A process for the preparation of aminocarboxamidopyrazole derivative compounds

Abstract

The present application relates to the technical field of pyrazole derivative compound synthesis, and particularly relates to a preparation method of an amino-formamido pyrazole derivative compound, which comprises the following steps: S1, synthesizing an intermediate 1 by using pyrazole amine and triphenyl chloromethane as raw materials; S2, synthesizing an intermediate 2 by means of a hydrazinolysis reaction of the intermediate 1; S3, oxidizing the intermediate 2 into an intermediate 3 by means of sodium nitrite; and S4, preparing a target product by condensing the intermediate 3 with Boc-ethylenediamine. The raw material in the present application is easy to obtain, and the reaction process is mild. The key intermediate acylhydrazine is synthesized by means of a hydrazinolysis reaction, and then the acylhydrazine is oxidized into the intermediate acyl azide by means of sodium nitrite, so that the use of an expensive reagent DPPA is avoided, and the material cost is greatly saved.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of pyrazole derivative compound synthesis, and particularly relates to a preparation method of an aminated formamidyl pyrazole derivative compound. BACKGROUND

[0002] The aminopyrazole amide derivative is a kind of chemical substance, which contains a pyrazole ring and an amide group in the basic structure, and is connected to other functional groups through an amino group on the pyrazole ring. These compounds have wide application and research in the fields of medicine and pesticide.

[0003] In the field of medicine, the aminopyrazole amide compound has anti-inflammatory, antibacterial, antitumor and other activities. The aminopyrazole amide compound is often used as a traditional Chinese medicine intermediate for synthesizing antibiotics and other drugs, and has great social and economic benefits.

[0004] However, the existing synthesis of the aminopyrazole amide compound often needs DPPA. For example, both the aminopyrazole amide compound intermediate in the publication No. CN113698406A and the publication No. CN105541719B is synthesized through azide phosphoric acid diphenyl ester (DPPA), which increases the production cost. Therefore, in view of the above background technical problems, a new synthesis method for synthesizing the aminated formamidyl pyrazole derivative compound without DPPA is proposed. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of an aminated formamidyl pyrazole derivative compound to solve the problems in the above background technology.

[0006] To achieve the above-mentioned purpose, the present application provides the following technical scheme:

[0007] A preparation method of an aminated formamidyl pyrazole derivative compound, the method comprising the following steps:

[0008] S1, in the presence of an acid binding agent, pyrazole amine and triphenylmethyl chloride are reacted in dichloromethane by warming and refluxing, the temperature is lowered and the temperature is kept for a period of time, the first suction filtration is carried out, the filtrate is concentrated to a viscous state, the normal temperature is crystallized by n-hexane, then the second suction filtration is continued, and vacuum drying is carried out to obtain an intermediate 1;

[0009]

[0010] S2, the intermediate 1 prepared in step S1 is reacted with hydrazine hydrate in methanol by warming and refluxing, the excess methanol is distilled at normal pressure, ethyl acetate is added after the temperature is lowered, the temperature is continuously lowered and kept for a period of time, the suction filtration is carried out, then the ethyl acetate is rinsed, and vacuum drying is carried out to obtain an intermediate 2;

[0011]

[0012] S3, stirring the intermediate 2 prepared in step S2 with water, adding dilute hydrochloric acid dropwise under cooling, stirring for a period of time, after the stirring is completed, slowly adding sodium nitrite solution under the same temperature, keeping for a period of time under the same temperature, filtering, and rinsing with cold water to obtain the intermediate 3;

[0013]

[0014] S4, dissolving the intermediate 3 prepared in step S3 in toluene, adding anhydrous sodium sulfate under room temperature, continuing to stir for a period of time, removing the sodium sulfate to obtain a dry solution, and adding the dry solution dropwise into a hot toluene solution containing Boc-ethylenediamine and TEA, and then precipitating and filtering after reaction for a period of time under cooling, rinsing with toluene and ethanol in sequence, and vacuum drying to obtain the target product.

