Preparation method of halauxifen-methyl

Abstract

The invention belongs to the field of fine chemical engineering, and discloses a preparation method of halauxifen-methyl, which comprises the following steps: by taking a compound I and a compound II as raw materials and acetonitrile or an acetonitrile-water mixed solution as a reaction solvent, under the protection of nitrogen, taking a palladium catalyst as a catalyst and under the condition that a cocatalyst exists or does not exist, carrying out a reaction on the compound I and the compound II to obtain the halauxifen-methyl. And carrying out Suzuki coupling reaction on the compound I and the compound II to obtain the halauxifen-methyl. The method for preparing the halauxifen-methyl is high in novelty, the product selectivity can be improved by adding the cocatalyst, the product yield is high and at least reaches 80%, and the product purity is high. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and particularly relates to a method for preparing florpyrauxifen-benzyl. Background Art

[0002] Halofop-butyl (HRF) is an aryl picolinate herbicide developed by Dow AgroSciences. It binds tightly to the plant target AFB5, inducing increased activity in sensitive plant cells. This leads to abnormal plant growth, such as tissue swelling and stem bending, and ultimately plant death. In 2012, the active ingredient was further derivatized to produce Halofop-butyl, and both the technical and formulation versions were registered in 2017.

[0003] There are three main routes for the synthesis of cloflupyridine: 1. fluorination coupling of piclopitidine, 2. enoneamine cyclization, and 3. trifluoroacetic acid cyclization.

[0004] The trifluoroacetic acid cyclization method uses trifluoroacetic acid as a raw material, undergoes a cyclization reaction with triphenylmethylamine, acetylene ether, and 2-fluoro-3-methoxy-4-chlorobenzylamine, and then undergoes hydrolysis, chlorination, oxidation, and finally reacts with a benzyl halide to obtain the target product. The raw materials of this method are difficult to obtain, the cyclization yield is low, the cost is high, and it has no industrial value.

[0005] Fluorination coupling is the primary method used in workshop production. Using a pyridine ring compound (e.g., amiloride) as the starting material, a series of operations, including amino protection, esterification, and fluorination, yield an intermediate. This intermediate is then coupled with 2-fluoro-3-methoxy-4-chlorophenylboronic acid to obtain the target product. The synthetic route is as follows:

[0006]

[0007] The method can be adjusted according to the specific experimental conditions, and the steps can be hydrolyzed first and then coupled, or coupled first and then hydrolyzed. Different raw materials (such as aminopyralid) can also be used for preparation. Except for some differences in individual steps, the overall synthesis method is not much different.

[0008] Among them, the synthesis route of the benzene ring intermediate (2-fluoro-3-methoxy-4-chloro-phenylboronic acid, CAS: 944129-07-1) is relatively simple. 2-Fluoro-6-chloroanisole is used as the raw material, reacting with n-butyl lithium at low temperature (-50°C to -60°C), and then undergoing alkaline hydrolysis and acidification after borate ester to obtain 2-fluoro-3-methoxy-4-chloro-phenylboronic acid.

[0009]

[0010] In the above preparation method, the coupling of the pyridyl intermediate and the phenyl intermediate is carried out by coupling the halogenated pyridyl intermediate and the phenylboronic acid intermediate. Summary of the Invention

[0011] The object of the present invention is to provide a new method for preparing cloflupyridine-methyl.

[0012] The present invention adopts the following technical solutions to achieve the above purpose:

[0013] A preparation method of cloflupyridine-methyl, the synthetic route is as follows:

[0014]

[0015] The method comprises the following steps: using compound I (chemical name: 3-chloro-4-amino-5-fluoro-6-boronic acid-2-pyridinecarboxylic acid benzyl ester) and compound II (chemical name: 1-bromo-4-chloro-2-fluoro-3-methoxybenzene) as raw materials, using acetonitrile or a mixture of acetonitrile and water as a reaction solvent, and under nitrogen protection, using a palladium catalyst as a catalyst, and in the presence or absence of a co-catalyst, allowing compound I and compound II to undergo a Suzuki coupling reaction to obtain chlorofluoropyridinium ester (III).

[0016] The molar ratio of compound I to compound II is 1:1.2 to 1:1.5, preferably 1:1.3 to 1:1.4.

[0017] The mass ratio of the compound I to the reaction solvent is 1:5 to 1:20, preferably 1:8 to 1:15, and more preferably 1:9 to 1:10.5.

[0018] The palladium catalyst is selected from triphenylphosphine palladium chloride or palladium acetate.

[0019] The mass ratio of the palladium catalyst to compound I is 1.5:100 to 10:100, preferably 1.8:100 to 2:100.

[0020] The co-catalyst is selected from cesium fluoride, potassium fluoride, potassium carbonate and the like.

[0021] The mass ratio of the co-catalyst to compound I is 0:100 to 15:100, preferably 2.5:100 to 6.5:100.

[0022] The temperature of the Suzuki coupling reaction is 50-120° C., preferably 60-100° C., more preferably 90-100° C.; the time of the Suzuki coupling reaction is 2-5 h, preferably 2.5-4 h.

[0023] As a preferred technical solution of the preparation method of clofopyralid of the present invention, the method further comprises: after the reaction is completed, filtering, washing the filter cake with 50% acetonitrile-water mixture to remove the catalyst and reaction impurities, and drying to obtain clofopyralid.

[0024] The preparation of 2-pyridineboronic acid is known (SYNTHETIC COMMUNICATIONS Vol. 33, No. 5, pp. 795-800, 2003; A. Bouillon et al. Tetrahedron 59 (2003) 10043-10049). Compound I is prepared from a halopyridyl compound IV (X selected from Cl and Br, chemical name: 3-chloro-4-amino-5-fluoro-6-halo-2-pyridinecarboxylic acid benzyl ester) by a series of synthetic methods, including esterification, fluorination, and halogenation, with amiloride. Compound I is then prepared using the general methods disclosed in the aforementioned literature for preparing pyridine borates.

