* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h; Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
82%
Stage #1: With sodium hydride In 1-methyl-pyrrolidin-2-one for 0.5 h; Stage #2: at 80℃; for 24 h;
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80percent) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 °C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82percent). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
53.76%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1 h; Stage #2: at 100℃; for 15 h;
Sodium hydride (188.6 mg, 4.72 mmol) in N, N- dimethylformamide (3 mL) was slowly added dropwise at room temperature and benzyl alcohol was dissolved in it and it was stirred at room temperature for 1 hour. It was added dropwise slowly to a mixture of 2-amino-3-chloro-pyrazine and heating at 100 °C refluxed for 15 hours. After cooling the reaction to room temperature and the solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filter and concentrate under reduced pressure . By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/4) to obtain the objective compound 300 mg at a yield of 53.76percent.
53.8%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: at 100℃; for 15 h; Inert atmosphere; Schlenk technique
General procedure: Sodium hydride (60percent in mineral oil, 0.04 g, 1 mmol) was addedto a stirred solution of benzyl alcohol derivative (1 mmol) inanhydrous N,N-dimethylformamide (3 mL of DMF) at room temperatureand stirring was continued for 1 h. 2-Amino-3-chloropyrazine (8b, 0.13 g, 1 mmol) was added to the reactionmixture and the reaction mixture was stirred at 100 °C for 15 h.After cooling, the solvent was evaporated and the residue waspartitioned betweenwater and dichloromethane. The organic layer was dried over sodium sulfate anhydrous, filtered, and concentrated.The residue was purified by column chromatography (SiO2,EA/n-Hex 1/5). 4.1.2.1 3-(Benzyloxy)pyrazin-2-amine (9g) Yellow solid, yield: 53.8percent, 1H NMR (400 MHz, CDCl3) δ = 5.45 (2H, s, OCH2Ph), 6.20 (2H, br, NH2), 7.38-7.48 (7H, m, ArH). Reported [ 48,49].
Reference：
[1] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[2] Patent: WO2005/34837, 2005, A2, . Location in patent: Page/Page column 43-44
[3] Patent: KR101481952, 2015, B1, . Location in patent: Paragraph 0797; 0798
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 529 - 543
[5] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
[6] Journal of Medicinal Chemistry, 1987, vol. 30, # 11, p. 2031 - 2046
[7] MedChemComm, 2014, vol. 5, # 3, p. 333 - 337
[8] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 268 - 278
2
[ 6863-73-6 ]
[ 100-51-6 ]
[ 110223-15-9 ]
[ 132972-99-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1639 - 1643
Benzyl alcohol (4.55 g, 42.15 mmol) was added under an inert atmosphere dropwise to a suspension of sodium hydride (1. 01 g, 42.13 mmol, 80%) in N-methylpyrrolidinone. Stirring of the reaction mixture was continued for 30 min. 2-Amino-3-chloropyrazine (Compound I in Scheme 1, 5.0 g, 38.6 mmol) was then added in incrememtal portions and the resultant mixture was heated at 80 C for 24 h. The reaction mixture was subsequently cooled and water (200 mL) was added. The aqueous solution was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (2 x 100 mL), dried (Mg04), and concentrated under reduced pressure to obtain a light brown residue. Addition of cold water to the residue, triggered crystallization of the desired product. The crystals were collected and dried over P2O5 (6.33 g, 82%). 1H-NMR (CDCl3) No. 7. 54 (d, J 3.1 Hz, 1H), 7.45-7. 32 (m, 6H), 5. 38 (s, 2H), 4. 78 (br s, 2H); MS (ESI) 202.2 ([M+H] +)
53.76%
Sodium hydride (188.6 mg, 4.72 mmol) in N, N- dimethylformamide (3 mL) was slowly added dropwise at room temperature and benzyl alcohol was dissolved in it and it was stirred at room temperature for 1 hour. It was added dropwise slowly to a mixture of 2-amino-3-chloro-pyrazine and heating at 100 C refluxed for 15 hours. After cooling the reaction to room temperature and the solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filter and concentrate under reduced pressure . By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/4) to obtain the objective compound 300 mg at a yield of 53.76%.
