METHOD FOR PREPARING 3,6-DICHLOROPYRAZINE-2-CARBONITRILE

Abstract

The present disclosure provides a method for preparing a pyrazine compound of formula (I). In the present disclosure, 3-hydroxyl-6-bromopyrazine-2-amide is subjected to a reaction in the presence of phosphorus oxychloride and DIEA, during which adding an organic inorganic chloride makes the content of impurities greatly decreased, thereby obtaining 3,6-dichloropyrazine-2-carbonitrile with high-purity. 3,6-dichloropyrazine-2-carbonitrile prepared in the present disclosure is high in purity, low in production cost and suitable for industrial scale-up production and is very helpful for follow-on production of favipiravir API.

##STR00001##

Claims

1. A method for preparing a pyrazine compound of formula (I), comprising, reacting 3-hydroxyl-6-bromopyrazine-2-amide with a chloride agent and an inorganic chloride at a temperature of 30 to 110° C. in the presence of a base with or without a solvent, ##STR00011##

2. The method according to claim 1, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, N,N-dimethylaniline and N,N-diethylaniline.

3. The method according to claim 2, wherein the base is selected from the group consisting of triethylamine and diisopropylethylamine.

4. The method according to claim 3, wherein the base is diisopropylethylamine.

5. The method according to claim 1, wherein the base is used in an amount of 1.0-5.0 equivalent.

6. The method according to claim 1, wherein the chloride agent is selected from the group consisting of phosphorus oxychloride, thionyl chloride and phosphorus pentachloride.

7. The method according to claim 6, wherein the chloride agent is phosphorus oxychloride.

8. The method according to claim 1, wherein the chloride agent is used in an amount of 3.0-6.0 equivalent.

9. The method according to claim 1, wherein the inorganic chloride is selected from the group consisting of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and calcium chloride.

10. The method according to claim 9, wherein the inorganic chloride is selected from the group consisting of lithium chloride and potassium chloride.

11. The method according to claim 10, wherein the inorganic chloride is lithium chloride.

12. The method according to claim 1, wherein the inorganic chloride is used in an amount of 1.0-3.0 equivalent.

13. The method according to claim 1, wherein the solvent is toluene or acetonitrile.

14. The method according to claim 13, wherein the solvent is toluene.

15. The method according to claim 1, wherein the reacting is performed at a temperature of 30 to 110° C.

16. The method according to claim 15, wherein the reacting is performed at a temperature of 50 to 90° C.

Description

DETAILED DESCRIPTION

[0024] The above contents of the present disclosure will be further described in detail below by specific embodiments in the form of examples. However, it should be understood that, the scope of the present disclosure is not only limited to examples below. All technologies achieved based on the above contents of the present disclosure should fall within the scope of the present disclosure.

[0025] Raw materials and equipment used in specific examples of the present disclosure are all known products that are commercially available.

EXAMPLE 1: SYNTHESIS OF 3,6-DICHLOROPYRAZINE-2-CARBONITRILE

[0026] ##STR00007##

[0027] 3-hydroxyl-6-bromopyrazine-2-amide (10 g) was mixed with lithium chloride (1.94 g) and phosphorus oxychloride (28 g), and then stirred and raised to a temperature of 50° C. After that, diisopropylethylamine (17.78 g) was added thereto, and the resulting mixture was raised to a temperature of 80° C. and then stirred for 1 hour. Later, the mixture was cooled to a temperature of about 30° C. and was slowly added into ice water for quenching, and then filtered to obtain a filter cake. The filter cake was pulped with isopropanol (15 mL), obtaining 3,6-dichloropyrazine-2-carbonitrile (6.6 g, light yellow solid).

EXAMPLE 2: SYNTHESIS OF 3,6-DIFLUOROPYRAZINE-2-CARBONITRILE

[0028] ##STR00008##

[0029] 3,6-dichloropyrazine-2-carbonitrile (10 g) was added into DMF (60 mL), and TBAF (in an amount of catalytic amount) and potassium fluoride (20 g) were added thereto. The resulting mixture was raised to a temperature of 60° C. and reacted for 12 hours. After the reaction was ended, the mixture was cooled to ambient temperature, and added into water for quenching, to obtain an aqueous phase and an organic phase. The aqueous phase was extracted with methyl tert-butyl ether (50 mL) for three times, and the organic phase was combined. The combined organic phase was washed with water (50 mL), dried and concentrated, obtaining 3,6-difluoropyrazine-2-carbonitrile (crude, which was directly used for the subsequence reaction without further purifying).

EXAMPLE 3: SYNTHESIS OF 3-HYDROXYL-6-FLUOROPYRAZINE-2-CYANO

[0030] ##STR00009##

[0031] 3,6-difluoropyrazine-2-carbonitrile (crude, 7 g) obtained in example 2 was added into DMF (30 mL), then the mixture was cooled with an ice water bath. Then acetic acid (6 g) and triethylamine (10 g) was added thereto in sequence. After the completion of adding, the mixture was heated and stirred overnight. After the reaction was ended, the resulting mixture was added into ice water, and pH value thereof was adjusted to 3-4. Then the mixture was extracted with methyl tert-butyl ether (100 mL) to obtain an aqueous phase and an organic phase. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Then the crude product was pulped with n-heptane obtaining 3-hydroxyl-6-fluoropyrazine-2-cyano (6 g, pale brown solid).

EXAMPLE 4: SYNTHESIS OF 3-HYDROXYL-6-FLUOROPYRAZINE-2-AMIDO

[0032] ##STR00010##

[0033] 3-hydroxyl-6-fluoropyrazine-2-cyano (6 g) obtained in example 3 was added into an aqueous NaOH solution, then the mixture was cooled to a temperature of 1 to 10° C. hydrogen peroxide was added dropwise thereto. After completion of adding hydrogen peroxide, the mixture was slowly returned to ambient temperature and continuously stirred for 6 hours. After the reaction was ended, the mixture was adjusted to have a pH value of 3 to 4 with hydrochloric acid, and then filtered to obtain a filter cake. The filter cake was leached with purified water, and the leached filter cake was collected and dried in vacuum, obtaining 3-hydroxyl-6-fluoropyrazine-2-amido (5.5 g, white solid).

[0034] The above descriptions are merely preferred embodiments of the present disclosure. Equivalent changes and modifications made in accordance with the scope of the present disclosure should fall within the scope of the present disclosure.