* 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.
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 Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
5
[ 6863-77-0 ]
[ 6863-73-6 ]
[ 33332-29-5 ]
[ 33332-28-4 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
6
[ 33332-28-4 ]
[ 6905-47-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium methylate In methanol
Pre Step A 6-(Methyloxy)-2-pyrazinamine A mixture of 6-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 6-(methyloxy)-2-pyrazinamine (154 mg, 1.231 mmol, 80percent yield). MS (ES+) m/z 125.8 (MH+).
Stage #1: With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.5 h; Inert atmosphere Stage #2: at 80℃; for 2 h; Inert atmosphere
To a mixture of MeOH (6 mL) in DMSO (12 mL) was added slowly NaH (1.2 g of 60percent in oil, 30 mmol) and stirred at room temperature for 30 min. 2-amino-6-chloropyrazine (1.29 g, 10 mmol) was added to the mixture portionwise and heated at 80 °C for 2 h. The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified bycolumn chromatography to give 2-amino-6-methoxypyrazine (888 mg, 71percent) as a slightly yellow solid. 1H NMR (200 MHz, CDCl3) δ 7.60 (s, 1H), 7.55 (s, 1H), 4.44 (br, 2H), 3.90 (s, 3H); 2-amino-6-methoxyprazine (186 mg, 1.45 mmol) was dissolved in MeOH. To the solution was added N-bromo-succinimide (568 mg, 3.19 mmol) and stirred at room temperature for 30 min. The reaction mixture was concentrated via vacuo, ethyl acetate was added and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give a product 1e (242 mg, 59percent). 1H NMR (200 MHz, CDCl3) δ4.91 (br, 2H), 3.96 (s, 3H);
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 12, p. 4271 - 4274
8
[ 4774-14-5 ]
[ 33332-28-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 100℃; for 5 h;
In the hydrothermal reaction kettle are respectively added with 2, 6 - two chlorine pyrrole qin (10.0 g, 67.1 mmol) and ammonia (100 ml), 100 °C lower reaction 5 h. The completion of the reaction, cooling to room temperature, filtered, the filter cake is hexane (16 ml) beating shall 2 - amino -6 - chloropyrazine white solid 8.2 g, yield is 95.0percent.
91%
With ammonia In water at 100℃; for 18 h; Sealed tube
2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28percent, 10 ml.) and heated to 100°C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 percent yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0°C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25percent EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42percent yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200°C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82percent yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).
80%
With ammonia In water at 135℃; Autoclave
A solution of compound 8 4500 g, 302 mol) in conc. aq. NH3 (3.0 L) was stirred at135°C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed completeconversion of the starting material. The reaction mixture was cooled to roomtemperature and filtered to afford a white solid. The solid was washed with water (200mL x 3), and then dried to afford compound 9 (312 g, 80percent yield) as a solid.1HNMR (400 MHz, DMSO-d6): 7,82 (s, 1 H), 712 (s, 1 H), 6.93 (s, 2H). MS Calcd.:129 MS Found: 130 ([M+Hj).
63%
With ammonia In water at 20 - 140℃; for 63 h; In sealed autoclave
EXAMPLE 5 2-amino-6-chloropyrazine 120 ml of water, 20.8 ml (0.31 mol, 4.6 eq) of an aqueous 28percent ammonia solution and 10 g (0.067 mol, 1 eq) of 2,6-dichloropyrazine were successively added to an autoclave reactor. The autoclave was sealed and the mixture heated at 140° C. for 3 h, then left at room temperature for 60 h. The mixture was filtered, the precipitate washed with water, then vacuum dried. The reaction produced 5.4 g of a fine powder (yield: 63percent). 1H NMR (CDCl3) δ (ppm): 7.88 (s, 1H, CH); 7.84 (s, 1H, CH); 4.68 (m, 2H, NH2). HPLC: t=1.07 min MS: 130 (MH+) HPLC purity: 100percent
60%
With ammonium hydroxide In water at 120℃; for 6 h; Large scale
A solution of 2,6-dichloropyrazine (15kg, 1O1.4mol, 1.00 equiv) in water(20 L), ammonia water (25 L, 25 percent) was placed in a 100 L pressure tank reactor. The resulting solution was stirred for 6 h at 120°C. The reaction progress was monitored by TLC (EA:PE = 1 : 1) until the starting material was consumed, and cooled to room temperature. Thesolids were collected by filtration. The solid was washed with water and dried. The solidwas washed with petroleum ether to remove the unreacted starting materials. The product (7.8kg, purity = 95 percent, 60percent yield) was obtained as a white solid.
59.7%
With ammonia In water at 140℃; for 14 h;
Example B-10: Preparation of (2S)-1-(4-(1-isopropyl-3-(5-methyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-10) <n="80"/>cr Et3NB-10-1 B-10-2 B-10-3Preparation of 6-chloropyrazin-2-amine (B-10-2). B-10-1 B-10-2A mixture of 2,6-dichloropyrazine (300 g, 2 mol) and 28percent aq. NH3 (8 L) was stirred at 14O0C in a sealed system for 14 hours. TLC (petroleum ether/EtOAc 3:1 ) indicated complete consumption of starting material. The reaction mixture was extracted with EtOAc (3 L x 3). The combined organic layers were washed with saturated aqueous NaCI (3 L), dried over Na2SO4 and concentrated in vacuo to give crude compound B-10-2, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to yield pure compound B-10-2 (410 g, yield: 59.7percent) as a white solid.
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
11
[ 67-56-1 ]
[ 3375-31-3 ]
[ 33332-28-4 ]
[ 118853-60-4 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 85℃; for 5 h; Large scale
A solution of 6-chloro-2-pyrazinamine (4 kg, 31 mol, 1.00 equiv), Et3N (4.7 kg,46.5 mol, 1.50 equiv), Pd(OAc)2 (139 g, 0.62mo1, 0.02 equiv), dppf (343 g, 0.62 mol, 0.02equiv) in methanol (60 L) was placed in a 100 L pressure tank reactor(10 atm).The resulting solution was allowed to react for 5 h while maintaining the temperature at 85°C. The reaction progress was monitored by TLC (DCM: MeOH = 20: 1) until the starting material was consumed completely, and cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was washed with water 50 L. Thefilter was collected and dried. The product (3.8 kg, purity = 95 percent, 80 percent yield)obtained as a pale brown solid.1H-NIVIR (300 MHz, DMSO-d6) : 8.27(1H, s), 8.06(1H, s), 6.87(2H, b), 3.84(3H, s). LC-MS: m / z = 154(M+H) +.
With N-Bromosuccinimide In methanol at 20℃; for 1 h;
6-chloropyrazine-2-amine (10.4 g, 80 mmol) was dissolved in methanol (300 ml), and N-bromosuccinimide (15.6 g, 88 mmol) was added thereto while stirring at room temperature. After stirring for additional 60 minutes, the reaction product was concentrated under reduced pressure, followed by adding water so that the reaction product was extracted 3 times with ethyl acetate. The organic later was collected, dried over magnesium sulfate, and then concentrated under reduced pressure. Thereafter, the residue was purified on a silica gel column using chromatography. The title compound (12.0 g, 72percent) was obtained by eluting as a mixed solvent (3:1 v/v) of hexane and ethyl acetate. 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 4.73 (s, 2H).
42%
With N-Bromosuccinimide In dichloromethane at 0℃; for 1 h;
2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28percent, 10 ml.) and heated to 100°C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 percent yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0°C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25percent EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42percent yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200°C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82percent yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).
42%
With N-Bromosuccinimide In dichloromethane at 0℃;
Synthesis 2-1 -B 5-bromo-6-chloropyrazin-2-amine 6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in dichloromethane (60 mL) and cooled to O°C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25percent ethyl acetate-hexane, gave the title compound as a yellow solid (1.69 g, 8.16 mmol, 42percent). 1HMR (d6-DMSO, 400 MHz) δ 7.65 (s, 1H), 7.1 (br s, 2H). LC-MS (1) rt 1.46 min; m/z (ESI-) 205 (M-H).
Reference：
[1] Patent: EP3231800, 2017, A2, . Location in patent: Paragraph 0050
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8328 - 8342
[3] Patent: WO2013/68755, 2013, A1, . Location in patent: Page/Page column 67, 68
[4] Patent: WO2009/103966, 2009, A1, . Location in patent: Page/Page column 88
[5] Patent: US5861401, 1999, A,
13
[ 33332-28-4 ]
[ 173253-42-4 ]
Yield
Reaction Conditions
Operation in experiment
28%
With N-Bromosuccinimide In chloroform at 0 - 20℃;
Preparation of 3-bromo-6-chloropyrazin-2 -amine (B-10-3).-10-2 B-10-3 B-10-3bTo a solution of compound B-10-2 (110 g, 0.85 mol) in CHCI3 (1.5 L) was added N-bromo-succinimide (151.3 g, 0.85 mol) portionwise at O0C under N2 atmosphere. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. TLC (petroleum ether/EtOAc 3:1 ) indicated most of compound B-10-2 was consumed. The reaction mixture was washed with saturated Na2CO3 (1 L x 3), H2O (1 L x 3) and saturated aqueous NaCI (1 L) in sequence, dried over Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography (silica gel, EtOAc/hexane 1 :20) to yield pure B-10-3b (35 g) and pure compound B-10-3 (45 g, 28percent) as a yellow solid.
With N-Bromosuccinimide In water; acetonitrile at 0 - 20℃; for 18 h;
Synthesis Example 1 2-Amino-3,5-dibromo-6-chloropyrazine (4) To a solution of 2-amino-6-chloropyrazine (3) (8.00 g, 61.8 mmol) in acetonitrile (80 mL) was gradually added N-bromosuccinimide (NBS) (27.5 g, 155 mmol) at 0° C. After elevating to room temperature, the mixture was stirred overnight (18 hours). To the mixture was added water and the product was extracted with diethyl ether (*3). The combined organic extract was washed successively with water (*1) and brine (*1), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g, 58.5 mmol, 94.7percent) as a yellow solid. TLC Rf=0.31 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) δ 5.14 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 120.7, 122.0, 146.1, 151.0.