53.8%
General procedure: Sodium hydride (60% in mineral oil, 0.04 g, 1 mmol) was addedto a stirred solution of benzyl alcohol derivative (1 mmol) inanhydrous N,N-dimethylformamide (3 mL of DMF) at room temperatureand stirring was continued for 1 h. 2-Amino-3-chloropyrazine (8b, 0.13 g, 1 mmol) was added to the reactionmixture and the reaction mixture was stirred at 100 C for 15 h.After cooling, the solvent was evaporated and the residue waspartitioned betweenwater and dichloromethane. The organic layer was dried over sodium sulfate anhydrous, filtered, and concentrated.The residue was purified by column chromatography (SiO2,EA/n-Hex 1/5). 4.1.2.1 3-(Benzyloxy)pyrazin-2-amine (9g) Yellow solid, yield: 53.8%, 1H NMR (400?MHz, CDCl3) delta?=?5.45 (2H, s, OCH2Ph), 6.20 (2H, br, NH2), 7.38-7.48 (7H, m, ArH). Reported [ 48,49].
General procedure: NaH (60% in mineral oil, 0.04 g, 1 mmol) was added to a stirredsolution of the appropriate benzyl alcohol derivative (1 mmol) inanhydrous DMF (3 mL) at room temperature and stirring wascontinued for 1 h. Commercially available 2-amino-3-chloropyrazine (0.13 g, 1 mmol) was added to the reactionmixture which was further stirred at 100 C for 15 h. After cooling,the solvent was evaporated and the residue was partitioned betweenwater and dichloromethane. The organic layer was driedover anhydrous Na2SO4, filtered, and concentrated. The residuewaspurified by flash column chromatography (SiO2, EA/n-Hex 1/5).
2-Bromo-3-oxo-butyric acid ethyl ester (15.6 g, 74.6 mmol) was added to a solution of <strong>[110223-15-9]2-amino-3-benzyloxypyrazine</strong> (Compound m in Scheme 1, 5 g, 24.9 mmol) in ethanol (20 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to r. t. and an off- white coloured solid precipitated out. The solid was collected and washed with ice-cold ethanol to give a white solid (1.08 g, 66%). 1H-NMR (DMSO-d6) No. 11.6 (br s, 1H), 7.97 (d, J5.7 Hz, 1H), 7.00 (t, J 5. 8-Hz, 1H), 4.35 (q, J 7.1 Hz, 2H), 2.52 (s, 3H), 1.34 (t, J 7.1 Hz, 3H); MS (ESI) 222.0 ([M+H])
2-Bromo-4'-methoxyacetophenone (1.64 g, 7.14 mmol) was added to a solution of 2- amino-3-benzyloxypyrazine (Compound m in scheme 1,1. 5 g, 6.80 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to r. t. and an off- white coloured solid precipitated out. The solid was collected and washed with ice-cold ethanol to give a white solid (1. 08 g, 66%). lH-NMR (CDC13) 6 11.4 (d, J4. 2 Hz, 1H), 8.23 (s, 1H), 7. 86 (t, J 2.9 Hz, 1H), 7. 83 (t, J2. 1 Hz, 1H), 7.52 (dd, J0. 7 & 5.5 Hz, 1H), 7.04 (t, J2. 9 Hz, 1H), 7.02 (t, J2. 0 Hz, 1H), 6.94 (t, J3.0 Hz, 1H), 3.79 (s, 3H) ; MS (ESI) 242.0 ([M+H]
2-Bromo-4,4, 4-trifluoro-3-oxo-butyric acid ethyl ester (2.61 g, 9.9 mmol) was added to a solution of <strong>[110223-15-9]2-amino-3-benzyloxypyrazine</strong> (Compound m in Scheme 1, 1 g, 5.0 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 5 h. Upon cooling, a yellow precipitate formed from the reaction mixture. The solid was collected and washed with ice-cold ethanol to give a light yellow solid (0. 82g, 61%). 1H-NMR (CD3OD-d4) No. 8. 23 (d, J5. 9 Hz, 1H), 7.10 (d, J5. 9 Hz, 1H), 4.47 (q, J 7.1 Hz, 2H), 1.41 (t, J7. 1 Hz, 3H); MS (ES1) 276.0 ([M+H] +).
