* 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.
With ammonia In water at 180℃; for 8 h; sealed vessel
60ml) at O0C was added, diethylmalonate (2.1moleq) in THF (60ml) and 2,6- dichloropyrazine (2Og) in THF (40ml). The mixture was then heated to reflux for 18hrs before being allowed to cool and 2M Hydrochloric acid (100ml) added. The resulting two layers were separated and the THF layer partially concentrated under vacuum to give a solution containing 2-(6-chloro-pyrazin-2-yl)-malonic acid diethyl ester. This solution was EPO <DP n="6"/>then cooled to 100C and 2M sodium hydroxide (328ml) added. After stirring for 24hrs the mixture was washed with methyl isobutyl ketone [MIBK] (200ml) and the organic layer discarded. The aqueous layer containing 2-(6-chloro-pyrazin-2-yl)-malonic acid was then added to 6M hydrochloric acid (135ml), maintaining a reaction temperature of 20-25°C to facilitate the decarboxylation.The resulting 6-chloro-pyrazin-2-yl-acetic acid partially precipitated from the mixture, but for ease of isolation was extracted into MIBK (130ml), dried using MgSO4, filtered and evaporated to give a yellow solid. The resulting crude solid 22.4g was then crystallised from methyl-t-butyl ether (MTBE) to give pure 6-chloro-pyrazin-2-yl-acetic acid , 15.4g 67percent yield based on 2,6-dichlorpyrazine.The 6-chloro-pyrazin-2-yl-acetic acid (20.Og) was then treated with aqueous ammonia (120ml) in a sealed vessel at 180°C (35 bar) for 8hrs. The mixture was then cooled to 20°C and water (40ml) added, before being concentrated under vacuum to remove the ammonia. The product was extracted into ethyl acetate and the solution treated with charcoal, before being dried using MgSO4, filtered and evaporated to give 6-methyl-2-pyrazin-2-ylamine as a pale green solid 9.Og, 71percent yield based on 6-chloro-pyrazin-2-yl-acetic acid. Analysis 2-(6-Chloro-pyrazin-2-yl)-malonic acid diethyl esterMS (EI +ve) 273/275 (M+H) IH NMR (CDCl3) :δ 8.7 (IHs), 8.5 (IHs), 4.9 (IHs), 4.2(2x2Hq), 1.2 (2x3Ht).6- Chloro-pyrazin-l-yl-acetic acidMS (EI +ve) 173/175 (M+H)IHNMR (CDCl3) :δ 8.55 (IH s), 8.50 (IH s); 3.9 (2Hs).6-Methyl-2-pyrazin-2-ylamine MS (GC/MS) : 100percent RT 2.0mins, M+H = 110IHNMR (CDC13) : δ 7.8 (IHs), 7.8 (IHs), 4.4 (2H bs), 2.4 (3Hs). Mpt : 124-1250C
Reference：
[1] Patent: WO2007/35153, 2007, A1, . Location in patent: Page/Page column 2; 4-5
[2] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 5, p. 1451 - 1456
[3] Patent: WO2007/35154, 2007, A1, . Location in patent: Page/Page column 28-29
2
[ 544-97-8 ]
[ 33332-28-4 ]
[ 5521-56-2 ]
Yield
Reaction Conditions
Operation in experiment
28%
at 105℃; for 16.25 h;
A. 6-Methylpyrazine-2-ylamine. To a solution containing 6-chloro-2- pyrazineamine (5.0 g, 38.75 mmol) in 1,4-dioxane (70 mL) was added [1,3- bis(diphenylphosphino]Ni(II)Cl2 (2.10 g, 38.76 mmol), followed by drop-wise addition of dimethylzinc in toluene (38.75 mL, 2.0 M, 77.50 mmol), over 15 min. The solution was allowed stir at 105 °C for 16 hours. The solution was then condensed under reduced pressure, diluted with ethyl acetate and filtered through celite to remove the nickel salts. The resultant slurry was purified via Biotage silica gel chromatography (0-8percent methanol in dichloromethane) to afford the title compound as an orange solid (1.18 g, 28percent yield). MS (ESI) m/z 1 10.3 [M+ 1]+.
