Synthesis method of halauxifen-methyl

Abstract

The invention discloses a synthesis method of halauxifen-methyl. The halauxifen-methyl is obtained by carrying out Suzuki coupling reaction on 4-amino-6-bromo-3-chloro-5-fluoropyridine carboxylic acid benzyl ester and 4-chloro-2-fluoro-3-methoxyphenylboronic acid, a catalytic system adopted by the Suzuki coupling reaction is a palladium catalyst, a phosphine ligand and a phase transfer catalyst; wherein the phosphine ligand is 4-(anthracene-9-yl)-3-(tert-butyl)-2, 3-dihydrobenzo [d] [1, 3] oxaphosphorus pentadiene, and the phosphine ligand is 4-(anthracene-9-yl)-3-(tert-butyl)-2, 3-dihydrobenzo [d] [1, 3] The molar use amount of the palladium catalyst is 0.1 to 0.5 mol percent of the molar use amount of the 4-amino-6-bromo-3-chloro-5-fluoropyridine benzyl formate. According to the invention, AntPhos is used as a phosphine ligand to form a catalytic system together with the palladium catalyst and the phase transfer catalyst, so that higher reaction yield and product purity can be obtained with very low dosage of the palladium catalyst, the synthesis cost of the halauxifen-methyl can be greatly reduced, the reaction condition is mild, the energy consumption is lower, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of herbicide preparation technology, specifically relating to a method for synthesizing chlorofluoropyridine ester. Background Technology

[0002] Florpyrauxifen-benzyl is a new generation of arylpyridine ester herbicide introduced by Dow AgroSciences. This herbicide is absorbed simultaneously by the leaves and roots of plants, translocated within the weed through the xylem and phloem, and accumulates in the meristematic tissue, thus effectively exerting its weed-controlling effect. Its novel mechanism of action allows florpyrauxifen-benzyl to address known resistance issues, including resistance to acetolactate synthase (ALS) inhibitors, acetyl-CoA carboxylase (ACCase) inhibitors, p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, as well as resistance to herbicides such as barnyardgrass, quinclorac, glyphosate, and triazine. Furthermore, florpyrauxifen-benzyl also exhibits excellent activity against resistant barnyardgrass in paddy fields.

[0003] The existing methods for synthesizing chlorofluoropyridine esters mainly include the following: I. Chinese patent document CN109415319A discloses a method for preparing benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridinecarboxylate, which is obtained by Suzuki coupling reaction of benzyl 4-amino-3,6-dichloro-5-fluoropyridinecarboxylate and 4-chloro-2-fluoro-3-methoxyphenylboronic acid in a palladium acetate + triphenylphosphine catalytic system [see paragraphs 113-114 of the specification].

[0004] This method has a low reaction yield (only 67.9%) and requires a large amount of catalyst (2 mol% palladium acetate and 4 mol% triphenylphosphine), resulting in high production costs and making it unsuitable for large-scale industrial production.

[0005] II. Chinese patent document CN115298167A discloses a method for preparing benzyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyridinecarboxylate, which is obtained by Suzuki coupling reaction of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate and 4-chloro-2-fluoro-3-methoxyphenylboronic acid in a palladium acetate + triphenylphosphine catalytic system [see paragraphs 166-168 and 172-174 of the specification].

[0006] This method uses benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate instead of benzyl 4-amino-3,6-dichloro-5-fluoropyridinecarboxylate as a raw material, which can significantly improve the reaction yield (89%). However, the amount of its catalytic system is still relatively large (palladium acetate is 1 mol%, triphenylphosphine is 2 mol%), and the production cost is still high, so it is still not suitable for large-scale industrial production.

[0007] III. Chinese patent document CN115819334A discloses a method for preparing chlorofluoropyridine ester, which is obtained by Suzuki coupling reaction of 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate and 4-chloro-2-fluoro-3-methoxyphenylboronic acid in a copper catalyst + N-containing ligand + phase transfer catalyst catalytic system.

[0008] This method not only has a low reaction yield (68.3-84.3%), but also requires a high reaction temperature (120℃) and high energy consumption. In particular, the amount of catalyst used is very large (about 10 mol% copper catalyst, about 20 mol% N-containing ligands, and about 100 mol% phase transfer catalyst). The price of N-containing ligands such as stigmaine is comparable to that of palladium catalysts, resulting in higher production costs for this method and making it less suitable for large-scale industrial production.

[0009] IV. Chinese patent document CN120518533A discloses a method for preparing chlorofluoropyridine ester, which is obtained by Suzuki coupling reaction of 3-chloro-4-amino-5-fluoro-6-boronic acid 2-pyridinecarboxylic acid benzyl ester and 1-bromo-4-chloro-2-fluoro-3-methoxybenzene under the catalysis of palladium acetate or triphenylphosphine palladium chloride.

