CN107540670B - Preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile - Google Patents
Preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile Download PDFInfo
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Abstract
The invention relates to a preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile, which takes 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile as a starting material and sequentially carries out the working procedures of etherification, purification, rearrangement, deacylation, filtration and drying. The preparation method has high reaction efficiency and mild reaction conditions, improves the production safety and the equipment universality, and the prepared finished product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile has the advantages of high yield, high purity and low production cost.
Description
Technical Field
The invention relates to a preparation method of an organic intermediate, in particular to a preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile, belonging to the technical field of chemical industry.
Background
1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile is a key intermediate for preparing pyraclonil, and the pyraclonil can be obtained by carrying out one-step chemical reaction on 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile. At present, a few documents describe a preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylamine pyrazole-4-carbonitrile, and a preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylamine pyrazole-4-carbonitrile, namely, a reaction of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile with methyl chloride, is disclosed in 2012, in phase 6 of "synthesis of pyraclonil, volume 38 of Anhui chemical engineering", namely, the chemical reaction formula is as follows:
however, the prior art described above has significant drawbacks and disadvantages: the method has the advantages that firstly, the methylating reagent is methyl chloride, the methyl chloride is gaseous and has high price, and the gaseous methyl chloride reacts with the liquid 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile solution, so that the defects of low reaction efficiency, low material utilization rate and high production cost exist; secondly, the chemical reaction is a pressurized reaction, so that the requirements on production equipment and production conditions are high, and the safety risk of production is increased; thirdly, the chemical reaction can not avoid the double methylation by-product, namely, the reaction can generate 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-dimethylamine pyrazole-4-carbonitrile, so that the yield and the purity of the 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile are reduced, and the subsequent purification process and the separation difficulty are increased.
Disclosure of Invention
The invention aims to provide a preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile, which has the advantages of high reaction efficiency, high yield, high product purity and low production cost, and meanwhile, the preparation method has mild reaction conditions and low requirements on equipment, and improves the production safety and the equipment universality.
The technical scheme for realizing the invention is as follows:
1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile is taken as a starting material, and the 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile is prepared by the working procedures of etherification, purification, rearrangement, deacylation, filtration and drying in sequence, and the specific chemical reaction steps are as follows:
1) and (3) etherification reaction: putting 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, trimethyl orthoformate, a solvent and a catalyst C1 into a reaction kettle, and reacting at 70-100 ℃ under negative pressure for 6-20 h to obtain a reaction solution A;
2) purifying, namely adding saturated sodium bicarbonate aqueous solution, water or 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring, standing, separating, adding anhydrous magnesium sulfate into an organic layer, standing, and filtering to obtain filtrate A;
3) rearrangement reaction: adding a catalyst C2 into the filtrate A, reacting for 5-12 h at 100-140 ℃, and cooling to obtain a reaction solution B;
4) and (3) deformylation reaction: adding water and inorganic acid into the reaction liquid B, and reacting for 4-10 hours at 40-70 ℃ to obtain reaction liquid C;
5) and (3) filtering and drying: cooling the reaction liquid C to 0-5 ℃, filtering, washing a filter cake with water, and drying to obtain 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile;
the catalyst C1 in the step 1) is Bronsted acid or Lewis acid, the catalyst C2 in the step 3) is tertiary ammonium salt, quaternary ammonium salt or quaternary phosphonium salt, and the inorganic acid in the step 4) is sulfuric acid or nitric acid.
The chemical reaction formulas of the etherification reaction, the rearrangement reaction and the demethylation reaction are as follows:
the etherification reaction formula is:
the rearrangement reaction formula is:
the deformylation reaction is represented by the formula:
preferably, the solvent in step 1) is ethylbenzene, xylene, trimethylbenzene or chlorobenzene, the boiling points of the solvents are all over 130 ℃, the solvents have a large difference with the boiling point of methanol (the boiling point is 64 ℃) which is a product of the etherification reaction, and the solvents do not influence the etherification reaction system when the methanol generated by the reaction is removed under the negative pressure condition.
Preferably, the catalyst C1 in step 1) is benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, m-nitrobenzenesulfonic acid, methanesulfonic acid, zinc chloride, zinc acetate, copper chloride, copper acetate, ferric chloride or aluminum chloride, and the catalyst can promote the reaction, accelerate the reaction process and shorten the reaction time.
