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[ CAS No. 5049-61-6 ]

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Chemical Structure| 5049-61-6
Chemical Structure| 5049-61-6
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CAS No. :5049-61-6MDL No. :MFCD00006137
Formula : C4H5N3 Boiling Point : 250.905°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :95.10Pubchem ID :78747
Synonyms :

Computed Properties of [ 5049-61-6 ]

TPSA : 51.8 H-Bond Acceptor Count : 3
XLogP3 : - H-Bond Donor Count : 1
SP3 : 0.00 Rotatable Bond Count : 0

Safety of [ 5049-61-6 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5049-61-6 ]

  • Upstream synthesis route of [ 5049-61-6 ]
  • Downstream synthetic route of [ 5049-61-6 ]

[ 5049-61-6 ] Synthesis Path-Upstream   1~17

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  • [ 532-55-8 ]
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Reference: [1] Patent: WO2004/96797, 2004, A1, . Location in patent: Page 33-34
[2] Patent: US2004/53982, 2004, A1,
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  • [ 1310-73-2 ]
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  • [ 31437-05-5 ]
Reference: [1] Patent: WO2004/78754, 2004, A1, . Location in patent: Page 24
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Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 3617,3618,3620
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  • [ 600-22-6 ]
  • [ 16298-03-6 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1989, vol. 54, # 5, p. 1306 - 1310
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  • [ 32111-21-0 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
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  • [ 107-20-0 ]
  • [ 274-79-3 ]
YieldReaction ConditionsOperation in experiment
50% at 100℃; for 48 h; Inert atmosphere Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40percent 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol).
After stirring for 48 hours at 100 °C, the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL*3).
The organic phase was combined, dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0percent) as a brown solid.
MS m/z (ESI): 120.1 [M+1]
50% at 100℃; for 48 h; Step 1
imidazo[1,2-c]pyrazine
Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40percent 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol).
After stirring for 48 hours at 100° C., the reaction mixture was cooled to room temperature, added with 100 mL of a saturated potassium carbonate solution, and extracted with dichloromethane (100 mL*3).
The organic phase was combined, dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain imidazo[1,2-a]pyrazine 4b (3 g, yield 50.0percent) as a brown solid.
MS m/z (ESI): 120.1 [M+1]
35% With sodium hydrogencarbonate In water at 100℃; for 48 h; A mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCO3 (33.1 g, 394 mmole) was heated for 2 days at 100° C. The reaction mixture was then cooled to RT, satd. K2CO3 solution (100 ml) was added, and the mixture was washed with DCM. The organic phase was dried over Na2SO4 and then concentrated by evaporation to dryness. Purification was carried out by column chromatography on silica gel (DCM/methanol, 95:5+5percent NH4OH [35percent].
35% With sodium hydrogencarbonate In water at 100℃; for 48 h; 5, 6 , 7 , 8-tetrahydroimidazo [1, 2-a] pyrazine A29Stage 1. was added to a mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCO3 (33.1 g, 394 mmole) and heated for 2 days at 1000C. The reaction mixture was then cooled to RT, saturated K2CO3 solution (100 ml) was added, and the mixture was washed with DCM. The organic phase was dried over sodium sulfate and then concentrated by evaporation to dryness . Purification was carried out by column <n="108"/>chromatography on silica gel (DCM / methanol, 95:5 + 5percent NH4OH [35percent] .
24% With sodium hydrogencarbonate In water at 100℃; for 48 h; A mixture of 2-aminopyrazine (25 g, 262.9 mmol) and chloroacetaldehyde (50percent solution in water, 50 ml, 394 mmol) was heated for 2 d at 100° C. in the presence of sodium hydrogen carbonate (33.1 g, 394 mmol). The reaction mixture was cooled to room temperature, and saturated potassium carbonate solution (100 ml) was added thereto. Extraction with dichloromethane was then carried out, and the organic phase was dried (Na2SO4) and concentrated. Purification was carried out by column chromatography (dichloromethane/methanol 95:5+5percent NH4OH [35percent]). Yield: 7.6 g (24percent)
0.8 g at 90℃; for 5 h; Sealed tube Imidazo[1,2-aJpyrazine: A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50percent wt in H,O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90°C5 in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichlorornethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purifiedsilica gel flash chromatography (eluted with 10percent MeOH/DCM) to provide 0.8 g of product.

