METHOD FOR SYNTHESIZING 3-(DIFLUOROMETHYL)-1-METHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID AND INTERMEDIATES THEREOF

Abstract

The present invention relates to a method for synthesizing a compound of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid, wherein including the steps of: (A) the diethyl ester compounds represented by the following Formula IV are reacted under the action of amine, alkali and carbonyl reagents to produce the acrylic diester compound represented by the following Formula I,

##STR00001## wherein

##STR00002## (B) the above compound represented by the Formula I is reacted with a fluoride reagent, a Lewis acid and a methyl hydrazine to form a pyrazole ring-containing diester compound represented by the Formula II,

##STR00003## (C) the heterocyclic-containing diester compound represented by the Formula II is reacted with a base to give 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid represented by the Formula III.

Claims

1. A method for synthesizing 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid represented by the following Formula III, ##STR00053## comprising the steps of: (A) a diethyl ester compound represented by the following Formula IV is reacted under the action of an amine, a base and a carbonylating agent to form an acrylic diester compound represented by the following Formula I, ##STR00054## wherein, ##STR00055## wherein the definition of R.sub.1 is the same as above; (B) the above compound represented by the Formula I is reacted with a fluoride reagent, a Lewis acid and a methyl hydrazine to form a pyrazole ring-containing diester compound represented by the following Formula II, ##STR00056## wherein the definition of R.sub.1 is the same as above; (C) a heterocyclic-containing diester compound represented by the Formula II is reacted with a base to form the 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid represented by the Formula III.

2. The method according to claim 1, wherein the R.sub.1 is ##STR00057## and the R.sub.2 is ##STR00058##

3. The method according to claim 1, wherein the base in the step (C) is an organic base or an inorganic base, the organic base is trimethylamine, triethylamine, ethylenediamine, triisopropanolamine, tripropylamine, imidazole, benzimidazole, 2-fluoropyridine, 4-dimethylaminopyridine, methylpyridine, pyrazine or n-methyldiphenylethylamine, the inorganic base is an alkali metal carbonate or an alkali metal hydroxide.

4. The method according to claim 1, wherein the step (C) is carried out in the presence of a solvent which is water or methanol.

5. The method according to claim 1, wherein the step (A) comprising the steps of: (A1) the diethyl ester compound represented by the Formula IV is reacted with the carbonylating agent under the action of the base; (A2) the reaction liquid obtained after the reaction of the step (A1) is reacted with the amine to obtain the acrylic diester compound represented by the Formula I.

6. The method according to claim 1, wherein the step (B) comprising the steps of: (B1) the acrylic diester compounds represented by the Formula I is reacted with the fluoride reagent and the Lewis acid in solvents; (B2) the reaction product obtained in step (B1) is reacted with the methyl hydrazine to produce the heterocyclic-containing diester compound represented by the Formula II.

7. The method according to claim 1, wherein the amine in the preparation of the acrylic diester compound is selected from methylamine, dimethylamine, ethylamine, diethylamine, cyclohexylamine, piperidine, morpholine, dimethylamine hydrochloride, diethylamine hydrochloride, cyclohexylamine hydrochloride or piperidine hydrochloride; the base is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydride or potassium hydride; the carbonylating agent in the preparation of the acrylic diester compound is selected from carbon monoxide, methyl formate, ethyl formate, trimethyl orthoformate or triethyl orthoformate.

8. The method according to claim 1, wherein the fluoride reagent is selected from N,N-dimethyl tetrafluoroethylamine, difluoroacetyl fluoride or difluoroacetyl chloride; the Lewis acid is boron trifluoride etherate.