Preferably, the vacuum degree of the negative pressure in the step 1) is 0.05-0.07 MPa. And (3) vacuumizing by using a vacuum pump during the etherification reaction to form and maintain the vacuum degree in the reaction kettle between 0.05 and 0.07 MPa.
Preferably, the amount of trimethyl orthoformate used in step 1) is 2-5 times of the mole number of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, the dosage of the catalyst C1 is 1-5% of the mole number of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, the dosage of the solvent is 5-10 times of the weight of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile.
Preferably, the tertiary ammonium salt in step 3) is one or more of trimethylamine hydrochloride, trimethylamine hydrobromide, triethylamine hydrochloride, triethylamine hydrobromide, tripropylamine hydrochloride, tripropylamine hydrobromide, tributylamine hydrochloride, tributylamine hydrobromide, pyridine hydrochloride, pyridine hydrobromide, 2-methylpyridine hydrochloride or 2-methylpyridine hydrobromide, and the quaternary ammonium salt is tetramethylammonium hydrochloride, tetramethylammonium hydrobromide, tetraethylammonium hydrochloride, tetraethylammonium hydrobromide, tetrapropylammonium hydrochloride, tetrapropylammonium hydrobromide, tetrabutylammonium hydrochloride, tetrabutylammonium hydrobromide, benzyltrimethylammonium hydrochloride, benzyltrimethylammonium hydrobromide, benzyltriethylammonium hydrochloride, benzyltriethylammonium hydrobromide, benzyltripropylammonium hydrochloride, benzyltripropylammonium hydrobromide, benzyltributylammonium hydrochloride, benzyltributylammonium hydrobromide, one or more of benzyltributylammonium hydrobromide, N-benzylpyridine hydrochloride, N-benzylpyridine hydrobromide, N-benzyl-2-methylpyridine hydrochloride or N-benzyl-2-methylpyridine hydrobromide, said quaternary phosphonium salt being one or more of tetramethylphosphonium chloride, tetramethylphosphonium bromide, tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetrapropylphosphonium chloride, tetrapropylphosphonium bromide, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, benzyltrimethylphosphonium chloride, benzyltrimethylphosphonium bromide, benzyltriethylphosphonium chloride, benzyltriethylphosphonium bromide, benzyltripropylphosphonium chloride, benzyltripropylphosphonium bromide, benzyltributylphosphonium chloride, benzyltributylphosphonium bromide. The catalyst promotes the reaction, accelerates the reaction process and shortens the reaction time.
Preferably, the amount of the catalyst C2 used in the step 3) is 5-15% of the mole number of the 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile.
Preferably, the temperature in the step 3) is reduced to 40-60 ℃, and the temperature after temperature reduction is approximately the same as the temperature of the demethylation acyl reaction.
Preferably, the amount of the inorganic acid used in the step 4) is 1.5 to 2 times of the mole number of the 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile.
Preferably, the filter cake of step 5) is washed with water to a pH above 5, e.g., pH5.0, pH5.1, pH5.2, pH 5.5.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention takes 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile as a starting material, and prepares 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile through etherification, rearrangement and deacylation in sequence, the three reactions are liquid-liquid reactions, the reaction efficiency is high, and the finished product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile prepared by the preparation method has high yield, High purity and low production cost.
2. The invention can avoid the side product of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile double methylation, namely avoid generating 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-dimethylamine pyrazole-4-carbonitrile, improve the purity and yield of finished products, and avoid subsequent separation and purification procedures.
3. The etherification reaction is a negative pressure reaction, and the negative pressure condition is favorable for removing methanol generated by the reaction, promoting the reaction and improving the reaction rate; the solvent used in the etherification reaction is ethylbenzene, dimethylbenzene, trimethylbenzene or chlorobenzene, the solvent does not influence the subsequent chemical reaction, has a larger difference with the methanol of the etherification reaction product in the boiling point, can effectively remove the methanol under the negative pressure condition, does not reduce the solvent used in the etherification reaction, and promotes the smooth operation of the reaction under the synergistic action of the negative pressure condition and the solvent.
4. The etherification reaction negative pressure reaction, the rearrangement reaction and the demethylation acyl reaction are normal pressure reaction, the reaction condition is mild, the production safety is improved, the special requirement on equipment is reduced, and the equipment universality is improved.