94.7%
With N-Bromosuccinimide In acetonitrile at 0 - 20℃; for 18 h;
N-bromosuccinimide(NBS) (27.5 g, 155 mmol) was slowly added, was warmed up to room temperatureovernight (18 hours) and the mixture was stirred. Water was added thereto andthe product was extracted with ethyl acetate (× 3). The organic layer waswashed with water (× 1) and saturated brine (× 1), and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under reducedpressure, and the residue was purified by silica gel flash columnchromatography (n- hexane / ethyl acetate = 3/1),2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g , 58.5 mmol, 94.7percent) as ayellow solid
82%
With N-Bromosuccinimide In methanol at 20℃; for 0.5 h; Inert atmosphere
2-Amino-6-chloropyrazine (0.6 g, 4.63 mmol) was dissolved in MeOH (50 mL), and N-bromosuccinimide (1.81 g, 10.19 mmol) was added to the solution with stirring. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, ethyl acetate was added and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-amino-3,5-dibromo-6-chloropyrazine 1c (1.09 g, 82percent) as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) δ5.26 (br, 2H).
38%
With N-Bromosuccinimide In chloroform at 20℃; for 5 h; Inert atmosphere
To a solution of 6-chloro-pyrazin-2-ylamine (5.0 g, 38.8 mmol) in chloroform (194 mL) was added N-bromosuccinimide (20.7 g, 116 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 5 h. The resulting mixture was poured into an aqueous solution of K2CO3 (300 mL) and extracted with dichloromethane (200 mL x 4). The combined organic extracts were dried and purified by chromatography (silica, 10-20 percent ethyl acetate in hexanes) to give 3,5-dibromo-6-chloro-pyrazin-2-ylamine (4.2 g, 38percent) as a yellow solid. LC-MS: 286.0 (M-H).
Reference：
[1] Patent: US2012/232272, 2012, A1, . Location in patent: Page/Page column 18
[2] Organic Letters, 2015, vol. 17, # 15, p. 3888 - 3891
[3] Patent: JP5837973, 2015, B2, . Location in patent: Paragraph 0180; 0181
[4] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 12, p. 4271 - 4274
[5] Patent: WO2014/29732, 2014, A1, . Location in patent: Page/Page column 88
[6] Patent: WO2012/7539, 2012, A1, . Location in patent: Page/Page column 144; 145
[7] Patent: US2013/184282, 2013, A1, . Location in patent: Paragraph 0359; 0360
[8] Patent: WO2004/108692, 2004, A1, . Location in patent: Page 34
16
[ 33332-28-4 ]
[ 960510-36-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With N-Bromosuccinimide In methanol at 50℃; for 19 h; Stage #2: With N-chloro-succinimide In methanol at 38 - 50℃; for 16 h;
A solution of 2-amino-6- chloropyrazine (25g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture was then cooled to 38 "C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50 0C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97percent yield) of 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) δ 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285
97%
Stage #1: With N-Bromosuccinimide In methanol at 50℃; for 19 h; Stage #2: With N-chloro-succinimide In methanol at 38 - 50℃; for 16 h;
A solution of 2-amino-6-chloropyrazine (25g, 193.1 mmol) in MeOH (500 ml_) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture15 was then cooled to 38 0C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 500C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 ml_). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97percent yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) δ 149.9 (s), 145.6 (s), 129.6 (s),20 121.5 (S). LCMS (15-95percent gradient acetonitrile in 0.1 percent TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285.
97%
Stage #1: With N-Bromosuccinimide In methanol at 50℃; for 19 h; Stage #2: With N-chloro-succinimide In methanol at 38 - 50℃; for 16 h;
A solution of 2-amino-6-chloropyrazine (25 g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50° C. for 2 hours. The mixture was then cooled to 38° C. and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50° C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97percent yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDC13) δ 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.
In the hydrothermal reaction kettle are respectively added with 2, 6 - two chlorine pyrrole qin (10.0 g, 67.1 mmol) and ammonia (100 ml), 100 C lower reaction 5 h. The completion of the reaction, cooling to room temperature, filtered, the filter cake is hexane (16 ml) beating shall 2 - amino -6 - chloropyrazine white solid 8.2 g, yield is 95.0%.
91%
With ammonia; In water; at 100℃; for 18h;Sealed tube;
2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28%, 10 ml.) and heated to 100C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 % yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42% yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82% yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).
80%
With ammonia; In water; at 135℃;Autoclave;
A solution of compound 8 4500 g, 302 mol) in conc. aq. NH3 (3.0 L) was stirred at135C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed completeconversion of the starting material. The reaction mixture was cooled to roomtemperature and filtered to afford a white solid. The solid was washed with water (200mL x 3), and then dried to afford compound 9 (312 g, 80% yield) as a solid.1HNMR (400 MHz, DMSO-d6): 7,82 (s, 1 H), 712 (s, 1 H), 6.93 (s, 2H). MS Calcd.:129 MS Found: 130 ([M+Hj).
80%
With ammonium hydroxide; at 135℃;Sealed tube;
A solution of compound 8 (450.0 g, 3.02 mol) in cone. aq. NH3 (3.0 L) was stirred at 135°C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered to afford a white solid. The solid was washed with water (200 mL x 3), and then dried to afford compound 9 (312 g, 80percent yield) as a solid. 1HNMR (400 MHz, DMSO- 6): delta 7.82 (s, 1 H), 7.12 (s, 1 H), 6.93 (s, 2H). MS Calcd.: 129 MS Found: 130 ([M+H]+).
63%
With ammonia; In water; at 20 - 140℃; for 63h;In sealed autoclave;
EXAMPLE 5 2-amino-6-chloropyrazine 120 ml of water, 20.8 ml (0.31 mol, 4.6 eq) of an aqueous 28% ammonia solution and 10 g (0.067 mol, 1 eq) of 2,6-dichloropyrazine were successively added to an autoclave reactor. The autoclave was sealed and the mixture heated at 140 C. for 3 h, then left at room temperature for 60 h. The mixture was filtered, the precipitate washed with water, then vacuum dried. The reaction produced 5.4 g of a fine powder (yield: 63%). 1H NMR (CDCl3) delta (ppm): 7.88 (s, 1H, CH); 7.84 (s, 1H, CH); 4.68 (m, 2H, NH2). HPLC: t=1.07 min MS: 130 (MH+) HPLC purity: 100%
60%
With ammonium hydroxide; In water; at 120℃; for 6h;Large scale;
A solution of 2,6-dichloropyrazine (15kg, 1O1.4mol, 1.00 equiv) in water(20 L), ammonia water (25 L, 25 %) was placed in a 100 L pressure tank reactor. The resulting solution was stirred for 6 h at 120C. The reaction progress was monitored by TLC (EA:PE = 1 : 1) until the starting material was consumed, and cooled to room temperature. Thesolids were collected by filtration. The solid was washed with water and dried. The solidwas washed with petroleum ether to remove the unreacted starting materials. The product (7.8kg, purity = 95 %, 60% yield) was obtained as a white solid.
59.7%
With ammonia; In water; at 140℃; for 14h;
Example B-10: Preparation of (2S)-1-(4-(1-isopropyl-3-(5-methyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-10) <n="80"/>cr Et3NB-10-1 B-10-2 B-10-3Preparation of 6-chloropyrazin-2-amine (B-10-2). B-10-1 B-10-2A mixture of 2,6-dichloropyrazine (300 g, 2 mol) and 28% aq. NH3 (8 L) was stirred at 14O0C in a sealed system for 14 hours. TLC (petroleum ether/EtOAc 3:1 ) indicated complete consumption of starting material. The reaction mixture was extracted with EtOAc (3 L x 3). The combined organic layers were washed with saturated aqueous NaCI (3 L), dried over Na2SO4 and concentrated in vacuo to give crude compound B-10-2, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to yield pure compound B-10-2 (410 g, yield: 59.7%) as a white solid.
41.98 g (48%)
In ammonia;
3. 2-Chloro-6-amino-pyrazine A suspension of 2,6-dichloropyrazine (100 g, 0.67 mole, Lancaster) in 0.880 ammonia (500 ml) was stirred and heated at 150 C. in a glass lined autoclave at 20 atm for 16 hrs. The cooled mixture was filtered, washed well with water (200 ml) and dried. The product was recrystallized from chloroform. Yield 41.98 g (48%), M.p. 150-152 C.
With ammonia; In water; at 100℃;Autoclave;
Svnthesis 2-1-A 6-Chloropyrazin-2-amine 2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous ammonia (28%, 10 mL) and heated to 100C overnight in a sealed tube. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave the title compound as a white solid (2.28 g, 17.6 mmol, 91%). 1H NMR (d6-DMSO, 400 MHz) delta 7.80 (d, 1 H1 J = 0.4 Hz), 7.70 (d, 1 H, J = 0.4 Hz), 6.9 (br s, 2H). LC-MS (2) rt 1.05 min; m/z (ESI+) 130/132.
[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.
A solution of 2-amino-6- chloropyrazine (25g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture was then cooled to 38 "C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50 0C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285
97%
A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25g, 193.1 mmol) in MeOH (500 ml_) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture15 was then cooled to 38 0C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 500C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 ml_). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) delta 149.9 (s), 145.6 (s), 129.6 (s),20 121.5 (S). LCMS (15-95% gradient acetonitrile in 0.1 % TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285.
97%
A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 C. for 2 hours. The mixture was then cooled to 38 C. and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50 C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDC13) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.
97%
A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50° C. for 2 hours. The mixture was then cooled to 38° C. and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50° C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum desiccator to afford 45.4 g (97percent yield) of 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCl3) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.