[0015]

[0016] Further, in the step S1, the acid-binding agent is triethylamine, the warming and reflux reaction is 4-10 h, the keeping under 10 ℃ is 0.5-2 h, the first filtering is performed after the first precipitation with n-hexane, the second filtering is performed, the temperature of the second filtering is 5 ℃, the temperature of the vacuum drying is 30 ℃, and the molar ratio of the pyrazole amine to the triphenylmethyl chloride is 1:1.

[0017] Further, in the step S2, the time of the warming and reflux reaction is 18-24 h, the temperature of adding the ethyl acetate is 20-30 ℃, the temperature is continuously cooled to 0-10 ℃ after adding the ethyl acetate and keeping for 0.5-2 h, the temperature of the vacuum drying is 30 ℃, and the molar ratio of the intermediate 1 to the hydrazine hydrate is 1:1.5.

[0018] Further, in the step S3, the concentration of the dilute hydrochloric acid dropwise added is 5%, the temperature of the dilute hydrochloric acid dropwise added is 0-10 ℃, the time of continuously stirring after the dilute hydrochloric acid dropwise added is 10-30 min, the concentration of the sodium nitrite is 20%, and the keeping under 0-10 ℃ after the sodium nitrite dropwise added is completed is 0.5-2 h.

[0019] Further, in the step S4, the time of stirring after adding the anhydrous sodium sulfate is 0.5-2 h, the dry toluene solution with the intermediate 3 is added into a hot toluene solution containing Boc-ethylenediamine and TEA under 80-100 ℃ and reacts for 1-2 h, the temperature of the precipitation and filtering after the reaction is 0-10 ℃, and the target product is obtained by vacuum drying under 40 ℃.

[0020] Compared with the prior art, the present application has the beneficial effects that:

[0021] The application prepares the aminoformamidyl pyrazole derivative compound by using pyrazole amine and triphenyl chloromethane as raw materials, refluxing in dichloromethane, and synthesizing the intermediate 2 through the hydrazinolysis reaction, the intermediate 3 through the sodium nitrite oxidation, and the target product through the condensation reaction with Boc-ethylenediamine. The complete synthesis path of the target product is as follows:

[0022] BRIEF DESCRIPTION OF DRAWINGS

[0023] Fig. 1 The synthesis path process flowchart of the application is as follows:

[0024] Fig. 2 The HNMR detection spectrum of the target product prepared in the application is as follows. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the application will be clearly and completely described below with reference to the drawings in the embodiments of the application. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments of the application. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the application.

[0026] Please refer to Figs. 1-2 The application provides a technical solution:

[0027] Embodiment 1

[0028] A preparation method of an aminoformamidyl pyrazole derivative compound, which comprises the following steps:

[0029] S1, 58 kg of dichloromethane, 13.14 kg of triethylamine, 7.3 kg of pyrazole amine and 11.97 kg of triphenyl chloromethane are added into a 100 L kettle under stirring, and refluxed for 8 h, and then the reaction is completed and cooled to 10 DEG C for 1.2 h, and then the first filtration is performed, the filtrate is concentrated to a viscous state, 32 kg of n-hexane is added at room temperature for crystallization, the second filtration is performed after cooling to 5 DEG C, and then vacuum drying is performed at 30 DEG C to obtain 17.52 kg of intermediate 1, and the intermediate 1 is a light yellow solid;

[0030] S2, 51 kg of methanol is added into a 100 L kettle, 17.52 kg of the intermediate 1 prepared in step S1 and 3.2 kg of hydrazine hydrate are added under stirring, and refluxed for about 20 h, and then the reaction is completed, 34 kg of methanol is distilled off under normal pressure, cooled to 26 DEG C, 51 kg of ethyl acetate is added, cooled to 6 DEG C and kept for 1.4 h, and then the filtration is performed, the filtered product is rinsed with ethyl acetate, and then vacuum drying is performed at 30 DEG C to obtain 13.3 kg of intermediate 2, and the intermediate 2 is a white solid;

