* 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.
Sodium nitrite (3.4 g, 50 mmol, 1.3 eq.) was added in small portionsto 98percent sulfuric acid (15 mL) ice bath, and the mixture was allowed towarm up and heated to 60. When getting clear, the solution wascooled in an ice bath again. A solution of 2-amino-pyrazine (9) (4 g,39.3 mmol, 1 eq.) in 98percent sulfuric acid (15 mL) was added dropwise.The reaction mixture was stirred at 40 for 1 h. After cooling to roomtemperature, it was slowly poured onto crushed ice and stirred until nonitrogen run out. The solution was adjusted to pH 6 with a 40percent solutionof sodium hydroxide, resulting in lots of sodium sulfate which wasfiltered off whereafter. The filtrate was extracted with EA (50 mL×3),and the combined organics were dried (Na2SO4), filtered and concentratedin vacuo to give the product as a white precipitate (6.38 g,53percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2019, vol. 27, # 5, p. 748 - 759
[2] Journal of the Chemical Society, 1947, p. 371
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 400
[4] Journal of Biological Chemistry, 1947, vol. 171, p. 321,324
2
[ 5049-61-6 ]
[ 70-23-5 ]
[ 1286754-14-0 ]
Yield
Reaction Conditions
Operation 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]
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]
EXAMPLE 15 By reacting aminopyrazine with 3-carbomethoxy-4-hydroxy-2-methylthieno[2,3-e]-1,2-thiazine 1,1-dioxide for 7 hours in a manner analogous to that described in Example 1, there is obtained 4-hydroxy-2-methyl-N-pyrazinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide of decomposition point 245-248 C (recrystallization from xylene).
4-(pyrazin-2-ylamino)-benzoic acid tert-butyl ester[ No CAS ]
4-fluoro-N-pyrazin-2-yl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With potassium tert-butylate; In tetrahydrofuran; N,N-dimethyl-formamide; at 80℃; for 18h;
Pyrazin-2-ylamine (475 mg, 5.0 mmol), <strong>[58656-98-7]4-fluorobenzoic acid tert-butyl ester</strong> (981 mg, 5.0 mmol) and potassium tert-butoxide (6.0 mL at 1.0 M in THF, 6.0 mmol) were combined in dry DMF (5 mL) and heated to 80 C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was triturated with ether/hexane. The solid by-product was filtered off and the filtrate concentrated and the residue chromatographed yielding 252 mg (17%, adjusted for presence of side product) of the title compound as a yellow solid contaminated with 20% of 4-fluoro-N-pyrazin-2-yl-benzamide.
EXAMPLE A1 2-Bromo-acetoacetaldehyde (0.1 mol) was added portionwise to pyrazinamine (0.1 mol) in ethanol (200 ml) while stirring. The reaction mixture was stirred and refluxed for one hour, then allowed to cool to room temperature. The precipitate was filtered off and dried. Yield: 13.5 g of 1-(imidazo[1,2-a]pyrazin-3-yl)ethanone (55%) (interm. 1).
EXAMPLE 3 6-Chloro-N-(pyrazin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide (No. 3 of the Table)400 mul of a 2M solution of trimethylaluminium in toluene are added dropwise to a solution, cooled to 0 C., of 120 mg of ethyl <strong>[67625-38-1]6-chloroimidazo[1,2-a]pyridine-2-carboxylate</strong> and 61 mg of pyrazin-2-ylamine in 1.2 ml of toluene. The reaction mixture is heated at 70 C. for 16 hours. After evaporating the toluene, the residue is taken up in 0.1N hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is triturated with ethyl ether to give 115 mg of 6-chloro-N-(pyrazin-2-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 4- bromothiazole (2) (328mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5ml_) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (15mg, 4%).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40.0h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (125mg, 1.3mmol), 2- bromo-1 ,7-naphthyridine (2) (250mg, 1.2mmol), Cs2C03 (0.78g, 2.4mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (55mg, 0.06mmol) and Xantphos (76mg, 0.13mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with CH2CI2 (15ml_). The organic layers were combined and Pd- scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (1 15mg, 43%). (0167) LCMS (ES): Found 224.2 [M+Hf.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 2- chloro-4-(pyrrolidin-1 -yl)pyrimidine (2) (367mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10mL) and brine (5ml_) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (18mg, 4%).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40.0h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (209mg, 2.2mmol), 2- chloro-3,5-dimethylpyrazine (2) (285mg, 2.0mmol), Cs2C03 (1.3g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15mL), H20 (10mL) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15mL). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4mL) and purified by basic prep LCMS to yield (3) as a solid (179mg, 45%). (0555) LCMS (ES): Found 202.3 [M+Hf.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere;
Under Ar(g), to a mixture of pyrazin-2-amine (1) (134mg, 1.4mmol), 3- chloro-6-(1 -methyl-1 H-pyrazol-4-yl)pyridazine (2) (250mg, 1.3mmol), Cs2C03 (0.84g, 2.6mmol) was added degassed dry 1 ,4-dioxane (13mL). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (59mg, 0.06mmol) and Xantphos (82mg, 0.14mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt and concentrated in vacuo, CH2CI2 (15ml_) and H20 (15mL) were added. The organic phase was separated and the water layer was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (7.4mg, 2%).
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