Synthetic method of 3-aminomethyl-1-H pyrazole

Abstract

The invention discloses a synthesis method of 3-aminomethyl-1-H pyrazole, and belongs to the technical field of synthesis of medical intermediates and new materials, and the synthesis method comprises the following steps: carrying out ammonolysis reaction on pyrazole-3-ethyl formate to generate pyrazole-3-formamide, and carrying out amide reduction reaction on the pyrazole-3-formamide to obtain the 3-aminomethyl-1-H pyrazole. Wherein in the ammonolysis reaction, pyrazole-3-ethyl formate is dissolved in an organic solvent and then added into a pressure container, an ammonia source is added into the pressure container, the reaction temperature is controlled to be constant, and stirring reaction is carried out. The amide reduction reaction comprises the following steps: dissolving pyrazole-3-formamide in an organic solvent, controlling the temperature, and dropwise adding a reducing agent to carry out the amide reduction reaction. Commercial pyrazole-3-ethyl formate is adopted as a reaction raw material, the raw material is easy to obtain and low in danger, the whole preparation process is safe and reliable, and the method is suitable for large-scale synthesis.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 3-aminomethyl-1-H pyrazole, and belongs to the technical field of pharmaceutical intermediates and new material synthesis. Background Art

[0002] 3-aminomethyl-1-H pyrazole is a reagent and intermediate in organic synthesis, and can also be used as a small molecule probe in the field of scientific research. At present, there are few public methods for synthesizing 3-aminomethyl-1-H pyrazole. One of the synthesis methods is to use diazomethane to undergo 1,3-dipolar cycloaddition and other reactions to obtain the target compound 3-aminomethyl-1-H pyrazole. In this synthesis method, the raw material diazomethane will explode when heated, exposed to fire, friction, and impact, which is highly dangerous and not suitable for large-scale production, which will limit the synthesis and application of 3-aminomethyl-1-H pyrazole. Summary of the invention

[0003] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a method for synthesizing 3-aminomethyl-1-H pyrazole, wherein the raw materials are easily available and have low risk, the entire preparation process is safe and reliable, and the method is suitable for large-scale synthesis.

[0004] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0005] A method for synthesizing 3-aminomethyl-1-H pyrazole comprises the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0006] The aminolysis reaction comprises the following steps: dissolving ethyl pyrazole-3-carboxylate in an organic solvent and then adding the solvent into a pressure vessel, adding an ammonia source into the pressure vessel, and controlling the reaction temperature to be constant to carry out stirring reaction.

[0007] The organic solvent includes an alcohol solvent, which is one or more of methanol, ethanol and isopropanol; and / or the ammonia source includes one or more of ammonia gas and ammonia methanol solution; and / or the mass volume ratio of ethyl pyrazole-3-carboxylate to the alcohol solvent is 1: (3~10) g / mL; and / or the reaction temperature is constant at 86~100 degrees; and / or the reaction time of the stirring reaction is 13~25 hours.

[0008] The post-treatment after the aminolysis reaction includes the following steps: cooling and stirring the reaction system to a temperature of 25-30 degrees, concentrating and removing the solvent of the organic phase to obtain a crude concentrated solution, replacing the crude concentrated solution with an organic solvent, cooling to 0-10 degrees and stirring for 2-5 hours, and filtering out pyrazole-3-carboxamide under reduced pressure.

[0009] The organic solvent for replacement includes one or more of toluene, heptane and methyl tert-butyl ether.

[0010] The amide reduction reaction comprises the following steps: dissolving pyrazole-3-carboxamide in an organic solvent, controlling the temperature, and then dropping a reducing agent to cause an amide reduction reaction.

[0011] The organic solvent comprises one or two of tetrahydrofuran and methyl tert-butyl ether; and / or, the mass volume ratio of the pyrazole-3-carboxamide to the organic solvent is 1: (5-10) g / mL; and / or, the reducing agent is a tetrahydrofuran solution of lithium aluminum tetrahydride, and the molar ratio of the pyrazole-3-carboxamide to the lithium aluminum tetrahydride is 1: (2-4); and / or, the temperature variation range of the reaction liquid system is 50-65 degrees.

[0012] The amide reduction reaction is followed by post-treatment, which includes the following steps: after the reaction is completed, quenching, filtering, extracting and concentrating to separate and obtain the target compound 3-aminomethyl-1-H pyrazole.

[0013] The quenching method uses sodium sulfate decahydrate or aqueous THF, and / or the extraction solvent includes one or more of tetrahydrofuran, methyl tert-butyl ether and n-butanol.