1-(3-(benzyloxy)pyrazin-2-yl)-3-(2-fluorophenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.43%
In tetrahydrofuran; for 8h;Reflux;
<strong>[110223-15-9]3-(benzyloxy)pyrazin-2-amine</strong> (100 mg, 0.5 mmol) and 2-fluoro isocyanate (0.67 mL, 0.60 mmol) in tetrahydrofuran (0.25 M) was dissolved in 8 hours during the heating under reflux thereby. After completion of the reaction, and concentrating the solvent under reduced pressure. The residue was washed with methanol and vacuum filter to give 122.6 mg of the desired compound in a yield of 69.43%.
69.4%
In tetrahydrofuran;Inert atmosphere; Schlenk technique; Reflux;
General procedure: 2-Amino-3-benzyloxypyridine or pyrazine derivative(2.5 mmol) was dissolved in dry THF (10 mL), isocyanate derivative(3.0 mmol) was added to the reaction mixture. The reaction wasrefluxed for 3-6 h. After cooling, the reaction mixture was evaporated and the residue was purified by solidification with cold methanol and filtered to give the target compounds.
1-(3-(benzyloxy)pyrazin-2-yl)-3-(adamantane-1-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.6%
With sodium hydride; In tetrahydrofuran; mineral oil; for 20h;Reflux;
3-(benzyloxy)pyridin-2-amine (100 mg, 0.50 mmol) and sodium hydride (60% in mineral oil, 22 mg, 0.55 mmol) was dissolved in tetrahydrofuran (0.25M) and then 1-adamantyl isocyanate (106 mg, 0.6 mmol) was added dropwise and heating at reflux for 20 hours. After the reaction was cooled to room temperature, water was added to terminate the reaction, and extracted with ethyl acetate, drying the extracted solution over sodium sulfate, it was filtered and concentrated under reduced pressure. By separation and purification of the residue by column chromatography (ethyl acetate / n-hexane = 1/2) to give the title compound 50 mg at a yield of 26.6%.
1-(3-(benzyloxy)pyrazin-2-yl)-3-(2-chloroethyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.33%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 15h;Reflux;
3-(3-benzyloxy)pyrazin-2-amine (100 mg, 0.50 mmol) and 2-chloroethyl isocyanate (50 muL, 0.60 mmol), DIPEA (0.26 mL, 1.50 mmol) was dissolved in tetrahydrofuran (0.25 M ) and heated under reflux for 15 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane = 1/2) to give the title compound 109 mg at a yield of 71.33%.
71.3%
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Inert atmosphere; Schlenk technique; Reflux;
General procedure: 2-Chloroethyl isocyanate (0.1 mL, 1.1 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.92 mmol) in dry THF (5 mL) in the presence of DIPEA (0.5 mL,2.75 mmol). The reaction mixture was refluxed for 18 h and evaporatedafter cooling. The residue was purified by flash columnchromatography (SiO2, EA/n-Hex 1/4).
1-(3-(benzyloxy)pyrazin-2-yl)-3-(3-fluorophenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.8%
In tetrahydrofuran;Inert atmosphere; Schlenk technique; Reflux;
General procedure: 2-Amino-3-benzyloxypyridine or pyrazine derivative(2.5 mmol) was dissolved in dry THF (10 mL), isocyanate derivative(3.0 mmol) was added to the reaction mixture. The reaction wasrefluxed for 3-6 h. After cooling, the reaction mixture was evaporated and the residue was purified by solidification with cold methanol and filtered to give the target compounds.
1-(3-(benzyloxy)pyrazin-2-yl)-3-cycloheptylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.2%
With sodium hydride; In tetrahydrofuran; mineral oil; for 5h;Inert atmosphere; Schlenk technique; Reflux;
General procedure: For aromatic urea derivatives; the appropriate aromatic isocyanate(3.0 mmol) was added to a solution of the appropriate 2-amino-3-benzyloxy pyrazine derivative (2.5 mmol) in THF(10 mL). The reaction was refluxed for 3e6 h. After cooling, thereaction mixture was evaporated and the residue was purified byprecipitation in cold methanol and filtered to give the targetcompound(s). For aliphatic urea derivatives; the appropriatealiphatic isocyanate derivative (1.02 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.85 mmol) in dry THF (5 mL) in the presence of NaH (60% inmineral oil, 68 mg, 1.71 mmol). The reaction was refluxed for 5 h.After cooling, the reaction mixture was evaporated and the residuewas purified by flash column chromatography (SiO2, EA/n-Hex 1/4).
