Synthesis method of pyrazine compound

Abstract

The invention provides a synthesis method of a pyrazine compound shown in the following formula (III). The method comprises steps as follows: a compound represented by the formula (I) shown in the specification and a compound represented by the formula (II) shown in the specification react in an organic solvent in the presence of a catalyst, an accelerant and an acid additive, so that the compound represented by the formula (III) shown in the specification is obtained, R1 is selected from C1-C6 alkyl groups or phenyl groups, and R2 and R3 are respectively and independently selected from H, the C1-C6 alkyl groups, halogens or the phenyl groups. According to the method, the catalyst, the accelerant, the acid additive and the organic solvent are properly selected and combined, so that target products can be obtained in a high yield manner, the reaction time is short, the reaction temperature is low, control is easy, the ideal reaction effect is realized, and the method has bright application prospect and industrial production potential in the field of organic synthesis, particularly medical intermediate synthesis.

Description

technical field

[0001] The invention relates to a synthesis method of nitrogen-containing heterocyclic compounds, more specifically to a synthesis method of pyrazine compounds, and belongs to the field of synthesis of pharmaceutical intermediates. Background technique

[0002] In the field of medicinal chemistry, pyrazine compounds are important N-heterocyclic structures in the field of chemistry, which widely exist in natural products and pharmaceutical preparations. For example, the following drugs containing pyrazine structures are widely used: potassium-sparing diuretics amiloride and triamterene can be used to treat hypertension and heart failure; pyrazinamide and molanamide can be used as antibacterial agents To treat tuberculosis etc.

[0003] It is precisely because of such an important role of pyrazine compounds that the development of new synthetic methods for pyrazine compounds will have a profound impact on the fields of chemical industry and medicine.

[0004] ...

Examples

Embodiment 1

[0035]

[0036] At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 150mmol of the above formula (II) compound, 4mmol of catalyst (for 2.7mmol [(CH 3 EN) 4 Cu]PF 6 with 1.3mmolNi(COD) 2 mixture), 10mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 10mmol acidic additive p-toluenesulfonic acid, then warming up to 70°C, and at this temperature The reaction was stirred well for 7 hours.

[0037] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out, and a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3 was used as the eluent to obtain the compound of the above ...

Embodiment 2

[0040]

[0041]At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 200mmol of the above formula (II) compound, 6mmol of catalyst (for 3mmol [(CH 3 EN) 4 Cu]PF 6 with 3mmolNi(COD) 2 mixture), 12mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 15mmol acidic additive p-toluenesulfonic acid, then warming up to 80°C, and at this temperature The reaction was stirred thoroughly for 5 hours.

[0042] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out using a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:3 as the eluent to obtain the compound of formula (III) with ...

Embodiment 3

[0045]

[0046] At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 250mmol of the above formula (II) compound, 8mmol of catalyst (5.2mmol [(CH 3 EN) 4 Cu]PF 6 with 2.8mmolNi(COD) 2 mixture), 15mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 20mmol acidic additive p-toluenesulfonic acid, then warming up to 90°C, and at this temperature The reaction was stirred well for 4 hours.

[0047] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out, and a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3 was used as the eluent to obtain the compound of the above form...

technical field

[0001] The invention relates to a synthesis method of nitrogen-containing heterocyclic compounds, more specifically to a synthesis method of pyrazine compounds, and belongs to the field of synthesis of pharmaceutical intermediates. Background technique

[0002] In the field of medicinal chemistry, pyrazine compounds are important N-heterocyclic structures in the field of chemistry, which widely exist in natural products and pharmaceutical preparations. For example, the following drugs containing pyrazine structures are widely used: potassium-sparing diuretics amiloride and triamterene can be used to treat hypertension and heart failure; pyrazinamide and molanamide can be used as antibacterial agents To treat tuberculosis etc.

[0003] It is precisely because of such an important role of pyrazine compounds that the development of new synthetic methods for pyrazine compounds will have a profound impact on the fields of chemical industry and medicine.

[0004] ...

Examples

Embodiment 1

[0035]

[0036] At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 150mmol of the above formula (II) compound, 4mmol of catalyst (for 2.7mmol [(CH 3 EN) 4 Cu]PF 6 with 1.3mmolNi(COD) 2 mixture), 10mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 10mmol acidic additive p-toluenesulfonic acid, then warming up to 70°C, and at this temperature The reaction was stirred well for 7 hours.

[0037] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out, and a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3 was used as the eluent to obtain the compound of the above ...

Embodiment 2

[0040]

[0041]At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 200mmol of the above formula (II) compound, 6mmol of catalyst (for 3mmol [(CH 3 EN) 4 Cu]PF 6 with 3mmolNi(COD) 2 mixture), 12mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 15mmol acidic additive p-toluenesulfonic acid, then warming up to 80°C, and at this temperature The reaction was stirred thoroughly for 5 hours.

[0042] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out using a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:3 as the eluent to obtain the compound of formula (III) with ...

Embodiment 3

[0045]

[0046] At room temperature, in an appropriate amount of organic solvent PEG-200, add 100mmol of the above formula (I) compound, 250mmol of the above formula (II) compound, 8mmol of catalyst (5.2mmol [(CH 3 EN) 4 Cu]PF 6 with 2.8mmolNi(COD) 2 mixture), 15mmol accelerator N-n-butyl-N-methylpyrrolidine bis(trifluoromethanesulfonyl)imide salt and 20mmol acidic additive p-toluenesulfonic acid, then warming up to 90°C, and at this temperature The reaction was stirred well for 4 hours.

[0047] After the reaction, filter, and cool the filtrate to room temperature naturally, then add saturated saline, shake and wash thoroughly, then extract with chloroform for 2-3 times, combine the organic phases, distill under reduced pressure, and pass the residue through 300-400 mesh silica gel column chromatography Separation was carried out, and a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:3 was used as the eluent to obtain the compound of the above form...

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