* 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.
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.
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)
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
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.
With bromine; sodium acetate; potassium bromide In methanol at -10℃; for 0.0833333 h;
Imidazo[1,2-α]pyrazine (90 mg, 0.76 mmol) and sodium acetate (75 mg, 0.91 mmol) were dissolved in methanol (2 ml) saturated with potassium bromide and cooled to -10° C. before dropwise addition of bromine (121 mg, 0.76 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1N sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was dissolved in water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (2*40 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give 3-bromoimidazo[1,2-α]pyrazine (150 mg, 100percent) as a white crystalline solid: δH (400 MHz, CDCl3) 7.80 (1H, s), 6.87 (1H, d, J 7), 7.71 (1H, s), 8.27 (1H, d, J 7).
619 mg
With N-Bromosuccinimide In acetonitrile at 20℃;
Imidazo[1,2-a]pyrazine (420 mg, 3.53 mmol) was dissolved in acetonitrile (10 mL).N-bromosuccinimide (691 mg, 3.88 mmol) was added thereto, and the mixture was reacted at room temperature overnight.After the reaction is completed, a saturated sodium hydrogencarbonate solution is added thereto.Extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and then dry the solvent.The residue was purified by silica gel column chromatography to give a yellow solid,619mg.
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
7
[ 274-79-3 ]
[ 87597-26-0 ]
Reference：
[1] Tetrahedron, 2011, vol. 67, # 47, p. 9063 - 9066
[2] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[3] Australian Journal of Chemistry, 1984, vol. 37, # 6, p. 1357 - 1361
8
[ 274-79-3 ]
[ 63744-21-8 ]
[ 87597-26-0 ]
[ 57948-41-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 206 - 212
9
[ 274-79-3 ]
[ 91476-80-1 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hydrogen In 2-methoxy-ethanol at 20℃;
Imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmol) was dissolved in 2-methoxyethanol (100 ml). Platinum(IV) oxide (1.2 g, 5.13 mmol) was added, and the mixture was stirred overnight at room temperature, under a hydrogen atmosphere of 4 bar, in an autoclave. The reaction mixture was flooded with nitrogen, filtered over Celite, concentrated and coevaporated with toluene. Purification was carried out by column chromatography dichloromethane/7 N ammonia in methanol 95:5). Yield: 5.7 g (76percent)
68%
With 5%-palladium/activated carbon; hydrogen In 1,2-dimethoxyethane at 20 - 25℃; for 30 h;
Step 1 The indole obtained [1,2-A] pyrazine (10g, 0.08mmol) was dissolved in 100mL of ethylene glycol monomethyl ether, was added 5percent palladium on carbon (2G), quickly replaced with hydrogen three times, at room temperature (20-25 ) The reaction was stirred, TLC detection reaction process, the reaction is complete after 30 hours, suction filtered through celite pad, and the filtrate was concentrated by rotary evaporation and purified by column chromatography by chromatography to give 5,6,7,8- hydrogen-imidazo [1,2-A] pyrazine 7g, the the yield of about 68percent
38.7%
With platinum(IV) oxide; hydrogen In 2-methoxy-ethanol for 12 h;
Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 4c (200 mg, yield 38.7percent) as a yellow oil. MS m/z (ESI): 124.1 [M+1]
38.7%
With platinum(IV) oxide; hydrogen In 2-methoxy-ethanol for 12 h;
Step 2 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 4c (200 mg, yield 38.7percent) as a yellow oil. MS m/z (ESI): 124.1 [M+1]
512 mg
With platinum(IV) oxide; hydrogen In methanol at 20℃; for 14 h;
The title compound was prepared from imidazo[1,2-a]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration gave the title compound (512 mg) as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 3.37 (t, 1H, J=5.5 Hz), 4.18 (t, 2H, J=5.6 Hz), 4.88 (s, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.33 (d, 1H)
With sodium hydrogencarbonate; at 100℃; for 48h;Inert atmosphere;
Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40% 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 50.0%) as a brown solid. MS m/z (ESI): 120.1 [M+1]
50.0%
With sodium hydrogencarbonate; at 100℃; for 48h;
Step 1 imidazo[1,2-c]pyrazine Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40% 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 50.0%) as a brown solid. MS m/z (ESI): 120.1 [M+1]
35%
With sodium hydrogencarbonate; In water; at 100℃; for 48h;
A mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50% 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+5% NH4OH [35%].
35%
With sodium hydrogencarbonate; In water; at 100℃; for 48h;
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 (50% 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 + 5% NH4OH [35%] .