97%
A solution of 82 <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in 83 MeOH (500 mL) was treated with 84 NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50° C. for 2 hours. The mixture was then cooled to 38° C. and treated with 85 NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50° C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with 39 water (500 mL). The precipitate was collected by filtration and dried in a vacuum desiccator to afford 45.4 g (97percent yield) of 86 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCl3) ? 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 80℃; for 1h;
To <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (3.1 mmol), l-Boc-5-fluoroindole-2-boronic acid (3.1 mmol), Pd(PPh3)4, (100 mg, 0.0865 mmol) and K2CO3 (7.2 mmol) were added 7 mL MeCN and 3 mL H2O and the mixture was heated in a sealed tube at 80 0C for 1 h. The water layer was separated and the organic phase was dried over MgSO4. Filtration and removal of the solvent gave 1.05 g of the title compound.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 85℃; for 20h;
[l-(tert-butoxycarbonyl)-lH-indol-2-yl]boronic acid (2.22 g, 8.49 mmol), 6- chloropyrazin-2-amine (1.00 g, 7.72 mmol), K2CO3 (2.67 g, 19.3 mmol) and Pd(PPh3)4 (180 mg, 0.15 mmol) were mixed in MeCN/water (3.5: 1) and stirred at 85 0C for 20 hours. The reaction mixture was concentrated and the residue was extracted with EtOAc (2x 40 mL) and water (50 mL). The organic layers were combined, dried (Na2SO^, filtered and concentrated to give 2.5 g of a brown solid of tert-butyl 2-(6-aminopyrazin-2-yl)- lH-indole-l-carboxylate. The material was used in the next step without further purification. To tert-butyl 2-(6-aminopyrazin-2-yl)-lH-indole- l-carboxylate (1.1 g, 3.5 mmol) in dry toluene (10 mL) were added methyl 6-chloronicotinate (0.67 g, 3.90 mmol), K2CO3 (7.35 g, 53.2 mmol), (+/-)-BINAP (0.1 1 g, 0.18 mmol) and Pd(OAc)2 (40 mg, 0.18 mmol). The mixture was re fluxed for 50 minutes. The solvent was evaporated and the residue was extracted with EtOAc (2x100 mL) and washed with water/brine (1 : 1 ; 100 mL). The organic layers were combined, dried (Na2Spsi4), filtered and concentrated to give 2 g of crude product. Purification was performed by flash chromatography (1percent NEt3 in DCM-> 1percent NEt3, 1percent MeOH in DCM). This gave tert-butyl 2-(6-[5-(methoxycarbonyl)pyridin-2- yl]amino}pyrazin-2-yl)-lH-indole- l-carboxylate (620 mg). The material was divided into four microwave tubes (155 mg, 0.35 mmol in each) and dissolved in MeOH. 2M aq NaOH (0.35 mL, 0.70 mmol) was added and the reaction mixture was irradiated in a microwave oven at 1 10 0C for 15 minutes. 6M aq HCl (0.12 mL, 0.70 mmol) was added. The reactions were combined and concen- trated in vacuo to give the crude title compound as a brown solid (720 mg). MS (ESI+) for C18H 13N5O2 m/z 332 (M+H)+.
With potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 120℃; for 5h;
6-Chloronicotinoyl chloride (1.00 g, 5.68 mmol) in dry DCM (4 mL) was added dropwise to an ice cold solution of 1 -methyl- 1,4-diazepane (648 mg, 5.68 mmol) and NEt3 (1.18 mL, 8.52 mmol) in dry DCM (16 mL). The mixture was allowed to attain rt and stirred for 2 hours. Saturated aq Na2CO3/water (1 : 1, 40 mL) was added and the mixture was extracted with DCM (2x 30 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to1.33 g of a light brown oil. MS (ESI+) for C12H 16C1N3O m/z 254 (M+H)+. Part of the material (294 mg, 1.16 mmol) was added to 6-chloropyrazin-2-amine (150 mg, 1.16 mmol), palladiumacetate (13 mg, 0.06 mmol), (+/-)-BINAP (36 mg, 0.06) and K2CO3 (2.4O g, 17.4 mmol) in dry toluene (12 mL) and stirred at 120 0C for 1.5 hours. The solvent was evaporated and the crude material was extracted with water/brine (1 : 1; 50 mL) and EtOAc (2x 50 mL). The organic layers were combined and concentrated. The title compound was obtained after purification by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10, MeCN), as a light brown solid (55 mg). MS (ESI+) for C16H19C1N6O m/z 347 (M+H)+.HPLC 92percent(System A), 85percent(System B).
With sodium hydride; In 1,4-dioxane; at 0 - 100℃; for 62h;
EXAMPLE 1C 6-(3-butenyloxy)-2-pyrazinamine A suspension of NaH (60percent, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31 percent). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) delta 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
31%
Example 1C 6-(3-butenyloxy)-2-pyrazinamine A suspension of NaH (60percent, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31percent). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) delta 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110 - 120℃; for 10h;
Preparation of 2-amino-6-(tri-n-butylstannyl)pyrazine (Example of the general procedure Tin-04, below): To a sealed tube, 2-amino-6-chloro-pyrazine (1 g), bis(tri-butyltin) (3.92 mL) and tetrakis-triphenylphosphine palladium, Pd(Ph3P)4 (100 mg) were combined in dioxane (10 mL). The reaction was heated at 110-120° C. for 10 h. After the mixture cooled down to room temperature, it was poured into 20 mL of water. The solution was extracted with EtOAc (4.x.20 mL). The combined extract was concentrated in vacuo to give a residue which was purified by silica gel chromatography to afford 2-amino-6-(tri-n-butylstannyl)pyrazine (0.5 g)
[0504] Compound 481A was prepared by an analogous method as that of 473B, except using compound 2-chloro-6-aminopyrazine in place of compound 2-bromo-6-aminopyridine.
With N-Bromosuccinimide; In water; acetonitrile; at 0 - 20℃; for 18h;
Synthesis Example 12-Amino-3,5-dibromo-6-chloropyrazine (4)To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (3) (8.00 g, 61.8 mmol) in acetonitrile (80 mL) was gradually added N-bromosuccinimide (NBS) (27.5 g, 155 mmol) at 0° C.After elevating to room temperature, the mixture was stirred overnight (18 hours).To the mixture was added water and the product was extracted with diethyl ether (*3).The combined organic extract was washed successively with water (*1) and brine (*1), followed by drying over anhydrous sodium sulfate.After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g, 58.5 mmol, 94.7percent) as a yellow solid. TLC Rf=0.31 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) delta 5.14 (s, 2H); 13C NMR (126 MHz, CDCl3) delta 120.7, 122.0, 146.1, 151.0.
94.7%
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 18h;
N-bromosuccinimide(NBS) (27.5 g, 155 mmol) was slowly added, was warmed up to room temperatureovernight (18 hours) and the mixture was stirred. Water was added thereto andthe product was extracted with ethyl acetate (× 3). The organic layer waswashed with water (× 1) and saturated brine (× 1), and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under reducedpressure, and the residue was purified by silica gel flash columnchromatography (n- hexane / ethyl acetate = 3/1),2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g , 58.5 mmol, 94.7percent) as ayellow solid
82%
With N-Bromosuccinimide; In methanol; at 20℃; for 0.5h;Inert atmosphere;
<strong>[33332-28-4]2-Amino-6-chloropyrazin</strong>e (0.6 g, 4.63 mmol) was dissolved in MeOH (50 mL), and N-bromosuccinimide (1.81 g, 10.19 mmol) was added to the solution with stirring. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, ethyl acetate was added and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-amino-3,5-dibromo-6-chloropyrazine 1c (1.09 g, 82percent) as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) delta5.26 (br, 2H).
70%
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;
To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol) in anhydrous acetonitrile (10 mL) was gradually added NBS (4.12 g, 23.16 mmol, 3 equiv.) at 0°C. The reaction mixture was slowly warmed up to r.t. and stirred overnight then diluted with water and extracted with Et20. Combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified byflash chromatography on silica eluting with Hexane/EtOAc (1:1)to give the title compound (1.55 g, 5.39 mmol, 70percent) as a pale yellow solid. ESI-MS: 287.90 [M+H]+.
38%
With N-Bromosuccinimide; In chloroform; at 20℃; for 5h;Inert atmosphere;
To a solution of 6-chloro-pyrazin-2-ylamine (5.0 g, 38.8 mmol) in chloroform (194 mL) was added N-bromosuccinimide (20.7 g, 116 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 5 h. The resulting mixture was poured into an aqueous solution of K2CO3 (300 mL) and extracted with dichloromethane (200 mL x 4). The combined organic extracts were dried and purified by chromatography (silica, 10-20 percent ethyl acetate in hexanes) to give 3,5-dibromo-6-chloro-pyrazin-2-ylamine (4.2 g, 38percent) as a yellow solid. LC-MS: 286.0 (M-H).
With N-Bromosuccinimide; In chloroform; for 20h;Reflux;
A solution of 6-chloropyrazin-2-amine (2 g, 15.44 mmol) and N BS (13.7 g, 77 mmol) in CHCI3 (100 ml) was heated at reflux for 20 hours. The resulting mixture was purified bychromatography on silica eluting with DCM. The relevant fractions were concentrated in vacuo and the crude product was dissolved in EtOAc (~100 ml), washed with 10 percent sodium thiosulfate (2 x 100 ml), brine, dried (MgS04) and were concentrated in vacuo to afford the title compound; 1 H NMR (400 MHz, CDCI3) delta 5.4-5.0 (2H, br s).
With N-Bromosuccinimide; In methanol; at 15 - 20℃; for 2h;Cooling with ice;
6-Chloropyrazin-2-amine (100 g, 772 mmol) in MeOH (2000 ml) cooled using a water bath was treated with N-bromosuccinimide (151.2 g, 170 mmol) portionwise over 30 mins, maintaining the reaction temperature between 15-20° C. After stirring for 1.5 hours, the mixture was poured carefully into a stirred vessel of ice-cooled water (4 litres). The resultant suspension was stirred for 2 hours in the ice bath, collected by filtration, rinsing the filter cake with water (800 ml) and dried in a vacuum oven to afford the titled compound; LC-MS Rt 0.99 mins; Method 2 minLowpH
With N-Bromosuccinimide; In chloroform; for 20h;Heating / reflux;
A stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0g) and JV-bromosuccinimide (13.71g) inchloroform (100 mL) was heated to reflux for 20 hours. The reaction mixture was cooledand concentrated onto silica gel (20g) and the residue loaded onto a column of silica gel(5cm x 2cm) and the column was eluted with dichloromethane. Concentration afforded3,5-dibromo-<strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> that was dissolved into methanol (200 mL) andsodium methoxide (32g of a 25percent solution in methanol) added. The reaction was heated to70°C for 1.5h, cooled and concentrated to approx. 50 mL capacity. The reaction mixturewas poured into water (200mL) and the sub-titled adduct (2.0g) collected as an off-whitesolid.m/e 235, 237 (M+l+, 100percent)
With sodium hydride; In 1,4-dioxane; at 140℃; for 1.11117h;Smith synthesizer;
EXAMPLE 4A 6-(allyloxy)-2-pyrazinamine A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60percent, 3.08 mmol), stirred for 30 minutes, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57percent). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) delta 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).