[0031] S3, 39 kg of water was added into a 100 L kettle, and 13.3 kg of intermediate 2 prepared in step S2 was added, stirred and cooled to 5°C, 23.85 kg of dilute hydrochloric acid with a concentration of 5% was added dropwise, after the dropwise addition was completed, stirring was carried out for 18 minutes, 12.4 kg of sodium nitrite solution with a concentration of 20% was slowly added dropwise while maintaining 5°C, after the dropwise addition was completed, the reaction was maintained at 5°C for 1.4 h, after the reaction was completed as detected by HPLC, the product was filtered and rinsed with cold water, 17.2 kg of intermediate 3 wet product was obtained, the intermediate 3 was a white solid, and the intermediate 3 wet product was directly used in the next step;

[0032] S4, 39 kg of toluene was added into one of the 100 L kettles, 17.2 kg of intermediate 3 prepared in step S3 was added while stirring, after stirring until the intermediate 3 was basically dissolved, 6.5 kg of anhydrous sodium sulfate was added, stirring was carried out at room temperature for 1.2 h, the sodium sulfate was removed by filtration to obtain a dry solution of the intermediate 3, another 100 L (reaction kettle 2) kettle was added with 13 kg of toluene, 5.2 kg of Boc-ethylenediamine and 6.6 kg of TEA, the temperature was raised to 95°C, and the dry solution of the intermediate 3 was slowly added dropwise into the reaction kettle 2, after the dropwise addition was completed, the reaction was carried out at 95°C for 1.5 h, the reaction was exothermic and released gas, after the reaction was completed as detected by HPLC, the temperature was lowered to 5°C and stirring was carried out for 1.4 h, the reaction solution was slowly cooled to induce crystallization, the product was filtered and rinsed with toluene and cold ethanol in sequence, and the product was dried at 40°C under vacuum to obtain 10.6 kg of the target product, which was a white solid.

[0033] Example 2

[0034] A method for preparing an aminated formamidyl pyrazole derivative compound, the method comprising the following steps:

[0035] S1, 58 kg of dichloromethane, 13.14 kg of triethylamine, 7.3 kg of pyrazole amine and 11.97 kg of triphenylmethyl chloride were added into a 100 L kettle while stirring, the temperature was raised to reflux, and the reaction was carried out for 10 h, after the reaction was completed as detected by HPLC, the temperature was lowered to 10°C and maintained for 2 h, and then the first filtration was carried out, the filtrate was concentrated to a viscous state, n-hexane was added at room temperature to induce crystallization, the second filtration was carried out after the temperature was lowered to 5°C, and then the product was dried under vacuum at 30°C to obtain 18.4 kg of intermediate 1, which was a yellow solid.

[0036] S2, 53 kg of methanol was added into a 100 L kettle, 18.4 kg of intermediate 1 prepared in step S1 and 3.36 kg of hydrazine hydrate were added while stirring, the temperature was raised to reflux, and the reaction was carried out for about 24 h, after the reaction was completed as detected by HPLC, 35 kg of methanol was distilled off under normal pressure, the temperature was lowered to 30°C, 53 kg of ethyl acetate was added, the temperature was lowered to 10°C and maintained for 2 h, and then the filtration was carried out, the filtered product was rinsed with ethyl acetate, and then the product was dried under vacuum at 30°C to obtain 14.6 kg of intermediate 2, which was a white solid.

[0037] S3, in a 100L kettle, 43kg water was added, and 14.6kg of intermediate 2 prepared in step S2 was added, stirred evenly, and cooled to 10℃, 26.37kg of 5% dilute hydrochloric acid was added dropwise, after the dropwise addition was completed, stirring for 30 minutes, keeping 10℃, slowly adding 13.6kg of 20% sodium nitrite solution, after the dropwise addition was completed, keeping 2h at 10℃, after HPLC detection of the reaction completion, filtration and cold water rinsing, 18.7kg of intermediate 3 wet product was obtained, intermediate 3 was a white solid, and the intermediate 3 wet product was directly used in the next step;