9. A pyrazole ring-containing diester compound represented by the Formula II, ##STR00059## wherein, ##STR00060##

10. The compound according to claim 9, wherein, the R.sub.1 is ##STR00061##

11. A method for preparing a pyrazole ring-containing diester compound represented by the Formula II, ##STR00062## wherein, ##STR00063## wherein the method comprises reacting a compound of Formula I with a fluoride reagent, a Lewis acid, and a methyl hydrazine, the structure of compound I is as follows: ##STR00064## Wherein, ##STR00065##

12. The method according to claim 11, wherein, the R.sub.1 is ##STR00066## the R.sub.2 is ##STR00067##

13. The method according to claim 11, wherein comprising the steps of (B1) the acrylic diester compounds represented by the Formula I is reacted with the fluoride reagent and the Lewis acid in solvents; (B2) the reaction product obtained in step (B1) is reacted with the methyl hydrazine to produce a heterocyclic-containing diester compound represented by the Formula II.

14. The method according to claim 11, wherein the fluoride reagent is selected from N,N-dimethyl tetrafluoroethylamine, difluoroacetyl fluoride or difluoroacetyl chloride.

15. The method according to claim 11, wherein the Lewis acid is boron trifluoride etherate.

16. The method according to claim 1, wherein the base in the step (C) is an organic base or an inorganic base, the inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

17. The method according to claim 5, wherein the amine in the preparation of the acrylic diester compound is selected from methylamine, dimethylamine, ethylamine, diethylamine, cyclohexylamine, piperidine, morpholine, dimethylamine hydrochloride, diethylamine hydrochloride, cyclohexylamine hydrochloride or piperidine hydrochloride; the base is selected from sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydride or potassium hydride; the carbonylating agent in the preparation of the acrylic diester compound is selected from carbon monoxide, methyl formate, ethyl formate, trimethyl orthoformate or triethyl orthoformate.

18. The method according to claim 6, wherein the fluoride reagent is selected from N,N-dimethyl tetrafluoroethylamine, difluoroacetyl fluoride or difluoroacetyl chloride; the Lewis acid is boron trifluoride etherate.

19. The method according to claim 12, wherein comprising the steps of: (B1) the acrylic diester compounds represented by the Formula I is reacted with the fluoride reagent and the Lewis acid in solvents; (B2) the reaction product obtained in step (B1) is reacted with the methyl hydrazine to produce a heterocyclic-containing diester compound represented by the Formula II.

20. The method according to claim 12, wherein the fluoride reagent is selected from N,N-dimethyl tetrafluoroethylamine, difluoroacetyl fluoride or difluoroacetyl chloride.

21. The method according to claim 13, wherein the fluoride reagent is selected from N,N-dimethyl tetrafluoroethylamine, difluoroacetyl fluoride or difluoroacetyl chloride.

22. The method according to claim 12, wherein the Lewis acid is boron trifluoride etherate.

23. The method according to claim 13, wherein the Lewis acid is boron trifluoride etherate.

Description

DESCRIPTION OF THE EMBODIMENTS

[0071] The specific embodiments of the present invention will be described in detail below, however, the scope of protection of the present invention is not limited.

[0072] Example A1 synthesis of ethylene glycol (3-n, n-dimethylamino)diacrylate

##STR00036##

[0073] Ethylene glycol diacetate (146 g, 1.0 mol) was dissolved in toluene (800 mL), sodium tert-butoxide (116 g, 1.2 mol) was added, and ethyl formate (89 g, 1.2 mol) was slowly added with stirring. Warmed (room temperature) and stirred overnight to obtain a suspension. The suspension was slowly added to a mixture of dimethylamine hydrochloride (122 g, 1.5 mol) and toluene, and stirred for 2 h. Filtration, the filtrate was washed once with saturated brine (300 mL) and dried with anhydrous sodium sulfate and evaporated to dryness to give pale yellow liquid ethylene glycol bis(3-N,N-dimethylamino) acrylate 216 g, the purity was 98% and the yield was 84%.

Example A2 Synthesis of Hexylene Glycol (3-N,N-dimethylamino) diacrylate

[0074] ##STR00037##

[0075] Ethylene glycol diacetate (101 g, 0.5 mol), sodium t-butoxide (120 g, 1.25 mol), toluene (500 mL) was added to the autoclave, the reaction was carried out by introducing co gas at a pressure of 20 bar and a temperature of 60 C. for 4 h, then cooling to room temperature. The reaction solution was slowly added to a mixture of dimethylamine hydrochloride (102 g, 1.25 mol) and toluene (200 mL) in an ice water bath, and reacted for 2 h after room temperature. Filtration, the filtrate was washed with water (300 mL*3), dried with anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow liquid bis(3-N,N-dimethylamino) acrylate 150 g, purity 99%. The rate was 96.1%.