24%
With sodium hydrogencarbonate; In water; at 100℃; for 48h;
A mixture of 2-aminopyrazine (25 g, 262.9 mmol) and chloroacetaldehyde (50% 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+5% NH4OH [35%]). Yield: 7.6 g (24%)
In ethanol; at 90℃; for 5h;
A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50% wt in H2O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 900C in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichloromethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product.
0.8 g
In ethanol; water; at 90℃; for 5h;Sealed tube;
Imidazo[1,2-aJpyrazine: A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50% wt in H,O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90C5 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 10% MeOH/DCM) to provide 0.8 g of product.
In ethanol;Reflux;
Step 1: Imidazo[1,2-a]pyrazine A round bottom set up with reflux condenser was charged with pyrazin-2-amine (1000 mg, 10.52 mmol), 2-chloroacetaldehyde (-50% wt) (2.03 ml, 31.55 mmol), and EtOH (23 mL) and heated under reflux overnight. Next day LC/MS showed completion. The mixture was concentrated and passed through a plug of silica (solvent used: 1% MeOH/DCM) to afford imidazo[1,2-a]pyrazine as off-white solid. MS [M+H]=120.1; Calc'd for C6H5N3: 119.1
Stage B: preparation of 3,5-dibromo<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong>. A solution of 12 ml of bromine in 10 ml of acetic acid is added dropwise to a solution of 6 g (50.5 mmol) of <strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> in 70 ml of acetic acid. The solution brought to reflux for one and a half hours is then evaporated under vacuum. The residue is then dissolved in water, alkalinized with Na2 CO3 and extracted with dichloromethane. After chromatography on a neutral alumina column (eluant=anhydrous ether), 8,38 g (Yld=60%) of 3,5-dibromo<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> (m.p. 150 C.) are obtained.
With hydrogen;platinum(IV) oxide; In 2-methoxy-ethanol; at 20℃; under 3000.3 Torr;
Imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmol) was dissolved in 2-methoxyethanol (100 ml). Platinum(IV) oxide (1.2 g, 5.13 mmol) was added, and the mixture was stirred overnight at room temperature, under a hydrogen atmosphere of 4 bar, in an autoclave. The reaction mixture was flooded with nitrogen, filtered over Celite, concentrated and coevaporated with toluene. Purification was carried out by column chromatography dichloromethane/7 N ammonia in methanol 95:5). Yield: 5.7 g (76%)
68%
With 5%-palladium/activated carbon; hydrogen; In 1,2-dimethoxyethane; at 20 - 25℃; for 30h;
Step 1 The indole obtained [1,2-A] pyrazine (10g, 0.08mmol) was dissolved in 100mL of ethylene glycol monomethyl ether, was added 5% palladium on carbon (2G), quickly replaced with hydrogen three times, at room temperature (20-25 ) The reaction was stirred, TLC detection reaction process, the reaction is complete after 30 hours, suction filtered through celite pad, and the filtrate was concentrated by rotary evaporation and purified by column chromatography by chromatography to give 5,6,7,8- hydrogen-imidazo [1,2-A] pyrazine 7g, the the yield of about 68%
38.7%
With platinum(IV) oxide; hydrogen; In 2-methoxy-ethanol; for 12h;
Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydro<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> 4c (200 mg, yield 38.7%) as a yellow oil. MS m/z (ESI): 124.1 [M+1]
38.7%
With platinum(IV) oxide; hydrogen; In 2-methoxy-ethanol; for 12h;
Step 2 5,6,7,8-tetrahydro<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> Imidazo[1,2-a]pyrazine 4b (500 mg, 4.20 mmol) was dissolved in 5 mL of 2-methoxyethanol, followed by addition of platinum dioxide (100 mg, 0.36 mmol), and the reactor was purged with hydrogen for three times. After stirring for 12 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydro<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> 4c (200 mg, yield 38.7%) as a yellow oil. MS m/z (ESI): 124.1 [M+1]
With hydrogen;platinum(IV) oxide; In 2-methoxy-ethanol; at 20℃; under 3000.3 Torr;
The <strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> (7.2 g, 60.44 mmole) was dissolved in 2-methoxyethanol (100 ml) and PtO2 (1.2 g, 5.13 mmole) was added. The reaction mixture was stirred overnight at RT in an autoclave under a hydrogen atmosphere (4 bar). The autoclave was then flushed with nitrogen, the reaction mixture was filtered through filter earth, concentrated, and the solvent residues were then extracted with toluene. Purification was carried out by column chromatography on silica gel (DCM/7 N NH3 in methanol, 95:5)