[0010] The raw material used in this method, benzyl 2-pyridinecarboxylate 3-chloro-4-amino-5-fluoro-6-boronic acid, is an unknown substance and is difficult to prepare according to the method described in the literature, making industrial production impossible. Summary of the Invention

[0011] The purpose of this invention is to solve the above-mentioned problems and provide a method for synthesizing chlorofluoropyridine esters that is not only mild in reaction conditions, low in energy consumption, high in yield, but also requires less catalytic system, has low production cost, and is suitable for large-scale industrial production.

[0012] The technical solution for achieving the objective of this invention is: a method for synthesizing chlorofluoropyridine esters, which is obtained by a Suzuki coupling reaction of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate and 4-chloro-2-fluoro-3-methoxyphenylboronic acid; characterized in that: the catalytic system used in the Suzuki coupling reaction is a palladium catalyst + phosphine ligand + phase transfer catalyst; the phosphine ligand is 4-(anthracite-9-yl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxophosphazenecyclopentadiene (hereinafter referred to as AntPhos); the molar amount of the palladium catalyst is 0.1 to 0.5 mol of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

[0013] Further, the molar amount of the palladium catalyst is preferably 0.2 to 0.3 mol% of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate, more preferably 0.2 mol%.

[0014] The palladium catalyst is a divalent palladium salt, a divalent palladium salt complex, or a zero-valent palladium complex; preferably palladium acetate, palladium dichloride, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium Pd(dppf)Cl2, tris(dibenzylideneacetone)dipalladium Pd2(dba)3, or tetra(triphenylphosphine)palladium Pd(PPh3)4; more preferably palladium acetate.

[0015] The molar amount of the phosphine ligand is 0.1 to 0.5 mol of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate, preferably 0.2 to 0.3 mol, more preferably 0.2 mol.

[0016] The phase transfer catalyst is one or more of tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, and tetramethylammonium chloride, preferably tetrabutylammonium bromide; the molar amount of the phase transfer catalyst is 1 to 10 mol% of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate, preferably 5 mol.

[0017] The Suzuki coupling reaction is carried out in the presence of an inorganic base; the inorganic base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, cesium carbonate, and potassium fluoride; the molar amount of the inorganic base is 100-300 mol% of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate, preferably 180-220 mol%.

[0018] The molar ratio of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate to 4-chloro-2-fluoro-3-methoxyphenylboronic acid is 1:1 to 1:1.5, preferably 1:1.1 to 1:1.2.

[0019] The Suzuki coupling reaction is carried out in the presence of an organic solvent, which is one or more of tetrahydrofuran, toluene, methanol, acetonitrile, methyl isobutyl ketone, and 1,4-dioxane.

[0020] The Suzuki coupling reaction temperature is 60–100°C, preferably 65°C.

[0021] The positive effects of this invention are as follows: After extensive experimentation, the applicant was surprised to find that by using AntPhos as a phosphine ligand in conjunction with a palladium catalyst and a phase transfer catalyst to form a catalytic system, a high reaction yield and product purity can be obtained with a very low amount of palladium catalyst, thereby greatly reducing the synthesis cost of chlorofluoropyridine esters. Moreover, the reaction conditions are mild and the energy consumption is low, making it suitable for industrial production. Detailed Implementation

[0022] (Example 1) The specific method for synthesizing chlorofluoropyridine ester in this embodiment is as follows: 54 g of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (0.15 mol), 35.2 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid (0.17 mol, 115 mol%), 360 g of tetrahydrofuran, 180 g of water, 30 g of potassium bicarbonate (0.3 mol, 200 mol%), and 2.4 g of tetrabutylammonium bromide (7.5 mmol, 5 mol%) were added to a 1 L round-bottom flask equipped with a condenser. The mixture was stirred until dissolved, purged with nitrogen, and then 67.4 mg of palladium acetate (0.3 mmol, 0.2 mol%) and 111.1 mg of AntPhos (0.3 mmol, 0.2 mol%) were added under nitrogen protection. The mixture was then heated to 65 °C and stirred. The reaction was monitored by HPLC until complete.

[0023] After the reaction was completed, the mixture was cooled to room temperature, separated, extracted with tetrahydrofuran, evaporated to dryness, dissolved in 120g methanol under heating, cooled to crystallize for 24h, filtered, dried, and 58.0g of chlorofluoropyridine ester was obtained, with a yield of 88.0% and an HPLC purity of 98.5%.

[0024] (Examples 2 to 7) The synthesis methods of chlorofluoropyridine esters in each embodiment are basically the same as those in Example 1, except for the amount of palladium acetate and AntPhos used, as shown in Table 1.

