Synthesis method of saflufenacil intermediate

Abstract

The invention relates to the technical field of pesticide synthesis, in particular to a method for synthesizing a saflufenacil intermediate, which comprises the following steps: taking ethyl trifluoroacetoacetate and 2-chloro-4-fluoro-5-aminobenzoate as raw materials, reacting under the action of alkali, and continuously evaporating out low-boiling-point alcohol in the reaction process to obtain an intermediate 1; then adding methylamine hydrochloride turbid liquid into the system, and performing azeotropic dehydration in the reaction process to obtain an intermediate 2; and finally, introducing a phosgene reagent into the system, and carrying out ring closing on the obtained intermediate 2 to obtain a target product. According to the method, cheap and easily available raw materials are used, a uracil ring is directly constructed through a one-pot three-step reaction, and the saflufenacil intermediate is synthesized, so that the process operation is greatly simplified; the target product synthesized by the method has higher yield and purity, the cost is reduced, the solvent can be recycled, the emission of three wastes is reduced, and the subsequent industrial production of saflufenacil is facilitated.

Description

Technical Field

[0001] This invention relates to the field of pesticide synthesis technology, specifically to a method for synthesizing an intermediate of benzosulfuron. Background Technology

[0002] Protoporphyrinogen oxidase (PPO) is the penultimate enzyme in chlorophyll synthesis in plants and heme synthesis in animals, belonging to a large enzyme system containing flavin adenine dinucleotide (FAD). Its function is to catalyze the conversion of protoporphyrinogen IX to protoporphyrin IX in plants. PPO inhibitor herbicides work by competing with their substrates for binding to the biocatalytic enzyme, leading to an excessive accumulation of protoporphyrinogen IX in plant cells, thus inhibiting chlorophyll synthesis. The large accumulation of protoporphyrinogen IX, under light conditions, produces highly reactive oxygen species, causing cell membrane damage, fluid leakage from the cell, and ultimately cell dehydration, leading to the death of the weed plant. Currently, the commercially available compounds among uracil-based PPO inhibitors mainly include flupropacil, butafenacil, saflufenacil, Benzfendizone, and tiafenacil, among which saflufenacil has the best market application prospects.

[0003] The construction of the uracil ring is a crucial step in the synthesis of this type of compound. Taking bensulfuron-methyl as an example, the main reported methods for synthesizing the uracil ring are as follows:

[0004]

[0005] 1) Patent WO2001083459A2 reports the construction of a uracil ring using 2-chloro-4-fluoro-5-aminobenzoic acid and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one as raw materials and acetic acid as solvent under reflux conditions; the synthesis process of 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one is as follows: using ethyl 3-amino-4,4,4-trifluorocrotonate as raw material, it reacts with N,N-dimethylcarbamoyl chloride in the presence of sodium hydrogen to synthesize ethyl 3-(3,3-dimethylurea)-4,4,4-trifluorobutenoate, and finally intramolecular cyclization in the presence of phosphorus pentachloride and phosphorus oxychloride to obtain the oxazinone. This method is relatively simple in the process of ring construction, but the preparation of the raw materials ethyl 3-amino-4,4,4-trifluorocrotonate or 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one requires sodium hydrogen, which is very expensive and the industrialization process is also relatively risky.

[0006] 2) Patents WO2005054208A1 and WO2009050120A1 report a method for constructing uracil rings under alkaline catalysis. Using N′-(2-chloro-4-fluoro-5-amino-benzoyl)-N-isopropyl-N-methanesulfonamide as a starting material, it reacts with methyl chloroformate or ethyl chloroformate to prepare an amide, or reacts with phosgene to prepare an isocyanate, which is then cyclically constructed with ethyl 3-amino-4,4,4-trifluorocrotonate under alkaline catalysis. This method suffers from the instability and easy decomposition of the product due to the use of isocyanate. Furthermore, during alkaline catalysis, the fluorine or chlorine atoms on the side chain or benzene ring are replaced by released lower alcohols. Additionally, isomerization issues arise during the subsequent N-methylation process, requiring more complex separation and purification methods.

[0007]

[0008] 3) Patent CN1636981A reports a process using aniline and ethyl trifluoroacetoacetate as raw materials, first undergoing an amine ester condensation reaction, then amination with ammonia, and finally cyclization with phosgene. However, this method cannot solve the problem of methylated isomers in the subsequent methylation process. Patent CN112574126A reports a process using aniline and ethyl trifluoroacetoacetate as raw materials, similarly first undergoing an amine ester condensation reaction, then amination with methylamine hydrochloride, and finally cyclization with ethyl chloroformate under alkaline conditions. This method has a long procedure, each step requires post-processing, and the route is complicated.

