CN116283904A - Preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine - Google Patents
Preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine Download PDFInfo
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- CN116283904A CN116283904A CN202310336637.7A CN202310336637A CN116283904A CN 116283904 A CN116283904 A CN 116283904A CN 202310336637 A CN202310336637 A CN 202310336637A CN 116283904 A CN116283904 A CN 116283904A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, which comprises the following steps: (1) Reacting 2-cyanopyridine with hydrazine in a solvent to obtain 2-pyridine hydrazide; (2) Reacting the 2-pyridine hydrazide of step (1) with benzil to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine. According to the preparation method provided by the invention, the triazine structure is skillfully synthesized by benzil in one step, so that good solubility of the product in isopropanol can be ensured, the product can be recrystallized, the yield and purity of the product can be ensured, the yield and purity of the product can reach more than 99%, compared with the existing reaction of coupling the amidrazone structure and benzil with a ring, the use of column chromatography to purify the product is avoided, the actual amplification of the reaction is facilitated, the industrial production is facilitated, the environment is protected, and the method accords with the concept of modern organic chemistry development.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and relates to a preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
Background
At present, with the rapid development of new medicine development fields in China, the demand potential for chemical reagent types is huge, and copper is considered as a control factor of the diversity of cancer development and progression processes, mainly cancer growth, angiogenesis and metastasis. Furthermore, alterations in copper metabolism may also constitute an effective target for cancer treatment. Therefore, various copper complexes have been developed as drugs for treating cancer, exhibiting excellent anticancer activity. First, a decisive aspect of drug development is the recognition of drug-protein interactions to verify the specificity of drug action, while copper is critical for the execution of different enzymes and proteins, in combination with respiration and DNA synthesis.
3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine is an important raw material for its research, so a process which can efficiently obtain and purify the product is of great importance. The development of novel synthetic methods for 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine is also in continuous optimization. Is generally obtained by coupling and closing a ring by 3- (2-pyridyl) amidrazone and benzil, and the purification method is obtained by a column chromatography method. However, the extremely high polarity of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, which is difficult to purify due to the indissolvable nature of common solvents, is very easy to pollute the environment due to the waste silica gel generated by column chromatography.
Therefore, aiming at the defects, a novel preparation method needs to be provided, is green and environment-friendly, and accords with the concept of modern organic chemistry development.
Disclosure of Invention
The technical problem to be solved by the invention is that the existing method is difficult to purify and cannot meet the actual production needs, and the aim of the invention is to provide the preparation method of the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, which can meet the requirements of pilot plant test or ton test and uses the method of column chromatography as little as possible.
In order to solve the technical problems, the invention provides a preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, which comprises the following steps:
(1) Reacting 2-cyanopyridine with hydrazine in a solvent to obtain 2-pyridine hydrazide;
(2) Reacting the 2-pyridine hydrazide of step (1) with benzil to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
According to the preparation method provided by the invention, the hydrazide structure is used as an intermediate product, so that the product has better solubility in the reaction process, the purification of the intermediate product can be realized without a column chromatography process, and further, the hydrazide structure is skillfully coupled with benzil to form the triazine structure by one step, so that the good solubility of the product in isopropanol can be ensured, the product can be recrystallized, the yield and purity of the product can be ensured, the use of the column chromatography to purify the product can be avoided, the actual amplification of the reaction is facilitated, and the industrial production is facilitated.
In the two-step reaction of the invention, both the two-step reaction is carried out under the anhydrous and anaerobic condition.
Preferably, the molar ratio of the 2-cyanopyridine to the hydrazine in the step (1) is 1:1.5-3, for example, 1:1.5, 1:1.7, 1:2, 1:2.5 or 1:3, and the like, preferably 1:2.
Preferably, the solvent in step (1) is isopropanol. In the present invention, isopropyl alcohol is preferably used as the solvent, and the highest yield is obtained. If other alcohols such as methanol or ethanol are used, the yield of the product is lowered and the post-treatment is complicated.
