Method for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate

Abstract

FIELD: organic synthesis.SUBSTANCE: invention relates to the field of organic synthesis, specifically to a method for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, which is used as a herbicide. The method includes carrying out the methylation reaction of 4-amino-3,6-dichloropyridine-2-carboxylic acid with methanol to release the methyl ester of 4-amino-3,6-dichloropyridine-2-carboxylic acid (1), the reaction of compound (1) with ditretbutylpyrocarbonate, followed by the release of the methyl ester of 4-(N,N-ditretbutyloxycarbonyl-diamido)-3,6-dichloropyridine-2-carboxylic acid (2), synthesis of methyl ester 4-(N,N-ditretbutyloxycarbonyl-diamido)-3,6-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid (3) by mixing compound (2) with 4-chloro-2-fluoro-3-methoxyphenylboronic acid and potassium fluoride dihydrate in the presence of a Pd(PPh3)4 catalyst. Compound (3) is isolated, and trifluoroacetic acid is added to obtain the final product. EFFECT: technical result of the invention lies in providing a method that ensures a high yield and purity of the target product.1 cl, 3 ex

Description

[0001] The invention relates to the field of organic synthesis, namely to a method for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, used as a herbicide.

[0002] 6-(polysubstituted aryl)-4-aminonicolinates are known (Patent 2 428 416 of 10.09.2011), including methods for producing esters of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid.

[0003] Also known is a method for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Patent 2 616 621 of 04 / 18 / 2017). This method includes adding methyl isobutyl ketone to an aqueous solution containing 4-chloro-2-fluoro-3-methoxyphenylboronic acid to obtain an organic phase containing 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase. Separation of the organic phase containing 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the aqueous phase, reaction of 4-chloro-2-fluoro-3-methoxyphenylboronic acid with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone to obtain methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate and deacetylation of methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to obtain methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

[0004] The prototype of the claimed invention is a method for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (patent CN 113603637 A, published 05.11.2021), including:

[0005] a) obtaining with the isolation of methyl 4-amino-3,6-dichloropyridine-2-carboxylate of formula (III) by the reaction of 4-amino-3,6-dichloropyridine-2-carboxylic acid (II) with methanol, with the addition of thionyl chloride (example 1, step 1);

[0006]

[0007] b) obtaining with isolation of methyl ester of 4-(N,N-ditert-butyloxycarbonyl-diamido)-3,6-dichloropyridine-2-carboxylic acid of formula (IV)

[0008]

[0009] by reaction of intermediate III with di-tert-butyl dicarbonate in the presence of dimethylaminopyridine and dichloromethane (Example 1, step 2);

[0010] c) obtaining with isolation of methyl ester of 4-(N,N-ditert-butyloxycarbonyl-diamido)-3,6-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid of formula VI by reaction of compound IV and 4-chloro-2-fluoro-3-methoxyphenylboronic acid (V) in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium as a catalyst (comparative example 4);

[0011] d) obtaining and isolating the target galauxifenmethyl by removing the N-protection from compound VI with trifluoroacetic acid (example 1, step 4).

[0012] The disadvantage of this method is the insufficiently high yield of the target product.

[0013] The objective of the invention is to expand the methods for producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

[0014] The technical result of the invention consists in the implementation of the said method, which ensures a high yield and degree of purity of the target product.

[0015] The technical result is achieved by carrying out a methylation reaction of 4-amino-3,6-dichloropyridine-2-carboxylic acid with methanol using thionyl chloride with the isolation of an intermediate product - methyl ester of 4-amino-3,6-dichloropyridine-2-carboxylic acid (compound I)

[0016]

[0017] by mixing compound I, methylene chloride, 4-dimethylaminopyridine and adding di-tert-butyl pyrocarbonate, followed by isolation of the intermediate product, 4-methyl ester

[0018]

[0019] (N,N-ditert-butyloxycarbonyl-diamido)-3,6-dichloropyridine-2-carboxylic acid (compound 2)

[0020] by mixing compound 2, 4-chloro-2-fluoro-3-methoxyphenylboronic acid, potassium fluoride dihydrate and carrying out the reaction in the presence of a tetrakis(triphenylphosphine)palladium Pd(PPh3)4 catalyst with the isolation of an intermediate product - methyl ester of 4-(N,N-di-tert-butyloxycarbonyl-diamido)-3,6-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid (compound 3)

[0021]

[0022] by reacting compound 3 with trifluoroacetic acid to isolate the target product - methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (compound 4)

[0023]

[0024] The method is as follows: thionyl chloride is added to 4-amino-3,6-dichloropyridine-2-carboxylic acid suspended in methanol under ice cooling.

