CN111057006B - Preparation method of 1- (4-chlorphenyl) -3-pyrazole alcohol - Google Patents
Preparation method of 1- (4-chlorphenyl) -3-pyrazole alcohol Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry synthesis, and particularly discloses a preparation method of 1- (4-chlorphenyl) -3-pyrazole alcohol, which comprises the following steps: in the presence of a copper catalyst, alkali and an organic solvent, 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester and 4-bromochlorobenzene or 4-iodochlorobenzene are subjected to Ullmann coupling reaction, and the obtained 1- (4-chlorophenyl) -3-pyrazole-4-carboxylic acid ethyl ester is subjected to acidic hydrolysis and decarboxylation to obtain the 1- (4-chlorophenyl) -3-pyrazole alcohol. The method disclosed by the invention avoids the use of raw material p-chlorophenylhydrazine which has serious environmental pollution and high toxicity, is cleaner and more environment-friendly, shortens the synthetic route, improves the yield and greatly reduces the production cost.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of 1- (4-chlorphenyl) -3-pyrazole alcohol.
Background
Pyraclostrobin, also known as pyraclostrobin, is the methoxy acrylate fungicide with the highest activity at present, is developed and researched in 1993 by Pasteur Germany and is released in the European market in 2002, is compounded with epoxiconazole to prevent and treat cereal diseases, can be used for over one hundred kinds of crops registered in over fifty countries, and can also be used for non-crops. The medicine for preventing and treating the cereal diseases has the characteristics of high efficiency, low toxicity, environmental friendliness, wide application range of crops and the like.
1- (4-chlorphenyl) -3-pyrazole alcohol is a key intermediate for producing pyraclostrobin, the using amount of the intermediate is continuously increased along with the continuous improvement of the global demand of the pyraclostrobin, the preparation of the intermediate is reported in a few documents in China, but a lot of places still need to be perfected to meet the requirement of industrial production, and the structure of the 1- (4-chlorphenyl) -3-pyrazole alcohol is shown as the following formula (I):
in the prior art, the main synthetic route of 1- (4-chlorphenyl) -3-pyrazole alcohol comprises the following steps: xuxi et al (CN109438354A) use parachloroaniline as raw material, and through three-step reaction of diazotization, reduction and acidification, parachlorophenylhydrazine hydrochloride is prepared, then the parachlorophenylhydrazine hydrochloride and methyl acrylate are reacted under the catalysis of sodium ethoxide to obtain 1- (4-chlorphenyl) pyrazolidin-3-one, and then the 1- (4-chlorphenyl) -3-pyrazole alcohol is obtained through air oxidation under the catalysis of ferric trichloride, and the specific synthetic route is as follows:
in the literature (Organic & Biomolecular Chemistry, 2011,9,1443), p-chlorophenylhydrazine hydrochloride and methyl acrylate are catalyzed by sodium methoxide to obtain 1- (4-chlorophenyl) pyrazolidin-3-one, and then the 1- (4-chlorophenyl) -3-pyrazolol is obtained by air oxidation under the catalysis of thionyl chloride, and the specific synthetic route is shown as follows:
in Jinma et al (CN103588708A), p-chlorophenylhydrazine hydrochloride, acrylamide and the like are used as raw materials by a one-pot method, and the 1- (4-chlorphenyl) -3-pyrazole alcohol is obtained through cyclization reaction and oxidation reaction, and the specific synthetic route is as follows:
sunworzen et al (CN108658866A) synthesized pyrazol-3-ketone under the action of sodium methoxide by using acrylate and hydrazine hydrate as raw materials, oxidized into pyrazol alcohol by ferric trichloride, and finally reacted with 4-bromochlorobenzene to generate 1- (4-chlorphenyl) -3-pyrazol alcohol, wherein the specific synthetic route is as follows:
the existing method for preparing 1- (4-chlorophenyl) -3-pyrazolol is basically as described above, but the method has the problems of high cost, uneconomical property, serious pollution, and harsh raw material storage and operation conditions.