Preferably, the temperature of the reaction in step (1) is 15 to 30 ℃, for example, 15 ℃, 20 ℃, 25 ℃, 30 ℃ or the like, preferably 20 ℃. Too high a temperature may produce byproducts, too low a temperature may be detrimental to the reaction, and the reaction time may be increased.
Preferably, the reaction in step (1) further comprises a post-treatment step;
preferably, the work-up comprises cooling the reaction product to 15 ℃, filtering, washing with isopropanol at 0 ℃ and filtering with ethyl acetate to give the 2-pyridine hydrazide. In the present invention, the reaction product is precipitated in the reaction solution after cooling to 15 ℃ or below, and the yield is lowered due to dissolution of the product when the temperature is too high.
Preferably, the molar ratio of the 2-pyridine hydrazide to the benzil in the step (2) is 1:0.5-1, for example, may be 1:0.5, 1:0.7, 1:0.8, 1:0.9 or 1:1, and preferably is 1:0.75.
Preferably, the solvent of the reaction in step (2) is isopropanol.
Preferably, after the reaction in step (2) is finished, a post-treatment step is further included.
Preferably, the post-treatment comprises the steps of: and filtering the product to collect a filter cake, flushing the filter cake by using isopropanol, dissolving the filter cake by using isopropanol at 90-100 ℃, and cooling to separate out crystals to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
In the post-treatment process of the present invention, if isopropanol is not used for washing, some impurities cannot be removed, and the purity of the product is lowered.
As a preferable technical scheme, the preparation method of the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine provided by the invention comprises the following steps:
(1) 2-cyanopyridine and hydrazine with the molar ratio of 1:1.5-3 are reacted in isopropanol, the reaction temperature is 15-30 ℃, after the reaction is finished, the reaction product is cooled to 15 ℃, filtered and then washed with isopropanol at 0 ℃, and then filtered by ethyl acetate to obtain 2-pyridine hydrazide; the specific reaction formula is as follows:
(2) And (3) reacting the 2-pyridine hydrazide and benzil in the molar ratio of 1:0.5-1 in isopropanol, filtering a product after the reaction is finished to collect a filter cake, flushing the filter cake by using isopropanol, dissolving the filter cake by using isopropanol at 90-100 ℃, and cooling to separate out crystals to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, thereby obtaining the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine. The specific reaction formula is as follows:
the implementation of the invention has the following beneficial effects:
according to the preparation method provided by the invention, the hydrazide structure is used as an intermediate product, so that the product has better solubility in the reaction process, the purification of the intermediate product can be realized without a column chromatography process, further, the hydrazide structure and nitrogen atoms in pyridine are utilized to smartly synthesize the triazine structure through benzil in one step, the good solubility of the product in isopropanol can be ensured, the product can be recrystallized, the yield and purity of the product can be ensured, the yield and purity of the product can reach more than 99%, and compared with the existing reaction of the aminohydrazone structure and benzil coupling ring, the use of the column chromatography to purify the product is avoided, the actual amplification of the reaction is facilitated, and the industrial production is facilitated.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
This example provides a 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine preparation method
(1) 1.0 liter isopropyl alcohol, 192 grams hydrazine hydrate and 200 grams 2-cyanopyridine were added to a 3 liter round bottom flask. The resulting reaction mixture was stirred at 20 ℃ for about 4 hours. The reaction mixture was then cooled until its temperature was below about 15 ℃. The cooled reaction mixture was then filtered through filter paper and the filter cake (white crystals of 2-pyridine hydrazide) was thoroughly washed with isopropanol at 0 ℃ to remove all possible hydrazine, the filtrate was extracted with ethyl acetate, the resulting organic phases were combined, and dried to give 2-pyridine hydrazide as pale yellow crystals.
(2) 460 g of benzil was dissolved in 2 l of isopropanol using a 5 l capped flask and stirred and heated to between about 53 c to allow complete dissolution of the benzil. All of the resulting 2-pyridinehydrazinium is dissolved in a minimum amount of isopropanol, then the 2-pyridinehydrazide solution is added to the benzil solution, stirred for about 2 hours, and a yellow solid gradually precipitates when stirred for about five minutes. The reaction mixture was filtered through medium filter paper. The obtained filter cake is the target product 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine filter cake which is fully washed by isopropanol, then isopropanol solution is added into the obtained product, the obtained product is heated to about 95 ℃ to be completely dissolved, the heating is closed, the temperature is naturally reduced to about 40 ℃, the product is gradually recrystallized in the temperature reduction process, the filter cake is filtered when the product is hot at about 40 ℃, and the filter cake is naturally air-dried to be yellow floccule. Yield 99%, purity: 99%.