[0014] After concentration and separation, the product was purified by distillation under reduced pressure.

[0015] Beneficial effects of the present invention: The present invention provides a method for synthesizing 3-aminomethyl-1-H pyrazole, which uses commercially available ethyl pyrazole-3-carboxylate as a raw material, performs aminolysis and chemical reduction to smoothly obtain the target 3-aminomethyl-1-H pyrazole, the conditions of the aminolysis and chemical reduction reactions are mild, the entire preparation process is safe and reliable, and is suitable for large-scale synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is a synthetic route diagram of a synthetic method of 3-aminomethyl-1-H pyrazole of the present invention;

[0017] Figure 2 It is the GC chart of 3-aminomethyl-1-H-pyrazole prepared in the example of the present invention. DETAILED DESCRIPTION

[0018] The present invention will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the protection scope of the present invention.

[0019] Example 1

[0020] like Figure 1As shown, the present application discloses a method for synthesizing pyrazole-3-carboxamide, comprising the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0021] Among them, the aminolysis reaction of ethyl pyrazole-3-carboxylate is as follows:

[0022] In a 200 mL stuffy tank, 10 g of ethyl pyrazole-3-carboxylate and 70 mL of ammonia methanol (7 eq.) were added. The mass volume ratio of ethyl pyrazole-3-carboxylate to ammonia methanol was 1:7 g / mL. The closed system was heated to 86-90 degrees and stirred for 20 hours. In addition, the aminolysis reaction includes post-treatment: After the reaction is completed, the reaction solution is cooled (about 25-30 degrees), concentrated under reduced pressure to remove the solvent, and then 30 mL of methyl tert-butyl ether is added, cooled (about 5-8 degrees) and stirred for 2 hours, filtered, washed once with 8 mL of methyl tert-butyl ether, and dried to obtain pyrazole-3-carboxamide (6.8 g). The purity of pyrazole-3-carboxamide obtained in this example is 98.3A%, and the yield is 85.8%.

[0023] Among them, the amide reduction reaction of pyrazole-3-carboxamide is as follows:

[0024] In a 100 mL reaction bottle, add 4.0 g of pyrazole-3-carboxamide, add 28 mL (7 vol.) of tetrahydrofuran, the mass volume ratio of pyrazole-3-carboxamide to tetrahydrofuran is 1:7 g / mL, the system is heated to 60-65 degrees, and 36 mL (2.5 M, 2.5 eq.) of tetrahydrofuran solution of lithium aluminum hydroxide is added dropwise, the molar ratio of pyrazole-3-carboxamide to lithium aluminum hydroxide is 1:2.5, and the mixture is stirred for 2.5 hours. In addition, the reduction reaction includes post-treatment: turn off the heating, control the temperature of the reaction liquid system to 0 to 5 degrees, add 20 g of sodium sulfate decahydrate solid, stir for 2 hours; filter to remove insoluble solids, separate the filtrate, and extract the aqueous phase with methyl tert-butyl ether three times with 20 mL each time, combine the organic layers, and wash once with 20 mL of saturated brine; concentrate to remove the solvent in the organic phase to obtain the residue 3-aminomethyl-1-H pyrazole. The gas chromatographic purity of 3-aminomethyl-1-H-pyrazole obtained in this example is 82.8A%.

[0025] Example 2

[0026] like Figure 1 As shown, the present application discloses a method for synthesizing pyrazole-3-carboxamide, comprising the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0027] Among them, the aminolysis reaction of ethyl pyrazole-3-carboxylate is as follows: 10 g of ethyl pyrazole-3-carboxylate is added to a 200 mL jar, 70 mL of ammonia methanol (7 eq.), the mass volume ratio of ethyl pyrazole-3-carboxylate to ammonia methanol is 1:7 g / mL, the closed system is heated to 90 degrees, and the mixture is stirred for 20 hours. In addition, the aminolysis reaction includes post-treatment: after the reaction is completed, the reaction solution is cooled (about 25-30 degrees), the solvent is removed by vacuum concentration, and then 30 mL of toluene is added, the temperature is cooled (about 5-10 degrees), stirred for 2 hours, filtered, washed once with 8 mL of toluene, and dried to obtain pyrazole-3-carboxamide (7.0 g). The purity of pyrazole-3-carboxamide obtained in this embodiment is 98.3 A%, and the yield is 88.3%.