With hydrogen;platinum(IV) oxide; In 2-methoxy-ethanol; at 20℃; under 3000.3 Torr;In autoclave;
Stage 2. The imidazo [1 , 2-a] pyrazine (7.2 g, 60.44 mmole) was dissolved in 2-methoxyethanol (100 ml) and Pttheta2 (1.2 g, 5.13 mmole) was added. The reaction mixture was stirred overnight at RT in an autoclave under a hydrogen atmosphere (4 bar). The autoclave was then flushed with nitrogen, the reaction mixture was filtered through filter earth, concentrated, and the solvent residues were then extracted with toluene. Purification was carried out by column chromatography on silica gel (DCM / 7 N NH3 in methanol, 95:5)
With hydrogen;platinum(IV) oxide; In methanol; at 25℃; under 760.051 Torr; for 24h;
Imidazo[1 ,2-a]pyrazine(l1 ) (4.38 g, 36.8 mmol) was dissolved in methanol (100 mL) and hydrogenated at 1 atm/25 0C hydrogen over platinum(IV) oxide (0.522 g, 1.838 mmol) for 24 h. The catalyst was filtered and the filtrate concentrated to afford afford product in 4.8 g that was used without further purification. LC/MS = 124 (M+H)+, retention time = 0.34 minutes (2 minute method (high pH)).
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In ethanol; under 2327.23 Torr; for 16h;
Step 2: 5,6,7,8-Tetrahydro<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> Imidazo[1,2-a]pyrazine (250 mg, 2.1 mmol) and palladium on carbon (10%) (55.8 mg, 0.53 mmol) were placed in a pressure resistant bottle and suspended under nitrogen in 0.5M HCl/EtOH. The mixture was stirred under at 45 psi H2 for 16 hrs. LC/MS showed completion. The next day, the reaction mixture was passed through celite cake. The filtrate was concentrated under reduced pressure to afford a tan solid. This was used directly without further purification. MS: [M+H]=124.2; Calc'd for C6H9N3: 123.2.
512 mg
With platinum(IV) oxide; hydrogen; In methanol; at 20℃; for 14h;
The title compound was prepared from <strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration gave the title compound (512 mg) as a viscous oil. 1H NMR (500 MHz, CD3OD) delta 3.37 (t, 1H, J=5.5 Hz), 4.18 (t, 2H, J=5.6 Hz), 4.88 (s, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.33 (d, 1H)
Synthesis of Imidazo[1,2-a]pyrazine-Intermediate C 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 (48%, 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 20% 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 94%). 1H-NMR (400 MHz, DMSO-d6) delta 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].
11
[ 123-38-6 ]
[ 274-79-3 ]
5-(1-hydroxypropyl)imidazo[1,2-a]pyrazine[ No CAS ]
3-(1-hydroxypropyl)imidazo[1,2-a]pyrazine[ No CAS ]
With hydrogen bromide; In ethanol; water; at 70 - 80℃; for 17h;
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 (48%, 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 20% 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 94%). 1H-NMR (400 MHz, DMSO-d6) delta 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 24h;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. 48% 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 10% 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 0-100% [25% 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1 ,2-a]pyrazine (2.86 g, 24.01 mmol, 24.01 % 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)
To a solution of <strong>[274-79-3]imidazo[1,2-a]pyrazine</strong> (intermediate C) (2.8 g, 23.5 mmol) in AcOH (acetic acid) (200 ml) was added bromine (6 ml, 5 eq.) via addition funnel, with the reaction flask protected from light. After addition, the flask was sealed. The mixture was stirred at rt for 24 hr., 6 ml (5 eq.) of additional Br2 was added to the reaction mixture, which was further stirred at rt for 48 hr. The mixture was evaporated to remove Br2 and acetic acid, and the residue was dissolved in 10% IPA/DCM, washed with sat. Na2CO3 (300 ml). The organics were combined, dried and concentrated to afford 5.9 g (yield 97%) of 3,5-dibromo-<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong>. 1H-NMR (400 MHz, DMSO-d6) delta 9.05 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H). MS m/z 278 [M++1].
With hydrogen bromide; In ethanol; water; for 18h;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 (48%, 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 1% conc. ammonia on a gradient of methanol (1-4%) gave imidazo[1,2-alpha]pyrazine (90 mg, 72%) as a white crystalline solid: deltaH (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).
