A method for synthesizing 5-bromo-1h-pyrazolo[3,4-b]pyrazine

Abstract

This invention relates to a method for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine, comprising the following steps: (S1) 2-aminopyrazine reacts with a bromine source to obtain 3,5-dibromo-2-aminopyrazine; (S2) 3,5-dibromo-2-aminopyrazine reacts with an iodine source and a diazotizing reagent to obtain 3,5-dibromo-2-iodopyrazine; (S3) 3,5-dibromo-2-iodopyrazine reacts with trimethylsilyldiazomethane under alkaline conditions and in the presence of a catalyst to obtain the product 5-bromo-1H-pyrazolo[3,4-b]pyrazine. This invention utilizes readily available and inexpensive 2-aminopyrazine as a starting material, and the synthetic route is completed in three steps. No hazardous or toxic controlled reagents are used in the synthesis, making it a highly industrially viable production method. The synthetic method of this invention achieves satisfactory yields and purity, and the entire synthesis process does not require column chromatography, saving solvents and being economical and environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine. Background Technology

[0002] Pyrazolo[3,4-b]pyrazine, as an important class of pyrazine compounds, has wide applications in pyrazine chemistry, especially in the field of pharmaceutical intermediates, where it is an important intermediate for many chemical drugs. In recent years, the exploration of SHP2 inhibitors has facilitated the discovery of a series of promising pyrazolopyrimidine drugs. These drugs possess excellent efficacy, but their in vivo pharmacokinetic (PK) properties are not ideal. Medicinal chemists have discovered that pyrazolo[3,4-b]pyrazine tricyclic derivatives, as SHP2 inhibitors, exhibit excellent activity and pharmacokinetic (PK) properties in the treatment of various cancers; 5-bromo-1H-pyrazolo[3,4-b]pyrazine is one of the important intermediates in this study.

[0003] CN109535164A reports a method for preparing 5-bromo-1H-pyrazolo[3,4-b]pyrazine. The method involves diazotization and bromination of methyl 3-amino-6-bromo-2-carboxylate to synthesize 3,6-dibromo-2-carboxylate pyrazine, followed by low-temperature reduction with DIBAl-H to obtain 3,6-dibromo-2-aldehyde pyrazine. Finally, the reaction with hydrazine yields 5-bromo-1H-pyrazolo[3,4-b]pyrazine, a total of three steps with an overall yield of 17.6%. The key to this type of reaction is the formation of the pyrazolium ring. Generally, a hydrazolysis reaction with an aldehyde group is used, but the aldehyde group is unstable on the pyrazine ring, leading to numerous side reactions and a low yield. Furthermore, the method requires hydrazine as a raw material, which is hazardous and a controlled chemical, making the use of hydrazine inconvenient for this patented synthesis method.

[0004]

[0005] The synthesis of the raw material methyl 3-amino-6-bromo-2-carboxylic acid, as described in 106866553A, involves the synthesis of methyl 3-amino-2-carboxylic acid pyrazine in methanol via sulfuric acid-catalyzed esterification, followed by bromination with NBS to synthesize methyl 3-amino-6-bromo-2-carboxylic acid, a total of 3 steps with an overall yield of 60%.

[0006]

[0007] It is evident that existing techniques for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine suffer from cumbersome synthetic routes and low yields. Therefore, there is a need to develop a method for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine that uses inexpensive and readily available raw materials, employs a simple synthetic route, and requires minimal operational and equipment requirements. Summary of the Invention

[0008] Existing techniques for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine lack a low-cost, simple, and industrially suitable preparation method. To address this issue, this invention proposes a method for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine, using inexpensive and readily available 2-aminopyrazine as a starting material. The product can be obtained through a three-step reaction. This invention achieves the above objectives through the following technical solution:

[0009] A synthetic method for 5-bromo-1H-pyrazolo[3,4-b]pyrazine, the synthetic route of which is as follows:

[0010]

