Process for the preparation of chloromethyl aryl triazolinone compounds

Abstract

This invention relates to the field of herbicides and discloses a method for preparing a chloromethylaryl triazolinone compound. The method includes: 1) reacting a compound with a nitrating agent to undergo a nitration reaction to obtain a compound with the structure shown in formula (1); 2) reducing the nitro group of the compound with the structure shown in formula (2) with hydrogen to obtain a compound with the structure shown in formula (3); 3) reacting the compound with R1SO2Cl in a first contact reaction, followed by a second contact reaction with SOCl2 to obtain a compound with the structure shown in formula (4); wherein X is a halogen and R1 is an alkyl group with 1-3 carbon atoms. This invention provides a novel method for preparing a chloromethylaryl triazolinone compound with high yield and few side reactions.

Description

Technical Field

[0001] This invention relates to the field of herbicides, and more specifically to a method for preparing a chloromethylaryltriazolone compound. Background Technology

[0002] Aryltriazolone compounds can be used as pharmaceutical or pesticide intermediates. Herbicides developed based on the aryltriazolone structure, such as metsulfuron-methyl and mesotrione, have been successfully commercialized, and the preparation of aryltriazolone compounds has also received much attention.

[0003] WO2017041230 discloses a method for synthesizing chloromethyltriazolinone, which uses a triazolinone intermediate after aromatic ring chlorination, further chlorinates the side chain of the heterocyclic ring, and then proceeds to nitration, reduction, and methanesulfonation to obtain a chloromethylated aryltriazolinone herbicide. However, due to the high reactivity of the chlorine atom in the aromatic ring side chain, it is easily reacted with other active groups during nitration, hydrogenation, and methanesulfonation, affecting the product yield.

[0004] Therefore, it is necessary to improve the existing synthesis method of chloromethylaryltriazolinone to avoid the corresponding side reactions caused by chlorine atoms. Summary of the Invention

[0005] The purpose of this invention is to overcome the problems of low product yield and numerous side reactions in the existing technology, and to provide a new method for preparing chloromethylaryltriazolinone compounds, which has high yield and fewer side reactions.

[0006] To achieve the above objectives, the present invention provides a method for preparing a chloromethylaryltriazolone compound, the structure of which is shown in formula (4). The method includes the following steps:

[0007] 1) The compound with the structure shown in formula (1) is subjected to a nitration reaction with a nitrating agent to obtain the compound with the structure shown in formula (1);

[0008] 2) The nitro group of the compound with the structure shown in formula (2) is reduced by hydrogenation to obtain the compound with the structure shown in formula (3);

[0009] 3) After the compound with the structure shown in formula (3) undergoes a first contact reaction with MeSO2Cl, it undergoes a second contact reaction with SO2Cl2 to obtain the compound with the structure shown in formula (4).

[0010]

[0011] Where X is a halogen and R1 is an alkyl group with 1-3 carbon atoms.

[0012] Preferably, X is F, Cl or Br, and R1 is a methyl group.

[0013] Preferably, in step 1), sulfuric acid is used as the solvent (preferably concentrated sulfuric acid with a concentration of 98% by weight) and nitric acid is used as the nitrating agent to carry out the nitration reaction.

[0014] Preferably, the nitration reaction conditions include: a reaction temperature of 40-70°C and a reaction time of 1-4 hours.

[0015] Preferably, in step 2), Pd carbon or Pt carbon is used as a catalyst and hydrogen is used as a reducing agent to carry out the reduction.

[0016] Preferably, in step 2), the reduction conditions include: a reaction temperature of 80-120°C and a reaction time of 1-5 hours.

[0017] Preferably, the first contact reaction is carried out in the presence of a catalyst, which is at least one of N,N-dimethylformamide, pyridine, and N,N-dimethyl-4-aminopyridine.

[0018] Preferably, the first contact reaction and the second contact reaction are carried out in the presence of an organic solvent, wherein the organic solvent is at least one of toluene, xylene and chlorobenzene.

