Pyrithiobac-sodium intermediate compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of agricultural herbicides, and relates to a pyrithiobac-sodium intermediate compound and a preparation method and application thereof.The pyrithiobac-sodium intermediate compound is shown in the structural formula (I), is a stable compound and can be conveniently crystallized, separated, purified, stored and transported; the three-step reaction for preparing the pyrithiobac-sodium intermediate compound (I) is stable in yield and mild in reaction condition, and the safety of the technological process is improved; in the reaction for synthesizing pyrithiobac-sodium (II) by adopting the intermediate compound (I), the reaction conditions of diazotization hydrolysis and salification steps are mild, and the yield can reach 90% or above. # imgabs0 #

Description

Technical Field

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

[0002] Pyrimidinesulfonate (II), chemical name: 2-chloro-6-(4,6-dimethoxypyrimidine-2-thiol)benzoic acid sodium salt, is a cotton field herbicide developed by Kumihiko Chemical Co., Ltd. of Japan, jointly developed by Shimahara Co., Ltd. and DuPont Co. of the United States, and launched on the market in 1994. It is used to control annual and perennial broadleaf weeds and barnyard grass in cotton fields, with an application rate of 35-105g / ha. Pyrimidinesulfonate is an acetolactate synthase (ALS) inhibitor that achieves the effect of controlling weeds by preventing the biosynthesis of amino acids.

[0003]

[0004] Literature reports that there are two main methods for the synthesis of thiosulfuron (II).

[0005] Method 1: CN1028171C reported that 2-amino-6-chlorobenzoic acid (Ⅳ) was used as a raw material, which was first diazotized and then reacted with 2-mercapto-4,6-dimethoxypyrimidine to obtain compound (Ⅲ), and compound (Ⅲ) was converted into sodium salt to obtain pyrimidine sulfide (Ⅱ). The two-step yield of compound (Ⅲ) in this route was only 23%, and the diazotization reaction was a dangerous chemical process. In addition, the diazotization process produced a lot of waste gas, wastewater and inorganic salts, resulting in serious pollution of the three wastes.

[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 document 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, which brings difficulties to actual production operations.

[0008]

[0009] In summary, the first method for synthesizing pyrimidine sulfide has the disadvantages of using a dangerous diazotization chemical process, low yield, and large amount of three wastes. The intermediate (V) of the second method is unstable and cannot be separated and purified. The methods currently reported for synthesizing intermediate (V) either use diazotization reaction or high temperature reaction, which have safety defects. Therefore, the existing synthesis process of pyrimidine sulfide cannot meet the requirements of economy, safety, and environmental protection. Summary of the invention

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

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

[0012] The thiopyrimidine 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 thiosulfuron intermediate compound, and the reaction formula 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 perform 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 raw material compound (VI) for synthesizing the thiosulfate intermediate (I) of the present invention is a cheap and readily available chemical product with a stable market supply. Due to the presence of the electron-withdrawing functional groups cyano and amide groups adjacent to the thiol group, the thiol groups of the intermediates (VII) and (VIII) are not easily oxidized and can be stably separated and purified. The three-step reaction for preparing the thiosulfate intermediate compound (I) has a stable yield and mild reaction conditions, thereby improving the safety of the process.

[0019] Furthermore, in the synthesis of compound (VII) in step (1), the thio reagent used is selected from sodium sulfide, sodium hydrosulfide, 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 a mixture of an alcohol solvent 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 alcohol solvents 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, chlorine, and more preferably methanesulfonyl.

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

[0023] The reaction formula for synthesizing thiosulfate (II) from the thiosulfate 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 a carboxyl compound (Ⅲ);

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

[0027] In the reaction of synthesizing pyrimidinesulfuron (II) by 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 and 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 thiosulfate (II) in step 2), the solvent used is water, a mixed solvent of toluene and water, 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 pyrimidine sulfide intermediate compound (I) provided by the present invention can avoid the disadvantages of low yield, serious three waste pollution and unstable intermediates in the traditional process when synthesizing pyrimidine sulfide (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 thiopyralid intermediate compound (I) of the present invention is cheap and easily 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 thiopyralid 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 deuterated water exchange of the compound (I) of the present invention 1 H NMR spectrum;

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

[0037] The principles and features of the present invention are described below in conjunction with 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: 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 to a reaction flask, heat to 60-70°C, stir and react for 3 h. Add 500 g of water, adjust the pH of the system to 4-5 with hydrochloric acid, cool to 0-5°C, 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 with a yield of 91%.