[0011] Furthermore, the method for synthesizing the 5-bromo-1H-pyrazolo[3,4-b]pyrazine includes the following steps:

[0012] (S1)2-aminopyrazine reacts with a bromine source to give 3,5-dibromo-2-aminopyrazine;

[0013] (S2)3,5-Dibromo-2-aminopyrazine reacts with an iodine source and a diazotizing agent to give 3,5-dibromo-2-iodopyrazine;

[0014] (S3)3,5-dibromo-2-iodopyrazine and trimethylsilyl diazomethane react under alkaline conditions and in the presence of a catalyst to give the product 5-bromo-1H-pyrazolo[3,4-b]pyrazine.

[0015] Further, in step (S1), the bromine source is selected from at least one of bromine, N-bromosuccinimide (NBS), perbromopyridine hydrobromide (PHP), dibromohydantoin (DBH), tetrabromocyclohexanone (TBCO), and dibromoisocyanuric acid, preferably DBH, because its bromination product yield and purity are satisfactory.

[0016] Further, in step (S1), the molar ratio of 2-aminopyrazine to bromine source is 1:1-2.5, and when the bromine source is DBH, the molar ratio of 2-aminopyrazine to DBH is 1:1-1.1.

[0017] Further, in step (S1), the solvent for the reaction is not particularly limited, such as one or more of chloroform, dichloromethane, acetonitrile, DMF (N,N-dimethylformamide), NMP (N-methylpyrrolidone), and DMSO (dimethyl sulfoxide), with a solvent volume to 2-aminopyrazine mass ratio of 5-10 mL: 1 g. The bromination reaction is carried out at 0-10 °C. After HPLC detection shows complete consumption of the starting material and that the monobromine product is <1%, the reaction is quenched, extracted, washed with the organic phase, dried, and evaporated to dryness to obtain the intermediate product 3,5-dibromo-2-aminopyrazine. Preferably, the bromine source is added in 2-5 batches, with an interval of 10-20 min between each batch; the quenching reaction is carried out with sodium bisulfite, and the extractant is selected from at least one of methyl tert-butyl ether (MTBE), isopropyl acetate, and ethyl acetate; the washing is done with saturated brine, and the drying is done with the addition of a desiccant, such as anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0018] Further, in step (S2), the iodine source is selected from at least one of hydroiodic acid (40-50 wt% aqueous solution of hydroiodic acid), cuprous iodide, sodium iodide, potassium iodide, and trimethyliodosilane; the diazotizing agent is selected from at least one of sodium nitrite, potassium nitrite, isoamyl nitrite, and tert-butyl nitrite. Preferably, the iodine source is hydroiodic acid, and the diazotizing agent is sodium nitrite and / or potassium nitrite. More specifically, the molar ratio of 3,5-dibromo-2-aminopyrazine, the iodine source, and the diazotizing agent is 1:6.5-7.5:2.5-4, for example, 1:6.5:3.

[0019] Further, the solvent in step (S2) is selected from at least one of water, acetic acid, tetrahydrofuran, ethanol, and isopropanol. The reaction conditions are -5°C to 0°C, with the diazotizing reagent added dropwise over 2-4 hours. After the addition is complete, the reaction continues for 1-5 hours. After the reaction is complete, the product is extracted, the organic phase is washed, dried, and evaporated to dryness to obtain the intermediate product 3,5-dibromo-2-iodopyrazine.

[0020] Further, in step (S3), the molar ratio of 3,5-dibromo-2-iodopyrazine and trimethylsilyldiazomethane is 1:1-1.2, preferably 1:1.05-1.1.

[0021] Further, in step (S3), the alkaline condition involves adding an alkali selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, and cesium carbonate, preferably potassium tert-butoxide. The amount of alkali used is 2-4 times the molar amount of 3,5-dibromo-2-iodopyrazine. The catalyst is selected from at least one of di-tert-butylmethylphosphine ontium tetrafluoroborate, tri-tert-butylphosphine ontium tetrafluoroborate, and tri-tert-butylphosphine, preferably di-tert-butylmethylphosphine ontium tetrafluoroborate. The amount of catalyst used is 0.5-5% of the molar amount of 3,5-dibromo-2-iodopyrazine, preferably 1-2%.