Reference: [1] Patent: EP2604610, 2013, A1, . Location in patent: Paragraph 0089; 0090
[2] Patent: US2013/131068, 2013, A1, . Location in patent: Paragraph 0115; 0116
[3] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 106; 107
[5] Patent: US2008/153843, 2008, A1, . Location in patent: Page/Page column 67
[6] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
[7] Patent: WO2007/75869, 2007, A2, . Location in patent: Page/Page column 50
[8] Patent: WO2013/162727, 2013, A1, . Location in patent: Page/Page column 53
[9] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0532
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YieldReaction ConditionsOperation in experiment
94% With hydrogen bromide In ethanol; water at 70 - 80℃; for 17 h; To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48percent, 26.5 ml).
The mixture was heated at 70-80° C. for 17 hours.
The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20percent IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture.
The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of imidazo[1,2-a]pyrazine (yield 94percent).
1H-NMR (400 MHz, DMSO-d6) δ 9.05 (m, 1H), 8.60 (dd, 1H), 8.13 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H).
MS m/z 120 [M++1].
24.01% With hydrogen bromide In ethanol for 24 h; Reflux 2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo- 1 ,1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48percent hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10percent ammonia-ice (300ml). The solution was extracted in to ethyl acetate (3 x 300ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100percent [25percent 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1 ,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01 percent yield).).1H NMR (CDCI3, 400 MHZ) d 9.11 (s, 1 H), 8.10 (d, 1 H, J = 4.8 Hz, 7.88 (d, 1 H. 4.8 Hz, 7.83 (s, 1 H), 7.71 (s, 1 H)
Reference: [1] Patent: US2004/220189, 2004, A1, . Location in patent: Page 21
[2] Patent: WO2010/125101, 2010, A1, . Location in patent: Page/Page column 50
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YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In ethanol; water at 70 - 80℃; for 12 h; 2-amino-pyrazine (10g, 0.1mmol) was dissolved in 150ml of absolute ethanol, and slowly added dropwise to the above solution chloroacetaldehyde dimethylacetal (18.7g, 0.15mmol), then added dropwise 37percent of concentrated hydrochloric acid, the pH of the reaction system is 3-4, after completion of the dropwise addition, the reaction system was heated to 70-80 , TLC detection progress of the reaction, 12 hours after the completion of the reaction, the reaction solution was cooled to room temperature, is added 1N sodium hydroxide solution to adjust the pH value of the reaction system to 8-9, then adding a mixed solvent of 200ml of isopropanol and methylene chloride (wherein the isopropanol / dichloromethane 1/5 volume ratio) was extracted, and extracted twice , the combined organic phases were dried over anhydrous sodium sulfate, filtered, dried organic solvent was spin-indole [1,2-A] pyrazine 11g, yield of about 90percent
Reference: [1] Patent: CN103864799, 2016, B, . Location in patent: Paragraph 0028 - 0031
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YieldReaction ConditionsOperation in experiment
72% With hydrogen bromide In ethanol; water for 18 h; Heating / reflux 2-Aminopyrazine (100 mg, 1.1 mmol) and bromoacetaldehyde dimethylacetal (253 mg, 1.6 mmol) were dissolved in ethanol (4.5 ml), hydrobromic acid (48percent, 0.5 ml) added and the mixture was heated under reflux for 18 h.
The solution was allowed to cool to room temperature then pre-adsorbed directly onto silica.
Purification by silica gel chromatography eluding with dichloromethane and 1percent conc. ammonia on a gradient of methanol (1-4percent) gave imidazo[1,2-α]pyrazine (90 mg, 72percent) as a white crystalline solid: δH (360 MHz, CDCl3) 6.70 (1H, s), 7.82 (1H, s), 7.88 (1H, d, J 4), 8.29 (1H, d, J 4), 9.12 (1H, s).