[0041] Synthesis method 2: 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 to a reaction flask, heat to 80-90°C, stir and react for 2 h. Add 550 g of water, adjust the pH of the system to 4-5 with hydrochloric acid, cool to 0-5°C, 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 with a yield of 88%.

[0042] 2. Synthesis of compound (VIII)

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

[0044] Synthesis method 2: Compound (VII) 20.0g (0.12mol), add 60.0g ethanol, 60g water, and continue to add 33.1g potassium carbonate (0.24mol), and heat to 75-85℃ for 8h. Remove the ethanol under reduced pressure, adjust the pH to 2-3 with hydrochloric acid. Filter, rinse with 30g water, and dry under reduced pressure to obtain 21.2g of khaki powder, with a yield of 96%.

[0045] 3. Synthesis of compound (I)

[0046] Synthesis method 1: Compound (VIII) 40.0g (0.213mol), add isopropanol 96.0g, triphenylphosphine 2.8g, 4,6-dimethoxy-2-methylsulfonylpyrimidine (compound IX, R is methylsulfonyl) 47.9g (0.213mol), 10% sodium hydroxide solution 96.0g, under nitrogen protection, heat to 75-85°C, react for 3h. Cool to room temperature, filter, wash the filter cake with 20g isopropanol, 40g water, and dry under reduced pressure to obtain 64.0g yellow powder, with a yield of 93%. [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: Compound (VIII) 40.0g (0.213mol), add 75% ethanol 210g, triphenylphosphine 5.6g, 2-chloro-4,6-dimethoxypyrimidine (compound IX, R is a chlorine atom) 40.9g (0.234mol), sodium hydroxide 12.8g. Under nitrogen protection, heat to 70-80℃, react for 6h. Filter at room temperature, rinse the filter cake with 50g 75% ethanol, and dry under reduced pressure to obtain 59.0g of yellow powder with a yield of 85%.

[0048] 4. Synthesis of compound (III)

[0049] Synthesis 1: Compound (I) 50g (0.153mmol), add 70% sulfuric acid 214.3g (1.53mol), add sodium nitrite solid 31.7g (0.459mol) in batches, heat to 60-70℃ and react for 1h. Add 250g water and 25% potassium hydroxide solution to adjust pH=2-3, filter, rinse with water, and dry under reduced pressure to obtain 47.1g of off-white powder with a yield of 94%.

[0050] Synthesis 2: Compound (I) 30.0g (0.0921mol) was added to 90g acetic acid, followed by 19.0g (0.184mol) of tert-butyl nitrite, and the temperature was raised to 70-80°C for 3h. 180g of water was added, filtered at room temperature, rinsed with water, and dried under reduced pressure to obtain 45.1g of off-white powder, with a yield of 90%.

[0051] 5. Synthesis of thiopyrasulfuron (II)

[0052] Compound (III) 10.0 g (0.031 mol) was added with 40.0 g toluene, 1.3 g sodium hydroxide and 3.0 g water, and stirred at room temperature for 1 hour. The water was evaporated, filtered at room temperature, washed with toluene, and dried under reduced pressure to obtain 10.6 g of a white solid with a yield of 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 of 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 formation 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 principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A thiosulfuron intermediate compound, characterized in that: The structural formula is shown in (Ⅰ):

2. A method for synthesizing the intermediate compound of thiosulfuron 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).

3. The synthesis method according to claim 2, characterized in that In the step (1), the thiolation agent is selected from sodium sulfide, sodium hydrosulfide 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; the leaving group R of the compound (IX) is selected from methanesulfonyl, fluorine, chlorine, bromine or iodine.

7. Use of the thiopyrasulfuron intermediate compound according to claim 1 in the synthesis of thiopyrasulfuron.

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

9. The use according to claim 8, 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.

10. The use according to claim 8, 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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