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3,6-dibromopyrazin-2-ylamine (4.0 g, 15.80 mmol) and bromoacetaldehyde diethyl acetal (3.7 mL, 24.00mmol) and tetrahydrofuran (5.3 mL) eere dissolved in distilled water (53 mL), the mixture was stirred for 4 hours at 120°C .Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition. The resulting solid was filtered and washed with distilled water and dried to give the title compound (2.75 g).
Reference:
[1] Patent: US2009/286798, 2009, A1, . Location in patent: Page/Page column 27
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 6, p. 2266 - 2270
[3] Patent: KR2015/113801, 2015, A, . Location in patent: Paragraph 0127-0130
Synthesis of compound (C) as described in the general reaction scheme; 3, beta-Diotabromo-pyraziotan-2- ylamine[00249] Diphenylphosphorylazide (2.59mL, 12mmol) and triethylamine (1.67mL, 12mmol) are added to a solution of 2,5-dibromo-3-pyrazoic acid (3.52g, 12mmol) in t-butanol (9OmL) The reaction is heated at reflux for 18 hours. The reaction is quenched with water, then concentrated in vacuo and taken up in DCM. The organic solution is washed with water and IN NaOH, dried over MgSCU and concentrated in vacuo. The resultant solid is filtered through a pad of silica using EtOAc, then concentrated and TFA:DCM (4 1, 12mL) is added to the solid and stirred for 30min. The solution is concentrated in vacuo then neutralised with IN NaOH and extracted with DCM The organic layer is dried over MgSO4 and concentrated in vacuo to give the product. 1H NMR (250MHz, dg-DMSO) delta(ppm) 7.25 (2H, br s), 7.68 (IH, s); m/z (APCI) 254 (M+H)+; m.p 135-139C.
Synthesis of compound D as desc?bed in the general reaction scheme; 5,8-DiotabromoiotamiotadazofJ ,2- ajpyrazine.[00250] Bromoacetaldehyde diethyl acetal (49mL, 326mmol) and 48% hydrobromic acid is heated to reflux for 1 5h, then poured into propan-2-ol (60OmL) and quenched with NaHCO3. After filtering, 2,5-dibromo-3-aminopyrazme (41.34g, 163mmol) is added to the solution and heated at reflux overnight. The reaction is cooled and solvents removed in vacuo, followed by addition of aq NaHCO3 and extraction with EtOAc. The organic phase is dried over MgSO4, filtered, and concentrated in vacuo to afford a brown solid. 1H NMR (250MHz, CDCl3) delta(ppm)7.86 (IH, s), 7 93-7.94 (IH, d), 7.98-7.99 (IH, d), m/z (APCI) 278 (M+H)+; m.p 132-135C
With pyridinium p-toluenesulfonate; In acetonitrile; for 72.0h;Heating / reflux;
Step 2 5 ,8-Diotabromo-3-methyliotamiotadazo[ 1 ,2 ajpyrazine[00298] 2,5-Dibromo-3-aminopyrazme (2 0 g, 7 9 mmol), 2-bromo-l,l -dimethoxypropane (7 25 g, 40 0 mmol) and py?dimum p-toluenesulfonate (2 0 g, 7 9 mmol) are stirred in acetomtrile (65 mL) at reflux for 3 days The mixture is cooled and the solvent evaporated under reduced pressure The residue is partitioned between DCM (150 mL) and water (50 mL) and the layers separated The organic fraction is washed with NaHCtheta3 (sat aq , 50 mL) and b?ne (50 mL) and d?ed over MgStheta4 Evaporation of the solvent under reduced pressure gives a viscous black oil (2 14 g) which is purified by silica chromatography, elutmg with 10% - 20% EtOAc in cyclohexane to afford the title compound as a red-brown solid (280 mg, 1 mmol)
Intermediate 2: 5,8-Dibromo-imidazo[1,2-a]pyrazine Bromoacetaldehyde diethyl acetal (49 mL, 326 mmol) and 48% hydrobromic acid is heated to reflux for 1.5 h, then poured into propan-2-ol (600 mL) and quenched with NaHCO3. After filtering, 3,6-dibromopyrazin-2-yl amine (41.34 g, 163 mmol) is added to the solution and heated at reflux overnight. The reaction is cooled and solvents removed in vacuo, followed by addition of aq. NaHCO3 and extraction with EtOAc. The organic phase is dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford a brown solid. 1H NMR (250 MHz, CDCl3) delta (ppm) 7.86 (s, 1H), 7.93-7.94 (d, 1H), 7.98-7.99 (d, 1H); m/z (APCI) 278 (M+H)+; m.p 132-135 C.
