A process for the preparation of 4-bromopyrazolo[3,4-d]-pyrimidine

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-bromopyrazole [3,4-D] -pyrimidine, and the specific steps are as follows: under the condition of anhydrous and anaerobic, 4-chloro-1H-pyrazolo [3,4-d] pyrimidine is reacted with a brominating reagent in an aprotic solvent to obtain 4-bromopyrazole [3,4-D] -pyrimidine. The preparation method provided by the application has the advantages of simple process route, clear steps, high yield of the target product, low cost, suitability for industrial production, considerable economic benefits, mild reaction condition and environmental protection.

Description

A method for preparing 4-bromopyrazole[3,4-D]-pyrimidine Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 4-bromopyrazole[3,4-D]-pyrimidine. Background Technology

[0002] Pyrimidines are often considered a parent structure in drug development. A wide variety of drugs use pyrimidines as their key skeleton, including antitumor drugs, antibacterial drugs, antihypertensive drugs, antiviral drugs, and immunotherapeutic drugs. Pyrazolopyrimidine, as an important structure in the large family of pyrimidines, has wide applications in pharmaceuticals and pesticides. Specifically, 4-bromopyrazole[3,4-D]pyrimidine can serve as a key intermediate in the synthesis of a series of compounds containing pyrazolopyrimidine fragments.

[0003] Patent DE2018345A1 discloses a method for preparing 4-bromopyrazole[3,4-D]-pyrimidine. This method uses highly toxic hydrazine hydrate, requires strict operational and protective measures, and necessitates highly skilled personnel. Furthermore, the raw materials are difficult to obtain and are rarely available commercially, making it unsuitable for industrial production. The synthetic route is as follows:

[0004]

[0005] The preparation method of 4-bromopyrazolo[3,4-D]pyrimidines reported in the literature (TS Leonova, VG Yashunskii. Some reactions of 4-aminopyrazolo[3,4-d]pyrimidines. 1983.) uses bromine, a highly corrosive material, which is not environmentally friendly; the diazotization and halogenation reactions themselves pose significant safety hazards, as diazonium salts are explosive and difficult to scale up; the reaction yield is low (40%), resulting in poor economic efficiency; the synthetic route is as follows:

[0006]

[0007] Based on the above, the synthetic route for preparing 4-bromopyrazole[3,4-D]-pyrimidine is not yet mature and its applicability is not very wide. Therefore, it is very necessary to find a method for preparing 4-bromopyrazole[3,4-D]-pyrimidine that is economical and environmentally friendly, has a high yield, and is simple to operate, for the research and mass production of pyrazolopyrimidine compounds. Summary of the Invention

[0008] To address the above problems, the present invention provides a method for preparing 4-bromopyrazole[3,4-D]-pyrimidine.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A method for preparing 4-bromopyrazole[3,4-D]-pyrimidine, the specific steps of which are as follows: under anhydrous and oxygen-free conditions, 4-chloro-1H-pyrazolo[3,4-d]pyrimidine is reacted with a brominating reagent in an aprotic solvent to obtain 4-bromopyrazole[3,4-D]-pyrimidine.

[0011] Preferably, the 4-chloro-1H-pyrazolo[3,4-d]pyrimidine: aprotic solvent = 1g: 15-30mL.

[0012] Preferably, the molar ratio of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine to brominated reagent is 1:2.5-5.

[0013] Preferably, the reaction temperature is 20–40°C; below 20°C the reaction is slow, and above 40°C the reaction solution is darker in color, produces more impurities, and the yield will decrease.

[0014] Preferably, the reaction is carried out under HPLC monitoring, with the 4-chloro-1H-pyrazolo[3,4-d]pyrimidine content ≤5% as the reaction endpoint, and the reaction time is 20-30 h.

[0015] Preferably, the aprotic solvent is selected from tetrahydrofuran, dimethyl sulfoxide, acetonitrile, or dichloromethane.

[0016] Preferably, the brominating agent is trimethylbromosilane.