[0038] S4, in one of the 100L kettles, 42.4kg of toluene was added, and 18.7kg of intermediate 3 wet product prepared in step S3 was added under stirring, after stirring to dissolve, 7.1kg of anhydrous sodium sulfate was added, stirring at room temperature for 2h, filtering to remove sodium sulfate to obtain intermediate 3 dry solution, another 100L (reaction kettle 2) kettle was added with 14.1kg of toluene, 5.65kg of Boc-ethylenediamine and 7.2kg of TEA, and the temperature was raised to 100℃, the intermediate 3 dry solution was slowly added to the reaction kettle 2, after the dropwise addition was completed, the reaction was carried out at 100℃ for 2h, the reaction was exothermic, after HPLC detection of the reaction completion, the temperature was lowered to 10℃ and stirred for 2h, the reaction solution was slowly cooled to crystallize, the product was filtered and rinsed with toluene and cold ethanol in turn, and vacuum dried at 40℃ to obtain 11.6kg of target product, which was a white solid.

[0039] Example 3

[0040] A method for preparing an aminated formamidyl pyrazole derivative compound, comprising the following steps:

[0041] S1, in a 100L kettle, 58kg of dichloromethane, 13.14kg of triethylamine, 7.3kg of pyrazole amine and 11.97kg of triphenylmethyl chloride were added under stirring, and the temperature was raised to reflux for 4h, after HPLC detection of the reaction completion, the temperature was lowered to 10℃ and kept for 0.5h, then first filtration was carried out, the filtrate was concentrated to a viscous state, 32kg of n-hexane was added at room temperature to crystallize, after the second filtration at 5℃, vacuum drying was carried out at 30℃ to obtain 16.4kg of intermediate 1, which was a yellow solid;

[0042] S2, in a 100L kettle, 48kg of methanol was added, and 16.4kg of intermediate 1 prepared in step S1 and 3.0kg of hydrazine hydrate were added under stirring, and the temperature was raised to reflux for about 18h, after HPLC detection of the reaction completion, 34kg of methanol was distilled at normal pressure, the temperature was lowered to 20℃, 50kg of ethyl acetate was added, the temperature was lowered to 0℃ and kept for 0.5h, then filtration was carried out, the filtered product was rinsed with ethyl acetate, and vacuum drying was carried out at 30℃ to obtain 11.5kg of intermediate 2, which was a white solid;

[0043] S3, in 100L kettle, add 35kg water, and add 11.5kg intermediate 2 prepared in step S2, stir evenly, and cool to 0℃, drop 20.6kg dilute hydrochloric acid with 5% concentration, after drop completion, stir for 10 minutes, keep 0℃, continue to slowly drop 10.7kg sodium nitrite solution with 20% concentration, after drop completion, keep 0℃ for 0.5h, after HPLC detection reaction completion, filter and rinse with cold water, obtain 14.3kg intermediate 3 wet product, intermediate 3 is white solid, intermediate 3 wet product is directly used in next step;

[0044] S4, in one of 100L kettle, add 36kg toluene, and add 14.3kg intermediate 3 prepared in step S3 under stirring, after stirring to be basically dissolved, add 5.8kg anhydrous sodium sulfate, stir at room temperature for 0.5h, remove sodium sulfate to obtain intermediate 3 dry solution, in another 100L (reaction kettle 2) kettle, add 11.5kg toluene, 4.4kg Boc-ethylenediamine and 5.5kg TEA, heat to 80℃, slowly drop intermediate 3 dry solution into reaction kettle 2, after drop completion, react at 80℃ for 1h, reaction is exothermic, after HPLC detection reaction completion, cool to 0℃ and stir for 0.5h, slowly cool the reaction solution to precipitate, filter the product, rinse with toluene and cold ethanol in turn, and dry at 40℃ under vacuum to obtain 8.4kg target product, which is white solid.

