Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a high-efficiency synthesis method of 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid.
In order to achieve the aim, the invention provides a technical scheme that the high-efficiency synthesis method of 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid,
The preparation method of the 3-chloropyridine-2-formaldehyde comprises the steps of preparing 3-chloropyridine, N-Dimethylformamide (DMF) and phosphorus oxychloride (POCl3), carrying out Vilsmeier-Haack reaction on the 3-chloropyridine, the DMF and the POCl3, and introducing aldehyde groups at the 2 position of a pyridine ring;
step two, preparing 5- (trifluoromethyl) -1H-tetrazole, namely preparing the 5- (trifluoromethyl) -1H-tetrazole by using trifluoroacetonitrile, sodium azide and ammonium chloride, and performing cyclization reaction on the trifluoroacetonitrile and the sodium azide in the presence of the ammonium chloride to generate the 5- (trifluoromethyl) -1H-tetrazole;
Step three, preparing ethyl 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylate, wherein the ethyl 1- (3-chloropyridine-2-carbaldehyde, 5- (trifluoromethyl) -1H-tetrazole, ethyl acetoacetate and potassium carbonate are prepared by condensation reaction of 3-chloropyridine-2-carbaldehyde, 5- (trifluoromethyl) -1H-tetrazole and ethyl acetoacetate under the catalysis of potassium carbonate to form a pyrazole ring, and introducing ester groups;
Step four, hydrolysis of 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid ethyl ester, namely, hydrolysis reaction of 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid ethyl ester, sodium hydroxide and ethanol under alkaline conditions to generate carboxylate;
step five, acidizing to obtain a crude product, namely reacting carboxylate with hydrochloric acid, and acidizing to obtain a crude product of a target product;
removing impurities, namely removing colored impurities and partial organic impurities in the crude product by using the adsorptivity of the activated carbon;
and seventhly, recrystallizing and purifying, namely recrystallizing by utilizing the solubility difference of the product in a mixed solvent of acetonitrile and water through gradient cooling, so as to further improve the purity of the product.
Preferably, the specific operation of the first step is that 3-chloropyridine (30 g,0.25 mol) and DMF (40 mL,0.52 mol) are added into a 500mL three-necked flask equipped with a stirrer, a thermometer and a reflux condenser, and stirred uniformly. Slowly dropwise adding POCl3 (50 g,0.33 mol) under ice bath cooling, and keeping the temperature at 0-5 ℃ during the dropwise adding process;
After the dripping is finished, the ice bath is removed, the temperature is slowly raised to 80-90 ℃, and the reaction is stirred for 6-8 hours. After the reaction is finished, pouring the reaction solution into ice water, and adjusting the pH to 7-8 by using sodium hydroxide solution, wherein the solution is layered;
Extraction with dichloromethane (3X 100 mL), combining the organic phases, drying the organic phases over anhydrous sodium sulfate for 2-3 hours, filtering to remove the anhydrous sodium sulfate, and distilling off the dichloromethane under reduced pressure to give 3-chloropyridine-2-carbaldehyde as a pale yellow liquid in 80% yield.
Preferably, the specific operation of the second step is that in a 250mL three-neck flask, trifluoroacetonitrile (20 g,0.2 mol), sodium azide (13 g,0.2 mol) and ammonium chloride (10 g,0.18 mol) are added, 100mL dimethyl sulfoxide (DMSO) is added as a solvent, and the mixture is stirred uniformly and reacted for 12 to 14 hours at 80 to 90 ℃. The color of the solution gradually becomes deep in the reaction process;
After the reaction, the reaction mixture was poured into ice water, the pH was adjusted to 2-3 with hydrochloric acid, and a white solid was precipitated. The solid was collected by filtration, washed 3-4 times with water, drained after each wash, and then dried under vacuum at 50-60 ℃ for 6-8 hours to give 5- (trifluoromethyl) -1H-tetrazole as a white solid in 75% yield.