Example A3 Synthesis of Ethylene Glycol (3-N,N-diethylamino)diacrylate

[0076] ##STR00038##

[0077] Ethylene glycol diacetate (146 g, 1.0 mol) was dissolved in toluene (800 mL), sodium tert-butoxide (116 g, 1.2 mol) was added, and ethyl formate (89 g, 1.2 mol) was slowly added with stirring. Warmed (room temperature) and stirred overnight to obtain a suspension. The suspension was slowly added to a mixture of diethylamine (109.5 g, 1.5 mol) and toluene, and stirred for 2 h. Filtration, the filtrate was washed once with saturated brine (300 mL) and dried with anhydrous sodium sulfate and evaporated to dryness to give pale yellow liquid ethylene glycol bis(3-N,N-diethyl amino) acrylate 220.4 g, the purity was 98.2% and the yield was 70.6%.

Example A4 Synthesis of Hexanediol (3-N,N-diethylamino) diacetate

[0078] ##STR00039##

[0079] Hexanediol diacetate (101 g, 0.5 mol) was dissolved in toluene (600 mL), potassium tert-butoxide (67.2 g, 0.6 mol) was added, and methylformate (45 g, 0.75 mol) was slowly added with stirring. Warmed (room temperature) and stirred overnight to obtain a suspension. The suspension was slowly added to a mixture of diethylamine ((54.8 g, 0.75 mol) and toluene, and stirred for 2 h. Filtration, the filtrate was washed once with saturated brine (300 mL) and dried with anhydrous sodium sulfate and evaporated to dryness to give pale yellow liquid hexanediol bis(3-N,N-diethylamino) acetate 141.6 g, the purity was 97.3% and the yield was 76.9%.

Example A5 Synthesis of Ethylene Glycol (3-piperidinyl) diacrylate

[0080] ##STR00040##

[0081] Ethylene glycol diacetate (146 g, 1.0 mol) was dissolved in toluene (800 mL), sodium tert-butoxide (116 g, 1.2 mol) was added, and ethyl formate (89 g, 1.2 mol) was slowly added with stirring. Warmed (room temperature) and stirred overnight to obtain a suspension. The suspension was slowly added to a mixture of piperidine (127.5 g, 1.5 mol) and toluene, and stirred for 2 h. Filtration, the filtrate was washed once with saturated brine (300 mL) and dried with anhydrous sodium sulfate and evaporated to dryness to give pale yellow liquid ethylene glycol bis(3-piperidinyl) acrylate 251.2 g, the purity was 98.6% and the yield was 74.7%.

Example A6 Synthesis of p-phenylene(3-N,N-dimethylamino)diacrylate

[0082] ##STR00041##

[0083] P-phenylenediacetate (97 g, 0.5 mol) was dissolved in toluene (600 mL), sodium tert-butoxide (58 g, 0.6 mol) was added, and ethyl formate (44.5 g, 0.6 mol) was slowly added with stirring. Warmed (room temperature) and stirred overnight to obtain a suspension. The suspension was slowly added to a mixture of dimethylamine hydrochloride (61 g, 0.75 mol) and toluene, and stirred for 2 h. Filtration, the filtrate was washed once with saturated brine (300 mL) and dried with anhydrous sodium sulfate and evaporated to dryness to give pale yellow liquid p-phenylene Bis(3-N,N-dimethylamino) acrylate 86.1 g, the purity was 97.1% and the yield was 56.6%.