[0045] Fig. 2 HNMR detection spectrum of the target product synthesized in the application, from the figure, it can be seen that:

[0046] 1HNMR, (CDCI3) δ 7.30-7.18 (m, 16H, Ar-H);

[0047] 4.99 (S, 1H, N-H);

[0048] 4.77 (S, 1H, N-H);

[0049] 4.67 (S, 1H, N-H);

[0050] 4.57 (s, 1H, N-H);

[0051] 3.19 (m, 4H, -CH2CH2-);

[0052] 3.93 (s, 3H, -CH3);

[0053] 1.41 (s, 9H, -C(CH3)3);

[0054] It is proved that the synthesis of the target product is completed.

[0055] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely exemplary of the principles and application of the present application. Numerous modifications and adaptions can be effected without departing from the spirit and scope of the present application, which is not limited to the exact construction and arrangement described. It is intended, therefore, to cover all modifications and adaptions that fall within the scope of the claims and their equivalents.

Claims

1. A process for the preparation of an aminocarboxamidopyrazole derivative compound, characterized by, The method comprises the following steps: S1, in the presence of an acid-binding agent, pyrazole amine and triphenyl chloromethane are reacted in dichloromethane by warming and refluxing, the temperature is lowered and the solution is kept for a period of time, first suction filtration is performed, the filtrate is concentrated to a viscous state, normal temperature crystallization is performed by using n-hexane, then second suction filtration is performed by continuously lowering the temperature, and vacuum drying is performed to obtain intermediate 1; S2, intermediate 1 prepared in step S1 is reacted with hydrazine hydrate in methanol by warming and refluxing, excess methanol is distilled off under normal pressure, ethyl acetate is added by lowering the temperature, the temperature is continuously lowered and the solution is kept for a period of time, then suction filtration is performed, and the target product is obtained by rinsing with ethyl acetate and vacuum drying; S3, intermediate 2 prepared in step S2 is stirred uniformly by adding water, dilute hydrochloric acid is added dropwise by lowering the temperature, stirring is performed for a period of time, after stirring is completed, sodium nitrite solution is slowly added dropwise at the same temperature, the solution is kept for a period of time at the same temperature, suction filtration is performed, and cold water rinsing is performed to obtain intermediate 3; S4, intermediate 3 prepared in step S3 is dissolved in toluene, anhydrous sodium sulfate is added at room temperature, stirring is continuously performed for a period of time, sodium sulfate is removed by filtration to obtain a dry solution, the dry solution is added dropwise to a hot toluene solution containing Boc-ethylenediamine and TEA, the solution is reacted for a period of time, then the temperature is lowered to perform crystallization and filtration, rinsing is performed by using toluene and ethanol in sequence, and vacuum drying is performed to obtain the target product; In step S1, the acid-binding agent is triethylamine, the warming and refluxing reaction is performed for 4-10 h, the solution is kept for 0.5-2 h at 10℃, the first suction filtration is performed, then the second suction filtration is performed after crystallization is performed by using n-hexane, the temperature of the second suction filtration is 5℃, the temperature of vacuum drying is 30℃, and the molar ratio of pyrazole amine to triphenyl chloromethane is 1:1; In step S2, the warming and refluxing reaction is performed for 18-24 h, the temperature of adding ethyl acetate is 20-30℃, the temperature is continuously lowered to 0-10℃ after adding ethyl acetate and the solution is kept for 0.5-2 h, the temperature of vacuum drying is 30℃, and the molar ratio of intermediate 1 to hydrazine hydrate is 1:1.5; In step S3, the concentration of the dilute hydrochloric acid added dropwise is 5%, the temperature of adding the dilute hydrochloric acid is 0-10℃, the solution is continuously stirred for 10-30 min after adding the dilute hydrochloric acid, the concentration of sodium nitrite is 20%, and the solution is kept for 0.5-2 h at 0-10℃ after adding dropwise sodium nitrite; In step S4, the solution is stirred for 0.5-2 h after adding anhydrous sodium sulfate, the dry toluene solution containing intermediate 3 is added dropwise to a hot toluene solution containing Boc-ethylenediamine and TEA at 80-100℃ and the solution is reacted for 1-2 h, then the temperature of lowering the temperature to perform crystallization is 0-10℃, and the target product is obtained by vacuum drying at 40℃.

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