1 H NMR(400MHz,CDCl 3 )δ8.93(d,J＝3.9Hz,1H),8.72(d,J＝7.9Hz,1H),7.94(dd,J＝10.8,4.7Hz,1H),7.77–7.54(m,4H),7.54–7.46(m,1H),7.46–7.30(m,6H).
Example 2
This example provides a 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine preparation method
(1) 1.0 liter isopropyl alcohol, 144.25 grams hydrazine hydrate and 200 grams 2-cyanopyridine were added to a 3 liter round bottom flask. The resulting reaction mixture was stirred at 20 ℃ for about 4 hours. The reaction mixture was then cooled until its temperature was below about 15 ℃. The cooled reaction mixture was then filtered through filter paper and the filter cake (white crystals of 2-pyridine hydrazide) was thoroughly washed with isopropanol at 0 ℃ to remove all possible hydrazine, the filtrate was extracted with ethyl acetate, the resulting organic phases were combined, and dried to give 2-pyridine hydrazide as pale yellow crystals.
(2) 400 g of benzil was dissolved in 2 l of isopropanol using a 5 l capped flask and stirred and heated to between about 53 c to allow complete dissolution of the benzil. All of the resulting 2-pyridinehydrazinium is dissolved in a minimum amount of isopropanol, then the 2-pyridinehydrazide solution is added to the benzil solution, stirred for about 2 hours, and a yellow solid gradually precipitates when stirred for about five minutes. The reaction mixture was filtered through medium filter paper. The obtained filter cake is the target product 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine filter cake which is fully washed by isopropanol, then isopropanol solution is added into the obtained product, the obtained product is heated to about 95 ℃ to be completely dissolved, the heating is closed, the temperature is naturally reduced to about 40 ℃, the product is gradually recrystallized in the temperature reduction process, the filter cake is filtered when the product is hot at about 40 ℃, and the filter cake is naturally air-dried to be yellow floccule. Yield 80%, purity: 98%.
Example 3
This example provides a 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine preparation method
(1) 1.0 liter isopropyl alcohol, 288.51 grams hydrazine hydrate and 200 grams 2-cyanopyridine were added to a 3 liter round bottom flask. The resulting reaction mixture was stirred at 20 ℃ for about 4 hours. The reaction mixture was then cooled until its temperature was below about 15 ℃. The cooled reaction mixture was then filtered through filter paper and the filter cake (white crystals of 2-pyridine hydrazide) was thoroughly washed with isopropanol at 0 ℃ to remove all possible hydrazine, the filtrate was extracted with ethyl acetate, the resulting organic phases were combined, and dried to give 2-pyridine hydrazide as pale yellow crystals.
(2) 520 g of benzil was dissolved in 2 l of isopropanol using a 5 l capped flask and stirred and heated to between about 53 c to allow complete dissolution of the benzil. All of the resulting 2-pyridinehydrazinium is dissolved in a minimum amount of isopropanol, then the 2-pyridinehydrazide solution is added to the benzil solution, stirred for about 2 hours, and a yellow solid gradually precipitates when stirred for about five minutes. The reaction mixture was filtered through medium filter paper. The obtained filter cake is the target product 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine filter cake which is fully washed by isopropanol, then isopropanol solution is added into the obtained product, the obtained product is heated to about 95 ℃ to be completely dissolved, the heating is closed, the temperature is naturally reduced to about 40 ℃, the product is gradually recrystallized in the temperature reduction process, the filter cake is filtered when the product is hot at about 40 ℃, and the filter cake is naturally air-dried to be yellow floccule. Yield 98%, purity: 95%.
Example 4
This example differs from example 1 in that this example replaces the solvent in step (1) with ethanol. Yield 82%, purity: 94%.