[0028] Among them, the amide reduction reaction of pyrazole-3-carboxamide is as follows: 24.0 g of pyrazole-3-carboxamide (which can be accumulated by repeating the above pyrazole-3-carboxamide synthesis multiple times) is added to a 500 mL reaction bottle, and 168 mL (7 vol.) of tetrahydrofuran is added, and the mass volume ratio of pyrazole-3-carboxamide to tetrahydrofuran is 1:7 g / mL. The system is heated to 60-65 degrees, and 190 mL (2.5 M, 2.2 eq.) of tetrahydrofuran solution of lithium aluminum tetrahydride is added dropwise, and the molar ratio of pyrazole-3-carboxamide to lithium aluminum tetrahydride is 1:2.2, and the mixture is stirred for 2.5 hours at this temperature. In addition, the reduction reaction includes post-treatment: turn off the heating, control the temperature of the reaction liquid system to 0 to 5 degrees, add 100 g of sodium sulfate decahydrate solid, and stir for 2 hours; filter to remove insoluble solids, separate the filtrate, and extract the aqueous phase three times with 120 mL of methyl tert-butyl ether, combine the organic layers, and wash once with 120 mL of saturated brine; concentrate to remove the solvent in the organic phase to obtain 20.9 g of crude residue 3-aminomethyl-1-H pyrazole. The crude product was distilled under reduced pressure at 2.3 mmHg, and 13.0 g of the fraction at 128~132 degrees was collected, with a GC purity of 97.2 A% and a yield of 61.7%. The GC graph of the product is as follows Figure 2 As shown. 1 H NMR detection method: 1 H NMR (400 MHz, DMSO) δ12.42 (s, 1H), 8.58 (s, 2H), 7. 68 (d, J =8.4 Hz, 1 H), 6.18 (d, J = 8.4 Hz, 1H), 4.38 (s, 2H).

[0029] Example 3

[0030] like Figure 1As shown, the present application discloses a method for synthesizing pyrazole-3-carboxamide, comprising the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0031] Among them, the aminolysis reaction of ethyl pyrazole-3-carboxylate is as follows: add 50 g of ethyl pyrazole-3-carboxylate and 350 mL (7 eq.) of ammonia methanol in a 500 mL sealed tank, the mass volume ratio of ethyl pyrazole-3-carboxylate to ammonia methanol is 1:7 g / mL, and the closed system is heated to 90-95 degrees, and stirred for 22 hours. In addition, the aminolysis reaction includes post-treatment: after the reaction is completed, the reaction solution is cooled (about 25-30 degrees), concentrated under reduced pressure to remove the solvent, and then 150 mL of toluene is added, cooled (about 0-5 degrees), stirred for 2 hours, filtered, washed once with 40 mL of 0-5 degree toluene, and dried to obtain pyrazole-3-carboxamide (36.6 g). The purity of pyrazole-3-carboxamide obtained in this example is 98.3 A%, and the yield is 92.3%. 1 H NMR detection method: 1 H NMR (400MHz, DMSO) δ12.22 (s, 1H), 8.38 (s, 2H), 7.86 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H).

[0032] Among them, the amide reduction reaction of pyrazole-3-carboxamide is specifically as follows: 12.0 g of pyrazole-3-carboxamide and 84 mL (7 vol.) of tetrahydrofuran are added to a 500 mL reaction bottle, the mass volume ratio of pyrazole-3-carboxamide to tetrahydrofuran is 1:7 g / mL, the system is heated to 60-65 degrees, 86.5 mL (2.5 M, 2.0 eq.) of tetrahydrofuran solution of lithium aluminum tetrahydride is added dropwise, the molar ratio of pyrazole-3-carboxamide to lithium aluminum tetrahydride is 1:2, and the mixture is stirred for 2.5 hours at this temperature. In addition, the reduction reaction includes post-treatment: turn off the heating, control the temperature of the reaction liquid system to 0 to 5 degrees, add 50 g of sodium sulfate decahydrate solid, and stir for 2 hours; filter to remove insoluble solids, separate the filtrate into layers, and extract the aqueous phase three times with 60 mL of methyl tert-butyl ether, combine the organic layers, and wash once with 60 mL of saturated brine; concentrate to remove the solvent in the organic phase to obtain 12 g of crude residue 3-aminomethyl-1-H pyrazole. The crude product was distilled under reduced pressure at 2.3 mmHg, and 7.1 g of the fraction at 128~132 degrees was collected. The GC purity was 97.1 A%, and the yield was 67.3%. 1 H NMR detection method: 1H NMR (400 MHz, DMSO) δ12.42 (s, 1H), 8.58 (s, 2H), 7. 68 (d, J = 8.4 Hz, 1 H), 6.18 (d, J = 8.4 Hz, 1H), 4.38 (s, 2H).