[0025] The resulting suspension is stirred while heating to 55-60°C for 8 hours until the precipitate is completely dissolved. The solvent is evaporated, and the isolated residue is treated with pre-cooled 25% ammonia solution, followed by filtration, washing with distilled water, and air drying for 12 hours. Compound 1 is obtained.

[0026] Prepare a mixture of compound 1, methylene chloride, and 4-dimethylaminopyridine, and add di-tert-butyl pyrocarbonate. The resulting mixture is stirred for 24 hours until the precipitate is completely dissolved. The mixture is diluted with methylene chloride, washed three times with distilled water, and two to four times with a 50% solution of sodium chloride in water, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, the residue is triturated with hexane, and the solidified precipitate is crystallized from acetonitrile. Compound 2 is obtained as crystals.

[0027] The diboronic acid derivative of compound 2 is combined with 4-chloro-2-fluoro-3-methoxyphenylboronic acid and potassium fluoride dihydrate, acetonitrile solution and distilled water are added, and the mixture is stirred under an argon atmosphere until the solids dissolve. The tetrakis(triphenylphosphine)palladium Pd(PPh3)4 catalyst is added to the resulting two-phase system, the mixture is heated to 64°C with stirring for 20 hours, then cooled and left for 24 hours. Next, the upper and lower layers of the two-phase system are separated in a separatory funnel. The upper layer is evaporated in vacuo. The resulting residue is dissolved in ethyl acetate, washed four times with distilled water and twice with 50 ml of a 50% solution of sodium chloride in water, dried over sodium sulfate for 12 hours, filtered, and evaporated. The residue is then dissolved in chloroform for 24 hours, filtered through a 500-800 mesh silica gel filter, and evaporated. Compound 3 is obtained.

[0028] Compound 3 is dissolved in trifluoroacetic acid, stirred for 2 hours with 150 g of ice, and neutralized with 50% sodium bicarbonate solution. The resulting precipitate is washed with distilled water and dried. Petroleum ether and ethyl acetate are added to the resulting precipitate, and the mixture is dried for 2 hours under vacuum. Compound 4 is obtained.

[0029] Examples of specific implementation.

[0030] Example 1. To 50.0 g of 4-amino-3,6-dichloropyridine-2-carboxylic acid suspended in 200.0 ml of methanol under ice cooling, add 58.0 g of thionyl chloride dropwise.

[0031] The resulting suspension is stirred while heating to 55-60°C for 8 hours until the precipitate is completely dissolved. The solvent is evaporated, and the isolated residue is treated with 300.0 ml of pre-cooled 25% ammonia solution, followed by filtration, washing with distilled water (twice, 150.0 ml of distilled water each), and air drying for 12 hours. This yields 51.75 g (97%) of compound 1.

[0032] A mixture of 40.0 g of compound 1, 200.0 ml of methylene chloride, and 1.1 g of 4-dimethylaminopyridine is prepared, and 80.0 g of di-tert-butyl pyrocarbonate is added. The resulting mixture is stirred for 24 hours until the precipitate is completely dissolved, diluted 2-fold with methylene chloride, washed three times with 150.0 ml of distilled water and four times with 50 ml of a 50% solution of sodium chloride in water, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, the residue is triturated with hexane, and the solidified precipitate is crystallized from acetonitrile. 70.0 g (92%) of compound 2 are obtained.

[0033] 68.0 g of the diboc derivative of compound 2 is combined with 42 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid and 51.0 g of potassium fluoride dihydrate, 140.0 ml of acetonitrile solution and 140.0 ml of distilled water are added, and the mixture is stirred under an argon atmosphere until the solids dissolve. 0.56 g of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 catalyst is added to the resulting two-phase system, the mixture is heated to 64°C with stirring for 20 hours, then cooled and left for 24 hours. The upper and lower layers of the two-phase system are then separated in a separatory funnel. The upper layer is evaporated in vacuum. The resulting residue is dissolved in 400.0 ml of ethyl acetate, washed four times with 50 ml of distilled water and twice with 50 ml of a 50% solution of sodium chloride in water, dried over sodium sulfate for 12 hours, filtered, and evaporated. The residue is then dissolved in 250.0 ml of chloroform for 24 hours, filtered through a filter pad containing 500-800 mesh silica gel packed with petroleum ether, and evaporated.68.0 g (77%) of compound 3 are obtained.