Example B1 Synthesis of Ethylene Glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate

[0084] ##STR00042##

[0085] Dichloromethane (400 mL), N,N-dimethyl tetrafluoroethylamine (70 g, 0.48 mol) and boron trifluoride etherate (68.1 g, 0.48 mol) were added to a 1 L three-necked flask, after stirring at room temperature for 30 min, ethylene glycol bis(3-N,N-dimethylamino) acrylate (51.2 g, 0.2 mol) was added and stirring was continued for 2 h. Dichloromethane was removed by evaporation in a water bath at 35 C., methyl hydrazine (23 g, 0.5 mol) was added and stirred at room temperature for 2 h, after concentrating under reduced pressure to remove acetonitrile, hexane (200 mL) was added, and the mixture was stirred at room temperature for 1h, filtered and dried to give pale yellow solid ethylene glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate 67.2 g, the purity was 98% and the yield was 89%.

Example B2 Synthesis of Ethylene Glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate

[0086] ##STR00043##

[0087] Toluene (300 mL), difluoroacetyl fluoride (49 g, 0.44 mol), ethylene glycol bis(3-N,N-dimethylamino) acrylate (51.2 g, 0.2 mol) and triethylamine (60.6 g, 0.60 mol) were added to a 1 L three-necked flask, after stirring at room temperature for 1 h, the reaction solution was slowly added dropwise to a mixture of toluene (100 mL), water (50 mL) and methyl hydrazine (23 g, 0.5 mol) at 0 C., and the reaction was continued for 1 h at 0 C., the toluene layer was separated, washed with water (100 mL*2), dried over anhydrous sodium sulfate and evaporated to remove toluene to give pale yellow solid bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate 62 g, the purity was 98.3% and the yield was 82%.

Example B3 Synthesis of Hexanediol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate

[0088] ##STR00044##

[0089] Dichloromethane (600 mL), N,N-dimethyl tetrafluoroethylamine (104.4 g, 0.72 mol) and boron trifluoride etherate (102.2 g, 0.72 mol) were added to a 1 L three-necked flask at room temperature. After stirring for 30 min, bis(3-N,N-dimethylamino) acrylate (93.6 g, 0.3 mol) was added and stirring was continued at room temperature for 2 h. Methylene chloride was removed by evaporation in a water bath at 35 C., and the residue was dissolved in acetonitrile (600 mL), methyl hydrazine (47 g, 1 mol) was added and stirred at room temperature for 2 h, after concentrating under reduced pressure to remove acetonitrile, hexane (500 mL) was added, and the mixture was stirred at room temperature for 1h, filtered and dried to give pale yellow solid bis (3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate 112 g, the purity was 99% and the yield was 86%.

Example B4 Synthesis of Ethylene Glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate

[0090] ##STR00045##

[0091] Dichloromethane (400 mL), N,N-dimethyl tetrafluoroethylamine (70 g, 0.48 mol) and boron trifluoride etherate (68.1 g, 0.48 mol) were added to a 1 L three-necked flask at room temperature. After stirring for 30 min, ethylene glycol bis(3-N,N-diethylamino) acrylate (62.4 g, 0.2 mol) was added and stirring was continued at room temperature for 2 h. Methylene chloride was removed by evaporation in a water bath at 35 C., and the residue was dissolved in acetonitrile (300 mL), methyl hydrazine (23 g, 0.5 mol) was added and stirred at room temperature for 2 h, after concentrating under reduced pressure to remove acetonitrile, hexane (200 mL) was added, and the mixture was stirred at room temperature for 1h, filtered and dried to give pale yellow solid bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate 57.2 g, the purity was 98%, the yield was 75.6%.

Example B5 Synthesis of Ethylene Glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate

[0092] ##STR00046##

[0093] Dichloromethane (400 mL), N,N-dimethyl tetrafluoroethylamine (70 g, 0.48 mol) and boron trifluoride etherate (68.1 g, 0.48 mol) were added to a 1 L three-necked flask at room temperature. After stirring for 30 min, ethylene glycol bis(3-piperidinyl) acrylate (67.2 g, 0.2 mol) was added and stirring was continued at room temperature for 2 h. Methylene chloride was removed by evaporation in a water bath at 35 C., and the residue was dissolved in acetonitrile (300 mL), methyl hydrazine (23 g, 0.5 mol) was added and stirred at room temperature for 2 h, after concentrating under reduced pressure to remove acetonitrile, hexane (200 mL) was added, and the mixture was stirred at room temperature for 1h, filtered and dried to give pale yellow solid bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate 45.8 g, the purity was 96.1%, the yield was 60.5%.

