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Diethylaminomalonate Aminomalondiamide 2-Carbamido-3-hydroxypynazine To an aqueous solution of diethylaminomalonate (hydrochloride form) was added sodium hydrogenocarbonate (pH> 7). After extraction, the organic phase was evaporated under reduced pressure and treated with an ammoniacal solution of methanol at 80C overnight to give aminomalondiamide quantitatively. This compound was used for next step without purification and dissolved in water. To that solution was added glyoxal sodium bisulfite hemihydrate, this reaction mixture was stirred at 90C for 3h, and then made basic with 58% NH4OH. Then, 30% H2O2 was added dropwise with rapid stirring to the cold solution (0C) [J. Med. Chem. 1983, 26, 283-86, J. Heterocyclic Chem. 1979, 16, 193]. The reaction mixture was <n="131"/>allowed to warm at room temperature and the desired 2-hydroxy-3- carboxamidopyrazine precipitated. The solid was collected (63% yield) and part of it recrystallized.
118 g
With phosphoric acid; sodium hydroxide; In water; at 20 - 30℃; for 1.5h;
13.7 g of sodium hydroxide, 19.7 g of 85% phosphoric acid and 600 mL of water were mixed to obtain a phosphate buffer solution. 100 g of aminomalonamide was added to this phosphate buffer solution and a solution of 34.2 g of sodium hydroxide in 105 mL of water and 130 g of 40% glyoxal aqueous solution were simultaneously added dropwise at 20 to 30 C. over 1 hour and stirred at the same temperature for 30 minutes . Concentrated hydrochloric acid (25 mL) was added to the reaction mixture, heated to 85 C., concentrated hydrochloric acid (60 mL) was added, and the mixture was cooled to 15 C. The solid was collected by filtration to obtain 118 g of 3-hydroxy-2-pyrazinecarboxamide as a brown solid.
118 mg
With phosphoric acid; sodium hydroxide; In aq. phosphate buffer; water; at 20 - 30℃; for 1.5h;
The Example was performed according to the method in Example 1 of JP 2010-24 1806 A. To obtain a phosphate buffer, 13.7 g of sodium hydroxide, 19.7 g of 85% phosphoric acid and 600 mL of water were mixed. To the phosphate buffer was added 100 g of aminomalonamide, and a solution of 34.2 g of sodium hydroxide in 105 mL of water and 130 g of a 40% aqueous glyoxal solution were simultaneously added at 20 to 30 C. over 1 hour, and the reaction mixture was stirred at that temperature for 30 minutes. To the reaction mixture was added 25 mL of concentrated hydrochloric acid, and the reaction mixture was heated to 85 C., and then 60 mL of concentrated hydrochloric acid was added, and the reaction mixture was cooled to 15 C. A solid was collected by filtration to obtain 118 g of 3-hydroxy-2-pyrazinecarboxam- ide (compound C) as a brown solid. The resulting compound C was a hydrate. Water content: 8.5% ?H-NMR (DMSO-d5) oe: 7.88-8.10 (3H, m), 8.69 (1H, s). The infrared absorption spectrum is illustrated inFIG. 9. The powder X-ray diffraction pattern is illustrated in FIG. 10 and the results are shown in Table 4.
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