[0025]

[0026] Beneficial effects of the present invention:

[0027] The method for preparing cloflupyridine-methyl of the present invention is highly novel, and can improve product selectivity by adding a co-catalyst, so that the product yield is high, reaching at least 80%, and the product purity is high. DETAILED DESCRIPTION

[0028] The present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto:

[0029] Example 1

[0030] 15.58 g (0.05 mol) of compound I and 15.61 g (0.065 mol) of compound II were placed in a four-necked flask, 160 g of acetonitrile was added, and under nitrogen protection, 0.4 g of cesium fluoride and 0.3 g of triphenylphosphine palladium chloride were added. The mixture was refluxed at 100° C. for 2.5 h, cooled to room temperature, filtered, and rinsed with 60 g of a mixture of acetonitrile and water (the volume fraction of acetonitrile was 50%) to remove the catalyst and reaction impurities. The mixture was dried to obtain 21.7 g of chlorofluoropyridinium ester with a yield of 90.1% and an HPLC purity of 91.2%.

[0031] Example 2

[0032] 31.18 g (0.1 mol) of compound I and 31.31 g (0.13 mol) of compound II were placed in a four-necked flask, and 302 g of acetonitrile was added. Under nitrogen protection, 1.5 g of potassium fluoride and 0.6 g of triphenylphosphine palladium chloride were added. The reaction was refluxed at 90° C. for 3 h, cooled to room temperature, filtered, rinsed with 110 g of a mixture of acetonitrile and water (50%), and dried to obtain 44.9 g of chlorofluoropyridamole with a yield of 93.2% and an HPLC purity of 91.1%.

[0033] Example 3

[0034] 31.15 g (0.1 mol) of compound I and 31.20 g (0.13 mol) of compound II were placed in a four-necked flask, 300 g of acetonitrile was added, and under nitrogen protection, 2.0 g of cesium fluoride and 0.6 g of palladium acetate were added. The mixture was refluxed at 90° C. for 3 h, cooled to room temperature, filtered, rinsed with 100 g of a mixture of acetonitrile and water (50%), and dried to obtain 45.5 g of chlorofluoropyridamole with a yield of 93.8% and an HPLC purity of 90.5%.

[0035] Example 4

[0036] 31.15 g (0.1 mol) of compound I and 31.20 g (0.13 mol) of compound II were placed in a four-necked flask, 300 g of acetonitrile was added, and 0.6 g of triphenylphosphine palladium chloride was added under nitrogen protection. The mixture was refluxed at 90° C. for 3 h, cooled to room temperature, filtered, rinsed with 100 g of a mixture of acetonitrile and water (50%), and dried to obtain 39.2 g of chlorofluoropyridamole with a yield of 80.0% and an HPLC purity of 89.5%.

[0037] Example 5

[0038] 15.61 g (0.05 mol) of compound I and 15.58 g (0.065 mol) of compound II were placed in a four-necked flask, 155 g of acetonitrile was added, and under nitrogen protection, 0.3 g of palladium acetate was refluxed at 100° C. for 2.5 h. The mixture was cooled to room temperature, filtered, rinsed with 60 g of a mixture of acetonitrile and water (50%), and dried to obtain 20.4 g of chlorofluoropyridamole with a yield of 82.0% and an HPLC purity of 88.2%.

Claims

1. A method for preparing clofopyralid, characterized in that: The synthetic route is as follows: The method comprises: using compound I and compound II as raw materials, using acetonitrile or a mixture of acetonitrile and water as a reaction solvent, and under nitrogen protection, using a palladium catalyst as a catalyst, and in the presence or absence of a co-catalyst, allowing compound I and compound II to undergo a Suzuki coupling reaction to obtain chlorfluazol-methyl.

2. A method for preparing clofopyralid according to claim 1, characterized in that: The molar ratio of compound I to compound II is 1:1.2 to 1:1.

5.

3. A method for preparing clofopyralid according to claim 1 or 2, characterized in that: The molar ratio of compound I to compound II is 1:1.3 to 1:1.

4.

4. The method for preparing clofopyralid according to claim 1, wherein: The mass ratio of the compound I to the reaction solvent is 1:5 to 1:20, preferably 1:8 to 1:15, and more preferably 1:9 to 1:10.

5.

5. A method for preparing clofopyralid according to claim 1, characterized in that: The palladium catalyst is selected from triphenylphosphine palladium chloride or palladium acetate; the mass ratio of the palladium catalyst to compound I is 1.5:100 to 10:

100.

6. The method for preparing clofopyralid according to claim 1 or 5, wherein: The mass ratio of the palladium catalyst to compound I is 1.8:100 to 2:

100.

7. The method for preparing clofopyralid according to claim 1, wherein: The co-catalyst is selected from one of cesium fluoride, potassium fluoride and potassium carbonate; the mass ratio of the co-catalyst to compound I is 0:100 to 15:

100.

8. The method for preparing clofopyralid according to claim 1 or 7, wherein: The mass ratio of the co-catalyst to the compound I is 2.5:100 to 6.5:

100.

9. The method for preparing clofopyralid according to claim 1, wherein: The temperature of the Suzuki coupling reaction is 50-120° C., preferably 60-100° C., more preferably 90-100° C.; the time of the Suzuki coupling reaction is 2-5 h, preferably 2.5-4 h.

10. The method for preparing clofopyralid according to claim 1, wherein: After the reaction is completed, the mixture is filtered, and the filter cake is washed with a 50% acetonitrile-water mixture to remove the catalyst and reaction impurities, and then dried to obtain clofopyralid.

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