[0025] Table 1 Palladium acetate AntPhos Chloropyridine ester yield purity Example 1 0.2 mol% 0.2 mol% 58.0g 88.0% 98.5% Example 2 0.1 mol% 0.1 mol% 53.9g 81.7% 96.5% Example 3 0.3 mol% 0.3 mol% 58.3g 88.4% 98.5% Example 4 0.5 mol% 0.5 mol% 58.7g 89.0% 98.7% Example 5 0.1 mol% 0.2 mol% 54.5g 82.6% 96.8% Example 6 0.2 mol% 0.3 mol% 58.1g 88.1% 98.4% Example 7 0.2 mol% 0.4 mol% 58.3g 88.4% 98.6%

[0026] As shown in Table 1, within the range of 0.1–0.5 mol%, increasing the dosage of palladium acetate and AntPhos does not significantly improve the yield and purity. Therefore, considering both production cost and effectiveness, the optimal dosage of palladium acetate and AntPhos is 0.2–0.3 mol%.

[0027] (Comparative Examples 1 to 6) The synthesis methods of chlorofluoropyridine esters in each comparative example are basically the same as those in Example 1, except for the type of phosphine ligand (the amount used is 0.2 mol%), as shown in Table 2.

[0028] Table 2 Phosphine ligand yield Example 1 AntPhos 88.0% Comparative Example 1 Triphenylphosphine 37.4% Comparative Example 2 Tricyclohexylphosphine 25.4% Comparative Example 3 Dppf 27.7% Comparative Example 4 Dtbpf 36.5% Comparative Example 5 AmPhos 42.0% Comparative Example 6 XantPhos 19.0%

[0029] In Table 2: the chemical name of Dppf is 1,1'-bis(diphenylphosphine)ferrocene [CAS No. 12150-46-8]; the chemical name of Dtbpf is 1,1'-bis(di-tert-butylphosphine)ferrocene [CAS No. 84680-95-5]; the chemical name of AmPhos is [(4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine [CAS No. 932710-63-9]; and the chemical name of XantPhos is 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene [CAS No. 161265-03-8].

[0030] (Comparative Examples 7 to 10) The synthesis methods of chlorofluoropyridine esters in each comparative example are basically the same as those in Example 1, except for the amount of palladium acetate and the type and amount of phosphine ligands, as detailed in Table 3.

[0031] Table 3 Palladium acetate Phosphine ligand yield Example 1 0.2 mol% 0.2 mol% AntPhos 88.0% Comparative Example 7 2mol% 4 mol% AntPhos 91.2% Comparative Example 8 2mol% 4 mol% triphenylphosphine 89.5% Comparative Example 9 2mol% 4 mol% Dtbpf 87.3% Comparative Example 10 2mol% 4 mol% AmPhos 90.2%

[0032] As can be seen from Tables 2 and 3, at low dosages (0.2 mol%), AntPhos has a significant effect compared to other phosphine ligands, with a significantly higher yield [Table 2]; while at the existing conventional dosages (2–4 mol%), AntPhos has no significant effect, and the yield is basically the same [Table 3].

Claims

1. A method for synthesizing chlorofluoropyridine esters, comprising a Suzuki coupling reaction of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate and 4-chloro-2-fluoro-3-methoxyphenylboronic acid; characterized in that: The catalytic system used in the Suzuki coupling reaction is palladium catalyst + phosphine ligand + phase transfer catalyst; the phosphine ligand is 4-(anthracite-9-yl)-3-(tert-butyl)-2,3-dihydrobenzo[d][1,3]oxophosphazenecyclopentadiene; the molar amount of the palladium catalyst is 0.1 to 0.5 mol of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

2. The method for synthesizing chlorofluoropyridine ester according to claim 1, characterized in that: The molar amount of the palladium catalyst is 0.2 to 0.3 mol of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

3. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The palladium catalyst is a divalent palladium salt, a divalent palladium salt complex, or a zero-valent palladium complex.

4. The method for synthesizing chlorofluoropyridine ester according to claim 3, characterized in that: The palladium catalyst is palladium acetate.

5. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The molar amount of the phosphine ligand is 0.1 to 0.5 mol of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

6. The method for synthesizing chlorofluoropyridine ester according to claim 5, characterized in that: The molar amount of the phosphine ligand is 0.2 to 0.3 mol of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

7. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The phase transfer catalyst is one or more of tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, and tetramethylammonium chloride; the molar amount of the phase transfer catalyst is 1 to 10 mol of benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

8. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The Suzuki coupling reaction is carried out in the presence of an inorganic base; the inorganic base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, cesium carbonate, and potassium fluoride; the molar amount of the inorganic base is 100 to 300 mol of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate.

9. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The molar ratio of the benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate to the 4-chloro-2-fluoro-3-methoxyphenylboronic acid is 1:1 to 1:1.

5.

10. The method for synthesizing chlorofluoropyridine ester according to claim 1 or 2, characterized in that: The Suzuki coupling reaction is carried out in the presence of an organic solvent; the organic solvent is one or more of tetrahydrofuran, toluene, methanol, acetonitrile, methyl isobutyl ketone, and 1,4-dioxane; the Suzuki coupling reaction temperature is 60–100 °C.