57%
Example 4A 6-(allyloxy)-2-pyrazinamine A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60percent, 3.08 mmol), stirred for 30 minutes, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57percent). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) delta 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).
Preparation 5 2-Amino-5,6-dichloropyrazine A mixture of 5 g. of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (commercially available), 10.3 g. of N-chlorosuccinimide, and 100 ml. of chloroform was refluxed for about 1.5 hours. The reaction mixture was cooled and filtered, the solid collected on the funnel being discarded. The filtrate was evaporated and the residue washed with water and hot aqueous sodium bisulfite solution, and the solid which formed under this treatment was collected on a funnel. The solid was chromatographed on a column of 5*8 mm. styrene and divinylbenzene copolymer beads using chloroform as solvent and eluant. There were obtained by this chromatography three compounds: Compound 1, having a melting point of about 132°-135° C., was identified as 2-amino-3,6-dichloropyrazine. Compound 2, having a melting point of about 132°-134° C., was identified as 2-amino-3,5,6-trichloropyrazine. Compound 3, having a melting point of about 143°-144° C., was identified as 2-amino-5,6-dichloropyrazine, the desired compound.
1F. 1-(2-Chlorobenzoyl)-3-(6-chloro-2-pyrazinyl)urea, having a melting point of about 202°-203° C., from 1.5 g. of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> and 2.0 g. of 2-chlorobenzoylisocyanate. 1G.
2-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrazine[ No CAS ]
trifluoroethylisothiocyanate[ No CAS ]
[ 33332-28-4 ]
[ 79668-20-5 ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
The 2-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrazine used as starting material may be obtained as follows: A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g.) in warm acetonitrile (15 ml.) was cooled to room temperature. Trifluoroethylisothiocyanate (1.6 g.) was added and the mixture stirred overnight. Further trifluoroethylisothiocyanate (1.6 g.) was added, and the mixture warmed gently on a steam bath for 2 hours, then heated under reflux for 2 hours. The mixture was allowed to cool and evaporated to dryness to yield a brown solid. This was washed with water, 2 N HCl solution, water again, and sucked dry. Recrystallisation from boiling toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.77 g.) of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine m.p. 170°-172°.
To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (6 g.) in acetonitrile (50 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6 ml.) and the mixture heated under reflux on a steam bath for 6 hours. The mixture was allowed to cool, the resulting solid filtered and recrystallized from toluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine.
In acetonitrile;
2,2,2-Trifluoroethylisothiocyanate (6 ml.) was added to <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (6 g.) in acetonitrile (50 ml.) and the mixture heated under reflux on the steam bath for 6 hours. On cooling the precipitated solid was recrystallized from toluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine, m.p. 170°-172°.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
EXAMPLE 11 N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1. Yield: 60percent of theory. Melting point: 278-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79): Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--45.91percent; H--3.09percent; Cl--9.60percent; N--15.00percent; S--8.78percent.
EXAMPLE 7 N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide A mixture of 5.1 g (20 mmols) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 3.0 g (23 mmols) of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> and 400 ml of xylene was refluxed for 12 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 A molecular sieve arranged in a Soxhlet attachment. After cooling, the reaction mixture was concentrated by evaporation, and the residue was purified by chromatography on a silicagel column, yielding 2.3 g (33percent of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. Melting point: 234°-235° C. (from ethanol). C13 H9 ClN4 O4 S (352.76): Calc.: C--44.26percent; H--2.57percent; N--15.88percent; Cl--10.05percent; S--9.09percent. Found: C--44.02percent; H--2.65percent; N--15.92percent; Cl--10.10percent; S--9.24percent.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 5,5-dimethyl-1,3-cyclohexadiene;
EXAMPLE 2 N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide A mixture of 5.2 g (17 mmols) of methyl 4-hydroxy-6-methoxy- 2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 2.5 g (19 mmols) of 2-amino-6-chloro-pyrazine and 200 ml of xylene was refluxed for 24 hours. The methanol formed during the reaction was removed with the aid of a 4 A molecular sieve arranged in a Soxhlet attachment. After cooling to room temperature, the reaction mixture was filtered, and the residue was recrystallized from tetrahydrofuran. 4.9 g (73percent of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-6-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained. Melting point: 289°-291° C. 1H-NMR (CDCl3 +d-TFA): delta=9.45 (s, 1,3'-H); 8.55 (s, 1,5'-H); 7.93 (d,l,J=10 Hz, 8-H); 7.62 (d,l,J=3 Hz, 5-H); 7.35 (dd,l,J1 =10 Hz, J2 =3 Hz, 7-H); 4.00 (s,3, OCH3); 3.00 (s,3, NCH3).
N-(6-chloro-pyrazin-2-yl)-2,6-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 5,5-dimethyl-1,3-cyclohexadiene;
EXAMPLE 3 N-(6-Chloro-pyrazin-2-yl)-2,6-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 2.0 g (7 mmols) of methyl 2,6-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.1 g (8.4 mmols) of 2-amino-6-chloro-pyrazine were reacted in 150 ml of xylene analogous to Example 2, and the reaction product was isolated and recrystallized from ethylene chloride. 2.1 g (79percent of theory) of N-(6-chloro-pyrazin-2-yl)-2,6-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained. Melting point: 296°-298° C. 1H-NMR (CDCl3 +d-TFA): delta=9.55 (s, 1,3'-H); 8.55 (s, 1,5'-H); 8.05-7.55 (m, 3,5-H, 7-H, 8-H); 3.00 (s,3,N-CH3); 2.60 (s,3,CH3).
EXAMPLE 4 N-(6-Chloro-pyrazin-2-yl)-2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 7.5 g (26 mmols) of methyl 2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 4.36 g (33 mmols) of 2-amino-6-chloro-pyrazine were reacted in 40 ml of xylene and worked up analogous to Example 2. 7.2 g (73percent of theory) of N-(6-chloro-pyrazin-2-yl)-2,7-dimethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained. IR (KBr): 1645 cm-1 (CO amide).
Example 5 N-(6-Chloro-pyrazin-2-yl)-7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 4.1 g (15 mmols) of methyl 7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2.3 g (18 mmols) of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> were reacted in 200 ml of xylene analogous to Example 2 and worked up in analogy thereto. 3.8 g (66percent of theory) of N-(6-chloro-pyrazin-2-yl)-7-fluoro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained. IR (KBr): 1645 cm-1 (CO amide).
Example 6 6-Chloro-N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 3.04 (10 mmols) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.5 g (12 mmols) of 2-amino-6-chloro-pyrazine were reacted in 150 ml of xylene analogous to Example 2. 3.2 g (80percent of theory) of 6-chloro-N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained. Melting point: 283°-284° C. (from dioxane). C14 H10 Cl2 N4 O4 S (401.23): Calc.: C--41.91percent; H--2.51percent; N--13.96percent; Cl--17.67percent; S--7.99percent. Found: C--42.05percent; H--2.62percent; N--14.09percent; Cl--17.54percent; S--7.80percent.
EXAMPLE 8 N-(6-Chloro-pyrazin-2-yl)-2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 8.5 g (30 mmols) of methyl 2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 3.9 g (30 mmols) of 2-amino-6-chloro-pyrazine were reacted in 600 ml of xylene and worked up analogous to Example 1, yielding 7.3 g (64percent of theory) of N-(6-chloro-pyrazin-2-yl)-2-ethyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. Melting point: 233°-235° C. (from xylene). C15 H13 ClN4 O4 S (380.83): Calc.: C--47.31percent; H--3.44percent; Cl--9.31percent; N--14.71percent; S--8.42percent. Found: C--47.42percent; H--3.44percent; Cl--9.50percent; N--14.62percent; S--8.51percent.
EXAMPLE 9 N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-n-propyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 2.97 g (10 mmols) of methyl 2-n-propyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.3 g (10 mmols) of 2-amino-6-chloro-pyrazine were reacted in 150 ml of xylene analogous to Example 1, yielding 2.05 g (52percent of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-n-propyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. C16 H15 ClN4 O4 S (394.86): Calc.: C--48.67percent; H--3.83percent; Cl--8.98percent; N--14.19percent; S--8.12percent. Found: C--48.91percent; H--3.79percent; Cl--8.90percent; N--14.18percent; S--8.03percent.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With toluene-4-sulfonic acid;
(b) N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from 4-hydroxy-2-methyl-N-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14. Yield: 68percent of theory. Melting point: 278°-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79): Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--45.61percent; H--3.14percent; Cl--9.71percent; N--15.02percent; S--8.58percent.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With toluene-4-sulfonic acid;
(c) N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from 4-hydroxy-2-methyl-N-ethyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14. Yield: 68percent of theory. Melting point: 278°-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79): Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--45.62percent; H--3.11percent; Cl--9.70percent; N--15.04percent; S--8.59percent.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With toluene-4-sulfonic acid;
(d) N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from 4-hydroxy-2-methyl-N-cyclohexyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14. Yield: 68percent of theory. Melting point: 278°-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79). Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--45.68percent; H--3.04percent; Cl--9.69percent; N--15.12percent; S--8.60percent.