Disclosure of Invention
The invention aims to provide a preparation method of 1- (4-chlorphenyl) -3-pyrazole alcohol, which not only avoids using p-chlorophenylhydrazine which is a raw material with serious environmental pollution and high toxicity, but also is cleaner and more environment-friendly, shortens the synthesis route, improves the yield and greatly reduces the production cost.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
a process for the preparation of 1- (4-chlorophenyl) -3-pyrazolol comprising: in the presence of a copper catalyst, alkali and an organic solvent, 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester and 4-bromochlorobenzene or 4-iodochlorobenzene are subjected to Ullmann coupling reaction, and the obtained 1- (4-chlorphenyl) -3-pyrazole-4-carboxylic acid ethyl ester is subjected to hydrolysis decarboxylation reaction under an acidic condition to obtain the 1- (4-chlorphenyl) -3-pyrazole alcohol.
Wherein the structure of the 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester is shown as the following formula (II), the structure of the 1- (4-chlorphenyl) -3-pyrazole-4-carboxylic acid ethyl ester is shown as the following formula (III), and a specific synthetic route is as follows:
the organic solvent is a solvent which is well known to those skilled in the art and is used for Ullmann coupling reaction, and can be selected from one or more of the following combinations: n, N-Dimethylformamide (DMF), N-Dimethylacetamide (DME), dimethyl sulfoxide (DMSO), Tetrahydrofuran (THF), dioxane, acetonitrile, toluene. In the present invention, the organic solvent is preferably dimethyl sulfoxide (DMSO).
The amount of the organic solvent used is not particularly limited, and a person skilled in the art can realize the ullmann coupling reaction, and in some embodiments, the volume of the organic solvent used is 0.8-1.0 mL/mmol based on the mole number of the 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester.
The copper catalyst is a cuprous salt, and can be specifically selected from one or a combination of more of the following: copper iodide (CuI), copper oxide (Cu)2O), cuprous chloride (CuCl), cuprous bromide (CuBr), cuprous acetate (cu (oac)), preferably cuprous iodide (CuI). The molar ratio of the copper catalyst to the 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester is (0.01-0.1): 1.0.
the alkali is one or a combination of more of the following: cesium carbonate (Cs)2CO3) Potassium carbonate (K)2CO3) Potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium carbonate (Na)2CO3) Is preferably Cs2CO3. The molar ratio of the alkali to the 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester is (1.5-2.0): 1.0.
preferably, a ligand is further added in the Ullmann coupling reaction, and the ligand is 1,2-N, N-dimethylethylenediamine, aminoethanol, 8-hydroxyquinoline, L-proline, 1,2-N, N-dimethylpropylenediamine or 1, 2-cyclohexanediamine; further preferred is 1,2-N, N-dimethylethylenediamine. The molar ratio of the ligand to the 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester is (0.01-1.0): 1.0.
Experiments of the invention show that the product yield can be further improved after a ligand is added in the Ullmann coupling reaction, and in addition, the yield of the product 1- (4-chlorphenyl) -3-pyrazole alcohol can also be improved by selecting the preferable copper catalyst and alkali.
The reaction temperature of the Ullmann coupling reaction is 80-150 ℃, and the reaction time is 8-16 h. The preferable reaction temperature is 100-110 ℃, and the preferable reaction time is 10-12 h.
The temperature of the acidic hydrolysis decarboxylation reaction is 100-150 ℃, and the reaction time is 5-10 h. The preferable reaction temperature is 110-120 ℃, and the preferable reaction time is 7-8 h. The acid used for the hydrolysis decarboxylation reaction under the acidic condition is preferably common hydrochloric acid, sulfuric acid or acetic acid, and the concentration of the acid is 10-14 mol/L.