[0019] Preferably, the conditions for the first contact reaction include: a reaction temperature of 110-130°C and a reaction time of 3-10 hours.

[0020] Preferably, the conditions for the second contact reaction include: a reaction temperature of 30-100°C and a reaction time of 2-10 hours.

[0021] According to the method of the present invention, by replacing the chloromethyltriazolone intermediate with the hydroxymethylaryltriazolone intermediate, there are fewer side reactions and the product conversion rate is higher. This avoids the problem of many side reactions caused by the introduction of chloromethyl into the intermediate. By using hydrogenation reduction, the waste solids problem caused by the reduction of iron powder is reduced, which is conducive to the further process scale-up production of chloromethylaryltriazolone herbicides. Detailed Implementation

[0022] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0023] This invention provides a method for preparing a chloromethylaryltriazolone compound, the structure of which is shown in formula (4). The method includes the following steps:

[0024] 1) The compound with the structure shown in formula (1) is subjected to a nitration reaction with a nitrating agent to obtain the compound with the structure shown in formula (1);

[0025] 2) The nitro group of the compound with the structure shown in formula (2) is reduced by hydrogenation to obtain the compound with the structure shown in formula (3);

[0026] 3) After the compound with the structure shown in formula (3) undergoes a first contact reaction with MeSO2Cl, it undergoes a second contact reaction with SOCl2 to obtain the compound with the structure shown in formula (4).

[0027]

[0028] Where X is a halogen and R1 is an alkyl group with 1-3 carbon atoms.

[0029] The steps are explained below.

[0030] Step 1): Nitrification reaction step

[0031] According to the present invention, preferably, in formula (1), X is F, Cl or Br; more preferably, in formula (1), X is Cl.

[0032] The compound having the structure described in formula (1) is preferably a compound having the structure shown in formula (1-1) below.

[0033]

[0034] According to the present invention, preferably, in step 1), sulfuric acid is used as a solvent and nitric acid is used as a nitrifying agent to carry out the nitration reaction.

[0035] Preferably, the molar ratio of the compound with the structure shown in formula (1) to sulfuric acid is 1:8-20, more preferably 1:10-15.

[0036] Preferably, the molar ratio of the compound with the structure shown in formula (1) to nitric acid is 1:2-4, more preferably 1:2-3.

[0037] Preferably, the nitration reaction conditions include: a reaction temperature of 40-70°C and a reaction time of 1-4 hours.

[0038] According to the present invention, there are no particular limitations on the post-treatment of the nitration reaction. It can be carried out in accordance with the methods commonly used in the art. For example, after the nitration reaction is completed, the reaction solution can be cooled to room temperature (5-40°C) and then extracted with water and dichloromethane. If necessary, the extracted product can also be washed and dried before column chromatography.

[0039] Step 2): Restore the steps

[0040] According to the present invention, preferably, in formula (2), X is F, Cl or Br; more preferably, in formula (2), X is Cl.

[0041] The compound having the structure described in formula (2) is preferably a compound having the structure shown in formula (2-1) below.

[0042]

[0043] According to the present invention, preferably, in step 2), Pd carbon or Pt carbon is used as a catalyst and hydrogen is used as a reducing agent to carry out the reduction.

[0044] More preferably, the reduction is carried out in the presence of an organic solvent. The organic solvent may be one or more of methanol, ethanol, and toluene.

[0045] Preferably, the weight ratio of the compound with the structure shown in formula (2) to Pd carbon or Pt carbon is 1:0.003-0.01, more preferably 1:0.005-0.007.

[0046] Preferably, the reduction conditions include: a reaction temperature of 80-120°C and a reaction time of 1-5 hours.

[0047] According to the present invention, there are no particular limitations on the post-treatment of the reduction reaction. It can be carried out in accordance with the methods commonly used in the art. For example, after the reduction reaction is completed, the catalyst can be removed by hot filtration, and the solvent can be removed from the filtrate to obtain the compound with the structure shown in formula (3).

[0048] Step 3): Chlorination reaction

[0049] According to the present invention, preferably, in formula (3), X is F, Cl or Br; more preferably, in formula (3), X is Cl.