536 mg With hydrogenchloride In ethanol for 14 h; Reflux To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-1,1-dimethoxyethane (2.5 mL, 21.03 mmol) followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (100percent ethyl acetate, 10percent methanol in ethyl acetate, then 10percent methanol in dichloromethane) to give 536 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 7.70 (bs, 1H), 7.82 (bs, 1H), 7.89 (d, 1H, J=4.4 Hz), 8.10 (d, 1H, J=4.6 Hz), 9.12 (s, 1H)
420 mg With hydrogen bromide In ethanolReflux 2-Aminopyrazine (500 mg, 5.26 mmol) was dissolved in ethanol (25 mL), and bromoacetaldehyde dimethyl acetal (0.93 mL, 7.89 mmol) and 40percent hydrobromic acid (3 mL) were added thereto. Heat to reflux overnight.After completion of the reaction, it was cooled to room temperature, and a 1N aqueous sodium hydroxide solution (20 mL) was added thereto.Extracted with 20percent isopropanol / dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was purified by silica gel column chromatography to give a white solid420mg.
Reference: [1] Patent: US2004/19057, 2004, A1, . Location in patent: Page/Page column 9
[2] Patent: US5028605, 1991, A,
[3] Patent: US2015/359793, 2015, A1, . Location in patent: Paragraph 0198
[4] Patent: CN104341425, 2018, B, . Location in patent: Paragraph 0169; 0171; 0172; 0173
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YieldReaction ConditionsOperation in experiment
84% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 7 h; Referring to Scheme 3, pyrazin-2-ylamine (1 g, 10.5 mmol) was dissolved in a solution of DMSO (40 ml)/H2O (1 ml) at 0° C. N-bromosuccinimide (3.93 g, 22 mmol) was added over an hour keeping the temperature below 5° C. Once addition was complete, the mixture was stirred for 6 hours at RT. The mixture was poured over ice water (150 ml) whilst stirring, then extracted with EtOAc (4.x.100 ml). The organic layers were combined, dried and evaporated to leave an orange oil, which solidified overnight under high vacuum. 3,5-dibromopyrazin-2-amine was produced as an orange/brown solid (2.24 g, 84percent). The product was used for the next reaction without further purification. [M+H] calc'd for C4H3Br2N3, 254; found, 254.
83% With N-Bromosuccinimide In dimethyl sulfoxide at 20℃; for 4 h; Pyrazin-2-amine (9, 4.00 g, 42.1 mmol, 1.0 equiv) was completely dissolved in DMSO (80 mL) in an argon-flushed, 500-mL round-bottomflask, and then NBS (18.7 g, 26.3 mmol, 2.5 equiv) was added over 3 h. The mixture was stirred a further 1 h at r.t. The reaction was complete within 4 h (TLC monitoring). The mixture was poured into H2O (200 mL), extracted with EtOAc (3 × 200 mL), and the combined organic layers were washed with H2O (3 × 200 mL), sat. brine (100 mL), and H2O (2 × 200 mL). The organic solution was dried (anhyd MgSO4) and concentrated by rotary evaporation. Finally the product was purified by crystallization (EtOH) to give 5 (8.736 g, 34.94 mmol, 83percent) as a pale yellow, needle-shaped, crystalline compound; Rf = 0.46 (silica gel, hexane–EtOAc, 2:1); mp 115–116 °C. Spectral results are in agreement with literature values.31
77% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 17 h; Inert atmosphere A solution of 2-aminopyrazine 4 (3.81 g, 40.1 mmol) in DMSO (80 mL) and water (2 mL) was stirred at 0 °C for 10 min. NBS (16.4 g, 92.2 mmol) was added portionwise to the solution over 50 min, keeping the temperature below 15 °C. The reaction mixture was warmed to rt and stirred for 16 h. The solution was poured into ice-water (250 mL) and stirred. The orange solid was collected by filtration and dried. The filtrate was extracted with ethyl acetate (200 mL). The organic layer was washed with 5percent aqueous sodium carbonate (50 mL) and water (50 mL), then dried, filtered and concentrated. The combined material was recrystallised from water (200 mL) to give 5 (7.80 g, 77percent) as a brown solid. (Found: C, 19.33; H, 1.10; N, 16.68; C4H3N3Br2 requires C, 19.00; H, 1.20; N, 16.62percent); δH (250 MHz; CDCl3) 5.08 (2H, br s, NH2), 8.07 (1H, s, 6-H); δC (125 MHz; CDCl3) 123.7, 123.9, 143.2, 151.9; LC-MS (15 min) m/z 256, 254, 252 (MH+); HPLC tR 4.45 min; purity 98percent; (HRMS found: MH+ m/z 251.8776; requires 251.8766).