[0034] 50.0 g of compound 3 is dissolved in 150.0 ml of trifluoroacetic acid, stirred for 2 hours, 150.0 g of ice is added, and the mixture is neutralized with a 50% solution of sodium bicarbonate in water. The resulting precipitate is washed twice with distilled water (150.0 ml each) and dried. 200.0 ml of petroleum ether and 10.0 ml of ethyl acetate are added to the resulting precipitate, and the mixture is dried for 2 hours under vacuum. Compound 4 is obtained, yield 29.0 g (98%).

[0035] 1 H NMR (DMSO-d6), δ ppm (J, Hz): 3.90 (s, 3H), 3.93 (s, 3H), 6.77 (s, 2H), 7.26 (s, 1H), 7.33 (d, 1H), 7.57 (t, 1H).

[0036] 13 NMR (DMSO-d6), δ, ppm (J, Hz): 52.35 s, 61.35 d, 110.45 d, 110.94 s, 125.03 d, 126.55 d, 127.80 d, 144.15 d, 148.78 d, 148.85 s, 151.08 s, 151.81 s, 156.11 s, 165.48 s.

[0037] 19 F NMR (DMSO-d6), δ, ppm (J, Hz): -130.61 s.

[0038] Example 2. To 50.0 g of 4-amino-3,6-dichloropyridine-2-carboxylic acid suspended in 200.0 ml of methanol while cooling with ice, add 58.0 g of thionyl chloride dropwise.

[0039] The resulting suspension is stirred while heating to 55-60°C for 8 hours until the precipitate is completely dissolved. The solvent is evaporated, and the isolated residue is treated with 300.0 ml of pre-cooled 25% ammonia solution, followed by filtration, washing with distilled water (twice, 150.0 ml of distilled water each), and air drying for 12 hours. This yields 51.75 g (97%) of compound 1.

[0040] A mixture of 40.0 g of compound 1, 200.0 ml of methylene chloride, and 1.1 g of 4-dimethylaminopyridine is prepared, and 80.0 g of di-tert-butyl pyrocarbonate is added. The resulting mixture is stirred for 24 hours until the precipitate is completely dissolved, diluted 2-fold with methylene chloride, washed three times with 150.0 ml of distilled water and twice with 50.0 ml of a 50% solution of sodium chloride in water, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, triturated with hexane, and the solidified precipitate is crystallized from acetonitrile. 70.0 g (92%) of compound 2 are obtained.

[0041] 68.0 g of the diboc derivative of compound 2 is combined with 42.0 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid and 51.0 g of potassium fluoride dihydrate, 140.0 ml of acetonitrile solution and 140.0 ml of distilled water are added, and the mixture is stirred under an argon atmosphere until the solids dissolve. 0.56 g of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 catalyst is added to the resulting two-phase system, the mixture is heated to 64°C with stirring for 20 hours, then cooled and left for 24 hours. The upper and lower layers of the two-phase system are then separated in a separatory funnel. The upper layer is evaporated in vacuum. The resulting residue is dissolved in 400.0 ml of ethyl acetate, washed four times with 50.0 ml of distilled water and twice with 50.0 ml of a 50% solution of sodium chloride in water, dried over sodium sulfate for 12 hours, filtered, and evaporated. The residue is then dissolved in 250.0 ml of chloroform for 24 hours, filtered through a filter pad lined with 500-800 mesh silica gel packed with petroleum ether, and evaporated.68.0 g (77%) of compound 3 are obtained.

[0042] 48.0 g of compound 3 is dissolved in 150.0 ml of trifluoroacetic acid, stirred for 2 hours, 150.0 g of ice is added, and the mixture is neutralized with a 50% solution of sodium bicarbonate in water. The resulting precipitate is washed twice with distilled water (150.0 ml each) and dried. 200.0 ml of petroleum ether and 10.0 ml of ethyl acetate are added to the resulting precipitate, and the mixture is dried for 2 hours under vacuum. Compound 4 is obtained, yield 27.3 g (96%).