[0022] Further, in step (S3), the solvent is selected from at least one of NMP, DMF, DMSO, 1,4-dioxane, tert-butanol, isopropanol, acetonitrile, and tetrahydrofuran. The reaction conditions are: under an inert atmosphere, in an ice-salt bath (-10 to -5°C), a hexane solution of trimethylsilyl diazomethane (concentration 1-2M) is added dropwise, the reaction is maintained at this temperature for 8-10 h, then an alkali is added, the temperature is raised to 70-90°C, the reaction is carried out for 10-15 h, the mixture is cooled, neutralized, distilled under reduced pressure, water is added, the mixture is filtered, the filter cake is washed, and dried to obtain the final product 5-bromo-1H-pyrazolo[3,4-b]pyrazine.

[0023] Compared with the prior art, the present invention achieves the following beneficial effects:

[0024] I. This invention uses 2-aminopyrazine as a raw material, which is inexpensive and readily available. The synthetic route is completed in three steps, and no dangerous or toxic controlled reagents are used during the process. It is a highly promising industrial production method.

[0025] Second, the three-step reaction of this invention yields satisfactory results and purity. Moreover, the entire synthesis process does not require column chromatography separation, saving solvents and making it economical and environmentally friendly. Attached Figure Description

[0026] Figure 1 This is the mass spectrum of the product from Example 1.

[0027] Figure 2 The image shows the hydrogen spectrum of the product from Example 1.

[0028] Figure 3 This is the mass spectrum of the product from Example 2.

[0029] Figure 4 The image shows the hydrogen spectrum of the product from Example 2.

[0030] Figure 5 This is the mass spectrum of the product from Example 3.

[0031] Figure 6 The image shows the hydrogen spectrum of the product from Example 3. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be described in detail below. The following embodiments are provided to better understand this invention, but do not limit the invention. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods.

[0033] Example 1

[0034] Add 1200 ml of DMSO to a 3000 ml reaction flask, add 2-aminopyrazine (200 g, 2.103 mol), and cool in an ice-water bath to a temperature T ≤ 10 °C. DBH (601.2 g, 2.103 mol) was added in five portions, 10 min apart. The system temperature rose significantly, and the temperature was controlled at 0-10 °C. After the DBH was added, the reaction was maintained at this temperature, and the reaction of the reactants was monitored by HPLC to ensure complete reaction. The monobrominated product was less than 1%. The reaction was stopped, and 3000 mL of 15 wt% sodium bisulfite was added dropwise to quench the reaction. The system temperature rose again, and the temperature was controlled at 0-10 °C using an ice-water bath. After the addition was complete, the mixture was extracted twice with 2000 mL of MTBE. The organic phases were combined and washed with 1000 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 483.9 g of light yellow flaky solid, which was the product 3,5-dibromo-2-aminopyrazine, with a purity of 98.2% and a yield of 90.9%. For LC-MS details, please refer to the appendix. Figure 1 For HNMR (solvent: CDCl3), please refer to the appendix. Figure 2 .

[0035] Example 2

[0036] A 47% aqueous solution of hydroiodic acid (700 g, 2.567 mol) was added to a 2000 ml reaction flask. The temperature was maintained at -5°C to 0°C using an ice-salt bath. Three batches of 3,5-dibromo-2-aminopyrazine (100 g, 0.395 mol) were added. No significant temperature rise was observed, and the system appeared as a brownish-yellow turbid liquid. The reaction was stirred for 30 minutes. Then, a 30% aqueous solution of sodium nitrite (81.76 g, 1.185 mol) was added dropwise. The system temperature rose significantly, and a reddish-brown gas was generated. The reaction was controlled at T ≤ 0°C, and the addition was completed in 4 hours. The reaction was maintained at this temperature for 2 hours. HPLC analysis confirmed complete reaction of the starting material. The system was extracted twice with 450 ml of methyl tert-butyl ether. The combined organic phases were washed twice with 200 ml of saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 110.75 g of a white granular solid, which was the product 3,5-dibromo-2-iodopyrazine, with a purity of 96.5% and a yield of 76.9%. GC-MS details are shown in the appendix. Figure 3 For HNMR details, please see the appendix. Figure 4 .