77.8% With pyridine; bromine In dichloromethane at 20℃; for 4 h; A 500ml three-neck flask, was added 2-amino pyrazine (19g, 0.2mol), dichloromethane (200ml) and pyridine (50ml) mixed solution at room temperature was slowly added dropwise bromine (67.2g, 0.42mol) in dichloro methane (100ml) solution, stirred at room temperature 4h, the reaction system was added to 100ml of water, stirred for 2h, the organic layer was washed with water (100ml × 3), the organic phase was moved to a flask with silica gel, and activated charcoal is heated at reflux for 1h, suction , the solvent was distilled off under reduced pressure, the resulting solid was added hexane (45 ml of) and refluxed for 2h and filtered while hot, and dried to give a yellow solid 39.4g, yield 77.8percent.
76.6% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; Cooling with ice; Inert atmosphere At room temperature,2-aminopyrazine (8.00 g, 84.12 mmol) was dissolved in dimethylsulfoxide (160 mL)Add water (4 mL),Ice bath,N-bromosuccinimide (31.50 g, 177.00 mmol) was added portionwise to the reaction solution over 30 min,Feeding is completed,Stirred at room temperature overnight,Add water (500mL) quenching,Ethyl acetate (500 mL x 3)Dried over anhydrous Na2SO4,The solvent was removed and the residue was subjected to column chromatography (eluent: PE / EtOAc (v / v) = 6/1) to give 16.40 g of light yellow Color solid, yield: 76.6percent.
69% With N-Bromosuccinimide In water; dimethyl sulfoxide for 5 h; Cooling with ice To a DMSO-water (4.61 kg-114 g) solution of pyrazine-2-amine (456 g, 4.79 mol), NBS (1.79 kg, 10.1 mol) was added under ice cooling and stirred at the same temperature for 5 hours. To the reaction solution under ice cooling, ice water was added and diluted with ethyl acetate and then the water phase was extracted with ethyl acetate. Organic phases were combined, washed with water, and dried over magnesium sulfate. The organic phase was filtrated and then concentrated under reduced pressure to obtain the titled compound (830 g, 3.28 mmol, 69percent) as a brown solid substance.MS (ESI) m/z=252 (M+H)+.
69% With N-Bromosuccinimide In chloroform at 40℃; for 6 h; Inert atmosphere In an argon atmosphere, aminopyrazine (600.0mg, 6.31mmol, 1.0equiv) was dissolved in chloroform (25mL) and then NBS (3.37g, 18.93mmol, 3.0equiv) was added over 1h at room temperature. When the addition was completed, the mixture was stirred a further 6h at 40°C. The mixture was poured into saturated Na2S2O3 solution (100mL), extracted with EtOAc (3×100mL) and the combined organic layers where washed with saturated brine (100mL). The organic solution was dried with Na2SO4 and concentrated by rotary evaporation. Finally the residue was purified by chromatography on silica gel (gradient elution: PE–EtOAc, 9:1→7:3) to give 10 (1.0856g, 4.29mmol, 69percent) as a pale yellow compound. Rf=0.65 (silica gel, PE–EtOAc, 7:3); mp 114–116°C; 1H NMR (400MHz, CDCl3): δ=8.02 (s, 1H), 5.17 (br s, 2H); 13C NMR (100MHz, CDCl3): δ=152.0, 143.2, 124.1, 123.6; IR (neat): νmax=3447, 3281, 3187, 3154, 2933, 1811, 1714, 1621, 1549, 1506, 1450, 1359, 1333, 1202, 1151, 1133, 1096, 1079, 1040, 908, 877, 801, 755, 696cm−1; HRMS (ESI): calcd for C4H479Br2N3+ 251.8766; found 251.8779; calcd for C4H479Br81BrN3+ 253,8746; found 253.8757; calcd for C4H481Br2N3+ 255.8726; found 255.8735. The spectroscopic data are in good agreement with those reported in the literature.14a
68% With N-Bromosuccinimide In dichloromethane at 20℃; 3,5-Dibromopyrazin-2-amine Pyrazin-2-amine (2.0g, 21 mmol) was dissolved in dichloromethane (50 mL)and the resulting solution was stirred at room temperature. N-bromosuccinimide(9.4g, 53mmol) was added. After completion, the mixture was concentrated underreduced pressure to give brown solid crude which was subsequently purified bychromatography (applied in hexane; eluted 10percent EtOAc/hexane) to give the title compound as a pale yellowsolid (3.6g 14 mmol, 68percent). Mpt: 106-108 oC; Rf = 0.80 (1:1 EtOAc/hexane);IR (νmax/cm-1, thin film): 3447, 3280, 3154, 1621, 1549,1506, 1450; 1H NMR (600 MHz, CDCl3): δH = 5.04(brs, 2H, NH2), 8.04(s, 1H, 6-H); 13C NMR(150 MHz, CDCl3): δC = 123.8 (C-5), 124.0 (C-3),143.3 (C-6), 152.0 (C-2); HRMS m/z (CI+): found251.87731 [M+H]+, C4H4Br2N3requires 251.87720.  