[0009] a)

[0010]

[0011] b)

[0012] Summary of the Invention

[0013] The purpose of this invention is to overcome the problems of difficult raw material preparation, numerous byproducts and isomers, long steps, and extensive post-processing in existing methods, and to provide a new method for synthesizing phenylsulfuron-methyl intermediates.

[0014] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0015] A method for synthesizing a bensulfuron-methyl intermediate includes the following steps:

[0016] i) Add 2-chloro-4-fluoro-5-aminobenzoate, ethyl trifluoroacetoacetate and the first base to the solvent in sequence, heat to 100℃-reflux, and react for 4-8 h to obtain intermediate 1;

[0017] ii) Slightly cool the reaction solution from step i to about 80°C, slowly add the solvent suspension of methylamine hydrochloride, and then heat to reflux for 6-8 hours to obtain intermediate 2;

[0018] iii) Cool the reaction solution from step ii to 65-75℃, add the second portion of alkali, and then introduce the phosgene reagent solution. After the introduction is complete, maintain the temperature for 3-5 hours. After the reaction is complete, cool the solution, add water to precipitate the solid, filter, wash, and dry to obtain the target product. The synthetic route is shown below:

[0019]

[0020] Furthermore, the solvent is one or more of benzene and halobenzene compounds;

[0021] Preferably, the solvent is one or more of toluene, xylene, chlorobenzene, and o-dichlorobenzene;

[0022] Furthermore, the volume-to-weight ratio (ml / g) of the solvent used in step i to 2-chloro-4-fluoro-5-aminobenzoate is 1.5 to 4:1, the volume-to-weight ratio (ml / g) of the solvent used in step ii to methylamine hydrochloride is 2 to 3:1, and the volume-to-weight ratio (ml / g) of the phosgene reagent solution used in step iii to the phosgene reagent is 1 to 2:1.

[0023] Furthermore, the alkali is one or more organic bases;

[0024] Preferably, the base is one or more of pyridine, N,N-dimethylaminopyridine, methylpyridine, dimethylpyridine, and trimethylpyridine;

[0025] More preferably, the base is pyridine;

[0026] Furthermore, the phosgene reagent is one or more of phosgene, diphosgene, and triphosgene;

[0027] Preferably, the phosgene reagent is triphosgene;

[0028] Furthermore, the molar ratio of the 2-chloro-4-fluoro-5-aminobenzoate to the first base is 1:1.05 to 1.2, preferably 1:1.05 to 1.1;

[0029] Furthermore, the molar ratio of the second portion of alkali to 2-chloro-4-fluoro-5-aminobenzoate is 2 to 3:1, preferably 2 to 2.5:1;

[0030] Furthermore, the molar ratio of 2-chloro-4-fluoro-5-aminobenzoate to ethyl trifluoroacetoate is 1:1.05 to 1.2, preferably 1:1.05 to 1.1;

[0031] Furthermore, the molar ratio of 2-chloro-4-fluoro-5-aminobenzoate to methylamine hydrochloride is 1:1.05 to 1.5, preferably 1:1.05 to 1.2;

[0032] Furthermore, the molar ratio of phosgene to 2-chloro-4-fluoro-5-aminobenzoate in the phosgene reagent is 1.5 to 1.8:1, preferably 1.5 to 1.6:1;

[0033] Furthermore, in step i, the low-boiling-point alcohol generated needs to be continuously distilled off during the reaction, and in step ii, the water generated needs to be continuously distilled off during the reaction.

[0034] Furthermore, the R-substituent is preferably a C1-6 alkyl group; specifically, it can be selected from methyl or ethyl, or other alkyl groups, such as isopropyl.

[0035] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0036] The beneficial effects of this invention are as follows: This invention uses 2-chloro-4-fluoro-5-aminobenzoate and ethyl trifluoroacetoacetate as the initial raw materials to directly construct the uracil ring through a one-pot, three-step method. The raw materials used are simple and readily available. By screening the solvent and alkali, the intermediate process is not separated, which greatly simplifies the post-processing. After the reaction, only the recovery of a single solvent, the recovery of a single acid-binding agent, and the treatment of a single salt are required. The target product prepared by this method has high yield and high purity, reduces production costs, and the solvent can be recycled, reducing the emission of waste. Compared with existing processes, it is safer and more environmentally friendly, and is suitable as an industrial production method for pyrimisulfuron-methyl intermediates. Attached Figure Description

[0037] Figure 1 The 1H NMR spectrum of intermediate 1 in Example 1;

[0038] Figure 2 The hydrogen spectrum of intermediate 2 in Example 1;

[0039] Figure 3 The image shows the proton spectrum data for Example 1. Detailed Implementation

[0040] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0041] Example 1:

[0042] In a 1000 mL four-necked flask, 101.5 g (0.5 mol) of methyl 2-chloro-4-fluoro-5-aminobenzoate, 101.26 g (0.55 mol) of ethyl trifluoroacetoacetate, 43.51 g (0.55 mol) of pyridine, and 200 g of toluene were added sequentially. The mixture was heated to 105 °C and reacted for 4 h. During the reaction, an external distillation apparatus was used to continuously collect the ethanol produced. After the starting material disappeared from the liquid phase, intermediate 1 was obtained. The mixture was then slightly cooled to 65–75 °C, and 100 g of methyl methacrylate (36.96 g (0.55 mol) of methylamine hydrochloride) was slowly added. A benzene suspension was heated to reflux and reacted for 6 hours. During the reaction, a water separator was used to continuously collect the water generated in the system to obtain intermediate 2. After the raw material disappeared in the liquid phase, the system was cooled to 70°C. First, 79.1 g (1 mol) of pyridine was added, followed by the dropwise addition of 74.19 g (0.25 mol) of a 100 g toluene solution of triphosgene. After the addition was completed, the system was kept at the temperature for 3 hours. After the raw material disappeared in the liquid phase, the system was cooled to room temperature, and water was added. A large amount of solid precipitated. The solid was filtered, washed with water, and dried to obtain 154.57 g of the target product, a white solid with a purity of 96.5% and a yield of 81.2%.

[0043] In this embodiment, the intermediate was separated, and the resulting NMR data were:

[0044] The proton NMR data for intermediate 1 are as follows: 1 H NMR (400MHz, DMSO) δ12.31(s,1H),9.06(d,J=8.6Hz,1H),7.54(d,J=11.0Hz,1H),4.64(s,1H),3.85(s,3H).

[0045] The proton NMR data for intermediate 2 are as follows: 1 H NMR (400MHz, DMSO) δ9.91(s,1H),8.74(d,J=8.5Hz,1H),8.69(d,J=4.6Hz,1H),7.63(d,J=10.8Hz,1H),5.62(s,1H),3.86(s,3H),2.94(d,J=5.2Hz,3H).

[0046] The proton NMR data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ8.09(d,J=7.8Hz,1H),7.90(d,J=9.6Hz,1H),6.61(s,1H),3.87(s,3H),3.41(s,3H).

[0047] Example 2:

[0048] In a 1000 mL four-necked flask, 101.5 g (0.5 mol) of methyl 2-chloro-4-fluoro-5-aminobenzoate, 110.46 g (0.6 mol) of ethyl trifluoroacetoacetate, 47.46 g (0.6 mol) of pyridine, and 200 g of chlorobenzene were added sequentially. The mixture was heated to 120 °C and reacted for 3 h. During the reaction, an external distillation apparatus was used to continuously collect the ethanol produced. After the starting materials disappeared from the liquid phase, the temperature was slightly lowered to 65–75 °C, and 100 g of chlorobenzene suspension containing 36.96 g (0.55 mol) of methylamine hydrochloride was slowly added. The mixture was heated to reflux and reacted for 4 hours. During the reaction, a water separator was used to continuously collect the water generated in the system. After the raw material was detected to have disappeared in the liquid phase, the system was cooled to 70°C. First, 87.01 g (1.1 mol) of pyridine was added, followed by the dropwise addition of 89.03 g (0.3 mol) of a 100 g chlorobenzene solution of triphosgene. After the addition was completed, the mixture was kept at the reflux temperature for 4 hours. After the raw material was detected to have disappeared in the liquid phase, the mixture was cooled to room temperature and water was added. A large amount of solid precipitated. The solid was filtered, washed with water, and dried to obtain 144.01 g of the target product, a white solid with a purity of 97.2% and a yield of 75.67%.

[0049] Example 3:

[0050] In a 1000 mL four-necked flask, 108.5 g (0.5 mol) of ethyl 2-chloro-4-fluoro-5-aminobenzoate, 101.26 g (0.55 mol) of ethyl trifluoroacetoacetate, 43.51 g (0.55 mol) of pyridine, and 200 g of toluene were added sequentially. The mixture was heated to 105 °C and reacted for 5 h. During the reaction, an external distillation apparatus was used to continuously collect the ethanol produced. After the starting material disappeared from the liquid phase, the temperature was slightly lowered to 65–75 °C, and 100 g of toluene containing 36.96 g (0.55 mol) of methylamine hydrochloride was slowly added. The suspension was heated to reflux and reacted for 6 hours. During the reaction, a water separator was used to continuously collect the water generated in the system. After the raw material disappeared in the liquid phase, the system was cooled to 70°C. First, 79.1 g (1 mol) of pyridine was added, followed by the dropwise addition of 74.19 g (0.25 mol) of a 100 g toluene solution of triphosgene. After the addition was completed, the system was kept at this temperature for 3 hours. After the raw material disappeared in the liquid phase, the system was cooled to room temperature, and water was added. A large amount of solid precipitated. The solid was filtered, washed with water, and dried to obtain 148.68 g of the target product, a white solid with a purity of 96.8% and a yield of 78.14%.