5. The etherification reaction of the invention uses Bronsted acid or Lewis acid as a catalyst, and the rearrangement reaction uses tertiary ammonium salt, quaternary ammonium salt or quaternary phosphonium salt as a catalyst, which can promote the reaction, accelerate the reaction process and shorten the reaction time.
6. The inorganic acid used in the demethylation reaction is high-boiling sulfuric acid or nitric acid, the volatility is low, and when the reaction temperature is controlled to be 40-70 ℃, the volatilization of the inorganic acid is low, and the environmental pollution is low.
Detailed Description
In order that those skilled in the art may better understand the present invention and enable its practice, the present invention is further described below in conjunction with the following specific embodiments.
First, the embodiment of the invention
Example 1
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 132g of ethylbenzene, 53g of trimethyl orthoformate and 0.22g of m-nitrobenzenesulfonic acid monohydrate into a reaction kettle, heating to 70-80 ℃ under stirring, and reacting for 20 hours under the condition that the vacuum degree is 0.05Mpa to obtain a reaction liquid A;
2) and (3) purification: adding 100ml of saturated sodium bicarbonate aqueous solution into the reaction solution A, stirring for 10min, standing for 30min, separating liquid, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain filtrate A;
3) rearrangement reaction: adding 1.1g of tributylamine hydrochloride into the filtrate A, reacting for 12 hours at 100-110 ℃, and cooling to 40 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 70ml of water into the reaction solution B, adding 15g of 98 wt% sulfuric acid, and reacting at 40-50 ℃ for 10 hours to obtain a reaction solution C;
5) and (3) filtering and drying: and cooling the reaction liquid C to 0 ℃, filtering, washing a filter cake to pH5.5 with water, and drying the filter cake for 8 hours in vacuum at 90-100 ℃ to obtain 23.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile.
Example 2
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 265g of xylene, 53g of trimethyl orthoformate and 0.68g of zinc chloride into a reaction kettle, heating to 90-100 ℃ under stirring, and reacting for 10 hours under the condition that the vacuum degree is 0.06MPa to obtain a reaction solution A;
2) and (3) purification: adding 100ml of water into the reaction liquid A, stirring for 10min, standing for 30min, separating liquid, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain a filtrate A;
3) rearrangement reaction: adding 3.2g of tetrabutylammonium bromide into the filtrate A, reacting for 5 hours at the temperature of 130-140 ℃, and cooling to 50 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 70ml of water into the reaction solution B, then adding 21g of 60 wt% nitric acid, and reacting for 4 hours at 50-60 ℃ to obtain reaction solution C;
5) and (3) filtering and drying: and cooling the reaction liquid C to 1 ℃, filtering, washing a filter cake to pH5.0 with water, and drying the filter cake for 10 hours in vacuum at the temperature of 90-100 ℃ to obtain 24.6g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile.
Example 3
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 150g of chlorobenzene, 21.2g of trimethyl orthoformate and 0.6g of copper acetate monohydrate into a reaction kettle, heating to 80-90 ℃ under stirring, and reacting for 15h under the condition that the vacuum degree is reduced to 0.07Mpa to obtain a reaction liquid A;
2) and (3) purification: adding 100ml of water into the reaction liquid A, stirring for 10min, standing for 30min, separating liquid, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 8h, and filtering to obtain a filtrate A;
3) rearrangement reaction: adding 1.86g of benzyltrimethylammonium chloride into the filtrate A, reacting for 10 hours at 120-130 ℃, and cooling to 60 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 70ml of water into the reaction solution B, adding 20g of 98 wt% sulfuric acid, and reacting at 60-70 ℃ for 8h to obtain reaction solution C;
5) and (3) filtering and drying: and cooling the reaction liquid C to 0 ℃, filtering, washing a filter cake to pH5.2 with water, and drying the filter cake for 8 hours in vacuum at the temperature of 90-100 ℃ to obtain 25.1g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile.