[0043] 1 H NMR (DMSO-d6), δ, ppm (J, Hz): 3.90 (s, 3H), 3.93 (s, 3H), 6.77 (s, 2H), 7.26 (s, 1H), 7.33 (d, 1H), 7.57 (t, 1H).

[0044] 13 NMR (DMSO-d6), δ, ppm (J, Hz): 52.35 s, 61.35 d, 110.45 d, 110.94 s, 125.03 d, 126.55 d, 127.80 d, 144.15 d, 148.78 d, 148.85 s, 151.08 s, 151.81 s, 156.11 s, 165.48 s.

[0045] 19 F NMR (DMSO-d6), δ, ppm (J, Hz): -130.61 s.

[0046] Example 3. To 50.0 g of 4-amino-3,6-dichloropyridine-2-carboxylic acid suspended in 200.0 ml of methanol under ice cooling, add 58.0 g of thionyl chloride dropwise.

[0047] The resulting suspension is stirred while heating to 55-60°C for 8 hours until the precipitate is completely dissolved. The solvent is evaporated, and the isolated residue is treated with 300.0 ml of pre-cooled 25% ammonia solution, followed by filtration, washing with distilled water (twice, 150.0 ml of distilled water each), and air drying for 12 hours. This yields 51.75 g of compound I.

[0048] A mixture of 40.0 g of compound 1, 200.0 ml of methylene chloride, and 1.1 g of 4-dimethylaminopyridine is prepared, and 80.0 g of di-tert-butyl pyrocarbonate is added. The resulting mixture is stirred for 24 hours until the precipitate is completely dissolved, diluted 2-fold with methylene chloride, washed three times with 150.0 ml of distilled water and three times with 50.0 ml of a 50% solution of sodium chloride in water, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, the residue is triturated with hexane, and the solidified precipitate is crystallized from acetonitrile. 70.0 g (92%) of compound 2 are obtained.

[0049] 68.0 g of the diboc derivative of compound 2 is combined with 42.0 g of 4-chloro-2-fluoro-3-methoxyphenylboronic acid and 51.0 g of potassium fluoride dihydrate, 140.0 ml of acetonitrile solution and 140.0 ml of distilled water are added, and the mixture is stirred under an argon atmosphere until the solids dissolve. 0.56 g of tetrakis(triphenylphosphine)palladium Pd(PPh3)4 catalyst is added to the resulting two-phase system, the mixture is heated to 64°C with stirring for 20 hours, then cooled and left for 24 hours. The upper and lower layers of the two-phase system are then separated in a separatory funnel. The upper layer is evaporated in vacuum. The resulting residue is dissolved in 400.0 ml of ethyl acetate, washed four times with 50.0 ml of distilled water and twice with 50.0 ml of a 50% solution of sodium chloride in water, dried over sodium sulfate for 12 hours, filtered, and evaporated. The residue is then dissolved in 250.0 ml of chloroform for 24 hours, filtered through a filter pad lined with 500-800 mesh silica gel packed with petroleum ether, and evaporated.68.0 g (77%) of compound 3 are obtained.

[0050] 46.0 g of compound 3 in 150 ml of trifluoroacetic acid, stir for 2 hours, add 150.0 g of ice and neutralize with 50% sodium bicarbonate solution in water. The resulting precipitate is washed twice with distilled water (150.0 ml each) and dried. 200.0 ml of nitroglycerin ether and 10.0 ml of ethyl acetate are added to the resulting precipitate and dried for 2 hours in vacuum. Compound 4 is obtained, yield 25.9 g (95%).

[0051] 1 H NMR (DMSO-d6), δ, ppm (J, Hz): 3.90 (s, 3H), 3.93 (s, 3H), 6.77 (s, 2H), 7.26 (s, 1H), 7.33 (d, 1H), 7.57 (t, 1H).

[0052] 13 NMR (DMSO-d6), δ, ppm (J, Hz): 52.35 s, 61.35 d, 110.45 d, 110.94 s, 125.03 d, 126.55 d, 127.80 d, 144.15 d, 148.78 d, 148.85 s, 151.08 s, 151.81 s, 156.11 s, 165.48 s.

[0053] 19 F NMR (DMSO-d6), δ, ppm (J, Hz): -130.61 s.

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