With concentrated aqueous HBr; In N-methyl-acetamide; ethanol; dichloromethane; water;
Stage preparation of imidazo[1,2-a]pyrazine A mixture of 34 g (0.2 mol) of bromoacetaldehyde dimethyl acetal, 6,6 ml of concentrated aqueous HBr solution and 28 ml of distilled water is brought to reflux for one hour. After reaction, the mixture is alkalinized and extracted with ether. This organic phase is added to a solution of 19 g (0.2 mol) of aminopyrazine in 50 ml of dimethylformamide (DMF). The ether is removed by distillation and the mixture is maintained with stirring and under a stream of nitrogen for 12 hours. After reaction, the DMF is distilled off; the reaction medium is dissolved in 150 ml of anhydrous ethanol, and then brought to reflux for one hour. The alcohol is then removed by distillation; the residue is dissolved in water, alkalinized with Na2 CO3 and extracted using dichloromethane. After chromatography on a neutral alumina column (eluant =anhydrous ether), 10.7 g (Yld=45%) of imidazo[1,2-a]pyrazine (m.p. 84 C.). are obtained.
536 mg
With hydrogenchloride; In ethanol; for 14h;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 (100% ethyl acetate, 10% methanol in ethyl acetate, then 10% methanol in dichloromethane) to give 536 mg of the title compound as a solid. 1H NMR (500 MHz, CDCl3) delta 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 ethanol;Reflux;
2-Aminopyrazine (500 mg, 5.26 mmol) was dissolved in ethanol (25 mL), and bromoacetaldehyde dimethyl acetal (0.93 mL, 7.89 mmol) and 40% 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 20% isopropanol / dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was purified by silica gel column chromatography to give a white solid420mg.
With bromine; sodium acetate; potassium bromide; In methanol; at -10℃; for 0.0833333h;
Imidazo[1,2-alpha]pyrazine (90 mg, 0.76 mmol) and sodium acetate (75 mg, 0.91 mmol) were dissolved in methanol (2 ml) saturated with potassium bromide and cooled to -10 C. before dropwise addition of bromine (121 mg, 0.76 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1N sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was dissolved in water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (2*40 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give 3-bromoimidazo[1,2-alpha]pyrazine (150 mg, 100%) as a white crystalline solid: deltaH (400 MHz, CDCl3) 7.80 (1H, s), 6.87 (1H, d, J 7), 7.71 (1H, s), 8.27 (1H, d, J 7).
With bromine; sodium acetate; potassium bromide; In methanol; at -10℃; for 0.166667h;
lmidazo[1 ,2-a]pyrazine (1.191 g, 10 mmol, Intermediate 1 ) and sodium acetate (0.984 g, 12.00 mmol) were suspended in methanol (10 ml) saturated with potassium bromide (excess) and cooled to -10 0C. Bromine (0.515 ml_, 10.00 mmol) was added dropwise and the mixture stirred at -10 0C for 10 min. The solution was quenched by the addition of 1 N sodium sulfite solution (10 ml) and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and 50% saturated sodium bicarbonate solution (100 ml). The aqueous phase was extracted with ethyl acetate (2 x 100 ml), combined, washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give crude 3-bromoimidazo[1 ,2-a]pyrazine (1.66 g, 8.38 mmol, 84 % yield) that was used in subsequent steps without further purification 3- bromoimidazo[1 ,2-a]pyrazine (1.66 g, 8.38 mmol, 84 % yield). LC/MS [M+H]+ = 198, 200, retention time = 0.53 minutes (2 minute method). 1H NMR (CDCI3, 400 MHz) d 9.09 (s, 1 H), 8.08 (s 1 H), 7.94 (s, 1 H), 7.81 (s, 1 H).
619 mg
With N-Bromosuccinimide; In acetonitrile; at 20℃;
Imidazo[1,2-a]pyrazine (420 mg, 3.53 mmol) was dissolved in acetonitrile (10 mL).N-bromosuccinimide (691 mg, 3.88 mmol) was added thereto, and the mixture was reacted at room temperature overnight.After the reaction is completed, a saturated sodium hydrogencarbonate solution is added thereto.Extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, filter, and then dry the solvent.The residue was purified by silica gel column chromatography to give a yellow solid,619mg.