Preferably, the specific operation of the third step is that 3-chloropyridine-2-formaldehyde (20 g,0.13 mol), 5- (trifluoromethyl) -1H-tetrazole (15 g,0.1 mol), ethyl acetoacetate (15 g,0.12 mol) and potassium carbonate (20 g,0.14 mol) are added into a 500mL three-neck flask, 200mL acetonitrile is added as a solvent, and the mixture is stirred uniformly and reacted for 18 to 20 hours under reflux;
After the reaction was completed, the potassium carbonate solid was removed by filtration, and acetonitrile was removed by distillation under reduced pressure. The residue was dissolved in methylene chloride, and washed with 5% hydrochloric acid solution (2X 100 mL), saturated sodium bicarbonate solution (2X 100 mL) and saturated brine (100 mL) in this order. After each washing, the organic phase was separated, dried over anhydrous sodium sulfate for 3-4 hours, filtered to remove the anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylate as a yellow solid in 65% yield.
Preferably, the specific operation of the fourth step is that 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid ethyl ester (15 g,0.04 mol) is added into a 250mL three-neck flask, 100mL ethanol and 50mL sodium hydroxide solution (2M) are added, and the mixture is reacted under reflux for 6 to 8 hours;
The solution becomes clear gradually in the reaction process, and after the reaction is finished, ethanol is removed by reduced pressure distillation to obtain an aqueous solution containing carboxylate.
Preferably, the specific operation of the fifth step is that the aqueous solution obtained in the last step is transferred into a beaker, hydrochloric acid (the mass fraction is 10%) is slowly added dropwise under stirring, the pH is regulated to 2-3, solids are gradually separated out, and stirring is continued for 1-2 hours, so that the reaction is fully carried out;
the solid was collected by filtration, washed 3-4 times with water, and dried after each washing to give crude 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid.
Preferably, the specific operation of the step six is that the crude product (10 g) is added into 100mL of acetonitrile, heated to 50-60 ℃ and stirred to be completely dissolved. Adding 1g of active carbon, continuously stirring for 30-40 minutes, filtering while the active carbon is hot, and removing the active carbon and insoluble impurities;
And cooling the filtrate to room temperature, separating out solid, filtering and collecting the solid, and washing with a small amount of cold acetonitrile to obtain a product after preliminary impurity removal.
Preferably, the specific operation of the step seven is that the product after preliminary impurity removal is added into a mixed solvent of acetonitrile and water (acetonitrile: water=3:7) according to the mass volume ratio of 1:10, heated to 50 ℃, and stirred to be completely dissolved. Then gradient cooling is carried out at a speed of 5 ℃ per hour until the temperature is reduced to 0-5 ℃, stirring is carried out for 3 hours at the temperature, a large amount of crystals are separated out, the crystals are collected by filtration, and are washed 2-3 times by a small amount of cold acetonitrile-water mixed solvent (acetonitrile: water=1:9), and the crystals are pumped out after each washing;
The crystals were placed in a vacuum oven and dried at 40-50 ℃ for 6-8 hours to give 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid of high optical purity, which was finally confirmed in form and purity by X-ray single crystal diffraction (XRD).
Compared with the prior art, the invention provides a high-efficiency synthesis method of 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid, which has the following beneficial effects:
1. The efficient synthesis method of the 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid avoids using a large amount of organic solvents, does not need to adopt a gradient cooling mode, and is more suitable for industrialized green production.
2. The high-efficiency synthesis method of the 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid reduces unnecessary intermediate links and side reactions and improves the overall synthesis efficiency by optimizing reaction conditions and steps on the basis of reasonably designing a reaction route. Compared with some traditional synthesis methods, the process can obtain the target product with higher yield in a relatively short time, thereby reducing the production cost and improving the production benefit.