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147
5
[ 6761-50-8 ]
[ 5521-56-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1997, vol. 32, # 3, p. 195 - 203
[2] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147
[3] Journal of the American Chemical Society, 1945, vol. 67, p. 802,804
[4] Journal of Organic Chemistry, 1959, vol. 24, p. 345,348
6
[ 38557-71-0 ]
[ 5521-56-2 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1580,1582
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1580,1582
9
[ 13401-38-2 ]
[ 5521-56-2 ]
Reference：
[1] Journal of the American Chemical Society, 1945, vol. 67, p. 802,804
10
[ 13401-38-2 ]
[ 5521-56-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1997, vol. 32, # 3, p. 195 - 203
11
[ 5521-56-2 ]
[ 74290-69-0 ]
Yield
Reaction Conditions
Operation in experiment
36%
With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 5.25 h; Inert atmosphere; Cooling with ice
Compound 10: 5-Bromo-6-methyl-pyrazin-2-ylamine. Under inert condition, to a solution 6-amino-2-methylpyrazine (100 mg, 1.0 equiv.) in a mixture of DMSO (4.6 mL) and water (0.2 mL) cooled by an ice bath, NBS (179 mg, 1.1 equiv.) was added in 3 portions. The light yellow mixture was stirred for 15 minutes, and then for 5 hrs at room temperature. The reaction mixture was hydrolysed with NaHCO3 saturated solution (25 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by flash-chromatography afforded compound 10 as a light yellow solid in 36percent yield. 1H-NMR (400 MHz, DMSO): 2.34 (bs, 3H, C-CH3); 6.52 (bs, 2H, NH2); 7.49 (s, 1H, Ar). M/Z (M[79Br]+H)+ = 188.2.
36%
With N-Bromosuccinimide In water; dimethyl sulfoxide at 20℃; for 5 h;
Under inert condition, to a solution 6-amino-2-methylpyrazine (100 mg, 1.0 equiv.) in a mixture of DMSO (4.6 ml) and water (0.2 ml) cooled by an ice bath, NBS (179 mg, 1.1 equiv.) was added in 3 portions. The light yellow mixture was stirred for 15 minutes, and then for 5 hrs at room temperature. The reaction mixture was hydrolysed with NaHCO3 saturated solution (255 ml) and extracted with EtOAc (30 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by flash-chromatography afforded compound 10 as alight yellow solid in 36percent yield. 1H-NMR (400 MHz, DMSO): 2.34 (bs, 3H, C-CH3); 6.52 (bs, 2H, NH2); 7.49 (s, 1H, Ar). M/Z(M[79Br]+H)+ = 188.2.
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147
13
[ 5521-56-2 ]
[ 74290-66-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
With pyridine; bromine In dichloromethane at 20℃;
To a solution of 6-methylpyrazin-2-amine (14.40 g, 132 mmol) and pyridine (26.0 g, 330 mmol) in DCM (300 mL) was added dropwise slowly bromine (53.00 g, 330 mmol). Afterthe addition, the mixture was stirred at rt overnight. Water (150 mL) was added to quench thereaction, and the resulting mixture was partitioned. The organic phase was washed with saturatedbrine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentratedin vacuo to give the title compound as a yellow solid (34.01 g, 96percent ).MS (ESI, pos. ion) m/z: 267.9 [M+Ht.
95%
With pyridine; bromine In chloroform at 20℃;
B. 3,5-Dibromo-6-methylpyrazine-2-ylamine. 6-Methylpyrazine-2- ylamine (1.18 g, 10.82 mmol) and pyridine (1.79 g, 22.72 mmol) were combined in chloroform (100 mL) at ambient temperature. Bromine (3.63 g, 22.72 mmol) in chloroform (5 mL) was then added drop-wise over 5 minutes. Upon consumption of the starting material, as indicated by TLC, the reaction solution was transferred to a sepratory funnel and the organic layer washed twice with water. The organics were dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (2.70 g, 95 percent yield). MS (ESI) m/z 268.0[M+2]+.
86%
With bromine In chloroform at 20℃; for 0.0833333 h;
At room temperature,Bromine (5.89 g, 36.54 mmol, 1.90 mL)Of chloroform (15 mL)The solution was slowly added dropwise over 5 minutes6-methylpyrazin-2-amine (2.00 g, 18.33 mmol)In chloroform (170 mL).After completion of the dropwise addition, the reaction was stirred at room temperature for 4.5 h.The reaction was quenched with water (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate and the organic layer was concentrated under reduced pressure.Column separation (petroleum ether / ethyl acetate (v / v) = 2/1)To give 4.20 g of a yellowish yellow solid in 86.0percent yield.