67% With N-Bromosuccinimide In water; dimethyl sulfoxide at 0 - 20℃; for 16 h; [0094] Pyrazin-2-amine (VIII) (1.91 g, 20.08 mmol) was dissolved in dimethylsulfoxide (DMSO) (40 mL) and distilled water (1 mL).
To the resulting solution was slowly added dropwise N-Bromosuccinimide (NBS) (8.20 g, 46.07 mmol) at 0 °C and the solution was stirred at room temperature for 16 hrs.
Ice was added to the solution and the solution was stirred to give a yellow solid which was filtered to give the title compound (3.40 mg, 67 percent).
1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.05 (br, 2H).
66% With bromine; sodium acetate In acetic acid at -5 - 20℃; 2-Aminopyrazine (9.5 g, 100 mmol) was placed in a reaction flask containing glacial acetic acid (70 mL) and warmed on a steam bath until it dissolved. Sodium acetate trihydrate (33 g, 243 mmol) was added with constant swirling. The slurry was stirred in an ice-salt bath maintained at -5 °C and bromine (16 mL) was added dropwise over a 4 h period (if the bromine addition was speeded up the reaction became turbulent and potentially hazardous). The mixture was stirred in the ice bath for 2 h and then at room temperature for 24 h. It was then poured into ice (50 g) and neutralized with concentrated ammonia (pH 8). The crude product was collected and recrystallized from methanol (Norit) to give colourless needles of 2-amino-3,5-dibromopyrazine(16.8 g, 66percent), m.p.: 113-114 °C (lit. [13,26] 114-115 °C).
65% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; for 20 h; Darkness Under absence of light and at 0° C., N-bromosuccinimide (15.68 g, 88.1 mmol) was added to a solution of 2-aminopyrazine (4.19 g, 44.06 mmol) in dry dichloromethane (250 ml).
The mixture was stirred for 20 h at 4° C. and then washed with four 40 ml portions of a saturated sodium carbonate solution in water.
The organic layer was dried (MgSO4) and evaporated under reduced pressure, affording the title compound as 12.8 g of a light brown solid.
Column chromatography, using silica and a dichloromethane/ethyl acetate (3/1) mixture as the eluent, yielded pure 2-amino-3,5-dibromopyrazine as 5.00 g (65percent) of a light yellow solid.
1H-NMR (CDCl3, 400 Mhz): 8.09 (s, I H), 4.95 (211, NH) ppm. 13C-NMR (CDCl3): 153.5 (C-2), 144.3, 131.9, 126.8 ppm.
64.9% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 23 h; To a solution of aminopyrazine (4l) (10.0 g, 105 mmol) in DMSO (200 mL) and water (5 mL) was added N-bromosuccinimide (39.3 g, 221 mmol) at room temperature, and the mixture was stirred for 23 hours.
To the mixture was added water and the product was extracted with diethyl ether (300 mL*4). The combined organic extract was washed successively with water (400 mL*2) and brine (500 mL*2), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 280 g, n-hexane/dichloromethane/ethyl acetate=5/4/1). The resulting solid was further purified by recrystallization (n-hexane/ethyl acetate) to give Compound 42 (17.3 g, 68.3 mmol, 64.9percent) as a colorless solid. Rf=0.48 (n-hexane/dichloromethane/ethyl acetate=5/4/1); 1H NMR (400 MHz, CDCl3) δ 5.05 (s, 2H), 8.05 (s, 1H).
