheap and readily available; the thiol groups of the intermediates (VII) and (VIII) in the synthesis are not easily oxidized and can be stably separated and purified; the three-step reaction for preparing the sulfhydryl intermediate compound (I) has a stable yield and mild reaction conditions, thereby improving the safety of the process. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the mass spectrum of compound (I) of the present invention;

[0034] Figure 2 The compound (I) of the present invention 1 H NMR spectrum;

[0035] Figure 3 For the deuterium exchange of compound (I) of the present invention 1 H NMR spectrum;

[0036] Figure 4 Compound (I) of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0037] The principles and features of the present invention are described below with reference to examples. The examples are only used to explain the present invention and are not used to limit the scope of the present invention.

[0038] Example

[0039] 1. Synthesis of compound (VII)

[0040] Synthesis Method 1: To a reaction flask, add 50.0 g (0.29 mol) of 2,6-dichlorobenzonitrile, i.e., compound (VI), 200.0 g of N,N-dimethylformamide, and 62.0 g (0.35 mol) of 44% sodium sulfide. Heat the mixture to 60-70°C and stir for 3 h. Add 500 g of water and adjust the pH of the mixture to 4-5 with hydrochloric acid. Cool the mixture to 0-5°C and filter. Rinse the filter cake with 100 g of water and dry under reduced pressure to obtain 44.8 g of a light yellow solid (91% yield).

[0041] Synthesis Method 2: To a reaction flask, add 50.0 g (0.29 mol) of compound (VI), 180.0 g of N-methylpyrrolidone, and 92.8 g (1.16 mol) of 70% sodium hydrosulfide. Heat to 80-90°C and stir for 2 h. Add 550 g of water and adjust the pH of the system to 4-5 with hydrochloric acid. Cool to 0-5°C and filter. Rinse the filter cake with 100 g of water and dry under reduced pressure to obtain 43.4 g of a light yellow solid (88% yield).

[0042] 2. Synthesis of compound (VIII)

[0043] Synthesis Method 1: 42.0 g (0.25 mol) of compound (VII) was added to 126.0 g of water, followed by 11.2 g (0.28 mol) of sodium hydroxide. The temperature was raised to 90-100°C and the reaction was allowed to proceed for 6 h. The mixture was cooled to room temperature and the pH was adjusted to 2-3 with hydrochloric acid. Solids precipitated. The mixture was filtered, rinsed with 60 g of water, and dried under reduced pressure to yield 45.6 g of a pale yellow powder (98% yield).

[0044] Synthesis Method 2: To 20.0 g (0.12 mol) of compound (VII), add 60.0 g of ethanol and 60 g of water, followed by 33.1 g (0.24 mol) of potassium carbonate. The mixture was heated to 75-85°C and reacted for 8 h. Ethanol was removed under reduced pressure, and the pH was adjusted to 2-3 with hydrochloric acid. The mixture was filtered, rinsed with 30 g of water, and dried under reduced pressure to yield 21.2 g of a khaki powder (96% yield).

[0045] 3. Synthesis of compound (I)

[0046] Synthesis Method 1: Compound (VIII) 40.0 g (0.213 mol) was added to 96.0 g of isopropyl alcohol, 2.8 g of triphenylphosphine, 47.9 g (0.213 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (Compound IX, R is methylsulfonyl), and 96.0 g of 10% sodium hydroxide solution. Under nitrogen, the mixture was heated to 75-85°C and reacted for 3 h. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with 20 g of isopropyl alcohol and 40 g of water. The mixture was then dried under reduced pressure to give 64.0 g of a yellow powder (93% yield). [M+Na]+ = 348.01. 1H NMR (400MHz,) δ7.81 (s, 1H), 7.75-7.64 (m, 2H), 7.58 (d, J = 7.9Hz, 1H), 7.47 (s, 1H), 5.97 (s, 1H), 3.72 (s, 6H). 13 C NMR(101MHz,)δ171.23,169.46,166.91,142.28,136.53,130.63,130.17,129.97,128.18,86.43,54.68.

[0047] Synthesis Method 2: To 40.0 g (0.213 mol) of compound (VIII) was added 210 g of 75% ethanol, 5.6 g of triphenylphosphine, 40.9 g (0.234 mol) of 2-chloro-4,6-dimethoxypyrimidine (compound IX, R is a chlorine atom), and 12.8 g of sodium hydroxide. Under nitrogen, the temperature was raised to 70-80°C and the reaction was allowed to proceed for 6 h. Filtered at room temperature, the filter cake was rinsed with 50 g of 75% ethanol, and dried under reduced pressure to yield 59.0 g of a yellow powder (85% yield).