11.9 g
With 2,6-dimethylpyridine; bromine In acetonitrile at 10℃;
Following a literature procedure (WO 2007/035154, p 29), bromine (12 mL, 231.0 mmol) was added portion-wise over 5 minutes into a cooled solution of 6-methylpyrazin-2-amine (9.72 g, 89.0 mmol) and lutidine (31.0 mL, 266.0 mmol) in dry acetonitrile at 10° C. The reaction was maintained overnight, allowing the cooling bath to expire. The reaction was queched with aqueous 2.0 M sodium sulfite solution and the pH was adjusted to 8 with the addition of 6 M NaOH. The mixture was concentrated in vacuo and the remaining aqueous portion was cooled to 5° C. overnight. The resulting brown solid was isolated by filtration and triturated with a 9:1 EtOAc-hexanes solution to furnish 11.9 g of 3,5-dibromo-6-methylpyrazin-2-amine. The collected filtrate was concentrated and the resulting solid triturated again to provide an additional 2.2 g of product: LCMS (m/z): 267.9 (MH++2), tR=0.80 min.
3.1 g
With N-Bromosuccinimide In tetrahydrofuran at 10 - 20℃; for 2.25 h;
[0280] 3,5-Dibromo-6-methylpyrazin-2-amine VII: To a solution of 6- methylpyrazin-2-amine VI (2.00 g, 18.3 mmol) in THF (40 mL) at 10 °C, was added N- bromosuccinimide (6.70 g, 37.6 mmol) portion wise over 15 min and the mixture allowed to warm to room temperature while stirring. After 2 h, the reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica, gradient, hexanes to EtOAc) to provide 3,5-dibromo-6- methylpyrazin-2-amine VII (3.10 g, 64percent) as an orange solid: NMR (400 MHz, CDCI3) δ: 4.93 (bs, 2H), 2.38 (s, 3H).
[1,3- bisdiphenylphosphino]Ni(II)Cl2; In 1,4-dioxane; toluene; at 105℃; for 16.25h;
A. 6-Methylpyrazine-2-ylamine. To a solution containing 6-chloro-2- pyrazineamine (5.0 g, 38.75 mmol) in 1,4-dioxane (70 mL) was added [1,3- bis(diphenylphosphino]Ni(II)Cl2 (2.10 g, 38.76 mmol), followed by drop-wise addition of dimethylzinc in toluene (38.75 mL, 2.0 M, 77.50 mmol), over 15 min. The solution was allowed stir at 105 °C for 16 hours. The solution was then condensed under reduced pressure, diluted with ethyl acetate and filtered through celite to remove the nickel salts. The resultant slurry was purified via Biotage silica gel chromatography (0-8percent methanol in dichloromethane) to afford the title compound as an orange solid (1.18 g, 28percent yield). MS (ESI) m/z 1 10.3 [M+ 1]+.
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In tetrahydrofuran; diethyl ether; for 3h;
Example 29: Preparation of:2-(4-Ch]oro-2-mophiholin-4-yl-1.24hiazol-5-yl)-5-(dicvcloprorhoyImethylV3,7-dimethyl-5H-pyitauolof2.3- ipyrazine; Part A: 2-Amino-6-methy] pyrazine; A solution of zinc chloride (2.0M in THF, 96.5 mL, 48.2 mmol, 5.0 equiv.) is treated dropwise with methylmagnesium bromide (3.0 M in Et2O, 32.2 mL, 96.5 mmoi, 10.0 equiv.) at 0 °C. The mixture is wanned to room temp and stirred for 45 min. A solution of 2-amino-6-chloro pyrazine (1.25 g. 9.65 mmol, 1.0 equiv) and NiC12(dppp) (157 mg, 0.29 mmol, 0.03 equiv) in THF (15 mL) is added to the freshly prepared dimethylzinc reagent. The reaction mixture is stirred under for 3h and cooied to room temp. The reaction is quenched carefully with sat'd NH4CI solution and allowed to stir overnight. The layers are separated and the aqueous layer is extracted with EtOAc (2 X 30 mL). The combined organic extracts are washed with brine, dried over Na2Spsi4 and concentrated under reduced pressure to give a cream-colored solid that is used without further purification. MS = 110.08 (M +1). 1H NMR (400 MHz, CDCI3) delta 7.78 (IH, s), 7.72 (IH, s), 4.59 (2H, bs), 2.35 (3H, s).
