Method for synthesizing bromophenyl pyrazolo[3,4-d]pyrimidine derivative

Abstract

The invention relates to the field of organic synthesis, in particular to a method for synthesizing a bromophenyl pyrazolo[3,4-d]pyrimidine derivative. 1-(4-bromophenyl)-4-chlorine-1H-yrazolo[3,4-d]pyrimidine is synthesized by two steps, and the method comprises the following steps of: performing condensation on 4-bromophenylhydrazine and 4,6-dichloropyrimidine-5-formaldehyde in a solvent of tetrahydrofuran in the presence of triethylamine, and separating and purifying a condensation product; and dissolving the condensation product with tetrahydrofuran again, adding a proper amount of triethylamine, reacting fully at room temperature, evaporating most solvent after the reaction is finished, adding water to separate out a brownish yellow solid crude product, and recrsystallizing the filtered solid with methanol to obtain the 1-(4-bromophenyl)-4-chlorine-1H-yrazolo[3,4-d]pyrimidine, wherein the product content is more than or equal to 97 percent; and the total yield is over 78 percent. The two steps of reactions are performed at room temperature without column separation, so that the cleanliness degree of the synthetic process is improved.

Description

technical field

[0001] The present invention relates to the field of organic synthesis, in particular to the synthesis of a bromophenylpyrazolo[3,4-d]pyrimidine derivative namely 1-(4-bromophenyl)-4-chloro-1H-pyrazolo[3 ,4-d] a new method of pyrimidine, using 4-bromophenylhydrazine and 4,6-dichloropyrimidine-5-carbaldehyde as raw materials to synthesize 1-(4-bromophenyl)-4-chloro- 1H-pyrazolo[3,4-d]pyrimidine. Background technique

[0002] As the structural units of important biomolecules DNA and ATP, pyrazolopyrimidine derivatives have a wide range of biological activities and are the dominant structures in the design of new drugs, which have always been highly valued by medicinal chemists. At present, many anticancer drugs have been developed based on 1H-pyrazolo[3,4-d]pyrimidine and other pyrimidine derivatives, which are widely used in the treatment of tumors, inflammation, cardiovascular, asthma and neurological diseases. treat. For example, allopurinol, which has be...

Examples

Embodiment 1

[0018] Step 1: Add 50ml of tetrahydrofuran and 5mmol p-bromophenylhydrazine to a 100ml three-necked flask, add 5mmol triethylamine at the same time, stir at room temperature for 0.5h, then slowly add 5mmol 4,6-dichloropyrimidine-5- formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1 hour, the reaction was completed, and the insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to 20ml, and put in the refrigerator to freeze overnight, and crystallized to obtain a bright yellow solid as the condensation product (A), with a yield of 80%.

[0019] Step 2: Add 50ml of tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 10mmol of triethylamine, continue stirring at room temperature for 32h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml of water, A large amount of brown-yellow solids precipitated, and the filtered solids were ...

Embodiment 2

[0021] Step 1: Add 50ml of tetrahydrofuran and 5mmol p-bromophenylhydrazine to a 100ml three-necked flask, add 6mmol triethylamine at the same time, after stirring at room temperature for 0.5h, slowly add 6mmol 4,6-dichloropyrimidine-5- formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1.5h, the reaction was completed, and the insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to 20ml, and put in the refrigerator to freeze overnight, and crystallized to obtain a bright yellow solid as condensation product (A), with a yield of 85%.

[0022] Step 2: Add 50ml of tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 12mmol of triethylamine, continue stirring at room temperature for 30h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml of water, A large amount of brown-yellow solids precipitated, and the filtered solids were r...

Embodiment 3

[0024] Step 1: Add 50ml of tetrahydrofuran and 5mmol of p-bromophenylhydrazine hydrochloride into a 100ml three-necked flask, add 11mmol of triethylamine at the same time, stir at room temperature for 0.5h, then slowly add 5mmol of 4,6-dichloropyrimidine under nitrogen protection -5-Formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1.5h, the reaction was completed, the insoluble matter was removed by filtration, the filtrate was distilled under reduced pressure to 20ml, and it was frozen in the refrigerator overnight, and a bright yellow solid was crystallized to obtain a condensation product (A), with a yield of 81%.