2.75 g
In tetrahydrofuran; water; at 120.0℃; for 4h;
<strong>[957230-70-5]3,6-dibromopyrazin-2-ylamine</strong> (4.0 g, 15.80 mmol) and bromoacetaldehyde diethyl acetal (3.7 mL, 24.00mmol) and tetrahydrofuran (5.3 mL) eere dissolved in distilled water (53 mL), the mixture was stirred for 4 hours at 120C .Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition. The resulting solid was filtered and washed with distilled water and dried to give the title compound (2.75 g).
Step 2: Synthesis of Compound (C) as Described in the General Reaction Scheme; 3,6-Dibromo-pyrazin-2-ylamine Diphenylphosphorylazide (2.59 1 mL, 12 mmol) and triethylamine (1.67 mL, 12 mmol) are added to a solution of 3,6-dibromo-pyrazin-2-carboxylic acid (3.52 g, 12 mmol) in t-butanol (90 mL). The reaction is heated at reflux for 18 hours. The reaction is quenched with water, then concentrated in vacuo and taken up in DCM. The organic solution is washed with water and 1N NaOH, dried over MgSO4 and concentrated in vacuo. The resultant solid is filtered through a pad of silica using EtOAc, then concentrated and TFA:DCM (4:1, 12 mL) is added to the solid and stirred for 30 min. The solution is concentrated in vacuo then neutralised with 1N NaOH and extracted with DCM. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo to give the product. 1H NMR (250 MHz, DMSO-d6) delta (ppm) 7.25 (br s, 2H), 7.68 (s, 1H); m/z (APCI) 254 (M+H)+; m.p 135-139 C.
Step 2: Synthesis of Intermediate 1a as described in the general reaction scheme; 3,6-Dibromo-pyrazin-2-ylamine Diphenylphosphorylazide (2.59 mL, 12 mmol) and triethylamine (1.67 mL, 12 mmol) are added to a solution of 3,6-dibromo-pyrazin-2-carboxylic acid (3.52 g, 12 mmol) in t-butanol (90 mL). The reaction is heated at reflux for 18 hours. The reaction is quenched with water, then concentrated in vacuo and taken up in DCM. The organic solution is washed with water and 1N NaOH, dried over anhydrous MgSO4 and concentrated in vacuo. The resultant solid is filtered through a pad of silica using EtOAc, then concentrated and TFA:DCM (4:1, 12 mL) is added to the solid and stirred for 30 min. The solution is concentrated in vacuo then neutralised with 1N NaOH and extracted with DCM. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo to give the product. 1H NMR (250 MHz, DMSO-d6) ppm 7.25 (br s, 2H), 7.68 (s, 1H); m/z (APCI) 254 (M+H)+; m.p 135-139 C.
With triethylamine;copper(l) iodide; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
The bromopyrazine (3 g, 11.87 mmol) was dissolved in THF (60 mL) and the resultant solution was purged with argon. Triethylamine (1.44 g, 14.24 mmol), CuI (180 mg) and PdCl-(PPh3)2 (83 mg, 0.118 mmol) were added. The reaction mixture was cooled to 0 C. Trimethylsilylacetylene (1.28 g, 13.05 mmol) was slowly added and the reaction was left to warm up to rt for 2 h. The reaction mixture was diluted with water and filtered through celite. The crude mixture was extracted three times with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 3.3 g (51%) of alkyne as a yellow solid.
Diphenylphosphoryl azide (488 mg, 1.77 mmol) and triethylamine (180 mg, 1.77 mmol) were added to a solution of the acid (500 mg, 1.77 mmol) in tert-butanol (12 mL). The reaction mixture was stirred at reflux for 18 h and then quenched with water. The volatiles were removed under reduced pressure. The residue was dissolved in 4:1 TFA/DCM (5 mL) and stirred at rt for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in DCM and washed with 1N aq. NaOH. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 120 mg (27%) of bromoanisol as a colorless oil. MS m/z (ES): 253 (M+H)+.
