ChemicalBook CAS DataBase List 2-Amino-6-methylpyrazine

2-Amino-6-methylpyrazine synthesis

11synthesis methods

Product Name:2-Amino-6-methylpyrazine
CAS Number:5521-56-2
Molecular formula:C5H7N3
Molecular Weight:109.13

930798-25-7

5521-56-2

1. A solution of diethyl malonate (2.1 mmol) in THF (60 ml) was mixed with a solution of 2,6-dichloropyrazine (20 g) in THF (40 ml) at 60 °C. 2. The mixture was heated to reflux for 18 hrs and subsequently cooled to room temperature and 2M hydrochloric acid (100 ml) was added. 3. The two layers of the reaction solution were separated and the THF layer was partially concentrated under vacuum to give a solution containing diethyl 2-(6-chloropyrazin-2-yl)malonate. 4. The above solution was cooled to 10 °C, 2 M sodium hydroxide (328 ml) was added and stirred for 24 hours. 5. The mixture was washed with methyl isobutyl ketone (MIBK, 200 ml) and the organic layer was discarded. 6. The aqueous layer containing 2-(6-chloropyrazin-2-yl)malonic acid was added to 6M hydrochloric acid (135 ml) and the reaction temperature was controlled at 20-25°C to promote the decarboxylation reaction. 7. 6-Chloropyrazin-2-ylacetic acid was partially precipitated and extracted into MIBK (130 ml) for separation, dried with MgSO4, filtered and evaporated to give a yellow solid. 8. The crude product (22.4 g) was crystallized from methyl tert-butyl ether (MTBE) to give pure 6-chloropyrazin-2-ylacetic acid in 67% yield (15.4 g) based on 2,6-dichloropyrazine. 9. 6-Chloropyrazin-2-ylacetic acid (20.0 g) was reacted with ammonia (120 ml) in a sealed vessel at 180 °C (35 bar) for 8 hours. 10. The reaction mixture was cooled to 20 °C, water (40 ml) was added and the ammonia was removed by vacuum concentration. 11. The product was extracted into ethyl acetate, the solution was treated with charcoal and subsequently dried over MgSO4, filtered and evaporated to give 6-methyl-2-pyrazinamine as a light green solid (9.0 g, 71% yield based on 6-chloropyrazin-2-ylacetic acid). Analytical Data: - Diethyl 2-(6-chloropyrazin-2-yl)malonate: MS (EI+ve) 273/275 (M+H); 1H NMR (CDCl3): δ 8.7 (1H, s), 8.5 (1H, s), 4.9 (1H, s), 4.2 (4H, q), 1.2 (6H, t). - 6-Chloropyrazin-2-ylacetic acid: MS (EI+ve) 173/175 (M+H); 1H NMR (CDCl3): δ 8.55 (1H, s), 8.50 (1H, s); 3.9 (2H, s). - 6-Methyl-2-pyrazinamine: MS (GC/MS): 100% RT 2.0 min, M+H = 110; 1H NMR (CDCl3): δ 7.8 (1H, s), 7.8 (1H, s), 4.4 (2H, bs), 2.4 (3H, s). Mpt: 124-125°C.

930798-25-7
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5521-56-2
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Yield: 71%

Reaction Conditions:

with ammonia in water at 180; under 26252.6 Torr; for 8 h;sealed vessel;

Steps:

1.c
60ml) at O⁰C was added, diethylmalonate (2.1moleq) in THF (60ml) and 2,6- dichloropyrazine (2Og) in THF (40ml). The mixture was then heated to reflux for 18hrs before being allowed to cool and 2M Hydrochloric acid (100ml) added. The resulting two layers were separated and the THF layer partially concentrated under vacuum to give a solution containing 2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl ester. This solution was EPO then cooled to 10⁰C and 2M sodium hydroxide (328ml) added. After stirring for 24hrs the mixture was washed with methyl isobutyl ketone [MIBK] (200ml) and the organic layer discarded. The aqueous layer containing 2-(6-chloro-pyrazin-2-yl)-malonic acid was then added to 6M hydrochloric acid (135ml), maintaining a reaction temperature of 20-25°C to facilitate the decarboxylation.The resulting 6-chloro-pyrazin-2-yl-acetic acid partially precipitated from the mixture, but for ease of isolation was extracted into MIBK (130ml), dried using MgSO₄, filtered and evaporated to give a yellow solid. The resulting crude solid 22.4g was then crystallised from methyl-t-butyl ether (MTBE) to give pure 6-chloro-pyrazin-2-yl-acetic acid , 15.4g 67% yield based on 2,6-dichlorpyrazine.The 6-chloro-pyrazin-2-yl-acetic acid (20.Og) was then treated with aqueous ammonia (120ml) in a sealed vessel at 180°C (35 bar) for 8hrs. The mixture was then cooled to 20°C and water (40ml) added, before being concentrated under vacuum to remove the ammonia. The product was extracted into ethyl acetate and the solution treated with charcoal, before being dried using MgSO₄, filtered and evaporated to give 6-methyl-2-pyrazin-2-ylamine as a pale green solid 9.Og, 71% yield based on 6-chloro-pyrazin-2-yl-acetic acid. Analysis 2-(6-Chloro-pyrazin-2-yl)-malonic acid diethyl esterMS (EI +ve) 273/275 (M+H) IH NMR (CDCl₃) :δ 8.7 (IHs), 8.5 (IHs), 4.9 (IHs), 4.2(2x2Hq), 1.2 (2x3Ht).6- Chloro-pyrazin-l-yl-acetic acidMS (EI +ve) 173/175 (M+H)IHNMR (CDCl₃) :δ 8.55 (IH s), 8.50 (IH s); 3.9 (2Hs).6-Methyl-2-pyrazin-2-ylamine MS (GC/MS) : 100% RT 2.0mins, M+H = 110IHNMR (CDC13) : δ 7.8 (IHs), 7.8 (IHs), 4.4 (2H bs), 2.4 (3Hs). Mpt : 124-125⁰C

References:

ASTRAZENECA AB WO2007/35153, 2007, A1 Location in patent:Page/Page column 2; 4-5

544-97-8 Synthesis