60% With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃; for 0.333333 h; Inert atmosphere A compound (1), (2.0 g, 21.0 mmol and 1.0 eq.), and THF (25 ml) were put in and stirred to the 200 ml three necked flask under a nitrogen atmosphere. Next, what dissolved N-bromosuccinimide (8.2 g, 46.1 mmol, 2.2 eq.) in THF (25 ml) was dropped by 0 C, and it agitated for 20 minutes at the room temperature.Cerite filtration of the impurity was carried out after ending reaction. And washed the filtrate by extraction, H2O, and sat.NH4Cl aq. with ethyl acetate, and it was made to dry by Na2SO4, and condensed. a part of obtained residue silica gel column chromatography (7 : n-hexane: eluate : ethyl acetate = 3) separation refinement condensing object compound (2) (3.16 g, yield:60 percent) It obtained as a white solid.
53% With N-Bromosuccinimide In dichloromethane at 0℃; for 2 h; Stage 1. 3, 5-Dibromopyrazin-2-amine To a solution of aminopyrazine (11.36 g, 0.12 mol) in DCM (700 mL) at 0°C was added N-bromosuccinimide (44.64 g, 0.25 mol) portion-wise. The reaction was stirred for 2 hrs. The reaction was washed with sat Na2CO3 (3 x 200 mL), dried over Mg504, filtered and concentrated in vacuo before purification by column chromatography (20percent EtOAc/heptane) to give the title compound as a yellow solid (15.9 g, 53percent). LCMS: m/z 252/254/256 [M+H].
51% With pyridine; bromine In chloroform at 20℃; for 2 h; To a solution of aminopyrazine (P) (1.902 g, 20 mmol, 1 eq.) in chloroform (160 ml) was added pyridine (3.4 ml, 42 mmol, 2.1 eq.) and bromine (2.15 ml, 2.1 eq.).
The mixture was stirred at rt for 2 hours.
The mixture was then diluted with DCM, washed with water, dried over sodium sulfate and concentrated to afford 2.583 g of title compound (yield 51percent) as a light brown solid.
1H-NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 6.98 (br s, 2H).
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; To a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 00C was added N-bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 00C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H2O (100 mL). The organic layer was separated, after which it was washed with saturated aqueous ΝaHCC>3, washed with brine, dried over MgSO4, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. 1H NMR (CDCl3, 300MHz) δ 8.02 (s, IH), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+ 1)+, calc. 251.
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; Preparation of 3,5-dibromopyrazin-2-amine Intermediate BA) [0322] To a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 0°C was added N-bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 0°C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H20 (100 mL). The organic layer was separated, after which it was washed with saturated aqueous NaHC03, washed with brine, dried over MgS04, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. 1H NMR (CDC13, 300MHz) δ 8.02 (s, 1H), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+l)+, calc. 251.
47% With N-Bromosuccinimide In dichloromethane at 0 - 4℃; Making reference to Scheme 6, to a stirred solution of aminopyrazine (8.21 g, 86.4 mmol) in anhydrous methylene chloride (215 mL) cooled to 0°C was added N- bromosuccinimide (32.3 g, 181 mmol) in portions over a six hour period, during which time the temperature of the reaction was kept below 0°C. The resulting mixture was stored at 4°C overnight, after which it was stirred vigorously and quenched with H20 (100 mL). The organic layer was separated, after which it was washed with saturated aqueous aHC03, washed with brine, dried over MgS04, filtered, and evaporated in vacuo to yield a residue that was triturated with 20percent EtOAc in hexanes to yield the title compound (10.3 g, 47percent) as a yellow/brown powder. NMR (CDC13, 300MHz) δ 8.02 (s, 1H), 5.05 (bs, 2H); HPLC retention time: 1.99 minutes; MS ESI (m/z): 252.0/254.0/256.2 (M+l)+, calc. 251.
47.8% With bromine In pyridine; dichloromethane at 40℃; for 1.5 h; Darkness A solution of dichloromethane (200 mL) and pyridine (25.3 mL, 0.315 mol) was added to a three-necked flask containing 2-aminopyrazine (14.27 g, 0.15 mol) and stirred well. In the dark and while refluxing a solution of bromine (16.2 mL, 0.315 mol) in dichloromethane (100 mL) was slowly added dropwise to the three-necked flask. About 1 h later the addition finished and the mixture was refluxed at 40 °C for 30 min more. After TLC monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature and distilled water (50 mL) was added and themixture was stirred vigorously for 10 min. Then the organic layer was collected and washed twice with distilled water. Silica gel (10 g) and activated carbon (1 g) were added to the organic layer and the mixture was decolorized under reflux for 30 min. After hot filtration, the filtrate was collected and vacuum distilled. The residue was refluxed with n-hexane (45 mL) for 2 h, filtered while hot again and the solid product was dried and weighed to give 18.15 g of a pale yellow solid (47.8percent yield). 1H-NMR(DMSO-d6) δ 8.14 (s, 1H), 7.01 (s, 2H).