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
(b) N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from butyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1. Yield: 58percent of theory. Melting point: 278°-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79): Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--46.01percent; H--3.01percent; Cl--9.60percent; N--15.51percent; S--8.70percent.
benzyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide[ No CAS ]
[ 33332-28-4 ]
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
(c) N-(6-Chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide This compound was prepared from benzyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-6-chloro-pyrazine analogous to Example 1. Yield: 49percent of theory. Melting point: 278°-279° C. (decomposition). C14 H11 ClN4 O4 S (366.79): Calc.: C--45.84percent; H--3.03percent; Cl--9.67percent; N--15.28percent; S--8.74percent. Found: C--46.10percent; H--3.16percent; Cl--9.78percent; N--15.01percent; S--8.56percent.
p. N-(6-Chloro-2-pyrazinyl)-4-hydroxy-2-methyl-2H-naphtho[2, 1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 209°-210° C (from ethanol), from 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1 -e]-1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide and 2-amino-6-chloro-pyrazine.
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 16h;
6-Pyridin-3-ylpyrazin-2-amine An oven dried resealable Schlenk tube was charged with 6-chloropyrazin-2-amine (0.73 g, 5.71 mmol), 3-pyridineboronic acid (0.91 g, 7.42 mmol), dioxane (50 mL) and a 2M aqueous solution of cesium carbonate (8.5 mL, 17.13 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1 ,1'- bis(diphenylphosphino)ferrocene-palladium(ll) dichloride dichloromethane complex (290mg, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 9O0C oil bath. After 16h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (845 mg, 86percent) as a solid. delta 1H-NMR (CDCI3): 9.18 (s, 1H), 8.67 (d, 1H), 8.38 (s, 1H), 8.25 (m, 1H), 7.99 (s, 1 H), 7.41 (m, 1 H), 4.77 (s, 2H). ESI/MS (m/e, percent): 172 [(M+1)\\ C9H8N4].
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃; for 4h;
6-(3-Fluorophenyl)pyrazin-2-amine To a stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0 g, 15.43 mmol) in a mixture of toluene (90 ml.) and ethanol (8.5 ml_) was added 3-fluorophenyl boronic acid (2.60 g, 18.51 mmol) and a 2M aqueous solution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (0.713 g, 0.617 mmol) was added. The mixture was subjected again to three cycles of evacuation-backfilling with argon the flask was capped and placed in a 11O0C oil bath. After 4h, the mixture was cooled, partitioned between dichloromethane and water the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (33percent ethyl acetate in hexanes to 50percent ethyl acetate in hexanes). Concentration in vaccuo of the product-rich fractions provided the titled compound (2.79 g, 95percent) as a yellowish solid (2.79 g, 95percent). delta 1H-NMR (CDCI3): 8.38 (s, 1 H), 7.95 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1 H), 4.65 (s, 2H).
tetrakis(triphenylphosphine) palladium(0); In xylene; at 150℃; for 20h;
6-Pyridin-2-ylpyrazin-2-amine An oven dried resealable Schlenk tube was charged with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1.00 g, 7.72 mmol), 2-(tributylstannyl)pyridine (3.55 g, 7.72 mmol) and xylene (40 ml_). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (446 mg, 0.38 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 15O0C oil bath. After 2Oh, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Silica gel flash chromatography (dichloromethane/methanol 98:2 to dichloromethane/methanol 90:10) provided the title compound as a light brown solid (950 mg, 71percent). delta 1H-NMR (CDCI3): 8.90 (s, 1H), 8.70 (d, 1H), 8.20 (d, 1H), 8.00 (s, 1H), 7.80 (dd, 1 H). 7.30 (m, 1 H), 4.65 (s, 2H).ESI/MS m/e: 173 ([M+H]+, C9H8N4)
60%
With tetrakis(triphenylphosphine) palladium(0); In 5,5-dimethyl-1,3-cyclohexadiene; at 150℃; for 16h;Sealed tube; Inert atmosphere;
To a stirred solution of 6-chloropyrazin-2-amine (0.500 g, 3.85 mmol, 1.0 eq.) in xylene (20.0 mL) was added 2-(tributylstannyl)pyridine reagent (1.42 g, 3.85 mmol, 1.0 eq.). The reaction mixture was deoxygenated using N2 gas and Pd(PPh3)4 (0.223 g, 0.05 eq. 0.192 mmol) was added. The reaction mixture was again purged with N2 and allowed to heat at 150° C. for 16 h in seal tube. Progress of the reaction was monitored by TLC and LCMS Reaction mixture was allowed to cool to RT and quenched by adding aq. NaOH and extracted using ethyl acetate (3*100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to get the solid which was purified by normal phase column chromatography to get the desired product (0.400 g, 60percent).
With N-iodo-succinimide; In dimethyl sulfoxide; at 25℃;
To a solution of 6-chloropyrazin-2-amine (10 g, 77.2 mmol) in DMSO (100 mL) was added NIS (17.4 g, 77.2 mmol) and the solution was stirred at 25C overnight. After the mixture was poured into water and extracted with EtOAc, the organic solutions were collected, washed with brine, dried over NaS04 and filtered. The filtrate was evaporated under reduced pressure and the residue purified by silica gel chromatograph using Petroleum Ether:EtOAc 1 :4 as eluting solvents to afford 6-chloro-5-iodopyrazin-2-amine as a yellow solid (17.2 g, 88%). MS (ESI) m/z: 255 [M+H]+.
76%
With N-iodo-succinimide; In water; dimethyl sulfoxide; at 0℃; for 72h;
6-Chloro-5-iodo-4-ylpyrazin-2-amine To a O0C cooled stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (3 g, 23 mmol) in a mixture of DMSO (90 mL) and water (2.2 mL), was added Lambda/-iodosuccinimide (5.2 g, 23 mmol) in EPO <DP n="54"/>portions. After stirring for 72h, the mixture was poured into water, extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Flash chromatography (98:2 dichloromethane/methanol) furnished the title compound as a yellow solid (4.43 g, 76%). delta 1H-NMR (CDCI3): 7.73 (s, 1H), 4.72 (s, 2H).ESI/MS (m/e, %): 255 [(M+1) C4H3CIIN3].
75%
With Iodine monochloride; potassium carbonate; In methanol; dichloromethane; at 0 - 20℃;
To a mixture of compound 9 (312.0 g, 2A mol) and K2C03 (664.0 g, 4.8 mol) in MeCH(1.0 L) was dropwise added lCl (704.0 g, 4.3 mol in 1.0 L of DCM) over 2 hours0C. Then the reaction mixture was stirred at room temperature overnight. Thereaction was quenched with Na2SO3 aqueous solution (2M, 1 .5 L). The mixture was extracted with DCM (1.0 L x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purifiedcolumn chromatography on silica gel (PEIEA = 10/1 to 4/1) to afford compound(460 g, 75% yield) as a solid.1HNMR (400 MHz, DMSQd6): 7.68 (s, 1H), 7.07 (s 2H). MS Calcd.: 255 MS Found: 256 ([M+Hfl.
75%
With Iodine monochloride; potassium carbonate; In methanol; dichloromethane; at 0 - 20℃;
To a mixture of compound 9 (312.0 g, 2.4 mol) and K2CO3 (664.0 g, 4.8 mol) in MeOH (1.0 L) was dropwise added IC1 (704.0 g, 4.3 mol in 1.0 L of DCM) over 2 hours at 0C. Then the reaction mixture was stirred at room temperature overnight. The reaction was quenched with NaiSC aqueous solution (2M, 1.5 L). The mixture was extracted with DCM (1.0 L x 3). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE/EA = 10/1 to 4/1) to afford compound 10 (460 g, 75% yield) as a solid. 1HNMR (400 MHz, DMSO- 6): delta 7.68 (s, 1H), 7.07 (s, 2H). MS Calcd.: 255 MS Found: 256 ([M+H]+).
42%
With N-iodo-succinimide; In acetonitrile; at 0 - 20℃;
Step-1: Synthesis of 6-chloro-5-iodopyrazin-2-amine To a stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0 g, 1.0 eq., 15.50 mmol) in acetonitrile (20 mL) was added NIS (3.46 g, 1.0 eq., 15.50 mmol) at 0 C. The reaction was allowed to stir at RT. Progress of the reaction was monitored by TLC and LCMS After completion of the reaction the solvent was evaporated under vacuum and the solid was extracted using ethyl acetate (3*100 mL). The combined organic layers were washed (brine), dried (anhydrous Na2SO4) and concentrated under vacuum to get the solid which was purified by normal phase column chromatography to get the desired product (1.7 g, 42%).
With N-iodo-succinimide; In water; dimethyl sulfoxide; at 0℃; for 72h;Darkness;
Step 1 To <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1eq) in DMSO and water is added at 0C NIS (1.1 eq) in 3 portions. The mixture is stirred in the dark for 72 h. The mixture is poured into water, extracted with EtOAe and-evaporated. The crude material is purified via flash column chromatography.
With N-iodo-succinimide; In dimethyl sulfoxide; at 20℃; for 48h;
A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml) was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). The reaction mixture was stirred at RT for 2 days and then added to water (800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO3 solution and the resulting suspension was filtered, washing with water (*3) and dried under vacuum to afford the titled compound as an orange solid; LC-MS Rt=0.83 mins; [MeCN+H]+ 296.0, Method 2 minLowpH.
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20 - 60℃;
Acetic acid (600mg, 10 mmol) was added to a solution of 3-(cyclopentyloxy)-4- methoxybenzaldehyde (440mg, 2 mmol) , 6-chloropyrazin-2-amine (258 mg, 2 mmol) and sodium triacetoxyborohydride (1.2 g, 5.6 mmol) in 30 mL dichloroethane at room temperature. The resulting mixture was warmed up to 600C and stirred for 4 hours. The reaction mixture was quenched with water. The product was extracted with DCM (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to dryness. The crude product was purified by SiO2 column chromatography to give lOOmg of 6-chloro-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyrazin-2-amine. Yield: 15percent
10%
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 50℃;
Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10percent. An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50 mg, 0.15 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 5.5 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}-propionic acid, yield 6percent. 1H-NMR (400 MHz, DMSO-d6): delta 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.0 (m, 1H), 4.45 (d, 2H), 4.65 (m, 1H), 6.90 (s, 2H), 6.95 (s, 1H), 7.32 (d, 2H), 7.60 (t, 1H), 7.90 (s, 1H), 7.95 (d, 2H), 8.25 (s, 1H).