[0050] The compound having the structure described in formula (3) is preferably a compound having the structure shown in formula (3-1) below.

[0051]

[0052] According to the present invention, preferably, in R1SO2Cl, R1 is an alkyl group having 1-3 carbon atoms; more preferably, R1 is methyl, ethyl or propyl; even more preferably, R1 is methyl.

[0053] According to the present invention, preferably, the first contact reaction is carried out in the presence of a catalyst, said catalyst being at least one of N,N-dimethylformamide, pyridine, and N,N-dimethyl-4-aminopyridine.

[0054] Preferably, the first contact reaction and the second contact reaction are carried out in the presence of an organic solvent, wherein the organic solvent is at least one of toluene, xylene and chlorobenzene.

[0055] Preferably, as the first contact reaction, the compound with the structure shown in formula (3) is first mixed with the above-mentioned organic solvent to obtain a mixture, and then R1SO2Cl is added dropwise to the mixture to carry out the first contact reaction.

[0056] As the second contact reaction, it is preferable to add SOCl2 directly dropwise to the reaction product of the first contact reaction.

[0057] Preferably, the conditions for the first contact reaction include: a reaction temperature of 110-130°C and a reaction time of 3-10 hours.

[0058] Preferably, the conditions for the second contact reaction include: a reaction temperature of 30-100°C and a reaction time of 2-10 hours.

[0059] According to the present invention, after the first contact reaction and the second contact are completed, the target compound (the compound with the structure shown in formula (4)) can be obtained in high yield and high purity by washing with water and crystallization, and the post-processing is very simple.

[0060] According to the present invention, the compound having the structure described in formula (4) is preferably a compound in which X is chlorine and R1 is methyl.

[0061] The present invention will be described in detail below through embodiments, but the present invention is not limited to the following embodiments.

[0062] In the following examples, the compounds with the structure shown in formula (1-1) were obtained according to the preparation method described in US5468868A.

[0063] Example 1

[0064] 1) 50 g of the compound with the structure shown in formula (1-1) was added to 160 g of concentrated sulfuric acid (98 wt%) and heated to 60 °C in a water bath. 30 g of 68 wt% nitric acid was added dropwise, and the reaction was continued at 60 °C for 3 hours. After the reaction was completed, the temperature was lowered to 25 °C, and the reaction solution was added to a mixture of water and dichloromethane. The mixture was separated, the organic layer was washed with water, washed with 10 wt% NaHCO3 solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to dryness. The crude product was purified by column chromatography to obtain 42.0 g of the compound with the structure shown in formula (2-1) with a purity of 96.0 wt% and a yield of 70.2%. Its NMR and mass spectrometry data are shown below.

[0065]

[0066] 1H NMR (500MHz, CD3SOCD3) δ: 8.49 (s, 1H, O2NC = CH), 8.34 (s, 1H, ClC = CHCCl), 7.42-7.65 (t, 1H, FCHF), 5.95 (t, 1H, OH), 4.55 (d, 2H, CH2OH).

[0067] ESI[M354+Na] + 377.1;

[0068] 2) Add 15g of the compound with the structure shown in formula (2-1), 75g of methanol, and 0.075g of Pd carbon catalyst to the autoclave. Purge with nitrogen three times, heat to 80℃, and introduce hydrogen gas until the pressure in the autoclave is 0.5MPa. Perform the hydrogenation reaction, and repeat the hydrogen introduction operation until the pressure in the autoclave no longer decreases. Control the reaction in the middle. After the hydrogenation reaction is completed, filter while hot to remove the catalyst. After removing the solvent from the filtrate, 12.5g of the compound with the structure shown in formula (3-1) is obtained with a purity of 95% by weight and a yield of 90%. Its NMR and mass spectrometry data are shown below.

[0069]

[0070] 1 H NMR (500MHz, CDCl3) δ: 7.42 (s, 1H, H2NC=CH), 6.96-7.20 (t, 1H, FCHF), 6.84 (s, 1H, ClC=CHCCl), 5.95 (t, 1H, OH), 4.78 (d, 2H, CH2OH).