Example 4
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 160g of xylene, 31.8g of trimethyl orthoformate and 0.51g of p-toluenesulfonic acid into a reaction kettle, heating to 70-80 ℃ under stirring, and reacting for 8 hours under the condition that the vacuum degree is 0.07Mpa to obtain a reaction solution A;
2) and (3) purification: adding 100ml of 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring for 10min, standing for 30min, separating, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain filtrate A;
3) rearrangement reaction: adding 1.82g of tetraethyl chloride scale into the filtrate A, reacting for 8 hours at 110-120 ℃, and cooling to 50 ℃ to obtain reaction liquid B;
4) and (3) deformylation reaction: adding 100ml of water into the reaction solution B, adding 18g of 98 wt% sulfuric acid, and reacting at 50-60 ℃ for 7 hours to obtain a reaction solution C;
5) and (3) filtering and drying: and cooling the reaction liquid C to 5 ℃, filtering, washing a filter cake to pH5.1 with water, and drying the filter cake for 8 hours in vacuum at 90-100 ℃ to obtain 23.3g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile.
Example 5
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 200g of mesitylene, 42.4g of trimethyl orthoformate and 0.32g of ferric chloride into a reaction kettle, heating to 80-90 ℃ under stirring, and reacting for 6 hours under the condition that the vacuum degree is reduced to 0.06Mpa to obtain a reaction solution A;
2) and (3) purification: adding 100ml of 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring for 10min, standing for 30min, separating, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain filtrate A;
3) rearrangement reaction: adding 3.75g of brominated N-benzylpyridine into the filtrate A, reacting for 6 hours at the temperature of 130-140 ℃, and cooling to 40 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 80ml of water into the reaction solution B, adding 15.8g of 60 wt% nitric acid, and reacting at 40-45 ℃ for 5 hours to obtain reaction solution C;
5) and (3) filtering and drying: and cooling the reaction liquid C to 0 ℃, filtering, washing a filter cake to pH5.1 with water, and drying the filter cake for 8 hours in vacuum at 90-100 ℃ to obtain 25.4g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile.
Second, comparative example section
Comparative example 1
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 200g of mesitylene and 42.4g of trimethyl orthoformate into a reaction kettle, heating to 80-90 ℃ under stirring, and reacting for 6 hours under the condition that the vacuum degree is reduced to 0.06Mpa to obtain a reaction solution A;
2) and (3) purification: adding 100ml of 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring for 10min, standing for 30min, separating, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain filtrate A;
3) rearrangement reaction: adding 3.75g of brominated N-benzylpyridine into the filtrate A, reacting for 6 hours at the temperature of 130-140 ℃, and cooling to 40 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 80ml of water into the reaction solution B, adding 15.8g of 60 wt% nitric acid, and reacting at 40-45 ℃ for 5 hours to obtain reaction solution C;
5) and (3) filtering and drying: the reaction solution C is cooled to 0 ℃ and no crystal is separated out.
Comparative example 2
1) And (3) etherification reaction: adding 26.5g of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, 200g of mesitylene, 42.4g of trimethyl orthoformate and 0.32g of ferric chloride into a reaction kettle, heating to 80-90 ℃ under stirring, and reacting for 6 hours under the condition that the vacuum degree is reduced to 0.06Mpa to obtain a reaction solution A;
2) and (3) purification: adding 100ml of 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring for 10min, standing for 30min, separating, removing a water layer, adding 10g of anhydrous magnesium sulfate into an organic layer, standing for 5h, and filtering to obtain filtrate A;
3) rearrangement reaction: reacting the filtrate A at 130-140 ℃ for 6h, and cooling to 40 ℃ to obtain a reaction solution B;
4) and (3) deformylation reaction: adding 80ml of water into the reaction solution B, adding 15.8g of 60 wt% nitric acid, and reacting at 40-45 ℃ for 5 hours to obtain reaction solution C;
5) and (3) filtering and drying: the reaction solution C is cooled to 0 ℃ and no crystal is separated out.
Third, Experimental example section
Experimental example 1 analysis of products prepared in examples 1 to 5 of the present invention and comparative examples 1 to 2
The mass and yield of the product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylamine pyrazole-4-carbonitrile prepared in the embodiments 1 to 5 and the comparative examples 1 to 2 are respectively obtained by weighing and calculating, and the purity analysis adopts high performance liquid chromatography. The results of testing the products prepared in examples 1-5 and comparative examples 1-2 are shown in Table 1.