With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; toluene; at 20 - 95℃;Inert atmosphere;
Following a literature procedure (Walters, I. A. S. Tetrahedron Lett. 2006, 47, 341), a solution of dimethylzinc (2.0 M in toluene, 75.0 mL, 150.0 mmol) was carefully added in 25 mL portions to a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (10.0 g, 77.0 mmol) and 1,3-bis(diphenylphosphino)propane-nickel (II) chloride (4.2 g, 7.8 mmol) were dry in dioxane (400 mL) under a nitrogen atmosphere. The reaction was stirred at rt for 2 h and then heated to 50° C. for 1 h and 95° C. overnight. The reaction was allowed to cool to rt and an additional charge of dimethylzinc was added (22 mL, 44 mmol) and the reaction was then maintained at 95° C. overnight. The reaction was cooled to rt, quenched over 15 min with MeOH and then concentrated to a brown solid. Water and EtOAc were added to the solid, and the mixture was sonicated. The solid was removed by filtration and brine was added to the EtOAc-water mixture. The layers were separated, and the organic layer was dried (Na2SO4), and concentrated to give 9.72 g (?70 purity) of 6-methylpyrazin-2-amine, which was carried forward without further purification: LCMS (m/z): 110.0 (MH+), tR=0.21 min.
Intermediate 1 : 6-Methyl-2-pyrazinamine <n="27"/>; Dimethyl zinc (15.44 ml, 30.9 mmol) was added to a solution of 6-chloro-2- pyrazinamine (2 g, 15.44 mmol) and NiCI2(dppp) (0.837 g, 1.544 mmol) in dry 1 ,4- dioxane (75 ml) and the mixture was refluxed for 24 hours. The mixture was then cooled to room temperature, quenched with methanol and concentrated in vacuum. The residue was partitioned between EtOAc and brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated. The residue was purified by silica chromatography (MeOH-NH3-DCM) to afford the title compound as a pale yellow solid.
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; toluene; at 20 - 95℃;Inert atmosphere;
Following a literature procedure (Walters, I.A.S. Tetrahedron Lett. 2006, 47, 341), a solution of dimethylzinc (2.0 M in toluene, 75.0 mL, 150.0 mmol) was carefully added in 25 mL portions to a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (10.0 g, 77.0 mmol) and l ,3-bis(diphenylphosphino)propane-nickel (II) chloride (4.2 g, 7.8 mmol) were <n="119"/>dry in dioxane (400 mL) under a nitrogen atmosphere. The reaction was stirred at rt for 2 h and then heated to 50 0C for 1 h and 95 0C overnight. The reaction was allowed to cool to rt and an additional charge of dimethylzinc was added (22 mL, 44 mmol) and the reaction was then maintained at 95 0C overnight. The reaction was cooled to rt, quenched over 15 min with MeOH and then concentrated to a brown solid. Water and EtOAc were added to the solid, and the mixture was sonicated. The solid was removed by filtration and brine was added to the EtO Ac-water mixture. The layers were separated, and the organic layer was dried (Na2SO^, and concentrated to give 9.72 g (~70 purity) of 6-methylpyrazin-2-amine, which was carried forward without further purification: LCMS (m/z): 110.0 (MH+), R = 0.21 min.
1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; for 18.5h;Heating / reflux;
Dimethylzinc (lOOmL of a 2M solution in toluene) was added dropwise over 0.5h to astirred solution of 6-chloro-2-pyrazinamine (12.9g) and [1,3-fe(diphenylphosphmo)propane]nickel(n) chloride (5.4g) in dioxane (200mL) under anitrogen atmosphere. The reaction mixture was heated at reflux for 18h, then cooled toroom temperature and quenched cautiously with zso-propanol (30mL) and methanol(50mL). After removal of solvent in vacua, the residue was partitioned betweendichloromethane and aqueous ammonium chloride. The organic phase was filtered throughcelite, dried (MgSO4), filtered and evaporated to give the crude product as an orange solid.Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the sub- title compound (5.1g). Used directly.