[0051] Example 4:

[0052] In a 1000 mL four-necked flask, 108.5 g (0.5 mol) of ethyl 2-chloro-4-fluoro-5-aminobenzoate, 110.46 g (0.6 mol) of ethyl trifluoroacetoacetate, 47.46 g (0.6 mol) of pyridine, and 200 g of xylene were added sequentially. The mixture was heated to 125 °C and reacted for 3 h. During the reaction, an external distillation apparatus was used to continuously collect the ethanol produced. After the starting material disappeared from the liquid phase, the temperature was slightly lowered to 65–75 °C, and 43.68 g (0.65 mol) of methylamine hydrochloride and 100 g of xylene were slowly added. A benzene suspension was heated to reflux and reacted for 6 hours. During the reaction, a water separator was used to continuously collect the water generated in the system. After the raw material disappeared in the liquid phase, the system was cooled to 70°C. First, 79.1 g (1 mol) of pyridine was added, followed by the dropwise addition of 89.03 g (0.3 mol) of a 100 g xylene solution containing triphosgene. After the addition was completed, the system was kept at this temperature for 4 hours. After the raw material disappeared in the liquid phase, the system was cooled to room temperature, and water was added. A large amount of solid precipitated. The solid was filtered, washed with water, and dried to obtain 138.60 g of the target product, a white solid with a purity of 95.8% and a yield of 72.82%.

[0053] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method of synthesizing an intermediate of Sulfentrazone, characterized in that, The method comprises the following steps: i) adding 2-chloro-4-fluoro-5-amino benzoate, ethyl trifluoroacetylacetate and the first base into a solvent, heating to 100℃-reflux, and reacting for 4-8 hours to obtain intermediate 1; ii) slightly cooling the reaction solution of step i) to about 80℃, slowly adding a solvent suspension of methylamine hydrochloride, heating to reflux, and reacting for 6-8 hours to obtain intermediate 2; iii) cooling the reaction solution of step ii) to 65-75℃, adding the second base, introducing a phosgene reagent solution, and reacting for 3-5 hours after the introduction is completed, then cooling and adding water to precipitate the solid, filtering, washing and drying to obtain the target product; the synthesis route is shown below:

2. The method of synthesis of claim 1, wherein, The solvent is one or more of benzene and halogenated benzene.

3. The method of synthesis of claim 2, wherein, The solvent is one or more of toluene, xylene, chlorobenzene and o-dichlorobenzene.

4. The method of synthesis of claims 1-3, wherein, The volume weight ratio (ml / g) of the solvent used in step i) to 2-chloro-4-fluoro-5-amino benzoate is 1.5-4:1, the volume weight ratio (ml / g) of the solvent used in step ii) to methylamine hydrochloride is 2-3:1, and the volume weight ratio (ml / g) of the phosgene reagent solution used in step iii) to phosgene reagent is 1-2:

1.

5. The method of synthesis of claim 1, wherein, The base is one or more of organic bases.

6. The method of synthesis of claim 1, wherein, The base is one or more of pyridine, N,N-dimethylaminopyridine, methylpyridine, dimethylpyridine and trimethylpyridine.

7. The method of synthesis of claim 1, wherein, The phosgene reagent is one or more of phosgene, bis-phosgene and tris-phosgene.

8. The method of synthesis of claim 1, wherein, The molar ratio of 2-chloro-4-fluoro-5-amino benzoate to ethyl trifluoroacetylacetate is 1:1.05-1.

2.

9. The method of synthesis of claim 1, wherein, The molar ratio of 2-chloro-4-fluoro-5-amino benzoate to the first base is 1:1.05-1.2, and the molar ratio of the second base to 2-chloro-4-fluoro-5-amino benzoate is 2-3:

1.

10. The method of synthesis of claim 1, wherein, The molar ratio of 2-chloro-4-fluoro-5-amino benzoate to methylamine hydrochloride is 1:1.05-1.

5.

11. The method of synthesis of claim 1, wherein, The molar ratio of the phosgene in the phosgene reagent to 2-chloro-4-fluoro-5-amino benzoate is 1.5-1.8:

1.

12. The method of synthesis of claim 1, wherein, In step i), the generated low-boiling alcohol needs to be continuously distilled off during the reaction, and in step ii), the generated water needs to be continuously distilled off during the reaction.

13. The method of synthesis of claim 1, wherein, The R group substituent of 2-chloro-4-fluoro-5-amino benzoate is C1-C6 alkyl.

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