[0071] ESI[M324+Na] + 347.0;

[0072] 3) 10 g of the compound with the structure shown in formula (3-1) was added to 8 g of toluene, 0.13 g of DMF catalyst was added, and 5.4 g of methanesulfonyl chloride was added dropwise. The mixture was heated to reflux and kept at that temperature for 5 hours. The temperature was then lowered to 60 °C, and 13.9 g of thionyl chloride was added dropwise. The mixture was kept at that temperature for another 8 hours. The mixture was then cooled, washed with water, and the organic phase was cooled to 25 °C to crystallize. The mixture was filtered to obtain a crude product. The crude product was recrystallized with methanol to obtain 10.3 g of the compound with the structure shown in formula (4-1), with a purity of 96.0% by weight and a yield of 80.3%. Its NMR and mass spectrometry data are shown below.

[0073]

[0074] 1H NMR (500MHz, CD3SOCD3) δ: 9.82 (s, 1H, NH), 8.01 (s, 1H, ClC = CHCCl), 7.75 (s, 1H, HNC = CH), 7.49-7.72 (t, 1H, FCHF), 4.91 (t, 2H, ClCH2), 3.13 (s, 3H, SO2CH3).

[0075] ESI[M420+Na] + :442.9;

[0076] Example 2

[0077] 1) 50 g of the compound with the structure shown in formula (1-1) was added to 200 g of concentrated sulfuric acid (98 wt%) and heated to 70 °C in a water bath. 30 g of 68 wt% nitric acid was added dropwise, and the reaction was continued at 70 °C for 2 hours. After the reaction was completed, the temperature was lowered to 25 °C, and the reaction solution was added to a mixture of water and dichloromethane. The mixture was separated, the organic layer was washed with water, washed with 10 wt% NaHCO3 solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to dryness. The crude product was purified by column chromatography to obtain 41.3 g of the compound with the structure shown in formula (2-1) (confirmed by NMR and mass spectrometry data), with a purity of 95.5 wt% and a yield of 68.7%.

[0078] 2) Add 15g of the compound with the structure shown in formula (2-1) to a high-pressure reactor, along with 50g of methanol, 50g of toluene, and 0.09g of Pd carbon catalyst. Purge with nitrogen three times, raise the temperature to 90℃, and introduce hydrogen gas until the reactor pressure reaches 0.7MPa. Perform the hydrogenation reaction, repeatedly introducing hydrogen gas until the pressure in the high-pressure reactor no longer decreases. Control the reaction until it ends. Filter while hot to remove the catalyst. After removing the solvent from the filtrate, obtain 12.9g of the compound with the structure shown in formula (3-1) (confirmed by NMR and mass spectrometry data), with a purity of 95.4% by weight and a yield of 93%.

[0079] 3) 10 g of the compound with the structure shown in formula (3-1) was added to 6 g of toluene, 0.15 g of DMF catalyst was added, and 5.7 g of methanesulfonyl chloride was added dropwise. The mixture was heated to reflux and kept at that temperature for 6 hours. The temperature was then lowered to 50 °C, and 14 g of thionyl chloride was added dropwise. The mixture was kept at that temperature for another 8 hours. The mixture was then cooled, washed with water, and the organic phase was cooled to 25 °C to crystallize. The mixture was filtered to obtain a crude product. The crude product was recrystallized with methanol to obtain 10.7 g of the compound with the structure shown in formula (4-1) (the structure shown in formula (4-1) was confirmed by NMR and mass spectrometry data), with a purity of 95.6% by weight and a yield of 82.7%.

[0080] Example 3

[0081] 1) 50 g of the compound with the structure shown in formula (1-1) was added to 170 g of concentrated sulfuric acid (98 wt%) and heated to 60 °C in a water bath. 35 g of 68 wt% nitric acid was added dropwise, and the reaction was continued at 60 °C for 3 hours. After the reaction was completed, the temperature was lowered to 25 °C, and the reaction solution was added to a mixture of water and dichloromethane. The mixture was separated, the organic layer was washed with water, washed with 10 wt% NaHCO3 solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to dryness. The crude product was purified by column chromatography to obtain 41.6 g of the compound with the structure shown in formula (2-1) (confirmed by NMR and mass spectrometry data), with a purity of 95.3 wt% and a yield of 69.1%.