Compared with the prior art, the invention has the following beneficial effects:
the process for synthesizing the 1- (4-chlorphenyl) -3-pyrazole alcohol avoids using p-chlorophenylhydrazine which has serious environmental pollution and high toxicity as a raw material, and organic solvents used in the method can be recycled, so that the problems of high three-waste content, serious pollution, low safety and the like in the existing 1- (4-chlorphenyl) -3-pyrazole alcohol preparation process are solved, the production cost is greatly reduced, the energy consumption is reduced, and the environment-friendly requirement in modern industrial production is met. In addition, the method disclosed by the invention is simple to operate, short in synthetic route, capable of enabling the total yield of the product to be more than 90% by controlling reaction conditions, extremely high in economic value and very suitable for large-scale production and application.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 1- (4-chlorophenyl) -3-pyrazolol obtained in example 1 of the present invention.
Detailed Description
In order to make the advantages, purposes and technical solutions of the present invention more apparent, the present invention is further described with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the following examples, ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (refer to Beilstein J. org. chem.2014,10, 752-760), which is represented by formula (II), is prepared by a method described in the following references, which is abbreviated as compound II, as a raw material, and is subjected to Ullmann coupling reaction to obtain ethyl 1- (4-chlorophenyl) -3-pyrazole-4-carboxylate (which is abbreviated as compound III), and is subjected to hydrolysis decarboxylation to obtain 1- (4-chlorophenyl) -3-pyrazole alcohol, which is represented by formula (I), wherein the specific synthetic route is as follows:
example 1: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen replacement is carried out, and the reaction is carried out by heating the mixture to about 110 ℃ in an oil bath under the protection of nitrogenA mixture was obtained in 11 hours.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate, concentrating the filtrate, adding 1mL of concentrated hydrochloric acid (12mol/L), heating the solution to 120 ℃ in an oil bath for reaction, detecting the content of the compound III to be less than 1% by HPLC after about 7 hours, and stopping the reaction. Adding a little water, filtering, drying to obtain 971mg of earthy yellow solid powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.3 percent, and the yield is 84 percent (calculated by the compound II).
Melting point of the product: 186.3 to 188.7 ℃ (181 to 182 ℃ is reported in the literature).1H NMR(500MHz，CD3OD)δ10.1(s，1H)，7.4(d，J＝5Hz，2H)，7.4(d，J＝5Hz，2H)，7.7(d，1H)，5.8(d，1H)。
Example 2: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), Cu2O (42mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 13 hours by oil bath heating to about 120 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, and after about 8 hours, the content of the compound III is detected by HPLC to be less than 1 percent, and the reaction is stopped. Adding a little water, filtering, drying to obtain 948mg of solid yellowish brown powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 97.1 percent, and the yield is 82 percent (calculated by the compound II).
Example 3: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuCl (29mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 15 hours by oil bath heating to about 120 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, carrying out suction filtration and drying to obtain 924mg of earthy yellow solid powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.1 percent, and the yield is 80 percent (calculated by the compound II).
Example 4: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single neck flask was charged with Compound II (927mg, 5.94mmol), CuBr (42mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 14 hours by oil bath heating to about 140 ℃ under the protection of nitrogen to obtain mixed liquid.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 948mg of solid yellowish brown powder, wherein the content of 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.7%, and the yield is 82% (calculated by the compound II).
Example 5: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), (Cu (OAc)) (36mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 16 hours by oil bath heating to about 130 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 140 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering by suction and drying to obtain solid powder 936mg of earthy yellow, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.2 percent, and the yield is 81 percent (calculated by the compound II).
Example 6: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMF (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 13 hours by oil bath heating to about 120 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 130 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 948mg of solid yellowish brown powder, wherein the content of 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.3%, and the yield is 82% (calculated by the compound II).
Example 7: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DME (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 11 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, carrying out suction filtration and drying to obtain 924mg of earthy yellow solid powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.4 percent, and the yield is 80 percent (calculated by the compound II).
Example 8: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and THF (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 13 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate was concentrated, 1mL of concentrated hydrochloric acid (12mol/L) was added, the temperature was raised to 140 ℃ in an oil bath for reaction, and after about 10 hours, the reaction was stopped when the content of the main peak of the raw material (Compound III) was not changed by HPLC. Adding a little water, filtering by suction, and drying to obtain 647mg of solid powder of khaki, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.6 percent, and the yield is 56 percent (calculated by the compound II).