3. The efficient synthesis method of the 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid adopts Vilsmeier-Haack reaction, can introduce aldehyde group at the 2 position of the 3-chloropyridine with high selectivity, and provides a key intermediate for the subsequent construction of the complex structure of a target compound. The high selectivity reduces the occurrence of side reactions and improves the purity and yield of the product.
4. The efficient synthesis method of the 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid successfully connects 3-chloropyridine-2-formaldehyde, 5- (trifluoromethyl) -1H-tetrazole and ethyl acetoacetate together through condensation reaction, forms a basic framework structure of a target compound, and lays a foundation for subsequent functional group conversion.
5. The efficient synthesis method of the 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazole-1-yl ] -1H-pyrazole-5-carboxylic acid can accurately hydrolyze ester groups into carboxylate under alkaline conditions, realizes specific conversion of functional groups, and provides preparation for subsequent acidification to obtain target products. The accurate functional group conversion ensures the smooth progress of the reaction and the correctness of the product structure, the hydrolysis reaction is carried out under the condition of reflux, and the reaction condition is relatively simple and easy to control. By controlling the reaction time and the alkali dosage, the reaction process can be effectively controlled, and excessive hydrolysis or other side reactions can be avoided.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
1.1- (3-Chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid,
The preparation method of the 3-chloropyridine-2-formaldehyde comprises the steps of preparing 3-chloropyridine, N-Dimethylformamide (DMF) and phosphorus oxychloride (POCl3), enabling the 3-chloropyridine to react with the DMF and POCl3 to generate Vilsmeier-Haack reaction, introducing aldehyde groups at the 2 position of a pyridine ring, and specifically comprises the steps of adding 3-chloropyridine (30 g,0.25 mol) and DMF (40 mL,0.52 mol) into a 500mL three-neck flask with a stirrer, a thermometer and a reflux condenser, and stirring uniformly. Slowly dropwise adding POCl3 (50 g,0.33 mol) under ice bath cooling, and keeping the temperature at 0-5 ℃ during the dropwise adding process;
After the dripping is finished, the ice bath is removed, the temperature is slowly raised to 80-90 ℃, and the reaction is stirred for 6-8 hours. After the reaction is finished, pouring the reaction solution into ice water, and adjusting the pH to 7-8 by using sodium hydroxide solution, wherein the solution is layered;
Extraction with dichloromethane (3X 100 mL), combining the organic phases, drying the organic phases over anhydrous sodium sulfate for 2-3 hours, filtering to remove the anhydrous sodium sulfate, and distilling off the dichloromethane under reduced pressure to give 3-chloropyridine-2-carbaldehyde as a pale yellow liquid in 80% yield.
The preparation method of the 5- (trifluoromethyl) -1H-tetrazole comprises the steps of preparing the 5- (trifluoromethyl) -1H-tetrazole through the cyclization reaction of trifluoroacetonitrile, sodium azide and ammonium chloride in the presence of ammonium chloride, specifically comprises the steps of adding trifluoroacetonitrile (20 g,0.2 mol), sodium azide (13 g,0.2 mol) and ammonium chloride (10 g,0.18 mol) into a 250mL three-neck flask, adding 100mL dimethyl sulfoxide (DMSO) as a solvent, stirring uniformly, and reacting for 12-14 hours at 80-90 ℃. The color of the solution gradually becomes deep in the reaction process;
After the reaction, the reaction mixture was poured into ice water, the pH was adjusted to 2-3 with hydrochloric acid, and a white solid was precipitated. The solid was collected by filtration, washed 3-4 times with water, drained after each wash, and then dried under vacuum at 50-60 ℃ for 6-8 hours to give 5- (trifluoromethyl) -1H-tetrazole as a white solid in 75% yield.