With pyridine; bromine; In dichloromethane; at 20℃;
To a solution of 6-methylpyrazin-2-amine (14.40 g, 132 mmol) and pyridine (26.0 g, 330 mmol) in DCM (300 mL) was added dropwise slowly bromine (53.00 g, 330 mmol). Afterthe addition, the mixture was stirred at rt overnight. Water (150 mL) was added to quench thereaction, and the resulting mixture was partitioned. The organic phase was washed with saturatedbrine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentratedin vacuo to give the title compound as a yellow solid (34.01 g, 96% ).MS (ESI, pos. ion) m/z: 267.9 [M+Ht.
95%
With pyridine; bromine; In chloroform; at 20℃;
B. 3,5-Dibromo-6-methylpyrazine-2-ylamine. 6-Methylpyrazine-2- ylamine (1.18 g, 10.82 mmol) and pyridine (1.79 g, 22.72 mmol) were combined in chloroform (100 mL) at ambient temperature. Bromine (3.63 g, 22.72 mmol) in chloroform (5 mL) was then added drop-wise over 5 minutes. Upon consumption of the starting material, as indicated by TLC, the reaction solution was transferred to a sepratory funnel and the organic layer washed twice with water. The organics were dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (2.70 g, 95 % yield). MS (ESI) m/z 268.0[M+2]+.
86%
With bromine; In chloroform; at 20℃; for 0.0833333h;
At room temperature,Bromine (5.89 g, 36.54 mmol, 1.90 mL)Of chloroform (15 mL)The solution was slowly added dropwise over 5 minutes6-methylpyrazin-2-amine (2.00 g, 18.33 mmol)In chloroform (170 mL).After completion of the dropwise addition, the reaction was stirred at room temperature for 4.5 h.The reaction was quenched with water (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate and the organic layer was concentrated under reduced pressure.Column separation (petroleum ether / ethyl acetate (v / v) = 2/1)To give 4.20 g of a yellowish yellow solid in 86.0% yield.
With N-Bromosuccinimide; In tetrahydrofuran; hexanes; at -10 - 0℃; for 1.66667h;
Part B: 2-Amino-3.5-dibromo-6-methyl pyrazine; A solution of 2-amino-6-m ethyl pyrazine (700 mg, 6.41 mmol, LO equiv.) in THF (15 ml) is cooled to - 10 0C and N-bromosuccinimide (2.34 g, 13.15 mmol, 2.05 equiv.) is added portion-wise over a period of 10 min. The reaction mixture Is warmed to 0 C and stirred for 1 h. Hexanes (10 mL) is added and the mixture is stirred for an additional 30 min at 0 3C, following which it is directly transferred to a pad of silica gel. The crude product is purified by column chromatography using a solvent gradient of 10% EtOAc in hexanes to 30% EtOAc in hexanes. MS = 267.82 (M +1). 1H nuMR (400 MHz, CDCl3) 4.95 (2H, bs) 2.47 (3H, s).
6-Methyl-2-pyrazinamine (18g) was suspended/partially dissolved in acetonitrile (25 rel vol) and 2,6-lutidine (3 mol eq) was added. The solution was then cooled to 50C and bromine (2.6 mol eq) was added. The mixture was then allowed to warm to room temperature (approximately 2O0C), and stirred overnight. The mixture was quenched by the addition of sodium sulfite solution (10% w/v) and adjusted to a pH >8 by the addition of 40% w/w sodium hydroxide solution. The mixture was then distilled under reduced pressure 350C to 4O0C (125 mBar) to remove acetonitrile and 2,6-lutidine, before being EPO <DP n="31"/>cooled to 10C and stirred for one hour. The product was collected by filtration, washed with water and dried in a vacuum oven at 4O0C, to give a brown solid 47g. Used directly
11.9 g
With 2,6-dimethylpyridine; bromine; In acetonitrile; at 10℃;
Following a literature procedure (WO 2007/035154, p 29), bromine (12 mL, 231.0 mmol) was added portion-wise over 5 minutes into a cooled solution of 6-methylpyrazin-2-amine (9.72 g, 89.0 mmol) and lutidine (31.0 mL, 266.0 mmol) in dry acetonitrile at 10 C. The reaction was maintained overnight, allowing the cooling bath to expire. The reaction was queched with aqueous 2.0 M sodium sulfite solution and the pH was adjusted to 8 with the addition of 6 M NaOH. The mixture was concentrated in vacuo and the remaining aqueous portion was cooled to 5 C. overnight. The resulting brown solid was isolated by filtration and triturated with a 9:1 EtOAc-hexanes solution to furnish 11.9 g of 3,5-dibromo-6-methylpyrazin-2-amine. The collected filtrate was concentrated and the resulting solid triturated again to provide an additional 2.2 g of product: LCMS (m/z): 267.9 (MH++2), tR=0.80 min.