[0048] 4. Synthesis of compound (III)

[0049] Synthesis 1: To 50 g (0.153 mmol) of compound (I) was added 214.3 g (1.53 mol) of 70% sulfuric acid, followed by 31.7 g (0.459 mol) of solid sodium nitrite, in batches. After addition, the temperature was raised to 60-70°C and the reaction was allowed to proceed for 1 h. 250 g of water and 25% potassium hydroxide solution were added to adjust the pH to 2-3. The mixture was filtered, rinsed with water, and dried under reduced pressure to yield 47.1 g of an off-white powder (94% yield).

[0050] Synthesis II: 30.0 g (0.0921 mol) of compound (I) was added to 90 g of acetic acid, followed by 19.0 g (0.184 mol) of tert-butyl nitrite. The temperature was raised to 70-80°C and the reaction was continued for 3 h. 180 g of water was added, the mixture was filtered at room temperature, rinsed with water, and dried under reduced pressure to yield 45.1 g of a large off-white powder (90% yield).

[0051] 5. Synthesis of sulfometuron (II)

[0052] To 10.0 g (0.031 mol) of compound (III) were added 40.0 g of toluene, 1.3 g of sodium hydroxide, and 3.0 g of water, and stirred at room temperature for 1 hour. The water was evaporated, filtered at room temperature, rinsed with toluene, and dried under reduced pressure to obtain 10.6 g of a white solid (yield 99%).

[0053] The pyrimidine sulfide intermediate compound (I) provided by the present invention is a stable compound that can be easily separated by crystallization, purified, stored and transported; the three-step reaction yields for preparing the pyrimidine sulfide intermediate compound (I) are stable and can reach more than 90%; and the reaction conditions are mild, which improves the safety of the process. In the reaction of obtaining the herbicide pyrimidine sulfide (II) from the pyrimidine sulfide intermediate compound (I), the reaction conditions of the diazotization hydrolysis and salt-forming steps are mild, and the yield can reach more than 90%. It can be seen that the use of the compound (I) provided by the present invention to synthesize pyrimidine sulfide (II) can avoid the shortcomings of low yield, serious pollution of three wastes, and unstable intermediates in traditional processes, and is more suitable for industrial production, thereby effectively reducing the production cost of the product and improving the quality controllability of the product.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A sulfamethoxaline intermediate compound, characterized in that: The structural formula is shown in (Ⅰ): 。 2. A method for synthesizing the sulfamethoxaline intermediate compound according to claim 1, characterized in that: The reaction formula is as follows: (1) Compound 2,6-dichlorobenzonitrile (VI) is dissolved in a solvent and substituted with a thio reagent to obtain compound (VII); (2) Hydrolysis of the cyano group of compound (VII) to obtain amide compound (VIII); (3) Compound (VIII) reacts with compound (IX) having a leaving group R to obtain compound (I); In the step (3), the leaving group R of the compound (IX) is selected from methanesulfonyl, fluorine, chlorine, bromine or iodine.

3. The synthesis method according to claim 2, characterized in that In the step (1), the thio reagent is selected from sodium sulfide, sodium bisulfide or potassium ethyl xanthate; and the solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone.

4. The synthesis method according to claim 3, characterized in that In the step (1), the thiolation reagent is sodium sulfide; and the solvent is N,N-dimethylformamide.

5. The synthesis method according to claim 2, characterized in that In the step (2), the hydrolysis reagent is selected from hydroxides or carbonates of alkali metals and alkaline earth metals; and the hydrolysis temperature is 50-100°C.

6. The synthesis method according to claim 2, characterized in that In the step (3), the reaction temperature is 50-100°C.

7. Use of the sulfamethoxam intermediate compound according to claim 1 in the synthesis of sulfamethoxam, characterized in that: The reaction formula for synthesizing sulfofuranoside (II) from the sulfofuranoside intermediate compound (I) is as follows: 1) The amide bond of compound (I) is diazotized and hydrolyzed with a diazotizing reagent to obtain the carboxyl compound (III); 2) Compound (III) is converted into sodium salt to obtain sulfhydryl sulfoxide (II).

8. The use according to claim 7, characterized in that In the step 1), the diazotization reagent is selected from sodium nitrite / sulfuric acid, sodium nitrite / hydrochloric acid, tert-butyl nitrosoester or isoamyl nitrite.

9. The use according to claim 7, characterized in that The solvent used in step 2) is water, a mixed solvent of toluene and water, or an alcohol solvent.

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