Example 9: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Cs2CO3(3.87g, 11.88mmol) followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and 1, 4-dioxane (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 11 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate was concentrated, 1mL of concentrated hydrochloric acid (12mol/L) was added, the reaction was carried out by heating in an oil bath to 120 ℃ and was stopped after about 9 hours when the content of the main peak of the starting material (Compound III) was not changed by HPLC. Adding a little water, filtering, drying to obtain 716mg of earthy yellow solid powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.1 percent, and the yield is 62 percent (calculated by the compound II).
Example 10: preparation of 1- (4-chlorophenyl) -3-pyrazolol
In a 50mL single-neck flask were added compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and K2CO3(1.64g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 12 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 947mg of solid yellowish brown powder, wherein the content of 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.0%, and the yield is 82% (calculated by the compound II).
Example 11: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and KOH (0.66g, 11.88mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 12 hours by oil bath heating to about 120 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering by suction and drying to obtain solid powder 936mg of earthy yellow, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.3 percent, and the yield is 81 percent (calculated by the compound II).
Example 12: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and NaOH (0.47g, 11.88mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 12 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering by suction and drying to obtain solid powder 936mg of earthy yellow, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 97.7 percent, and the yield is 81 percent (calculated by the compound II).
Example 13: preparation of 1- (4-chlorophenyl) -3-pyrazolol
In a 50mL single-neck flask were added compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol) and Na2CO3(1.26g, 11.88mmol) followed by additional 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 15 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, carrying out suction filtration and drying to obtain 924mg of earthy yellow solid powder, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.8 percent, and the yield is 80 percent (calculated by the compound II).
Example 14: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and 1,2-N, N-dimethylethylenediamine (26mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 10 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 110 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, carrying out suction filtration and drying to obtain 1.05g of solid powder with khaki color, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.5 percent, and the yield is 91 percent (calculated by the compound II).
Example 15: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and aminoethanol (38mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 11 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 994mg of solid yellowish powder, wherein the content of 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.3 percent, and the yield is 86 percent (calculated by the compound II).
Example 16: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and 8-hydroxyquinoline (43mg, 0.297mmol), followed by 4-bromochlorobenzene (1)70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 11 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain the solid powder 982mg of earthy yellow, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.0 percent, and the yield is 85 percent (calculated by the compound II).
Example 17: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and L-proline (34mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 12 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 1.01g of solid powder with earthy yellow color, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 97.9 percent, and the yield is 88 percent (calculated by the compound II).
Example 18: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and 1,2-N, N-dimethylpropanediamine (30mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 10 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 110 ℃ by oil bath for reaction, after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 994mg of solid yellowish powder, wherein the content of 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.3 percent, and the yield is 86 percent (calculated by the compound II).
Example 19: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and 1, 2-cyclohexanediamine (34mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 12 hours by oil bath heating to about 110 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of concentrated hydrochloric acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1%, and the reaction is stopped. Adding a little water, filtering, drying to obtain 1.00g of solid powder with earthy yellow color, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.2 percent, and the yield is 87 percent (calculated by the compound II).
Example 20: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0.297mmol), and Cs2CO3(3.87g, 11.88mmol) and 1,2-N, N-dimethylethylenediamine (26mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 10 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of sulfuric acid (12mol/L) is added, the temperature is raised to 100 ℃ by oil bath for reaction, and after about 7 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1 percent, and the reaction is stopped. Adding a little water, carrying out suction filtration and drying to obtain 1.05g of solid powder with khaki color, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.1 percent, and the yield is 91 percent (calculated by the compound II).
Example 21: preparation of 1- (4-chlorophenyl) -3-pyrazolol
A50 mL single-neck flask was charged with Compound II (927mg, 5.94mmol), CuI (56mg, 0).297mmol)、Cs2CO3(3.87g, 11.88mmol) and 1,2-N, N-dimethylethylenediamine (26mg, 0.297mmol), followed by 4-bromochlorobenzene (1.70g, 8.91mmol) and DMSO (5 mL). After the addition, nitrogen is replaced, and the mixture is reacted for 10 hours by oil bath heating to about 100 ℃ under the protection of nitrogen.