With N-Bromosuccinimide; In tetrahydrofuran; at 10 - 20℃; for 2.25h;
To a solution of 6-methylpyrazin-2-amine VI (2.00 g, 18.3 mmol) in THF (40 mL) at 10 C., was added N-bromosuccinimide (6.70 g, 37.6 mmol) portion wise over 15 min and the mixture allowed to warm to room temperature while stirring. After 2 h, the reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica, gradient, hexanes to EtOAc) to provide 3,5-dibromo-6-methylpyrazin-2-amine VII: 1H NMR (400 MHz, CDCl3) delta: 4.93 (bs, 2H), 2.38 (s, 3H).
With N-Bromosuccinimide; In tetrahydrofuran; at 10 - 20℃; for 2.25h;
To a solution of 6- methylpyrazin-2-amine VI (2.00 g, 18.3 mmol) in THF (40 mL) at 10 C, was added N- bromosuccinimide (6.70 g, 37.6 mmol) portion wise over 15 min and the mixture allowed to warm to room temperature while stirring. After 2 h, the reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica, gradient, hexanes to EtOAc) to provide 3,5-dibromo-6-methylpyrazin-2-amine VII: 1H NMR (400 MHz, CDC13) delta: 4.93 (bs, 2H), 2.38 (s, 3H).
3.1 g
With N-Bromosuccinimide; In tetrahydrofuran; at 10 - 20℃; for 2.25h;
[0280] 3,5-Dibromo-6-methylpyrazin-2-amine VII: To a solution of 6- methylpyrazin-2-amine VI (2.00 g, 18.3 mmol) in THF (40 mL) at 10 C, was added N- bromosuccinimide (6.70 g, 37.6 mmol) portion wise over 15 min and the mixture allowed to warm to room temperature while stirring. After 2 h, the reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica, gradient, hexanes to EtOAc) to provide 3,5-dibromo-6- methylpyrazin-2-amine VII (3.10 g, 64%) as an orange solid: NMR (400 MHz, CDCI3) delta: 4.93 (bs, 2H), 2.38 (s, 3H).
With N-Bromosuccinimide; In tetrahydrofuran; at 10 - 20℃; for 2.25h;
To a solution of 6-methylpyrazin- 2-amine VI (2.00 g, 18.3 mmol) in THF (40 mL) at 10 C, was added N-bromosuccinimide (6.70 g, 37.6 mmol) portion wise over 15 min and the mixture allowed to warm to room temperature while stirring. After 2 h, the reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica, gradient, hexanes to EtOAc) to provide 3,5-dibromo-6-methylpyrazin-2-amine VII: l NMR (400 MHz, CDC13) delta: 4.93 (bs, 2H), 2.38 (s, 3H).
With 2,6-dimethylpyridine; bromine; In acetonitrile; at 10℃;
Following a literature procedure (WO 2007/035154, p 29), bromine (12 mL, 231.0 mmol) was added portion-wise over 5 minutes into a cooled solution of 6-methylpyrazin-2-amine (9.72 g, 89.0 mmol) and lutidine (31.0 mL, 266.0 mmol) in dry acetonitrile at 10 0C. The reaction was maintained overnight, allowing the cooling bath to expire. The reaction was queched with aqueous 2.0 M sodium sulfite solution and the pH was adjusted to 8 with the addition of 6 M NaOH. The mixture was concentrated in vacuo and the remaining aqueous portion was cooled to 5 0C overnight. The resulting brown solid was isolated by filtration and triturated with a 9 : 1 EtOAc-hexanes solution to furnish 11.9 g of 3,5- dibromo-6-methylpyrazin-2-amine. The collected filtrate was concentrated and the resulting solid triturated again to provide an additional 2.2 g of product: LCMS (m/z): 267.9 (MH+ + 2), tR = 0.80 min.
