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Stage #1: at 90℃; for 16 h; sealed tube protected from light Stage #2: With sodium carbonate In water
A mixture of 3-chloro-pyrazin-2-ylamine (48.7 g, 375.8 mmol) and chloroacetone (120 ml, 1504.5 mmol) was stirred at 90 °C for 16 h. in a sealed tube protected from light. After cooling to RT, Et20 was added and the solid formed was filtered off, washed with further Et20, suspended in a saturated solution of sodium carbonate and extracted with DCM. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was precipitated from Et20 to yieldintermediate 4 (43.2 g, 68percent) as a white solid which was used in the next step without further purification. m.p. 133.5-138.6 °C (WRS-2A).
68%
Stage #1: at 90℃; for 16 h; Sealed tube; Darkness Stage #2: With sodium carbonate In water
Example A4 8-Chloro-2-methyl-imidazol[1,2-a]pyrazine A mixture of 3-chloro-pyrazin-2-ylamine (48.7 g, 375.8 mmol) and chloroacetone (120 ml, 1504.5 mmol) was stirred at 90° C. for 16 h. in a sealed tube protected from light. After cooling to RT, Et2O was added and the solid formed was filtered off, washed with further Et2O, suspended in a saturated solution of sodium carbonate and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was precipitated from Et2O to yield intermediate 4 (43.2 g, 68percent) as a white solid which was used in the next step without further purification. m.p. 133.5-138.6° C. (WRS-2A).
68%
at 90℃; for 16 h; Sealed tube; Darkness
A mixture of 3-chloro-pyrazin-2-ylamine (48.7 g, 375 8 mmol) and chloroacetone (120 ml, 1504.5 mmol) was stirred at 90 ° C. for 16 h. in a sealed tube protected from light. After cooling to RT, Et2O was added and the solid formed was filtered off, washed with further Et2O, suspended in a saturated solution of sodium carbonate and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was precipitated from Et2O to yield intermediate 6 (43.2 g, 68percent) as a white solid which was used in the next step without further purification. m.p. 133.5-138.6° C. (WRS-2A).
53%
at 90℃; for 16 h; Sealed tube
A mixture of 3-chloropyrazin-2-amine (2 g, 15.4 mmol) and 1-chloropropan-2-one (4mL) was heated to 90 °C for 16 h in a sealed tube. The reaction mixture was then cooled to roomtemperature and the solid formed was filtered, washed with ether and dried to get the titled compound (1.4 g, 53percent). LC-MS: 168.3 [M+Hj.
7.7%
at 88℃; Heating / reflux
A solution of 2-amino-3-chloropyrazine (1Og, 77.5mmol), chloroacetone (3OmL, 387mmol) in MeOH (25ml_) is refluxed overnight at 88°C. It is then stirred for Ih at O0C and any solid that forms, is filtered off and washed twice with MeOH (5ml_). The mother liq. are evaporated, diluted with EtOAc, and washed with HCI 2N, water and brine. The water and HCI mother liq. are evaporated to give a yellow solid that is neutralized with a saturated solution of K2CO3 in water, extracted with DCM, dried with MgSO4 anh. filtered and concentrated. The crude material is purified by column chromatography using a gradient of (DCM/MeOH: 1/0 to 99/1) to give 8-Chloro-2-methyl-imidazo[l,2-a]pyrazine as an orange solid (1.02g, 7.7percent).