TABLE 1 examination results of the products prepared in examples 1 to 5 and comparative examples 1 to 2
In comparative examples 1-2, the reaction solution C is cooled to 0 ℃, no crystal is separated out, and the high performance liquid chromatography does not detect 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylamine pyrazole-4-carbonitrile in the reaction solution C, namely the yield is 0; the yield of the product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile prepared in the embodiments 1-5 is between 84.3% and 91.9%, the product purity is between 98% and 99%, the yield and the purity are high, and unexpected experimental results are obtained; the research also finds that in the reaction product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile, the disubstituted product 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-dimethylamine pyrazole-4-carbonitrile is not detected by high performance liquid chromatography, and the interference of homologous impurities on the finished product is avoided.
Claims (6)
1. A process for the preparation of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylaminopyrazole-4-carbonitrile comprising the steps of:
1) and (3) etherification reaction: putting 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile, trimethyl orthoformate, a solvent and a catalyst C1 into a reaction kettle, and reacting at 70-100 ℃ under negative pressure for 6-20 h to obtain a reaction solution A;
2) and (3) purification: adding saturated sodium bicarbonate aqueous solution, water or 5 wt% hydrochloric acid aqueous solution into the reaction solution A, stirring, standing, adding anhydrous magnesium sulfate into an organic layer after liquid separation, standing, and filtering to obtain filtrate A;
3) rearrangement reaction: adding a catalyst C2 into the filtrate A, reacting for 5-12 h at 100-140 ℃, and cooling to obtain a reaction solution B;
4) and (3) deformylation reaction: adding water and inorganic acid into the reaction liquid B, and reacting for 4-10 hours at 40-70 ℃ to obtain reaction liquid C;
5) and (3) filtering and drying: cooling the reaction liquid C to 0-5 ℃, filtering, washing a filter cake with water, and drying to obtain 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-methylamine pyrazole-4-carbonitrile; step 1) the catalyst C1 is m-nitrobenzenesulfonic acid, zinc chloride, copper acetate, p-toluenesulfonic acid and ferric trichloride, step 3) the catalyst C2 is tributylamine hydrochloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, tetraethylphosphonium chloride and N-benzylpyridine bromide, and step 4) the inorganic acid is sulfuric acid or nitric acid;
the solvent in the step 1) is ethylbenzene, dimethylbenzene, trimethylbenzene or chlorobenzene;
the vacuum degree of the negative pressure in the step 1) is 0.05-0.07 MPa.
2. The method for preparing 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylaminopyrazole-4-carbonitrile according to claim 1, wherein the amount of trimethyl orthoformate used in step 1) is 2 to 5 times the number of moles of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile, the amount of the catalyst C1 used is 1 to 5% of the number of moles of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile, the dosage of the solvent is 5-10 times of the weight of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridine-2-yl) -5-aminopyrazole-4-carbonitrile.
3. The method for preparing 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylaminopyrazole-4-carbonitrile according to claim 1, wherein the amount of the catalyst C2 used in the step 3) is 5 to 15% by mole of the 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile.
4. The preparation method of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylamine pyrazole-4-carbonitrile according to claim 1, characterized in that the temperature in step 3) is reduced to 40-60 ℃.
5. The method for preparing 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylaminopyrazole-4-carbonitrile according to claim 1, wherein the inorganic acid used in the step 4) is 1.5 to 2 times the molar amount of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-aminopyrazole-4-carbonitrile.
6. The process for the preparation of 1- (3-chloropyrazolo [1,5a ] -4,5,6, 7-tetrahydropyridin-2-yl) -5-methylaminopyrazole-4-carbonitrile according to claim 1, characterized in that the filter cake of step 5) is washed with water to a pH of 5 or more.
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| CN1060478C (en) * | 1992-10-12 | 2001-01-10 | 先灵公司 | Substituted pyrazole derivatives |
| CN105001221A (en) * | 2015-08-25 | 2015-10-28 | 湖北相和精密化学有限公司 | Synthetic method of pyraclonil |
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| CN1060478C (en) * | 1992-10-12 | 2001-01-10 | 先灵公司 | Substituted pyrazole derivatives |
| CN1225635A (en) * | 1996-07-18 | 1999-08-11 | 赫彻斯特-舍林农业发展有限公司 | Substituted pyrazolyl-pyrazole derivatives, process for their prepn. and their use as agents with herbicidal effect |
| CN105001221A (en) * | 2015-08-25 | 2015-10-28 | 湖北相和精密化学有限公司 | Synthetic method of pyraclonil |
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