[0037] Example 3

[0038] 3,5-Dibromo-2-iodopyrazine (50 g, 0.137 mol) was added to a 1000 mL reaction flask, followed by 500 mL of 1,4-dioxane solvent. Nitrogen gas was then added under nitrogen purging. Tri-tert-butylphosphine tetrafluoroborate (0.80 g, 2.75 mmol) was added, and the mixture was cooled in an ice-salt bath at T ≤ -5 °C. 72 mL of trimethylsilyl diazomethane (0.144 mol, 2 M n-hexane solution) was added dropwise over 40 minutes. The reaction was maintained at this temperature for 8 h. Then, potassium tert-butoxide (46.18 g, 0.412 mol) was added under nitrogen purging. The system changed from a colorless clear liquid to a white turbid liquid. The mixture was then heated to reflux and reacted for 12 h. The reaction was monitored by HPLC until complete. The system was cooled to room temperature, and 45 ml of concentrated hydrochloric acid was added dropwise to adjust the pH to 6.7. 1,4-dioxane was removed by vacuum distillation. 300 mL of water was added, and the mixture was stirred for 30 minutes before filtration. The filter cake was washed with 100 ml of water twice, and then dried. 20.4 g of the light brown powdery solid obtained from the dried filter cake was the final product, 5-bromo-1H-pyrazolo[3,4-b]pyrazine, with a purity of 98.3% and a yield of 74.5%. LC-MS details are shown in the appendix. Figure 5 For HNMR details, please see the appendix. Figure 6 .

[0039] Comparative Example 1

[0040] All other conditions were the same as in Example 3, except that trimethylsilyldiazomethane was replaced with an equimolar amount of diazomethane. The final product had a purity of 96.5% and a yield of 34.2%.

Claims

1. A method for synthesizing 5-bromo-1H-pyrazolo[3,4-b]pyrazine, characterized in that, Includes the following steps: (S1)2-aminopyrazine reacts with a bromine source to give 3,5-dibromo-2-aminopyrazine; (S2)3,5-Dibromo-2-aminopyrazine reacts with an iodine source and a diazotizing agent to give 3,5-dibromo-2-iodopyrazine; (S3)3,5-Dibromo-2-iodopyrazine and trimethylsilyldiazomethane react under alkaline conditions and in the presence of a catalyst to give the product 5-bromo-1H-pyrazolo[3,4-b]pyrazine; the alkaline conditions are the addition of a base, which is selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, and cesium carbonate; the catalyst is selected from at least one of di-tert-butylmethylphosphonium tetrafluoroborate, tri-tert-butylphosphonium tetrafluoroborate, and tri-tert-butylphosphonium tetrafluoroborate.

2. The synthesis method according to claim 1, characterized in that, In step (S1), the bromine source is selected from at least one of bromine, N-bromosuccinimide (NBS), perbromopyridine hydrobromide (PHP), dibromohydantoin (DBH), tetrabromocyclohexanone (TBCO), and dibromoisocyanuric acid.

3. The synthesis method according to claim 1, characterized in that, In step (S1), the molar ratio of 2-aminopyrazine to bromine source is 1:1-2.

5.

4. The synthesis method according to claim 3, characterized in that, When the bromine source is DBH, the molar ratio of 2-aminopyrazine to DBH is 1:1-1.

1.