47.8% With pyridine; bromine In dichloromethane; water at 40℃; for 1.5 h; To a three-necked flask equipped with 2-aminopyrazine (14.27 g, 0.15 mol) was added dichloromethane (200 mL) and pyridine(25.3 mL, 0.315 mol); immersed in water at 40 ° C, slowly added dropwise bromine (16.2 mL,0.315 mol) in dichloromethane (100 mL). After the reaction, the solution changed from orange to orange to orange1h was added dropwise; reflux was continued at 40 ° C for 30 min; cooling to room temperature, adding distilled water (50 mL) to the reaction system,Stirring for 10 min, standing on the stratified layer; collecting the lower liquid, the collected liquid was washed twice with distilled water (100 mL); the organic phaseWas transferred to a flask equipped with silica gel (10 g) and activated carbon (1 g), boiled and refluxed for 30 min. The filtrate was collected by filtration and distilled under reduced pressure,The solid obtained after the distillation was transferred to a flask equipped with n-hexane (45 mL) and refluxed at 80 ° C for 2 h. The filtrate was filtered while hotThe solid product was dried and weighed to give 18.15 g of a pale yellow solid, i.e., 3,5-dibromo-2-aminopyrazine, in a yield of 47.8percent.
41% With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 4 h; To a solution of the compound 2-aminopyrazine (3.8 g, 40.00 mmol) in dimethyl sulfoxide (30 mL) and water (2 mL) was added N-bromosuccinimide (17.80 g, 0.10) in an ice bath. Mol). After stirring at room temperature for 4 hours, the reaction was poured into ice water (250 mL). Extract with ethyl acetate (50 mL×4). Combine the organic phases, filter, and wash the filtrate with 5percent sodium carbonate solution (200 mL) and saturated aqueous sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, and concentrate. The residue is subjected to silica gel column chromatography. Purification by chromatography (petroleum ether/ethyl acetate=5:1) gave compound 56-b (4.10 g, 41percent).
38% With N-Bromosuccinimide In dichloromethane at 20℃; for 2 h; NBS (100 g, 561.8 mmol) was added in small portions to a stirred solution of 2-aminopyrazine (25 g, 263 mmol) in dichloromethane (600 ml) over a period of 1 hour. The reaction was stirred at r.t. for Ih and washed with water. The organic phase was dried (MgSψ4) and evaporated. The crude product was filtered through a plug of silica using 2.5percent MeOH in dichloromethane as the elu- ent.Yield 25 g (38percent). HPLC 99percent (System A). MS (electronspray) M+H+ m/z 254.4. IH NMR (400 MHz, CHLO ROFORM-D) δ ppm 5.04 (s, 2 H) 8.03 (s, 1 H).
38% With pyridine; bromine In dichloromethane at 0 - 20℃; for 16 h; Step-(i): Synthesis of 3,5 -dibromopyrazin-2-amine: To a stirred solution of pyrazin-2-amine (0.5 g, 5.2 mmol) in DCM (10 mL), was added pyridine (0.95 mL, 11.05 mmol) at 0°C followed by bromine (0.56 mL, 11.05 mmol) which was stirred at RT for 16h. After the reaction was completed, it was cooled to room temperature, quenched with Na2CO3 (30 mL), extracted with DCM (2 x 100 mL). The combined organicphases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by colunm chromatography using 100-200 mesh silica gel and 2percent MeOH in DCM as eluent to give the titled product as an off white solid (510 mg, 38percent); MS (ES) mz 254 (M+1).
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; To a mixture of 2-amino pyrazine (50 g, 0.5 mol) in chloroform (1000 ml) cooled to 0°C was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) dropwise. The mixture was stirred at rt for 16h, then water was added. The organic phase was extracted, dried (MgS04), filtered and evaporated to obtain I- 01 , 48 g (Y: 36 percent) of a yellow solid which was dried in vacuo.