[0033] Example 4

[0034] like Figure 1 As shown, the present application discloses a method for synthesizing pyrazole-3-carboxamide, comprising the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0035] Among them, the aminolysis reaction of ethyl pyrazole-3-carboxylate is as follows:

[0036] In a 200 mL stuffy tank, 10 g of ethyl pyrazole-3-carboxylate and 30 mL of ammonia methanol (3 eq.) were added. The mass volume ratio of ethyl pyrazole-3-carboxylate to ammonia methanol was 1:3 g / mL. The closed system was heated to 86-90 degrees and stirred for 20 hours. In addition, the aminolysis reaction includes post-treatment: After the reaction is completed, the reaction solution is cooled (about 25-30 degrees), concentrated under reduced pressure to remove the solvent, and then 30 mL of methyl tert-butyl ether is added, cooled (about 5-8 degrees) and stirred for 2 hours, filtered, washed once with 8 mL of methyl tert-butyl ether, and dried to obtain pyrazole-3-carboxamide (6.5 g). The purity of pyrazole-3-carboxamide obtained in this example is 98.0A%, and the yield is 82.0%.

[0037] Among them, the amide reduction reaction of pyrazole-3-carboxamide is as follows: 24.0 g of pyrazole-3-carboxamide (which can be accumulated by repeating the above pyrazole-3-carboxamide synthesis multiple times) is added to a 500 mL reaction bottle, and 168 mL (7 vol.) of tetrahydrofuran is added, and the mass volume ratio of pyrazole-3-carboxamide to tetrahydrofuran is 1:7 g / mL. The system is heated to 60-65 degrees, and 173 mL (2.5 M, 2.0 eq.) of tetrahydrofuran solution of lithium aluminum tetrahydride is added dropwise, and the molar ratio of pyrazole-3-carboxamide to lithium aluminum tetrahydride is 1:2. The mixture is stirred for 2.5 hours at this temperature. In addition, the reduction reaction includes post-treatment: turn off the heating, control the temperature of the reaction liquid system to 0 to 5 degrees, add 100 g of solid sodium sulfate decahydrate, and stir for 2 hours; filter to remove insoluble solids, separate the filtrate into layers, and extract the aqueous phase three times with 120 mL of methyl tert-butyl ether, combine the organic layers, and wash once with 120 mL of saturated brine; concentrate to remove the solvent in the organic phase to obtain 22 g of crude residue 3-aminomethyl-1-H pyrazole. The crude product was distilled under reduced pressure at 2.3 mmHg, and 13.5 g of the fraction at 128~132 degrees was collected. The GC purity was 97.4 A%, and the yield was 64%. 1 H NMR detection method: 1 H NMR (400 MHz, DMSO) δ12.42 (s, 1H), 8.58 (s, 2H), 7. 68 (d, J = 8.4 Hz, 1 H), 6.18 (d, J =8.4 Hz, 1H), 4.38 (s, 2H).

[0038] Example 5

[0039] like Figure 1 As shown, the present application discloses a method for synthesizing pyrazole-3-carboxamide, comprising the following steps: subjecting ethyl pyrazole-3-carboxylate to an aminolysis reaction to generate pyrazole-3-carboxamide, and then subjecting pyrazole-3-carboxamide to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

[0040] Among them, the aminolysis reaction of ethyl pyrazole-3-carboxylate is as follows: 10 g of ethyl pyrazole-3-carboxylate is added to a 200 mL stuffy tank, 100 mL of ammonia methanol is added (10 eq.), the mass volume ratio of ethyl pyrazole-3-carboxylate to ammonia methanol is 1:10g / mL, the closed system is heated to 86-90 degrees, and the mixture is stirred for 20 hours. In addition, the aminolysis reaction includes post-treatment: After the reaction is completed, the reaction solution is cooled (about 25-30 degrees), concentrated under reduced pressure to remove the solvent, and then 30 mL of methyl tert-butyl ether is added, cooled (about 5-8 degrees) and stirred for 2 hours, filtered, washed once with 8 mL of methyl tert-butyl ether, and dried to obtain pyrazole-3-carboxamide (6.9g). The purity of pyrazole-3-carboxamide obtained in this embodiment is 98.4 A%, and the yield is 87.0%.