With potassium carbonate; triphenylphosphine;palladium diacetate; In 1,4-dioxane; at 75℃; for 24h;
Preparation of compound 4a: 3-(6-Chloropyrazin-2-yl)<strong>[274-79-3]imidazo[1,2-a]pyrazine</strong>A mixture of imidazo[1 ,2-a]pyrazine (2.0 g, 16.8 mmol), 2-bromo-6-chloropyrazine (4.9 g, 25.2 mmol), palladium (II) acetate (0.78 g, 3.36 mmol), thphenylphosphine (0.45 g, 1.7 mmol), and potassium carbonate (2.3 g, 16.8 mmol) in dioxane (40 mL) was heated at 75 0C for 24 h. The reaction was filtered hot, rinsed with dioxane, and the filtrate was concentrated under reduced pressure. The product was recrystallized from EtOAc which gave the title compound 4a as a beige solid (2.2 g, 55% yield). 1 H NMR (400 MHz, DMSO-c/6) delta ppm 9.43 (s, 2 H), 9.29 (s, 1 H), 8.87 (s, 1 H), 8.72 (s, 1 H), 8.23 (s, 1 H).
palladium diacetate; triphenylphosphine; In ISOPROPYLAMIDE; at 150℃; for 5h;Microwave irradiation;
lmidazo[1 ,2-a]pyrazine (0.715 g, 6 mmol, Intermediate 1 ), 2-bromopyridine (0.644 ml_, 6.60 mmol), triphenylphosphine (0.315 g, 1.200 mmol), and palladium(ll) acetate (0.135 g, 0.600 mmol) were heated in Lambda/,Lambda/-dimethylacetamide (DMA) (8 ml.) at 150 0C for 5 hr in a microwave reactor. The bulk of the DMA was removed in vacuo and the residue partitioned between 10% isopropanol/DCM (100 ml) and saturated sodium bicarbonate solution (50 ml). Solids were removed by filtration through celite and the filtrated separated. The aqueous phase was extracted with 10% isopropanol/DCM (3 x 50 ml. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil, (2.6 g). The crude oil was partially purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of [(2M ammonia methanol/Ethyl acetate]/ethyl acetate) to afford material (1.59 g) which was repurified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of [(2M ammonia methanol/Ethyl acetate]/ethyl acetate) to afford 3-(2-pyridinyl)imidazo[1 ,2-a]pyrazine (0.319 g, 1.626 mmol, 27.1 % yield).1H NMR (CDCI3, 400 MHZ) d 9.82 (dd, 1 H, J = 3.6, 1.2 Hz), 9.19 (d, 1 H, J = 1.6Hz), 8.72 (1 H, m), 8.03 (d, 1 H, J = 4.8 Hz), 7.84-7.91 m (2H), 7.29-7.21 m (2H).
With hydrogenchloride; In ethanol; water; at 70 - 80℃; for 12h;pH 3-4;
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 37% 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 90%
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; Trimethylacetic acid; In water; N,N-dimethyl-formamide; at 110℃; for 24h;
General procedure: Imidazo[1,2-a]pyrazines (0.3 mmol), 2-chlorobenzaldehyde (0.33 mmol, 1.1 equiv.), K2CO3 (0.9 mmol, 3 equiv.), PivOH (30 molpercent), Pd(OAc)2 (7.5 mol percent), and Xantphos (15 mol percent) were added to a 10 mL round-bottomed flask, and then a mixed solvent of 3 mL of DMF and 30 uL of H2O was added. The mixture was stirred under air at 110 °C for 24 h. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using dichloromethane/methanol as the eluent to give the pure product.
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; Trimethylacetic acid; In water; N,N-dimethyl-formamide; at 110℃; for 24h;Catalytic behavior;
General procedure: Imidazo[1,2-a]pyrazines (0.3 mmol), 2-chlorobenzaldehyde (0.33 mmol, 1.1 equiv.), K2CO3 (0.9 mmol, 3 equiv.), PivOH (30 mol%), Pd(OAc)2 (7.5 mol %), and Xantphos (15 mol %) were added to a 10 mL round-bottomed flask, and then a mixed solvent of 3 mL of DMF and 30 uL of H2O was added. The mixture was stirred under air at 110 C for 24 h. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using dichloromethane/methanol as the eluent to give the pure product.
Stage #1: trifluoromethylsulfonic anhydride; 5-(diphenylphosphaneyl)-2-(trifluoromethyl)pyridine; imidazo[1,2-a]pyrazine In dichloromethane at -50℃; for 1h; Inert atmosphere;
Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at -78 - 20℃; for 0.333333 - 0.5h; Inert atmosphere;
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