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; Preparation of Intermediate I-01. To a mixture of 2-amino pyrazine (50 g, 0.5 mol) in chloroform (1000 ml) cooled to 0° C. was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) dropwise. The mixture was stirred at rt for 16 h, then water was added. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtain I-01, 48 g (Y: 36percent) of a yellow solid which was dried in vacuo.
36% With pyridine; bromine In chloroform at 0 - 20℃; for 16 h; To a mixture of 2-amino pyrazine (50 g, 0.5 mol) inchloroform (1000 ml) cooled to 0° C. was added pyridine (100 ml, 1.21 mol) and bromine (54 ml, 1.05 mmol) drop- wise. The mixture was stirred at it for 16 h, then water was added. The organic phase was extracted, dried (MgSO4), filtered and evaporated to obtain 1-01, 48 g (Y: 36percent) of ayellow solid which was dried in vacuo.
34% With N-Bromosuccinimide In water; dimethyl sulfoxide at 5 - 20℃; A I L three-necked round bottom flask was charged with pyrazin-2-amine (20 g, 0.21 mol), DMSO (600 mL) and water (15 mL). To the above was added in portions N-Bromosuccinimide (77.9 g, 0.44 mol) while keeping the inner temperature below 5 °C. The resulting mixture was stirred at 20 °C overnight. The solvent was evaporated and the residue was purified by flash columnchromatography on silica gel with a 1 :10 EtOAc/petroleum ether, to afford 18 g (34percent) of the product as a yellows solid. *H NMR (300 MHz, CDC13) δ: 8.02 (s, 1H), 4.72 (br, 2H).
1.51 g With N-Bromosuccinimide In water; dimethyl sulfoxide at 15 - 20℃; for 16 h; 3,5-Dibromo-2-aminopyrazine N-Bromosuccinimide (5.1 g, 28.7 mmol) was added slowly and portion wise to a mixture of aminopyrazine (1.3 g, 13.6 mmol) in dimethylsulfoxide (11 ml) and water (17 ml). During the addition of N-bromosuccinimide, the temperature of the reaction mixture was maintained below 15 °C. After the addition, the reaction mixture was stirred for 16 h at RT. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10 percent Na2C03 solution followed by washing with water and brine. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo to obtain crude product. The product was purified using column chromatography. Yield: 1.51 g 1H NMR (CDC13): 5.04 (2H, s), 8.03 (1H, s)
4.0 g With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In N,N-dimethyl-formamide; acetonitrile at 0℃; for 1 h; A solution of 2-aminopyrazine 1 (4.5 g, 47.4 mmol) in 50 mL DMF/MeCN solvent mixture (1:3) and a solution of l,3-dibromo-5,5-dimethylhydantoin 2 (13.6 g, 47.6 mmol, 2 eq. of "Br") in 40 mL DMF/MeCN solvent mixture (1:3) were simultaneously added (using two syringe needles) to a solution of MeCN (100 mL) at 0°C. The reaction mixture was stirred for one hour, quenched with aqueous sodium thiosulfate (I N, 200 mL) and concentrated under vacuum. The crude product (>99percent conversion, 8 g) was dissolved in EtOAc and filtered through celite/charcoal and recrystallized from acetonitrile (4.0 g, 50percent recovery). The reaction was scaled up to 12.0 g in two batches and the desired product 3 was analyzed by NMR and LC-MS. IH NMR (500 MHz, CDC13) δ 7.99 (s, IH); 13C NMR (126 MHz, CDC13) δ 151.92, 143.16, 142.99, 123.95, 123.56.

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YieldReaction ConditionsOperation in experiment
28.9% at 0 - 30℃; for 4.5 h; Inert atmosphere Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol).
After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 °C and stirred for 30 minutes until a solid precipitated.
The reaction mixture was filtered, and the filter cake was washed with ether (10 mLx3).
The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours.
The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid.
MS m/z (ESI): 192.1 [M+1]
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  • 17
  • [ 5049-61-6 ]
  • [ 64-17-5 ]
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YieldReaction ConditionsOperation in experiment
28.9%
Stage #1: at 20 - 30℃; for 4 h;
Stage #2: for 4 h; Reflux
Step 1
ethyl imidazo[1,2-c]pyrazine-3-carboxylate
Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol).
After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated.
The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3).
The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours.
The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid.
MS m/z (ESI): 192.1 [M+1]
Reference: [1] Patent: US2013/131068, 2013, A1, . Location in patent: Paragraph 0176; 0177
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