1-(3-(benzyloxy)pyrazin-2-yl)-3-(2,4,4-trimethylpentane-2-yl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.1%
With sodium hydride; In tetrahydrofuran; mineral oil;Inert atmosphere; Schlenk technique; Reflux;
General procedure: For aromatic urea derivatives; the appropriate aromatic isocyanate(3.0 mmol) was added to a solution of the appropriate 2-amino-3-benzyloxy pyrazine derivative (2.5 mmol) in THF(10 mL). The reaction was refluxed for 3e6 h. After cooling, thereaction mixture was evaporated and the residue was purified byprecipitation in cold methanol and filtered to give the targetcompound(s). For aliphatic urea derivatives; the appropriatealiphatic isocyanate derivative (1.02 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.85 mmol) in dry THF (5 mL) in the presence of NaH (60% inmineral oil, 68 mg, 1.71 mmol). The reaction was refluxed for 5 h.After cooling, the reaction mixture was evaporated and the residuewas purified by flash column chromatography (SiO2, EA/n-Hex 1/4).
1-(3-(benzyloxy)pyrazin-2-yl)-3-(tert-butyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.3%
With sodium hydride; In tetrahydrofuran; mineral oil;Inert atmosphere; Schlenk technique; Reflux;
General procedure: For aromatic urea derivatives; the appropriate aromatic isocyanate(3.0 mmol) was added to a solution of the appropriate 2-amino-3-benzyloxy pyrazine derivative (2.5 mmol) in THF(10 mL). The reaction was refluxed for 3e6 h. After cooling, thereaction mixture was evaporated and the residue was purified byprecipitation in cold methanol and filtered to give the targetcompound(s). For aliphatic urea derivatives; the appropriatealiphatic isocyanate derivative (1.02 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.85 mmol) in dry THF (5 mL) in the presence of NaH (60% inmineral oil, 68 mg, 1.71 mmol). The reaction was refluxed for 5 h.After cooling, the reaction mixture was evaporated and the residuewas purified by flash column chromatography (SiO2, EA/n-Hex 1/4).
1-(3-(benzyloxy)pyrazin-2-yl)-3-phenylurea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91.8%
In tetrahydrofuran; mineral oil;Inert atmosphere; Schlenk technique; Reflux;
General procedure: For aromatic urea derivatives; the appropriate aromatic isocyanate(3.0 mmol) was added to a solution of the appropriate 2-amino-3-benzyloxy pyrazine derivative (2.5 mmol) in THF(10 mL). The reaction was refluxed for 3e6 h. After cooling, thereaction mixture was evaporated and the residue was purified byprecipitation in cold methanol and filtered to give the targetcompound(s). For aliphatic urea derivatives; the appropriatealiphatic isocyanate derivative (1.02 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.85 mmol) in dry THF (5 mL) in the presence of NaH (60% inmineral oil, 68 mg, 1.71 mmol). The reaction was refluxed for 5 h.After cooling, the reaction mixture was evaporated and the residuewas purified by flash column chromatography (SiO2, EA/n-Hex 1/4).
1-(3-(benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.1%
In tetrahydrofuran; mineral oil;Inert atmosphere; Schlenk technique; Reflux;
General procedure: For aromatic urea derivatives; the appropriate aromatic isocyanate(3.0 mmol) was added to a solution of the appropriate 2-amino-3-benzyloxy pyrazine derivative (2.5 mmol) in THF(10 mL). The reaction was refluxed for 3e6 h. After cooling, thereaction mixture was evaporated and the residue was purified byprecipitation in cold methanol and filtered to give the targetcompound(s). For aliphatic urea derivatives; the appropriatealiphatic isocyanate derivative (1.02 mmol) was added to a solutionof the appropriate 2-amino-3-benzyloxy pyrazine derivative(0.85 mmol) in dry THF (5 mL) in the presence of NaH (60% inmineral oil, 68 mg, 1.71 mmol). The reaction was refluxed for 5 h.After cooling, the reaction mixture was evaporated and the residuewas purified by flash column chromatography (SiO2, EA/n-Hex 1/4).
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