And after the mixed solution is cooled, carrying out suction filtration and collecting filtrate. After the filtrate is concentrated, 1mL of acetic acid (12mol/L) is added, the temperature is raised to 120 ℃ by oil bath for reaction, and after about 8 hours, the content of the raw material (compound III) is detected by HPLC to be less than 1 percent, and the reaction is stopped. Adding a little water, filtering, drying to obtain 1.04g of solid powder with earthy yellow color, wherein the content of the 1- (4-chlorphenyl) -3-pyrazole alcohol is 98.8 percent, and the yield is 90 percent (calculated by the compound II).
Claims (6)
1. A method for preparing 1- (4-chlorophenyl) -3-pyrazolol, which comprises the following steps: in the presence of a copper catalyst, alkali and an organic solvent, enabling 3-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester and 4-bromochlorobenzene or 4-iodochlorobenzene to perform Ullmann coupling reaction to obtain 1- (4-chlorphenyl) -3-hydroxy-pyrazole-4-carboxylic acid ethyl ester;
the 1- (4-chlorphenyl) -3-hydroxy-pyrazole-4-carboxylic acid ethyl ester is subjected to hydrolysis decarboxylation reaction under an acidic condition to obtain 1- (4-chlorphenyl) -3-pyrazole alcohol;
the copper catalyst is one or a combination of more of the following: cuprous iodide, cuprous oxide, cuprous chloride, cuprous bromide, and cuprous acetate;
the alkali is one or a combination of more of the following: cesium carbonate, potassium hydroxide, sodium carbonate;
the organic solvent is one or a combination of more of the following: n, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile and toluene;
the Ullmann coupling reaction is also added with a ligand, wherein the ligand is N, N '-dimethylethylenediamine, aminoethanol, 8-hydroxyquinoline, L-proline, N' -dimethylpropylenediamine or 1, 2-cyclohexanediamine.
2. The process for the preparation of 1- (4-chlorophenyl) -3-pyrazolol according to claim 1, wherein the molar ratio of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate to copper catalyst and base is 1: (0.01-1.0): (1.5-2.0).
3. The method for producing 1- (4-chlorophenyl) -3-pyrazolol according to claim 1, wherein the volume of the organic solvent is 0.8 to 1.0mL/mmol in terms of moles of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate.
4. The process for producing 1- (4-chlorophenyl) -3-pyrazolol according to claim 1, wherein the molar ratio of the ligand to ethyl 3-hydroxy-1H-pyrazole-4-carboxylate is (0.01 to 1.0) to 1.0.
5. The method for preparing 1- (4-chlorophenyl) -3-pyrazolol according to claim 1, wherein the Ullmann's coupling reaction is carried out at a temperature of 80 to 150 ℃ for a reaction time of 8 to 16 hours.
6. The method for preparing 1- (4-chlorophenyl) -3-pyrazolol according to claim 1, wherein the temperature of the acidic hydrolysis decarboxylation reaction is 100 to 150 ℃ and the reaction time is 5 to 10 hours.
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| WO2010015656A2 (en) * | 2008-08-05 | 2010-02-11 | Institut Pasteur | New alkoxypyrazoles |
| WO2017117708A1 (en) * | 2016-01-05 | 2017-07-13 | Hua Medicine (Shanghai) Ltd. | Pyrazole derivatives |
| CN108658866A (en) * | 2018-06-07 | 2018-10-16 | 武穴市旭日化工有限责任公司 | A kind of preparation method of 1- (4- chlorphenyls) -3- pyrazoles alcohol |
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| WO2010015656A2 (en) * | 2008-08-05 | 2010-02-11 | Institut Pasteur | New alkoxypyrazoles |
| WO2017117708A1 (en) * | 2016-01-05 | 2017-07-13 | Hua Medicine (Shanghai) Ltd. | Pyrazole derivatives |
| CN108658866A (en) * | 2018-06-07 | 2018-10-16 | 武穴市旭日化工有限责任公司 | A kind of preparation method of 1- (4- chlorphenyls) -3- pyrazoles alcohol |
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