[0017] Preferably, the preparation method further includes a post-processing step, the specific steps of which are as follows:

[0018] After the reaction was completed, the reaction solution containing 4-bromopyrazole[3,4-D]-pyrimidine was quenched in water, cooled, and the pH was adjusted to 7-8. Then, it was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered and washed, and dried under vacuum to obtain pure 4-bromopyrazole[3,4-D]-pyrimidine.

[0019] Preferably, the aprotic solvent to water ratio is 1:1 to 3 by volume.

[0020] Preferably, the post-treatment temperature is 10-20℃; the extraction efficiency is low below 10℃, and 4-bromopyrazole[3,4-D]-pyrimidine is prone to deterioration at temperatures above 20℃.

[0021] Compared with the prior art, the present invention has the following technical solution:

[0022] (1) The preparation method provided by the present invention has a simple process route, clear steps, and the target product can be obtained in one step. It is easy to operate and has a high yield of more than 75%.

[0023] (2) The preparation method provided by the present invention has low cost. The raw materials used, 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and trimethylbromosilane, are commercially available products in large quantities, which are inexpensive and readily available. They have good stability, can be produced continuously, and have considerable economic benefits.

[0024] (3) The preparation method provided by the present invention is green and environmentally friendly, produces less waste, causes less environmental pollution, and has controllable emissions;

[0025] (4) The preparation method provided by the present invention is safe and controllable, does not involve highly toxic substances, and does not pose any safety risks such as explosion; the reaction temperature is between 20 and 40°C, and the reaction conditions are mild. Attached Figure Description

[0026] Figure 1 is the NMR spectrum of the 4-bromopyrazole[3,4-D]-pyrimidine of the present invention;

[0027] Figure 2 is the HPLC chromatogram of 4-bromopyrazole[3,4-D]-pyrimidine of the present invention. Detailed Implementation

[0028] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more readily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention. The present invention can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the inventive concept to those skilled in the art.

[0029] Unless otherwise specified, the aprotic solvents used in the examples are all anhydrous aprotic solvents.

[0030] Example 1

[0031] Under anhydrous and oxygen-free conditions, 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 2318.4 mL of tetrahydrofuran were added to a three-necked flask and stirred until dissolved. At an internal temperature of 20 °C, 382.73 g (2.5 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 2350 mL of water. The internal temperature was controlled at 10 °C–15 °C. Sodium bicarbonate was added to adjust the pH to 7. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered, and washed to obtain a yellow product. After vacuum drying, 162.5 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 81.6% and an HPLC yield of 97.7%.

[0032] Example 2

[0033] Under anhydrous and oxygen-free conditions, 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 3400.32 mL of tetrahydrofuran were added to a three-necked flask and stirred until dissolved. At an internal temperature of 25 °C, 765.45 g (5 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 5440 mL of water. The internal temperature was controlled at 15 °C–20 °C, and sodium bicarbonate was added to adjust the pH to 8. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether under stirring, filtered, and washed to obtain a yellow product. After vacuum drying, 163.4 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 82.1% and an HPLC yield of 97.6%.

[0034] Example 3

[0035] Under anhydrous and oxygen-free conditions, 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 3091.2 mL of acetonitrile were added to a three-necked reaction flask and stirred until dissolved. At an internal temperature of 30 °C, 459.27 g (3 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 4637 mL of water. The internal temperature was controlled at 12 °C–17 °C, and sodium bicarbonate was added to adjust the pH to 7. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered, and washed to obtain a yellow product. After vacuum drying, 154.3 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 77.5% and an HPLC yield of 97.4%.

[0036] Example 4

[0037] Under anhydrous and oxygen-free conditions, 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 3864 mL of dimethyl sulfoxide were added to a three-necked reaction flask and stirred until dissolved. At an internal temperature of 35 °C, 796.04 g (4 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 7728 mL of water. The internal temperature was controlled at 14 °C–19 °C, and sodium bicarbonate was added to adjust the pH to 8. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered, and washed to obtain a yellow product. After vacuum drying, 160.8 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 80.8% and an HPLC yield of 97.6%.