With pyridine; bromine; In chloroform; at 20℃; for 0.5h;
A solution of bromine (1.85g) in chloroform (5mL) was added dropwise to a stirredsolution of 2-amino-6-methylpyrazine (0.6g) andpyridine (0.9 ml) in chloroform (50mL).The reaction mixture was stirred at room temperature for 0.5h, then washed twice withwater, dried (MgSO.^), filtered and evaporated to give the crude product as an orange solid.Chromatography on silica gel eluting with dichloromethane gave the title compound(0.95g). Used directly.
With N-Bromosuccinimide; In water; dimethyl sulfoxide; at 20℃; for 5.25h;Inert atmosphere; Cooling with ice;
Compound 10: 5-Bromo-6-methyl-pyrazin-2-ylamine. Under inert condition, to a solution 6-amino-2-methylpyrazine (100 mg, 1.0 equiv.) in a mixture of DMSO (4.6 mL) and water (0.2 mL) cooled by an ice bath, NBS (179 mg, 1.1 equiv.) was added in 3 portions. The light yellow mixture was stirred for 15 minutes, and then for 5 hrs at room temperature. The reaction mixture was hydrolysed with NaHCO3 saturated solution (25 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by flash-chromatography afforded compound 10 as a light yellow solid in 36% yield. 1H-NMR (400 MHz, DMSO): 2.34 (bs, 3H, C-CH3); 6.52 (bs, 2H, NH2); 7.49 (s, 1H, Ar). M/Z (M[79Br]+H)+ = 188.2.
36%
With N-Bromosuccinimide; In water; dimethyl sulfoxide; at 20℃; for 5h;
Under inert condition, to a solution 6-amino-2-methylpyrazine (100 mg, 1.0 equiv.) in a mixture of DMSO (4.6 ml) and water (0.2 ml) cooled by an ice bath, NBS (179 mg, 1.1 equiv.) was added in 3 portions. The light yellow mixture was stirred for 15 minutes, and then for 5 hrs at room temperature. The reaction mixture was hydrolysed with NaHCO3 saturated solution (255 ml) and extracted with EtOAc (30 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by flash-chromatography afforded compound 10 as alight yellow solid in 36% yield. 1H-NMR (400 MHz, DMSO): 2.34 (bs, 3H, C-CH3); 6.52 (bs, 2H, NH2); 7.49 (s, 1H, Ar). M/Z(M[79Br]+H)+ = 188.2.
With N-Bromosuccinimide; In chloroform; for 12h;
Step 5: 5-bromo-6-methylpyrazin-2-amine A 10-L, 4-necked round-bottom flask was charged with 6-methylpyrazin-2-amine (590 g, 5.4lmol, 1.00 equiv), chloroform (7 L) and NBS (960 g, 5.39 mol, 1.29 equiv). The reaction mixture was stirred for 12 h at room temperature. The resulting solid was filtered out and the filtrate was concentrated under vacuum to give the title compound, which was used in the next step without further purification.
To a solution of anhydrous zinc(II) chloride (26.3 g, 193 mmol) in THF (150 mL) at 0° C., was added 3M methyl magnesium bromide in diethyl ether (129 mL) drop wise over a period of 1 h. [1,3-bis(diphenylphosphino)propane] nickel(II) chloride (2.08 g, 3.85 mmol) was then added and the mixture allowed to warm to room temperature. To the above mixture, a solution of <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (5.00 g, 38.6 mmol) in anhydrous THF (25 mL) was added and the reaction stirred, under a nitrogen atmosphere, at reflux for 6 h. After this time, the mixture was cooled to room temperature, then to 0° C. and carefully quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated under reduced pressure to provide crude 6-methylpyrazin-2-amine VI, which was used in the next step without purification: 1H NMR (400 MHz, CDCl3) delta: 7.63 (s, 1H), 7.53 (s, 1H), 4.96 (bs, 2H), 2.16 (s, 3H).