With pyridine; In tetrahydrofuran; acetonitrile; for 18h;
Example 27; Synthesis of N-(6-chloropyrazin-2-yl)-4-(3-[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide; Step 1; Phenyl 6-chloropyrazin-2-ylcarbamate; A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0 g, 15.44 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (1.28, 16.2 mmol) was treated dropwise with phenylchloroformate (2.54 g, 16.2 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 53percent).
Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10percent.
10%
With acetic acid;
Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10percent.
EXAMPLE 5 General Synthetic Procedure E Preparation of 2-Chloro-6-(2-chlorothiophen-5-ylmetllylamino . pyrazine To a stirred solution of the <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (149 mg, 1.15 mmol) in THF (2 ml) was added Bu4NI (5 mg, cat. ) and then the NaH (56 mg, 1.39 mmol) at room temperature under an atmosphere of nitrogen. After 10 minutes, 2-chloro-5- (chloromethyl) thiophene (138 mg, 1.15 mmol) was added. The reaction was left for 3 hours at room temperature, quenched with water, and then partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried (MgS04), filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica (eluent 20percent ethyl acetate/petrol) to afford the title compound; LCMS: m/z 260 (M+H), RT 4.13 min.
tert-butyl 2-(5-(6-chloropyrazin-2-ylamino)-2-methylphenylamino)-2-oxoethyl(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.0%
With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane; at 85℃; for 4h;
B. tert-Butyl 2-(5-bromo-2-methylphenylamino)-2- oxoethyl(methyl)carbamate. tert-Butyl 2-(5-bromo-2-methylphenylamino)-2- oxoethyl(methyl)carbamate (1.31 g, 3.67 mmol), 6-chloropyrazin-2-amine (0.523 g, 4.03 mmol), Xantphpos (0.212 g, 0.367 mmol), palladium acetate (0.041 g, 0.183 mmol), and potassium carbonate (2.53 g, 18.33 mmol) were suspended in 1,4-dioxane (10 mL). The reaction mixture was stirred at 85°C for 4 h. The reaction was partitioned between ethyl acetate and aqueous sodium chloride. The aqueous layer was extracted with ethyl acetate (3 x 25 mL), and the organic layers were combined and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo. The residue was purified by silica gel chromatography (30-55percent ethyl acetate in hexanes) to give the title compound as a white solid (0.3873 g, 0.954 mmol, 26.0percent yield) ); MS (ESI) MS (ESI) m/z 406.1 [M+l]+.
Example 24; N-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazin-2-yl)-3-methylbenzamide; Example 24A; N-(6-chloropyrazin-2-yl)-3-methylbenzamide; <strong>[33332-28-4]2-Amino-6-chloropyrazin</strong>e (496.0 mg, 3.83 mmol) was dissolved in pyridine (15 mL). 3-Methylbenzoyl chloride (760 muL, 5.77 mmol) was added to the reaction mixture. The reaction was heated to 100° C. for 16 h then concentrated under vacuum. The residue was partitioned between 1M K2CO3 (50 mL) and CH2Cl2 (4.x.50 mL). The organic extracts were combined, washed with and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (5percent EtOAc in CH2Cl2, Rf=0.39) to afford the title compound as a white solid (919.0 mg, 97percent). MS m/z 248 (M+H)+.
EXAMPLE 6 1-(6-chloro-pyrazin-2-yl)-3-ethyl-urea At 0° C. in a nitrogen atmosphere, 5.5 g (42.5 mmol, 1 eq) of the compound of example 5 were placed in 40 ml of tetrahydrofuran, then 1.79 g (46.7 mmol, 1.1 eq) of a 60percent suspension of sodium hydride in mineral oil were added incrementally. The mixture was stirred and the temperature brought to 30° C., until no more hydrogen was given off. After cooling to room temperature, a solution of 5.1 ml (63.8 mmol, 1.5 eq) of ethyl isocyanate in 10 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 16 h at room temperature, then vacuum evaporated. The residue was taken up in a water/ethyl acetate mixture, triturated for 1 h and filtered. The precipitate was washed with ethyl acetate. The reaction produced 7.9 g of a brown solid (yield: 93percent). 1H NMR (CDCl3) delta (ppm): 8.23 (s, 1H, CH); 8.14 (s, 1H, CH); 3.44 (q, J=7 Hz, 2H, NCH2); 1.26 (t, J=7 Hz, 3H, CH3). HPLC: t=1.43 min MS: 201 (MH+) HPLC purity: 100percent
Example 78; (3R)-1-{2-[(6-Chloropyrazin-2-yl)amino]-2-oxoethyl}-3-[2-piperidin-1-yl-2-(2-thienyl)propanoyl]oxy}-1-azoniabicyclo[2.2.2]octane bromide (Isomer 1); a) 2-Bromo-N-(6-chloropyrazin-2-yl)acetamide; 6-Chloropyrazin-2-amine (2.5 g) was suspended in water (50 mL) containing sodium bicarbonate (16.21 g). To the stirred suspension was added 2-bromoacetyl bromide (19.48 g) dropwise. After the addition was complete the mixture was stirred at RT for 0.5 h then extracted with ether (2.x.100 mL). The combined extracts were dried over magnesium sulphate and concentrated to an oil. The crude product was purified on silica gel eluting with dichloromethane/Ether (1:1) to afford the subtitled compound (0.600 g).1H NMR (400 MHz, DMSO) delta 11.52 (1H, s), 9.26 (1H, s), 8.54 (1H, s), 4.17 (2H, s).
With hydrogen bromide; sodium hydrogencarbonate; In isopropyl alcohol;Reflux;
Example 186Preparation of 1-Benzothiazol-6-yl-3-imidazo[1,2-a]pyrazin-5-yl-imidazolidin-2-one (186A) Synthesis of Intermediate 5-Chloro-imidazo[1,2-a]pyrazine (I-186a) NaHCO3 (4.215 g, 50.1736 mmol) and IPA (40 mL) were added to a mixture of 2-bromo-1,1-dimethoxy-ethane (6.37 mL, 10.8066 mmol), 40percent HBr (475 mL, 2.3157 mmol) and 2 drops of water previously refluxed for 1 hr. The reaction mixture was stirred for 5 mins and filtered. To the filtrate was added 6-chloro-pyrazin-2-ylamine (1 g, 7.7190 mmol) and the resulting mixture was refluxed for overnight. The reaction was monitored by TLC (50percent ethylacetate in hexane). The reaction mixture was neutralized with Na2CO3 and partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1-2percent MeOH in CHCl3) afforded 300 mg of the product (25.31percent yield).1H NMR (400 MHz, CDCl3): delta 9.05 (s, 1H), 7.98 (s, 1H), 7.92-7.85 (m, 2H).LCMS: 97.85percent, m/z=154.0 (M+1)
25.31%
NaI KX); (4.215g, 50.1736miotanol) and IPA (4OmL) were added to a mixture of 2- 0 brorno- 1.1 -dhneihoxs -ethane (6.37ml... I O.8066mmol), 40percent HBr (475mL. 2.3157mmol ) and 2 drops of water previously reUuxed tor I hr. The reaction mixture was stirred for 5mins and filtered. To the filtrate was added 6-chloro-pyra/in-2-ylamine (I g, 7.7190miotanol) and the resulting mixture was reflux ed for overnight. The reaction was monitored by TLC (50percent ethylacetate in hexane). The reaction mixture was neutrali/od 5 with Na2(X).; and partitioned between ethylacetate and water. The organic layer was washed with water, brine, dried over Na>SO; and concentrated. Purification by column ehromatograph) on silica gel ( 1-2percent McOH in CHC I4) afforded 30(.)mg of the product (25.31percent yield >.1H NMR (400 MIIz, CDCIj): 6 9.05 (s, I M). 7.98 (v IH), 7 92 -7.85 (m. 211).IX MS: 97.85percent. m// 154.0 (M .bul. 1)
With N-Bromosuccinimide; In chloroform; for 1.5h;Reflux;
Example 62; Step 1; To a solution of 1 (10.0 g, 77.19 mmol) in CHCl3 (300 mL), N-bromo succinimide (13.73 g, 77.19 mmol) was slowly added in portions at reflux. The reaction was stirred at reflux for 1.5 h. TLC (100percent DCM) showed complete consumption of SM. The reaction mixture was cooled to 25° C., washed with water (3.x.200 mL), dried over Na2SO4, and concentrated under reduced pressure to afford crude compound 2. This material was purified by column chromatography over silica gel (100-200 mesh) eluting with DCM to afford 2 as cream colored solid (5.0 g, 31percent). MS m/z (ES): 207 (M+H)+.
31%
With N-Bromosuccinimide; In dichloromethane; at -10℃; for 4h;
To a solution of 6-chloropyrazin-2-amine (15.0 g, 115 mmol) in DCM (150 mL), Nbromo succinimide (20.6 g, 115 mmol) was slowly added in portions at -10°C and stined for 4h.The reaction mixture was washed with water and the organic layer was separated. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) eluting with DCM to afford 3-bromo-6-chloropyrazin-2-amine (7.5g, 3 1percent).
28%
With N-Bromosuccinimide; In chloroform; at 0 - 20℃;Inert atmosphere;
Under N2 flow, /V-bromosuccinimide (121 g; 679 mmol) was added dropwise to a mixture of 6-chloro-2-pyrazinamine (88 g; 679 mmol) in CHCI3 (1000 ml) at 0°C. The reaction mixture was stirred at room temperature overnight then was poured out onto water and DCM was added. The organic layer was washed, dried over MgS04, filtered and evaporated. The residue was purified by chromatography over silica gel (mobile phase : 91 percent petroleum ether, 9percent EtOAc). The pure fractions were collected and the solvent was evaporated to afford 40 g (28percent) of intermediate 1
25%
With N-Bromosuccinimide; In chloroform;Reflux;
l -Bromopyrrolidine-2,5-dione (27.5 g, 1 54 mmol) was added portionwise over 30 min. to a solution of 6-chloropyrazin-2-amine (59; 20 g, 1 54 mmol) in chloroform (200 mL) heated under reflux. After the addition was complete, the reaction mixture was allowed to cool, washed with water and concentrated. The residue was purified by silica gel chromatography eluting with CH2CI2 to obtain a 3-bromo-6-chloropyrazin-2-amine (60; 8 g, 25percent yield). MS (ESI) calcd for C4H3BrClN3: 208.44; found.