Example B6 Synthesis of Benzo(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate

[0094] ##STR00047##

[0095] Dichloromethane (400 mL), N,N-dimethyl tetrafluoroethylamine (70 g, 0.48 mol) and boron trifluoride etherate (68.1 g, 0.48 mol) were added to a 1 L three-necked flask at room temperature. After stirring for 30 min, p-phenylene (3-N,N-dimethylamino) acrylate (60.8 g, 0.2 mol) was added and stirring was continued at room temperature for 2 h. Methylene chloride was removed by evaporation in a water bath at 35 C., and the residue was dissolved in acetonitrile (300 mL), methyl hydrazine (23 g, 0.5 mol) was added and stirred at room temperature for 2 h, after concentrating under reduced pressure to remove acetonitrile, hexane (200 mL) was added, and the mixture was stirred at room temperature for 1h, filtered and dried to give pale yellow solid Bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-)carboxylate 38.2 g, the purity was 96.1%, the yield was 50.5%.

Example C1 Synthesis of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic Acid

[0096] ##STR00048##

[0097] Water (200 mL), methanol (200 mL), sodium hydroxide (10 g, 0.25 mol), ethylene glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylic ester (37.8 g, 0.1 mol) were added to a 1 L three-necked flask and reacted at 60 C. for 4 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure, and then slowly cooled to 0-5 C., stirred for 2 hours, filtered and dried to give a white solid 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid 32.4 g, the purity was 99.2%, the yield was 92%.

Example C2 Synthesis of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic Acid

[0098] ##STR00049##

[0099] Water (200 mL), methanol (200 mL), lithium hydroxide monohydrate (10.5 g, 0.25 mol), ethylene glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylic ester (37.8 g, 0.1 mol) were added to a 1 L three-necked flask and reacted at 60 C. for 4 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure, and then slowly cooled to 0-5 C., stirred for 2 hours, filtered and dried to give a white solid 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid, 31.2 g, the purity was 99.4%, the yield was 88.6%.

Example C3 Synthesis of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic Acid

[0100] ##STR00050##

[0101] Water (200 m L), methanol (200 m L), potassium hydroxide (18 g, 0.25 mol), ethylene glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylic ester (37.8 g, 0.1 mol) were added to a 1 L three-necked flask and reacted at 60 C. for 4 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure, and then slowly cooled to 0-5 C., stirred for 2 hours, filtered and dried to give a white solid 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid, 29.7 g, the purity was 98.6%, the yield was 84.3%.

Example C4 Synthesis of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic Acid

[0102] ##STR00051##

[0103] Water (300 m L), methanol (300 m L), sodium hydroxide (15 g, 0.38 mol), hexanediol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylate (80 g, 0.18 mol) were added to a 1 L three-necked flask and reacted at 60 C. for 4 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure, and then slowly cooled to 0-5 C., stirred for 2 hours, filtered and dried to give a white solid 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid, 62.5 g, the purity was 99.8%, the yield was 96.3%.

Example C5 Synthesis of 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic Acid

[0104] ##STR00052##

[0105] Water (200 mL), methanol (200 mL), sodium hydroxide (10 g, 0.25 mol), ethylene glycol bis(3-(difluoromethyl)-1-methyl-1h-pyrazole-4-) carboxylic ester (42.6 g, 0.1 mol) were added to a 1 L three-necked flask and reacted at 60 C. for 4 hours. After cooling to room temperature, the methanol was removed by concentration under reduced pressure. The residue was diluted with 200 mL of water, extracted with EA (200 m L*2), the aqueous layer was acidified with dilute hydrochloric acid to ph=4, then the aqueous layer was extracted again with EA (200 m L*2), and EA layer was concentrated to dry to give a white solid 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid 18.6 g, the purity was 98.1%, the yield was 52.8%.