[0038] Example 5

[0039] Under anhydrous and oxygen-free conditions, 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 4327.68 mL of dichloromethane were added to a three-necked flask and stirred until dissolved. The internal temperature was controlled at 40 °C. 796.04 g (4 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 10820 mL of water. The internal temperature was controlled at 15 °C to 20 °C. Sodium bicarbonate was added to adjust the pH to 7.5. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered and washed to obtain a yellow product. After vacuum drying, 149.8 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 75.3% and an HPLC yield of 97.1%.

[0040] Comparative Example 1

[0041] This comparative example does not strictly control the anhydrous and oxygen-free conditions; the rest of the experimental procedures and conditions are the same as in Example 1.

[0042] 154.56 g (1 mol) of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine and 2318.4 mL of tetrahydrofuran were added to a three-necked flask and stirred until dissolved. At an internal temperature of 20 °C, 382.73 g (2.5 mol) of trimethylbromosilane was added in three batches. The reaction was monitored by HPLC. When the remaining content of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine was less than 5%, the reaction solution was quenched in 2350 mL of water. The internal temperature was controlled at 10 °C–15 °C. Sodium bicarbonate was added to adjust the pH to 7. The mixture was extracted three times with ethyl acetate, and the ethyl acetate phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether, filtered, and washed to obtain a yellow product. After vacuum drying, 50.3 g of pure 4-bromopyrazolo[3,4-D]pyrimidine was obtained, with a yield of 25.3% and an HPLC yield of 37.1%.

[0043] Comparative Example 2

[0044] 4-bromopyrazole[3,4-D]-pyrimidine was prepared by changing the brominating reagent alone. The rest of the experimental procedures and conditions were the same as in Example 1. The results are shown in Table 1.

[0045] Table 1 Yield and Purity Table

[0046]

[0047] As can be seen from Table 1, none of these brominating reagents can yield high purity and high yield of 4-bromopyrazole[3,4-D]-pyrimidine.

[0048] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions conceived without inventive effort should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A method for preparing 4-bromopyrazole[3,4-D]-pyrimidine, characterized in that, The specific steps are as follows: Under anhydrous and oxygen-free conditions, 4-chloro-1H-pyrazolo[3,4-d]pyrimidine reacts with a brominating reagent in an aprotic solvent to obtain 4-bromopyrazol[3,4-D]pyrimidine; the aprotic solvent is selected from tetrahydrofuran; the brominating reagent is trimethylbromosilane; the preparation method further includes a post-treatment step, the specific steps of which are as follows: after the reaction is completed, the reaction solution containing 4-bromopyrazol[3,4-D]pyrimidine is poured into water for quenching, cooled, and the pH is adjusted to 7-8; then extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under negative pressure, dispersed with petroleum ether by stirring, filtered and washed, and dried under vacuum to obtain pure 4-bromopyrazol[3,4-D]pyrimidine; the post-treatment temperature is 10-20℃.

2. The method for preparing 4-bromopyrazole[3,4-D]-pyrimidine according to claim 1, characterized in that, The 4-chloro-1H-pyrazolo[3,4-d]pyrimidine: aprotic solvent = 1g: 15-30mL.

3. The method for preparing 4-bromopyrazole[3,4-D]-pyrimidine according to claim 1, characterized in that, The molar ratio of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine to brominated reagent is 1:2.5 to 5.

4. The method for preparing 4-bromopyrazole[3,4-D]-pyrimidine according to claim 1, characterized in that, The reaction temperature is 20–40℃.

5. The method for preparing 4-bromopyrazole[3,4-D]-pyrimidine according to claim 1, characterized in that, The reaction was carried out under HPLC monitoring. The reaction endpoint was defined as ≤5% 4-chloro-1H-pyrazolo[3,4-d]pyrimidine. The reaction time was 20-30 h.

6. The method for preparing 4-bromopyrazole[3,4-D]-pyrimidine according to claim 1, characterized in that, The aprotic solvent to water ratio is 1:1 to 3 by volume.

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