Stage #1: With hydrogenchloride In water at 90℃; for 0.25 h; Stage #2: With sodium hydrogencarbonate In water at 20℃; Stage #3: at 90℃; for 2.5 h;
A mixture of l-bromo-2, 2-dimethoxypropane (42.4 g, 231.5 mmol) and conc. HC1 (890 uL, 28.9 mmol) in water (6.25 mL) was heated to 90°C, for 15 min, cooled to r. t. and quenched with NaHC03. 2-Amino-3-chloropyrazine (Compound I in Scheme 1,0. 2 g, 1.54 mmol) was added and the resultant mixture was heated to 90°C for 2h 30 min. The cooled reaction mixture was partitioned between 2M NaHC03 aq (100 mL) and dichloromethane (100 mL). The aqueous layer was separated and extracted with dichloromethane (5 x 100 mL). The combined organic extracts were dried over anhydr. Na2S04 and concentrated in vacuo to yield the crude title compound. Purification by recrystallization from the minimum amount of hot dichloromethane provided 7.0 g (54 percent yield) of the pure title compound.'H NMR (CH30H-d4) 8 8. 38 (d, J 4. 5 Hz, 1H), 7.88 (s, 1H), 7.65 (d, J4.5 Hz, 1H), 2.49 (s, 3H); MS (ESI) 167. 8 ([M+H] +, Cl35), 169.8 ([M+H] +, C137)
54%
Stage #1: With hydrogenchloride In water at 90℃; for 0.25 h; Stage #2: With sodium hydrogencarbonate In water at 20℃; Stage #3: at 90℃; for 2.5 h;
A mixture of l-bromo-2, 2-dimethoxypropane (42.4 g, 231.5 mmol) and conc. HC1 (890 uL, 28.9 mmol) in water (6.25 mL) was heated to 90°C, for 15 min, cooled to r. t. and quenched with NaHC03. 2-Amino-3-chloropyrazine (Compound I in Scheme 1,0. 2 g, 1.54 mmol) was added and the resultant mixture was heated to 90°C for 2h 30 min. The cooled reaction mixture was partitioned between 2M NaHC03 aq (100 mL) and dichloromethane (100 mL). The aqueous layer was separated and extracted with dichloromethane (5 x 100 mL). The combined organic extracts were dried over anhydr. Na2S04 and concentrated in vacuo to yield the crude title compound. Purification by recrystallization from the minimum amount of hot dichloromethane provided 7.0 g (54 percent yield) of the pure title compound.'H NMR (CH30H-d4) 8 8. 38 (d, J 4. 5 Hz, 1H), 7.88 (s, 1H), 7.65 (d, J4.5 Hz, 1H), 2.49 (s, 3H); MS (ESI) 167. 8 ([M+H] +, Cl35), 169.8 ([M+H] +, C137)
A mixture of l-bromo-2, 2-dimethoxypropane (42.4 g, 231.5 mmol) and conc. HC1 (890 uL, 28.9 mmol) in water (6.25 mL) was heated to 90C, for 15 min, cooled to r. t. and quenched with NaHC03. 2-Amino-3-chloropyrazine (Compound I in Scheme 1,0. 2 g, 1.54 mmol) was added and the resultant mixture was heated to 90C for 2h 30 min. The cooled reaction mixture was partitioned between 2M NaHC03 aq (100 mL) and dichloromethane (100 mL). The aqueous layer was separated and extracted with dichloromethane (5 x 100 mL). The combined organic extracts were dried over anhydr. Na2S04 and concentrated in vacuo to yield the crude title compound. Purification by recrystallization from the minimum amount of hot dichloromethane provided 7.0 g (54 % yield) of the pure title compound.'H NMR (CH30H-d4) 8 8. 38 (d, J 4. 5 Hz, 1H), 7.88 (s, 1H), 7.65 (d, J4.5 Hz, 1H), 2.49 (s, 3H); MS (ESI) 167. 8 ([M+H] +, Cl35), 169.8 ([M+H] +, C137)
A mixture of 8-chloro-2-methylimidazo [1, 2-a] pyrazine (Compound IIa in Scheme 1, 2.5 g, 15 mmol) and conc. HC1 (1.5 mL, 1.2 eq. , 18 mmol) in water (20 mL) was refluxed for 3 h. The cooled reaction mixture was concentrated in vacuo and the residual solid was extracted with hot ethanol (4 x 100 mL). The combined ethanolic filtrates were treated with KHC03 (1. 8 g, 1.2 eq. , 18 mmol), the resultant insoluble material was filtered and the filtrate was concentrated in vacuo to provide 2.0 g (89% yield) of the title compound. 1H NMR (DMSO-d6) S 12.15 (br s, 1H), 7.90 (s, 1H), 7. 68 (d, J 5. 5 Hz, 1H), 7.20 (t, J5. 5 Hz, 1H), 2.38 (s, 3H)
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 2h;
To a solution of 8-Chloro-2-methyl-imidazo[l,2-a]pyrazine (0.7 g, 4.18 mmol) in DCM (20 ml) is added N-bromosuccinimide (0.74 g, 4.18 mmol) and the reaction stirred at room temperature for 2h. After this time the solution is washed with saturated aqueous solution of Na2CO3 (2 x 20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-8-chloro- 2-methyl-imidazo[l,2-a]pyrazine (0.771 g, 75 %).