[0041] Among them, the amide reduction reaction of pyrazole-3-carboxamide is as follows: 24.0 g of pyrazole-3-carboxamide (which can be accumulated by repeating the above pyrazole-3-carboxamide synthesis multiple times) is added to a 500 mL reaction bottle, and 168 mL (7 vol.) of tetrahydrofuran is added, and the mass volume ratio of pyrazole-3-carboxamide to tetrahydrofuran is 1:7 g / mL. The system is heated to 60-65 degrees, and 346 mL (2.5 M, 4.0 eq.) of tetrahydrofuran solution of lithium aluminum tetrahydride is added dropwise, and the molar ratio of pyrazole-3-carboxamide to lithium aluminum tetrahydride is 1:4, and the mixture is stirred for 2.5 hours. In addition, the reduction reaction includes post-treatment: turn off the heating, control the temperature of the reaction liquid system to 0 to 5 degrees, add 100 g of solid sodium sulfate decahydrate, and stir for 2 hours; filter to remove insoluble solids, separate the filtrate into layers, and extract the aqueous phase three times with 120 mL of methyl tert-butyl ether, combine the organic layers, and wash once with 120 mL of saturated brine; concentrate to remove the solvent in the organic phase to obtain 22.6 g of crude residue 3-aminomethyl-1-H pyrazole. The crude product was distilled under reduced pressure at 2.3 mmHg, and 13.1 g of the fraction at 128~132 degrees was collected. The GC purity was 97.1 A%, and the yield was 65.9%. 1 H NMR detection method: 1 H NMR (400MHz, DMSO) δ12.42 (s, 1H), 8.58 (s, 2H), 7. 68 (d, J = 8.4 Hz, 1 H), 6.18 (d, J = 8.4 Hz, 1H), 4.38 (s, 2H).

[0042] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 3-aminomethyl-1-H-pyrazole, characterized in that: The following steps are involved: Ethyl pyrazole-3-carboxylate is subjected to an aminolysis reaction to generate pyrazole-3-carboxamide, and then pyrazole-3-carboxamide is subjected to an amide reduction reaction to obtain 3-aminomethyl-1-H pyrazole.

2. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 1, wherein: The aminolysis reaction comprises the following steps: dissolving ethyl pyrazole-3-carboxylate in an organic solvent and then adding the solvent into a pressure vessel, adding an ammonia source into the pressure vessel, and controlling the reaction temperature to be constant to carry out stirring reaction.

3. The synthetic method of 3-aminomethyl-1-H pyrazole according to claim 2, characterized in that: The organic solvent includes an alcohol solvent, which is one or more of methanol, ethanol and isopropanol; and / or the ammonia source includes one or more of ammonia gas and ammonia methanol solution; and / or the mass volume ratio of ethyl pyrazole-3-carboxylate to the alcohol solvent is 1: (3~10) g / mL; and / or the reaction temperature is constant at 86~100 degrees; and / or the reaction time of the stirring reaction is 13~25 hours.

4. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 3, characterized in that: The post-treatment after the aminolysis reaction includes the following steps: cooling and stirring the reaction system to obtain a temperature of 25-30 degrees, concentrating and removing the solvent of the organic phase to obtain a crude concentrated solution, replacing the crude concentrated solution with an organic solvent, cooling to 0-10 degrees and stirring for 2-5 hours, and filtering out pyrazole-3-carboxamide under reduced pressure.

5. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 4, characterized in that: The organic solvent for replacement includes one or more of toluene, heptane and methyl tert-butyl ether.

6. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 1, characterized in that: The amide reduction reaction comprises the following steps: dissolving pyrazole-3-carboxamide in an organic solvent, controlling the temperature, and then dropping a reducing agent to cause an amide reduction reaction.

7. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 6, characterized in that: The organic solvent comprises one or two of tetrahydrofuran and methyl tert-butyl ether; and / or, the mass volume ratio of the pyrazole-3-carboxamide to the organic solvent is 1:(5-10) g / mL; and / or, the reducing agent is a tetrahydrofuran solution of lithium aluminum tetrahydride, and the molar ratio of the pyrazole-3-carboxamide to the lithium aluminum tetrahydride is 1:(2-4); and / or, the temperature variation range of the reaction liquid system is 50-65 degrees.

8. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 7, characterized in that: The amide reduction reaction is followed by post-treatment, which includes the following steps: after the reaction is completed, quenching, filtering, extracting and concentrating to separate and obtain the target compound 3-aminomethyl-1-H pyrazole.

9. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 8, characterized in that: The quenching method uses sodium sulfate decahydrate or aqueous THF; and / or the extraction solvent includes one or more of tetrahydrofuran, methyl tert-butyl ether and n-butanol.

10. The method for synthesizing 3-aminomethyl-1-H-pyrazole according to claim 8, characterized in that: After concentration and separation, the product was purified by distillation under reduced pressure.

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