[0025] Step 2: Add 50ml tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 8mmol triethylamine, continue stirring at room temperature for 27h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml water, A large amount of brown-yellow solids precipitated...

technical field

[0001] The present invention relates to the field of organic synthesis, in particular to the synthesis of a bromophenylpyrazolo[3,4-d]pyrimidine derivative namely 1-(4-bromophenyl)-4-chloro-1H-pyrazolo[3 ,4-d] a new method of pyrimidine, using 4-bromophenylhydrazine and 4,6-dichloropyrimidine-5-carbaldehyde as raw materials to synthesize 1-(4-bromophenyl)-4-chloro- 1H-pyrazolo[3,4-d]pyrimidine. Background technique

[0002] As the structural units of important biomolecules DNA and ATP, pyrazolopyrimidine derivatives have a wide range of biological activities and are the dominant structures in the design of new drugs, which have always been highly valued by medicinal chemists. At present, many anticancer drugs have been developed based on 1H-pyrazolo[3,4-d]pyrimidine and other pyrimidine derivatives, which are widely used in the treatment of tumors, inflammation, cardiovascular, asthma and neurological diseases. treat. For example, allopurinol, which has be...

Examples

Embodiment 1

[0018] Step 1: Add 50ml of tetrahydrofuran and 5mmol p-bromophenylhydrazine to a 100ml three-necked flask, add 5mmol triethylamine at the same time, stir at room temperature for 0.5h, then slowly add 5mmol 4,6-dichloropyrimidine-5- formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1 hour, the reaction was completed, and the insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to 20ml, and put in the refrigerator to freeze overnight, and crystallized to obtain a bright yellow solid as the condensation product (A), with a yield of 80%.

[0019] Step 2: Add 50ml of tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 10mmol of triethylamine, continue stirring at room temperature for 32h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml of water, A large amount of brown-yellow solids precipitated, and the filtered solids were ...

Embodiment 2

[0021] Step 1: Add 50ml of tetrahydrofuran and 5mmol p-bromophenylhydrazine to a 100ml three-necked flask, add 6mmol triethylamine at the same time, after stirring at room temperature for 0.5h, slowly add 6mmol 4,6-dichloropyrimidine-5- formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1.5h, the reaction was completed, and the insoluble matter was removed by filtration, and the filtrate was distilled under reduced pressure to 20ml, and put in the refrigerator to freeze overnight, and crystallized to obtain a bright yellow solid as condensation product (A), with a yield of 85%.

[0022] Step 2: Add 50ml of tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 12mmol of triethylamine, continue stirring at room temperature for 30h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml of water, A large amount of brown-yellow solids precipitated, and the filtered solids were r...

Embodiment 3

[0024] Step 1: Add 50ml of tetrahydrofuran and 5mmol of p-bromophenylhydrazine hydrochloride into a 100ml three-necked flask, add 11mmol of triethylamine at the same time, stir at room temperature for 0.5h, then slowly add 5mmol of 4,6-dichloropyrimidine under nitrogen protection -5-Formaldehyde ， TLC tracking (developing agent V 丙酮 :V 石油醚 =1:2), after about 1.5h, the reaction was completed, the insoluble matter was removed by filtration, the filtrate was distilled under reduced pressure to 20ml, and it was frozen in the refrigerator overnight, and a bright yellow solid was crystallized to obtain a condensation product (A), with a yield of 81%.

[0025] Step 2: Add 50ml tetrahydrofuran to a 100ml three-necked flask, add the above bright yellow solid (A), stir to dissolve, add 8mmol triethylamine, continue stirring at room temperature for 27h, distill under reduced pressure to concentrate the solution to 10ml, add 20ml water, A large amount of brown-yellow solids precipitated...