With potassium carbonate; triphenylphosphine;palladium diacetate; In 1,4-dioxane; water; at 80℃; for 16h;
Palladium (II) acetate (0.47 g, 2.09 mmol) was added to a stirred solution of intermediate 4 (5.0 g, 29.83 mmol), 4-pyridineboronic acid (8.15 g, 59.67 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) in a mixture of 1,4-dioxane (125 ml) and a 1.5 M solution of potassium carbonate (74.5 ml, 111.87 mmol). The mixture was stirred at 80 C for 16h. and then the solvents were evaporated in vacuo. The mixture was partitioned between water and DCM and the organic layer was separated, dried(Na2S04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 5/95). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 (4.2 g, 53%) as a pale brown solid.
53%
With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; at 80℃; for 16h;
Example A11 2-Methyl-8-pyridin-4-yl-imidazol[1,2-a]pyrazine Palladium (II) acetate (0.47 g, 2.09 mmol) was added to a stirred solution of intermediate 4 (5.0 g, 29.83 mmol), 4-pyridineboronic acid (8.15 g, 59.67 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) in a mixture of 1,4-dioxane (125 ml) and a 1.5 M solution of potassium carbonate (74.5 ml, 111.87 mmol). The mixture was stirred at 80 C. for 16 h. and then the solvents were evaporated in vacuo. The mixture was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 5/95). The desired fractions were collected and evaporated in vacuo to yield intermediate 11 (4.2 g, 53%) as a pale brown solid.
With N-iodo-succinimide; acetic acid; In dichloromethane; at 0 - 20℃; for 16h;
N-Iodosuccinimide (14.1 g, 62 mmol) was added to a stirred solution of intermediate 4 (9.58 g, 57 mmol) in a mixture of DCM and acetic acid at 0 C. The mixture was allowed to warm to RT and then stirred for 16 h. The mixture was diluted with further DCM and washed with a saturated solution of sodium carbonate and sodium thiosulfite. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude product was precipitated from diisopropyl ether to yieldintermediate 25 (16 g, 97%) as a pale brown solid which was used in the next step without further purification.
97%
With N-iodo-succinimide; acetic acid; In dichloromethane; at 0 - 20℃; for 16h;
Example A25 3-Iodo-<strong>[85333-43-3]8-chloro-2-methyl-imidazo[1,2-a]pyrazine</strong> N-Iodosuccinimide (14.1 g, 62 mmol) was added to a stirred solution of intermediate 4 (9.58 g, 57 mmol) in a mixture of DCM and acetic acid at 0 C. The mixture was allowed to warm to RT and then stirred for 16 h. The mixture was diluted with further DCM and washed with a saturated solution of sodium carbonate and sodium thiosulfite. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was precipitated from diisopropyl ether to yield intermediate 25 (16 g, 97%) as a pale brown solid which was used in the next step without further purification.