13%
With N-Bromosuccinimide; In dichloromethane; at 25℃; for 16h;
Preparative Example 16 Step 1: 3-bromo-6-chloropyrazin-2-amine To a solution of 6-chloropyrazin-2-amine (20 g, 154.44 mmol) in dichloromethane (400 mL) was added N-bromosuccinimide (28.86 g, 162.16 mmol) portion wise. The reaction mixture was stirred at 25 °C for 16 h and subsequently concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 20percent ethyl acetate in hexane) affording 3- bromo-6-chloropyrazin-2-amine (4.2 g ,13percent): H NMR (400 MHz, DMSO-d6) delta 7.63 (s, 1H), 7.23 (br, 2H).
11%
With N-Bromosuccinimide; In chloroform; at 20℃; for 5h;Reflux;
A mixture of 6-chloropyrazin-2-amine (120 g, 0.93 mmol) in CHC13(1 L) was stirred at r.t. for 0.5h. Then NBS (247 g, 1.39 mmol) was added in portions. The reaction mixture was stirred at rt for 2h and heated to reflux for 3h. The reaction mixture was cooled to rt and treated with water (1 L). The mixture was extracted with CH2C12 (5x300 mL). The combined organic layers were washed with brine (200 mL), dried over Na2 SO4and evaporated in vacuo. The resulting residue was purified by column chromatography onsilica gel (PE: DCM = 5:1) to afford the crude product, which was recrystallized in DCM:PE (1:5) to afford the product (21.7 g, 11percent), as a yellowish solid. 1H NIVIR (400 MHz, CDC13): 7.68(s, 1H), 5.32(s, 2H).
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 20 - 90℃; for 16.1667h;Inert atmosphere;
To a stirred solution of 6-chloropyrazin-2-amine (50 g, 0.3861 mol) in dioxane:water (400 mL; 100 mL) was added benzeneboronic acid (56.4 g, 0.46 mol). The reaction mixture was purged with nitrogen for 20 min then charged Na2CO3 (70.6 g, 0.57 mol) and Pd(PPh3)Cl2 (13.5 g, 0.01930 mol). The reaction mixture was again purged with nitrogen. The reaction mixture was stirred at RT for 10 min followed by heating at 90° C. for 16 h. The reaction was monitored by TLC & LCMS. The reaction mixture was filter through celite and distilled. The reaction was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (anhydrous Na2SO4) & concentrated under vacuum to get the solid which was purified by column chromatography over silica gel (100-200 mesh) [Ethyl acetate: Hexane (3:7) as eluent] to get the desired product (55 g, 83percent). LCMS: 172 [M+1]+. 1H NMR (400 MHz, CHLOROFORM-d) delta 8.38 (s, 1H), 7.83-7.99 (m, 3H), 7.40-7.49 (m, 3H), 4.82 (br. s., 2H)
55%
With potassium phosphate; 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; at 100℃; for 5h;Inert atmosphere; Sealed tube;
General procedure: To a solution of the requisite chloro-amino-substituted heteroaromatic in anhydrous 1,4-dioxane (30 volumes wrt chloride) in a sealed tube was introduced phenylboronic acid (1.5 equiv) and finely ground potassium phosphate (2.0 equiv). The solution was degassed (N2 bubbling) for 5 min, Pd(OAc)2 (5 mol percent wrt chloride) and di-tert-butylphosphinoferrocene (5 mol percent wrt chloride) introduced and degassing continued for a further 5 min. The tube was sealed under nitrogen and heated with rapid stirring at 100 °C for 5 h. After cooling, the reaction mixture was filtered in vacuo through a celite pad and the precipitated material washed with 1,4-dioxane. The combined filtrates were evaporated and purified by flash column chromatography (neat hexane to 1:1 hexane/EtOAc gradient containing 2.5percent by volume Et3N) to furnish the biarylanilines 13, 14 and 15.
To a solution of solketal (48.7 g, 0.369 mol) in 1,4-dioxane (1500 mL) was added NaH (14.8 g, 369 mmol) at room temp and stirred for 2 h. Then 6-chloropyrazin-2-amine (34; 16.0 g, 123 mmol) was added and the mixture was stirred at 120 °C for 12 h. The solvent was removed and ethyl acetate (1000 mL) was added. The mixture was washed with brine (1000 mL x 3), The organic solvent was dried over Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (dichloromethane:methanol=30:l-10:l) to give 6-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)pyrazin-2-amine (35; 13.8 g, 61.3 mmol, 50percent) as a yellow solid. MS (ESI) calcd for C10H15N3O3 (m/z) 225.24, found: 226 [M+ H].
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20℃; for 20h;Reflux;
6-Chloropyrazin-2-amine (0.96 g, 7.41 mmol) was added to a degassed suspension of Na2CO3 (2.0 M aqueous solution, 7.4 mL, 14.82 mmol), Pd(dppf)Cl2·CH2Cl2 (0.49 g, 0.59 mmol) and (4-fluorophenyl)boronic acid (1.55 g, 11.11 mmol) in 1,4-dioxane (20 mL). The reaction was refluxed for 5 h and stirred at room temperature for 15 h. The mixture was poured into water (40 mL) and extracted with Et2O. The combined organic layers were dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (20percent to 40percent EtOAc/hexanes) to give the title compound (off-white solid, 1.5 g, quantitative yield). HPLC-MS (Method A): Ret, 8.01 min; ESI+-MS m/z: 190 (M+1).
To a solution of 6-chloropyrazin-2-amine (0.5 g, 3.86 mmol) in DME (3 mL) at room temperature was slowly added 2-chloroacetaldehyde (45percent aqueous solution, 2.4 mL, 14 mmol). The resulting mixture was heated to 66 °C for 90 minutes, cooled to room temperature, and then basified with IN NaOH. This basified mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude material was purified by silica gel chromatography (eluting with 0-10percent MeOH in DCM) to provide Intermediate 59 (430 mg, 73percent yield). MS (ES): m/z= 153.9 [M+H]+. XH NMR (400 MHz, DMSO-d6) delta ppm 9.12 (1 H, s), 8.27 (1 H, s), 8.15 (1 H, s), 7.85 (1 H, s). Intermediate 59 was used in the synthesis of Example 251.
To a solution of 6-chloropyrazin-2-amine (0.3 g, 2.31 mmol) in THF (11.5 ml) was added (Boc)2O (1.34 ml, 5.79 mmol) and DMAP (0.141 g, 1.16 mmol) at room temperature. After stiffing for 2 hours at room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=4:1) to give 6-chloro-2-(N,N-bis(boc-amino)pyrazine (0.747 g, 98percent) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) delta 1.47 (18H, s), 8.48 (1H, d, J=0.8 Hz), 8.53 (1H, d, J=0.8 Hz).
88.4%
With dmap; In tetrahydrofuran; at 20℃; for 8h;
To a solution of 6-chloropyrazin-2-amine (1 g, 7.72 mmol) in tetrahydrofuran(30 mL) were added 4-dimethylaminopyridine (94.3 mg,0.772 mol and (Boc)2O (5.05 g, 23.2 mmol). The mixture was stirred atroom temperature for 8 h. The mixture was concentrated in vacuo andEtOAc (200 mL) was added. After washed with water (100 mL×3), theorganic phase was dried over Na2SO4, filtered, and concentrated invacuo. The residue was purified by flash column chromatography (silicagel, petroleum ether/ EtOAc=10/1) to afford compound 21 (2.25 g,88percent) as white solid.
General procedure: To the N,N-diethylformamide (1ml) was added dropwise phenyl chloroformate (3.5equiv). The mixture was stirred for 10min at room temperature. Then <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (1mmol) was introduced to the mixture. After 5min at 45°C, the mixture was basified with K2CO3(aq), extracted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give the product.
General procedure: To the N,N-diethylformamide (1ml) was added dropwise phenyl chloroformate (3.5equiv). The mixture was stirred for 10min at room temperature. Then <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (1mmol) was introduced to the mixture. After 5min at 45C, the mixture was basified with K2CO3(aq), extracted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give the product.
N'-(6-chloropyrazin-2-yl)-N,N-dimethylformamidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
General procedure: To the DMF (1ml) was added dropwise phenyl chloroformate (2equiv). The mixture was stirred for 5min at room temperature. Then <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (1mmol) was introduced to the mixture. After 5min, the solvent (isopropyl alcohol:diethyl ether, v/v=1:2) was poured into the mixture. The precipitated product 6a was filtered off, washed with the solvent and dried.
General procedure: To the N,N-diethylformamide (1ml) was added dropwise phenyl chloroformate (3.5equiv). The mixture was stirred for 10min at room temperature. Then <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (1mmol) was introduced to the mixture. After 5min at 45°C, the mixture was basified with K2CO3(aq), extracted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give the product.