With bromine; potassium hydroxide; In water; at -5 - 15℃; for 1.08333h;
Step 4: Synthesis of Intermediate 1aTo a stirred solution of potassium hydroxide (130 g, 2.314 M) in water (1.3 L) at -5 C. is added bromine (23.7 mL, 463 mM) over 0.5-1 h. Intermediate D' (100 g, 356 mM) is added to the reaction mixture and stirred for 15 min at -5 C. The temperature of the reaction mixture is raised to 15 C. over 20 min and stirred at this temperature for an additional 30 min. The resulting solid is separated by filtration, washed with water (50 mL×3) and dried at 50-55 C. under vacuum to afford crude Intermediate 1a.Intermediate 1a (51 g) is heated in a 10% aq. solution of potassium hydroxide (510 mL) at 70 C. for 2 hrs, then cooled to 30 C., and the solid is filtered. The cake is washed with water (25 mL×2) and dried to afford clean Intermediate 1a.
6-bromo-3-(2-fluoro-5-methoxyphenyl)pyrazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In methanol; water; toluene; at 50℃; for 72h;Inert atmosphere;
A. 6-Bromo-3-(2-fluoro-5-methoxyphenyl)pyrazin-2-amine, 1a (0234) (0235) A mixture of <strong>[957230-70-5]3,6-dibromopyrazin-2-amine</strong> (8.5 g, 34 mmol), (2-fluoro-5-methoxyphenyl)boronic acid (5.1 g, 30 mmol), Pd(PPh3)4 (3.1 g, 2.7 mmol), Na2CO3 (2M aqueous solution, 33 mL, 67 mmol), toluene (132 mL) and methanol (33 mL) was stirred for 72 h at 50 C. under N2. The reaction mixture was allowed to cool to RT and treated with 500 mL of H2O. The resulting mixture was extracted with EtOAc (3×500 mL). The organic layers were combined, dried (Na2SO4) and concentrated. The residue obtained was purified by flash chromatography on silica gel (EtOAc/petroleum ether 1:5-1:2 v/v) to obtain the title compound 1a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C11H9BrFN3O: 298.0 (M+H)+; found: 298.0.
With tetrafluoroboric acid; sodium nitrite; at 0 - 20℃; for 2h;
Specifically for weighing <strong>[957230-70-5]2-amino-3,6-dibromopyrazine</strong>2.53g and NaNO21.38g in a 100ml round bottom flask,425 ml of HBF was slowly added dropwise thereto at 0 C, and the reaction was performed at 20 C for 2 hours.The reaction mixture was washed with water and extracted three times with dichloromethane.The organic phase was collected.The obtained organic phase was purified by silica gel column chromatography,This gave 2,5-dibromo-3-fluoropyrazine.Then, 140 mg of the obtained 2,5-dibromo-3-fluoropyrazine, 523 mg of 4- (diphenylamino) phenylboronic acid pinacol ester, and 119 mg of bis (triphenylphosphine) palladium (II) dichloride were taken.142 mg of tetrabutylammonium bromide was placed in a 50 ml reaction tube, 5 ml of K2CO3 solution (6 mol / L) and 10 ml of toluene were added under N2 protection, and the reaction was performed at 85 C. for 24 h.The reaction product was washed with water and extracted three times with dichloromethane, and the organic phase was collected.Purified by silica gel column chromatography.54 mg of 4,4 '-(3-fluoropyrazine-2,5-diyl) bis (N, N-diphenylaniline) was obtained as a yellow solid.
5-bromo-N2-(2,2,6,6-tetramethylpiperidin-4-yl)pyrazine-2,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 180℃; for 3.5h;Microwave irradiation;
Step 1: To a solution of <strong>[957230-70-5]3,6-dibromopyrazin-2-amine</strong> (504 mg, 2 mmol) and 2, 2,6,6-tetramethylpiperidin-4-amine (0.35 mL, 2 mmol) in EtOH (2 mL) was added DIEA (0.38 mL, 2 mmol). The reaction mixture was subjected to microwave irradiation at 180 C for 3.5 h. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography eluting with a MeOH (2.5% NH40H)/CH2Cl2 gradient (0-30% MeOH/NH4OH) to provide 5-bromo-N2-(2, 2, 6, 6-tetramethylpiperidin-4-yl)pyrazine-2, 3-diamine (0.35 g, 54%). MS m/z 328.0, 330.0 [M+H]+.