97%
With N-iodo-succinimide; acetic acid; In dichloromethane; at 0 - 20℃; for 16h;
N-Iodosuccinimide (14.1 g, 62 mmol) was added to a stirred solution of intermediate 6 (9.58 g, 57 mmol) in a mixture of DCM and acetic acid at 0 C. The mixture was allowed to warm to RT and then stirred for 16 h. The mixture was diluted with further DCM and washed with a saturated solution of sodium carbonate and sodium thiosulfite. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was precipitated from diisopropyl ether to yield intermediate 7 (16 g, 97%) as a pale brown solid which was used in the next step without further purification.
With N-iodo-succinimide; In dichloromethane; acetic acid; at 0 - 20℃; for 16h;
N-Iodosuccinimide (14.1 g, 62 mmol) was added to a stirred solution of intermediate 6(9.58 g, 57 mmol) in a mixture ofDCM and acetic acid at 0 C. The mixture was allowed to warm toRT and then stirred for 16 h. The mixture was diluted with further DCM and washed with a saturated solution of sodium carbonate and sodium thiosulfite.The organic layer was separated, dried (Na2S04), filtered and the solvents evaporatedin vacuo. The crude product was precipitated from diisopropyl ether to yieldintermediate 7 (16 g, 97%) as a pale brown solid which was used in the next step without further purification.
(2S,5R)-tert-butyl-5-hydroxy-2-methylpiperidine-1-carboxylate[ No CAS ]
[ 85333-43-3 ]
(2R,5R)-tert-butyl 2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.6 g
To a suspension of NaIl (556 mg, 13.9 mmol, 6() wt% in oil) in I)MF (10 mL) was added (2S, 5R)..teri-.hutyi 5hydroxy2methyipiperidine I carboxyiate (1.0 g, 4.7 mnioi) under nitrogen at RI. The mixture was stirred at RT for 1 hour, then a solution of 8-chioro-2- methylimidazo[i,2a1pyrazine (1.5 g, 8.9 mmoi) was added. The mixture was stirred at RT for 3hours, quenched with 20 mL of water and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.6 g) as a light yellow solid. LRIVIS mi?z (M+H?) 347.1 found, 347.1 required.
(2-(2H-1,2,3-triazol-2yl)phenyl)((2R,5R)-2-methyl-5-((2-methylimidazo[1,2-a]pyrazin-8-yl)amino)piperidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10 mg
With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
To a mixture of product from step 2 (51.3 mg, 0.18 mmol), 8-chloro2 methyhmidazo[1,2-?aipyrazine (30 mg, 0.18 mmol), Cs2CO3 (114 mg, 0.35 mmoi), and Xphos(10 mg) in DMF (3 mL) was added Pd2(dba)3 (8 mg). The mixture was heated to 100 C under N2 protection overnight. LCMS indicated that starting material disappeared, the mixture was filtered, and the filtrate was purified by Prep?HPLC to give the title compound (10.0 rng) as yellow oil. LRMS m/z (M-fH) 417.1 found, 417.1 required.
8-chloro-3-fluoro-2-methylimidazo[ 1,2-a]pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With Selectfluor; In tetrahydrofuran; water; acetonitrile; at 0 - 20℃; for 72h;
To a solution of <strong>[85333-43-3]8-chloro-2-methylimidazo[1,2-a]pyrazine</strong> (2.5g, 14.9 mmol) inacetonitrile (25 mL) at 0C, was added a solution of Selectfluor (5.3g, 14.9 mmol) in THF:Water(1:1, 25 mL) for 20 mm. The reaction mixture was allowed to warm to room temperature and stined at room temperature for 72h. The reaction mixture was concentrated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure to get the crude product. The crude product was purified by column chromatography (60 - 120 mesh silica gel and 0-30% ethyl acetate in hexane) to get 8-chloro-3-fluoro-2-methylimidazo[1,2-a]pyrazine (0.8g, 27%). ?H NMR (300 MHz, CDC13): oe 7.82 (d, J= 4.5 Hz, 1H), 7.70 (d, J= 4.5 Hz, 1H), 2.51 (s, 3H); LC-MS: 186.2[M+Hj
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