The preparation method of the ethyl 1- (3-chloropyridine-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylate comprises the steps of preparing the ethyl 3-chloropyridine-2-formaldehyde, 5- (trifluoromethyl) -1H-tetrazole, ethyl acetoacetate and potassium carbonate, carrying out condensation reaction on the 3-chloropyridine-2-formaldehyde, 5- (trifluoromethyl) -1H-tetrazole and the ethyl acetoacetate under the catalysis of the potassium carbonate to form a pyrazole ring, introducing an ester group, and specifically comprises the steps of adding 3-chloropyridine-2-formaldehyde (20 g,0.13 mol), 5- (trifluoromethyl) -1H-tetrazole (15 g,0.1 mol), ethyl acetoacetate (15 g,0.12 mol) and potassium carbonate (20 g,0.14 mol) into a 500mL three-neck flask, adding 200mL acetonitrile as a solvent, uniformly stirring, and reacting for 18-20 hours under reflux;
After the reaction was completed, the potassium carbonate solid was removed by filtration, and acetonitrile was removed by distillation under reduced pressure. The residue was dissolved in methylene chloride, and washed with 5% hydrochloric acid solution (2X 100 mL), saturated sodium bicarbonate solution (2X 100 mL) and saturated brine (100 mL) in this order. After each washing, the organic phase was separated, dried over anhydrous sodium sulfate for 3-4 hours, filtered to remove the anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylate as a yellow solid in 65% yield.
Hydrolysis of ethyl 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylate, sodium hydroxide and ethanol under alkaline conditions to form a carboxylate, which comprises adding ethyl 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylate (15 g,0.04 mol), adding 100mL of ethanol and 50mL of sodium hydroxide solution (2M), and reacting under reflux for 6-8 hours in a 250mL three-necked flask;
The solution becomes clear gradually in the reaction process, and after the reaction is finished, ethanol is removed by reduced pressure distillation to obtain an aqueous solution containing carboxylate.
Step five, acidizing to obtain a crude product, namely, reacting carboxylate with hydrochloric acid, and acidizing to obtain a crude product of a target product, wherein the specific operation is that the aqueous solution obtained in the previous step is transferred into a beaker, hydrochloric acid (the mass fraction is 10%) is slowly added dropwise under stirring, the pH is regulated to 2-3, solids are gradually separated out, and stirring is continued for 1-2 hours to fully carry out the reaction;
the solid was collected by filtration, washed 3-4 times with water, and dried after each washing to give crude 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid.
Removing impurities by utilizing the adsorptivity of active carbon to remove colored impurities and partial organic impurities in the crude product, specifically, adding 10g of the crude product into 100mL of acetonitrile, heating to 50-60 ℃, and stirring to completely dissolve the crude product. Adding 1g of active carbon, continuously stirring for 30-40 minutes, filtering while the active carbon is hot, and removing the active carbon and insoluble impurities;
And cooling the filtrate to room temperature, separating out solid, filtering and collecting the solid, and washing with a small amount of cold acetonitrile to obtain a product after preliminary impurity removal.
And seventhly, recrystallizing and purifying, namely recrystallizing by gradient cooling according to the solubility difference of the product in a mixed solvent of acetonitrile and water, and further improving the purity of the product, wherein the specific operation is that the product after preliminary impurity removal is added into the mixed solvent of acetonitrile and water (acetonitrile: water=3:7) according to the mass volume ratio of 1:10, heated to 50 ℃, and stirred to be completely dissolved. Then gradient cooling is carried out at a speed of 5 ℃ per hour until the temperature is reduced to 0-5 ℃, stirring is carried out for 3 hours at the temperature, a large amount of crystals are separated out, the crystals are collected by filtration, and are washed 2-3 times by a small amount of cold acetonitrile-water mixed solvent (acetonitrile: water=1:9), and the crystals are pumped out after each washing;
The crystals were placed in a vacuum oven and dried at 40-50 ℃ for 6-8 hours to give 1- (3-chloropyridin-2-yl) -3- [5- (trifluoromethyl) -1H-tetrazol-1-yl ] -1H-pyrazole-5-carboxylic acid of high optical purity, which was finally confirmed in form and purity by X-ray single crystal diffraction (XRD).
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.