General procedure: To the N,N-diethylformamide (1ml) was added dropwise phenyl chloroformate (3.5equiv). The mixture was stirred for 10min at room temperature. Then <strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> (1mmol) was introduced to the mixture. After 5min at 45°C, the mixture was basified with K2CO3(aq), extracted with ethyl acetate and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give the product.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 130℃; for 1h;Microwave irradiation;
17.1 6-(1- pyrazin-2-ylamine To a solution of 2-amino-6-chloro pyrazine (0.5 g, 3.86 mmol) in toluene / ethanol (9:1 , 10 ml), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (0.8 g, 4.24 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) and cesium carbonate (2.5 g, 7.72 mmol) are added, degassed briefly and irradiated in microwave at 130 °C for an hour. The reaction mixture is passed through celite, washed with dichloromethane/methanol (1:1, 25 ml), the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as yellow solid (0.51 g, 75.44 percent); TLC: chloroform/methanol (9.5/0.5) R - 0.3; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.16 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 6.32 (br s, 2H), 3.86 (s, 3H); LCMS: Mass found (M+, 176.0) Method: A-0.1percent TFA in H20, B-0.1percent TFA in ACN: Flow - 0.6 ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 1.09 area percent -96.86 (Max).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 130℃; for 1h;Microwave irradiation;
6-quinolin-3-yl-p razin-2-ylamine To a solution of 2-amino-6-chloro-pyrazine (0.3 g, 2.31 mmol) in toluene / ethanol (9:1 , 10 ml), quinoline-3-boronic acid pinacol ester (0.65 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.069 mmol) and cesium carbonate (1.5 g, 4.60 mmol) are added, degassed briefly and irradiated in microwave at 130°C for an hour. The reaction mixture is passed through celite, washed with dichloromethane/methanol (1:1, 25 ml), the filtrate is concentrated and purified by silica column using (230-400) mesh to get the product as yellow solid (0.25 g, 49.61 percent); TLC: chloroform/methanol (9.5/0.5) Rf- 0.4; LCMS: Mass found (M+, 223.0) Method: A-0.1percent TFA in H2O, B-0.1percent TFA in ACN: Flow - 2.0 ml/min. Column: XBridge?8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 1.67 area percent -99.35 (Max).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 120℃; for 0.25h;Microwave irradiation;
6-(3-methoxy-phenyl)-pyrazin-2ylamine To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (0.5 g, 3.85 mmol) in a mixture of toluene/ethanol (4:1 , 10 ml), 3-methoxyphenylboronic acid (0.64 g, 4.24 mmol), tetrakis(triphenylphosphino)palladium(0) (0.13 g, 0.11 mmol) and cesium carbonate (2.51 g, 7.71 mmol) are added, degassed briefly and irradiated in microwave at 120°C for 15 minutes. The reaction mixture is passed through celite, washed with dichloromethane, the filterate is concentrated and purified by column using silica gel (60-120) mesh to get the product as yellow solid (0.34 g, 44.15 percent); TLC: Pet ether/Ethylacetate(7/3) Rf - 0.2; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.27 (s, 1 H), 7.83 (s, 1H), 7.57-7.52 (m, 2H), 7.37 (t, J = 7.88 Hz, 1 H), 7.00-6.97 (m, 1 H), 6.51 (br s, 2H), 3.80 (s, 3H); LCMS: Mass found (M+, 202.3) Method: A-0.1 percent TFA in H20, B-0.1 percent TFA in ACN: Flow - 2.0ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 2.48 area percent -98.79 (Max), 99.35 (254 nm).
13.1 5-chloro-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-ylamine To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (15.0 g, 115.8 mmol) in dry tetrahydrofuran (150 ml), ethoxycarbonylisothiocyante (16.7g, 127.4 mmol) is added and heated to 50°C for 12 hours. The reaction mixture is concentrated and suspended in ethanol/methanol (1:1 , 300 ml), hydroxylamine hydrochloride (40.09 g, 576.9 mmol) and diisopropylethylamine (44.73 g, 346.1 mmol) are added and heated to 80°C for 3 hours. The reaction mixture is concentrated and the crude mass is taken in water and filtered, washed with water, cold acetonitrile, diethylether, to get the product as pale yellow solid (14.0 g, 71.42 percent); TLC: chloroform/methanol (9.5/0.5) Rf- 0.2. 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.80 (s, 1H), 8.18 (s, 1 H), 6.75 (br s, 2H); LCMS: Mass found (M+, 170.0) Method: A-0.1percent TFA in H20, B-0.1percent TFA in ACN: Flow - 1.0 ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 2.01 area percent -99.66 (Max), 99.51 (220 nm); HPLC Method: A- A-0.1percent TFA in H20, B- percent TFA in ACN: Flow - 1.0ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm) Rt (min): 2.02 area percent - 99.23 (Max), 99.05 (220nm).
With N-chloro-succinimide; In tetrahydrofuran; for 1h;Reflux;
The 2 - amino -6 - chloropyrazine (2.0 g, 15.4 mmol) dissolved in THF (50 ml) in, adding N - chloro succinimide (8.3 g, 61.8 mmol), heated to reflux the reaction 1 h. The completion of the reaction, cooling to room temperature, the reaction liquid is poured into the water, ethyl acetate (40 ml × 3) extraction, the collection of organic phase, anhydrous sodium sulfate drying, filtering solid, decompressing to evaporate the solvent to obtain 2 - amino - 3, 5, 6 - trichloro pyrrole qin white solid 2.8 g, yield 91.3percent.
90%
With N-chloro-succinimide; In tetrahydrofuran; at 80℃; for 1h;Inert atmosphere;
<strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (260 mg, 2.0 mmol) was dissolved in THF, and N-chlorosuccinimide (616 mg, 4.6mmol) was added to the solution with stirring. The mixture was heated at 80 °C for 1 h. After cooling, the solvent was evaporated in vacuo. Ethyl acetate was added to the mixture and washed with water and brine. The combined organiclayer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 3,5,6-Trichloro-2-aminopyrazine 1d (357 mg, 90percent) as a light yellowgreen solid. 1H NMR (400 MHz, CDCl3) delta5.17 (br, 2H).
NaH (60percent in oil, 1.24 g, 30.9 mmol) was washed twice with pentane and dried under vacuum. Dioxane (50 mL) was added, followed by (3-methyloxetan-3-yl)methanol (3.0 mL, 30.9 mmol) dropwise. This was allowed to stir 2 h at room temp before addition of 6-chloropyrazin-2-amine (2.0 g, 15.4 mmol). The reaction was heated to reflux for 16 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with water and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10percent MeOH/CH2 ) to give 6-((3-methyloxetan-3- yl)methoxy)pyrazin-2-amine (3.02 g, quant). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H]
100%
NaH (60percent in oil, 1.24 g, 30.9 mmol) was washed twice with pentane and dried under vacuum. Dioxane (50 mL) was added, followed by (3-methyloxetan-3-yl)methanol (3.0 mL, 30.9 mmol) dropwise. This was allowed to stir 2 h at room temp before addition of 6-chloropyrazin-2-amine (2.0 g, 15.4 mmol). The reaction was heated to reflux for 16 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with water and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10percent MeOH/CH2Cl2) to give 6-((3-methyloxetan-3-yl)methoxy)pyrazin-2-amine (3.02 g, quant.). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H].
With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;
0.60g (0.0152 mol) of sodium hydroxide was added to a solution of 0.93g (0.0072 mol) of 6-chloropyrazin-2-amine in 40 mL of DMF, followed by addition of 2.02g (0.0076 mol) of 2,4,5,6-tetrachloroisophthalonitrile under stirring,the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatographymonitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phasewas washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentratedunder reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling pointrange 60-90°C) = 1:4, as an eluent) to give 0.98 g of compound B-146 as yellow solid, m.p. 254-256°C.[0111] 1H-NMR (300MHz, internal standard TMS, solvent CDCl3) delta(ppm): 6.88(s, 1H, Py-4-1H), 7.20(br, 1H, NH),7.88(s, 1H, Py-4-1H).
0.98 g
With sodium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 5h;
0.60 g (0.0152 mol) of sodium hydroxide was added to a solution of 0.93 g (0.0072 mol) of 6-chloropyrazin-2-amine in 40 mL of DMF, followed by addition of 2.02 g (0.0076 mol) of 2,4,5,6-tetrachloroisophthalonitrile under stirring, the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90° C.)=1:4, as an eluent) to give 0.98 g of compound B-146 as yellow solid, m.p. 254-256° C. [0176] 1H-NMR (300 MHz, internal standard TMS, solvent CDCl3) delta (ppm): 6.88 (s, 1H, Py-4-1H), 7.20 (br, 1H, NH), 7.88 (s, 1H, Py-4-1H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 25 - 90℃;Inert atmosphere;
Example 9C Synthesis of (S)-6-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine A flask was charged with (S)-2-(2-methylpyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (7.1 g, 24.55 mmol), 6-chloropyrazin-2-amine (2.89 g, 22.32 mmol), Pd(PPh3)4 (2.58 g, 2.232 mmol) and 1,4-dioxane (74.4 mL). The reaction mixture was purged with nitrogen for several minutes before aqueous 2M sodium carbonate (22.32 mL, 44.6 mmol) solution was added. The reaction mixture was then purged with nitrogen for another 10 minutes at 25° C. before it was heated to 90° C. under nitrogen overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel chromatography to yield 3.38 g (13.2 mmol, 84percent) of the title product as a light brown solid. ESI-MS (EI+, m/z): 258.26, 1H NMR (Chloroform-d) delta: 8.92 (d, J=5.3 Hz, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 4.60 (s, 2H), 4.39 (d, J=5.8 Hz, 1H), 3.81-3.68 (m, 1H), 3.68-3.55 (m, 1H), 2.24-1.95 (m, 3H), 1.78 (s, 1H), 1.31 (d, J=6.3 Hz, 3H)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
Example 8C Synthesis of (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine A round bottom flask was charged with 6-chloropyrazin-2-amine (0.401 g, 3.09 mmol), (S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (1.062 g, 3.09 mmol), Pd(PPh3)4 (0.358 g, 0.309 mmol) and 1,4-Dioxane (Volume: 7.74 ml). The reaction mixture was purged with nitrogen for several minutes before an aqueous 2M sodium carbonate (3.09 ml, 6.19 mmol) was added. The reaction mixture was purged for another 10 minutes under nitrogen before it was placed in a 90° C. oil bath and allowed to stir overnight. 1,4-Dioxane was removed in vacuo and the crude mixture was diluted with EtOAc. The product was wash with water (3*) and brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on silica gel using normal phase flash chromatography, eluting with CH2Cl2:MeOH to yield 0.655 g (2.11 mmol, 68.2percent) of the title product; 1H NMR (300 MHz, DMSO-d6) delta 9.01 (s, 2H), 8.26 (s, 1H), 7.83 (s, 1H), 6.55 (s, 2H), 5.16-5.02 (m, 1H), 3.77-3.60 (m, 2H), 2.29-2.01 (m, 4H); m/z [M+H]+=311.12
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