Example 5
This example differs from example 1 only in that this example replaces the solvent in step (1) with n-butanol. Yield 85%, purity: 96%.
Example 6
This example differs from example 1 only in that this example replaces the solvent in step (2) with ethanol. Yield 80%, purity: 95%.
Example 7
The difference between this example and example 1 is only that the reaction temperature in step (1) of this example was 10 ℃. The reaction time is long, the yield is 85%, and the purity is 93%.
Example 8
The difference between this example and example 1 is only that the reaction temperature in step (1) of this example was 40 ℃. The yield thereof was found to be 91% and the purity thereof was found to be 93%.
Example 9
The difference between this example and example 1 is only that filtration was performed without decreasing the temperature to 15℃after completion of the reaction in step (1) of this example. Yield 57%, purity 94%.
Example 10
The difference between this example and example 1 is that in step (2) of this example, the reaction was completed without sufficient washing with isopropyl alcohol, but with methanol. The yield thereof was found to be 82% and the purity thereof was found to be 92%.
Example 11
The difference between this example and example 1 is that in step (2) of this example, the recrystallization operation was directly performed without sufficiently washing with isopropyl alcohol after the completion of the reaction. The yield was 86% and the purity was 95%.
The data of the above examples show that the preparation process and the post-treatment process provided by the invention can make the prepared product have higher yield and better purity, and are more beneficial to industrial production compared with other existing methods.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. A process for the preparation of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, said process comprising the steps of:
(1) Reacting 2-cyanopyridine with hydrazine in a solvent to obtain 2-pyridine hydrazide;
(2) Reacting the 2-pyridine hydrazide of step (1) with benzil to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
2. The process according to claim 1, wherein the molar ratio of 2-cyanopyridine to hydrazine in step (1) is 1:1.5-3, preferably 1:2.
3. The process according to claim 1 or 2, wherein the solvent in step (1) is isopropanol.
4. A method according to any one of claims 1 to 3, wherein the temperature of the reaction in step (1) is 15 to 30 ℃, preferably 20 ℃.
5. The process according to any one of claims 1 to 4, wherein the reaction in step (1) further comprises a step of post-treatment;
preferably, the work-up comprises cooling the reaction product to 15 ℃, filtering, washing with isopropanol at 0 ℃ and filtering with ethyl acetate to give the 2-pyridine hydrazide.
6. The process according to any one of claims 1 to 5, wherein the molar ratio of 2-pyridine hydrazide to benzil in step (2) is 1:0.5 to 1, preferably 1:0.75.
7. The process according to any one of claims 1 to 6, wherein the solvent of the reaction in step (2) is isopropanol.
8. The method according to any one of claims 1 to 7, wherein after the reaction of step (2) is completed, further comprising a step of post-treatment;
preferably, the post-treatment comprises the steps of: and filtering the product to collect a filter cake, flushing the filter cake by using isopropanol, dissolving the filter cake by using isopropanol at 90-100 ℃, and cooling to separate out crystals to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
9. The preparation method according to any one of claims 1 to 8, characterized in that the preparation method comprises the steps of:
(1) 2-cyanopyridine and hydrazine with the molar ratio of 1:1.5-3 are reacted in isopropanol, the reaction temperature is 15-30 ℃, after the reaction is finished, the reaction product is cooled to 15 ℃, filtered and then washed with isopropanol at 0 ℃, and then filtered by ethyl acetate to obtain 2-pyridine hydrazide;
(2) And (3) reacting the 2-pyridine hydrazide and benzil in the molar ratio of 1:0.5-1 in isopropanol, filtering a product after the reaction is finished to collect a filter cake, flushing the filter cake by using isopropanol, dissolving the filter cake by using isopropanol at 90-100 ℃, and cooling to separate out crystals to obtain the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine, thereby obtaining the 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine.
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| CN202310336637.7A CN116283904A (en) | 2023-03-31 | 2023-03-31 | Preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine |
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| CN202310336637.7A CN116283904A (en) | 2023-03-31 | 2023-03-31 | Preparation method of 3- (2-pyridyl) -5, 6-diphenyl-1, 2, 4-triazine |
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