[0082] 2) Add 15g of the compound with the structure shown in formula (2-1), 75g of methanol, and 0.075g of Pd carbon catalyst to a high-pressure reactor. Purge with nitrogen three times, heat to 100℃, and introduce hydrogen gas until the reactor pressure reaches 0.5MPa. Perform the hydrogenation reaction, and repeat the hydrogen introduction operation until the pressure of the high-pressure reactor no longer decreases. Control the reaction in the middle. After the hydrogenation reaction is completed, filter while hot to remove the catalyst. After removing the solvent from the filtrate, 12.4g of the compound with the structure shown in formula (3-1) is obtained (the compound with the structure shown in formula (3-1) is confirmed by NMR and mass spectrometry data). The purity is 95.2% by weight, and the yield is 91%.

[0083] 3) 10 g of the compound with the structure shown in formula (3-1) was added to 4 g of toluene, 0.13 g of DMF catalyst was added, and 5.5 g of methanesulfonyl chloride was added dropwise. The mixture was heated to reflux and kept at that temperature for 7 hours. The temperature was then lowered to 70 °C, and 14 g of thionyl chloride was added dropwise. The mixture was kept at that temperature for another 6 hours. The mixture was then cooled, washed with water, and the organic phase was cooled to 20 °C to crystallize. The mixture was filtered to obtain a crude product. The crude product was recrystallized with methanol to obtain 10.5 g of the compound with the structure shown in formula (4-1) (the structure shown in formula (4-1) was confirmed by NMR and mass spectrometry data), with a purity of 95.5% by weight and a yield of 81.3%.

[0084] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a chloromethylaryltriazolone compound, wherein the structure of the chloromethylaryltriazolone compound is shown in formula (4), characterized in that, This method Includes the following steps, 1) The compound with the structure shown in formula (1) is subjected to a nitration reaction with a nitrating agent to obtain the compound with the structure shown in formula (2); 2) The nitro group of the compound with the structure shown in formula (2) is reduced by hydrogenation to obtain the compound with the structure shown in formula (3); 3) After the compound with the structure shown in formula (3) undergoes a first contact reaction with R1SO2Cl, it undergoes a second contact reaction with SOCl2 to obtain the compound with the structure shown in formula (4). Equation (1), Equation (2), Equation (3), Equation (4), Where X is Cl, and R1 is an alkyl group with 1-3 carbon atoms. In step 1), sulfuric acid is used as a solvent and nitric acid is used as a nitrifying agent to carry out the nitration reaction. The conditions for the nitration reaction include: a reaction temperature of 40-70°C and a reaction time of 1-4 hours.

2. The method according to claim 1, wherein, R1 is a methyl group.

3. The method according to claim 1, wherein, In step 2), the reduction is carried out using Pd carbon or Pt carbon as a catalyst and hydrogen as a reducing agent.

4. The method according to claim 3, wherein, In step 2), the reduction conditions include: a reaction temperature of 80-120℃ and a reaction time of 1-5 hours.

5. The method according to claim 1, wherein, The first contact reaction is carried out in the presence of a catalyst, which is at least one of N,N-dimethylformamide, pyridine, and N,N-dimethyl-4-aminopyridine.

6. The method according to claim 1, wherein, The first contact reaction and the second contact reaction are carried out in the presence of an organic solvent, wherein the organic solvent is at least one of toluene, xylene and chlorobenzene.

7. The method according to any one of claims 1-6, wherein, The conditions for the first contact reaction include: a reaction temperature of 110-130℃ and a reaction time of 3-10 hours.

8. The method according to any one of claims 1-6, wherein, The conditions for the second contact reaction include: a reaction temperature of 30-100℃ and a reaction time of 2-10 hours.

Images