5. The synthesis method according to claim 1, characterized in that, In step (S1), the solvent for the reaction is selected from one or more of chloroform, dichloromethane, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, and the volume ratio of the solvent to the mass of 2-aminopyrazine is 5-10 mL: 1 g. The bromination reaction is carried out at 0-10 °C. After HPLC detection shows that the raw material is completely consumed and the monobromine product is <1%, the reaction is quenched, extracted, washed with the organic phase, dried, and evaporated to dryness to obtain the intermediate product 3,5-dibromo-2-aminopyrazine. The quenching reaction is quenched with sodium bisulfite, and the extractant is selected from at least one of methyl tert-butyl ether, isopropyl acetate, and ethyl acetate. The washing is done with saturated brine, and the drying is done with the addition of a desiccant.

6. The synthesis method according to claim 5, characterized in that, The bromine source is added in 2-5 batches, with an interval of 10-20 minutes between each batch.

7. The synthesis method according to claim 5, characterized in that, The desiccant is selected from anhydrous sodium sulfate or anhydrous magnesium sulfate.

8. The synthesis method according to claim 1, characterized in that, In step (S2), the iodine source is selected from at least one of hydroiodic acid, cuprous iodide, sodium iodide, potassium iodide, and trimethyliodosilane; the diazotizing agent is selected from at least one of sodium nitrite, potassium nitrite, isoamyl nitrite, and tert-butyl nitrite.

9. The synthesis method according to claim 8, characterized in that, The iodine source is hydroiodic acid, and the diazotizing reagent is sodium nitrite and / or potassium nitrite.

10. The synthesis method according to claim 8, characterized in that, The molar ratio of 3,5-dibromo-2-aminopyrazine, iodine source, and diazotizing reagent is 1:6.5-7.5:2.5-4.

11. The synthesis method according to claim 1, characterized in that, The solvent in step (S2) is selected from at least one of water, tetrahydrofuran, ethanol, and isopropanol; the reaction conditions are -5℃ to 0℃, the diazotizing reagent is added dropwise over 2-4 hours, and the reaction continues for 1-5 hours after the addition is complete. After the reaction is complete, the product is extracted, the organic phase is washed, dried, and evaporated to dryness to obtain the intermediate product 3,5-dibromo-2-iodopyrazine.

12. The synthesis method according to claim 1, characterized in that, In step (S3), the molar ratio of 3,5-dibromo-2-iodopyrazine and trimethylsilyldiazomethane is 1:1-1.

2.

13. The synthesis method according to claim 12, characterized in that, The molar ratio of 3,5-dibromo-2-iodopyrazine to trimethylsilyldiazomethane is 1:1.05-1.

1.

14. The synthesis method according to claim 1, characterized in that, In step (S3), the amount of base used is 2-4 times the amount of 3,5-dibromo-2-iodopyrazine; the amount of catalyst used is 0.5-5% of the amount of 3,5-dibromo-2-iodopyrazine.

15. The synthesis method according to claim 14, characterized in that, The amount of catalyst used is 1-2% of the molar amount of 3,5-dibromo-2-iodopyrazine.

16. The synthesis method according to claim 1, characterized in that, In step (S3), the solvent is selected from at least one of NMP, DMF, DMSO, 1,4-dioxane, tert-butanol, isopropanol, acetonitrile, and tetrahydrofuran. The reaction conditions are: under an inert atmosphere, in an ice-salt bath at -10 to -5°C, a hexane solution of trimethylsilyl diazomethane is added dropwise, and the reaction is maintained at this temperature for 8-10 h. Then, an alkali is added, the temperature is raised to 70-90°C, and the reaction is carried out for 10-15 h. After cooling, neutralization, vacuum distillation, addition of water, filtration, washing of the filter cake, and drying are performed to obtain the final product 5-bromo-1H-pyrazolo[3,4-b]pyrazine.

17. The synthesis method according to claim 16, characterized in that, The concentration of the hexane solution of trimethylsilyl diazomethane is 1-2 M.

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