To a solution of anhydrous zinc(II) chloride (26.3 g, 193 mmol) in THF (150 mL) at 0 °C, was added 3M methyl magnesium bromide in diethyl ether (129 mL) drop wise over a period of 1 h. [l,3-bis(diphenylphosphino)propane] nickel(II) chloride (2.08 g, 3.85 mmol) was then added and the mixture allowed to warm to room temperature. To the above mixture, a solution of <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (5.00 g, 38.6 mmol) in anhydrous THF (25 mL) was added and the reaction stirred, under a nitrogen atmosphere, at reflux for 6 h. After this time, the mixture was cooled to room temperature, then to 0 °C and carefully quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated under reduced pressure to provide crude 6- methylpyrazin-2-amine VI, which was used in the next step without purification: 1H NMR (400 MHz, CDC13) delta: 7.63 (s, 1H), 7.53 (s, 1H), 4.96 (bs, 2H), 2.16 (s, 3H).
With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); zinc(II) chloride; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 6h;Inert atmosphere; Reflux;
[0279] 6-Methylpyrazin-2-amine VI: To a solution of anhydrous zinc(II) chloride (26.3 g, 193 mmol) in THF (150 mL) at 0 °C, was added 3M methyl magnesium bromide in diethyl ether (129 mL) drop wise over a period of 1 h. [1,3- Bis(diphenylphosphino)propane]nickel(II) chloride (2.08 g, 3.85 mmol) was then added and the mixture allowed to warm to room temperature. To the above mixture, a solution of <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (5.00 g, 38.6 mmol) in anhydrous THF (25 mL) was added and the reaction stirred, under a nitrogen atmosphere, at reflux for 6 h. After this time, the mixture was cooled to room temperature, then to 0 °C and carefully quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated under reduced pressure to provide crude 6-methylpyrazin-2 -amine VI (2.60 g, 62percent) as a light yellow solid which was used in the next step without purification: NMR (400 MHz, CDC13) delta: 7.63 (s, 1H), 7.53 (s, 1H), 4.96 (bs, 2H), 2.16 (s, 3H).
To a solution of anhydrous zinc(II) chloride (26.3 g, 193 mmol) in THF (150 mL) at 0 °C, was added 3M methyl magnesium bromide in diethyl ether (129 mL) drop wise over a period of 1 h. [l ,3-bis(diphenylphosphino)propane] nickel(II) chloride (2.08 g, 3.85 mmol) was then added and the mixture allowed to warm to room temperature. To the above mixture, a solution of <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (5.00 g, 38.6 mmol) in anhydrous THF (25 mL) was added and the reaction stirred, under a nitrogen atmosphere, at reflux for 6 h. After this time, the mixture was cooled to room temperature, then to 0 °C and carefully quenched with saturated aqueous ammonium chloride (50 mL). The organic layer was separated and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated under reduced pressure to provide crude 6-methylpyrazin-2- amine VI, which was used in the next step without purification: XH NMR (400 MHz, CDC13) delta: 7.63 (s, 1H), 7.53 (s, 1H), 4.96 (bs, 2H), 2.16 (s, 3H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 4h; Inert atmosphere;
EM /V-(6-Methylpyrazin-2-yl)-5-(trifluoromethyl)-/V-({5-[5-(trifluoromethyl)-1,2,4- oxadiazol-3-yl]thiophen-2-yl}methyl)pyridazin-3-amine
A suspension of 3-chloro-5-(trifluoromethyl)pyridazine (1) (100mg, 0.44mmol), 2-amino-6-methylpyrazine (2) (48mg, 0.44mmol), Cs2C03 (285mg, 0.88mmol) and Xantphos (25mg, 0.04mmol) in 1 ,4-dioxane (3mL) was purged with Ar(g) for 0.5h. Pd2(dba)3 (20mg, 0.02mmol) was added and the reaction mixture was heated up to 90°C for 4h. Once cooled down to rt, it was poured into a mixture of H20 (20mL) and brine (10mL), then extracted with EtOAc (5 x 20mL). The combined organics were washed with brine (20mL), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-2:3) yielded (3) as a solid (60mg, (1081) 54%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
