* 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
2
[ 770-00-3 ]
[ 27825-21-4 ]
[ 23611-75-8 ]
[ 33332-25-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[2] Journal of Chemical Research, Miniprint, 1984, # 10, p. 2860 - 2875
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
[4] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 5, p. 1177 - 1180
3
[ 23611-75-8 ]
[ 940-07-8 ]
Reference：
[1] New Journal of Chemistry, 2013, vol. 37, # 2, p. 391 - 402
4
[ 23611-75-8 ]
[ 118853-60-4 ]
Yield
Reaction Conditions
Operation in experiment
82.4%
Stage #1: With sodium azide; triphenylphosphine In dimethyl sulfoxide at 120℃; for 4 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide at 120℃; for 12 h;
Methyl 6-(chloropyrazine)-2-carboxylate (13) (2g, 0.0115mmol) was dissolved in 80mL of 87 DMSO. 88 Sodium azide (3g, 0.0463mmol) and 39 triphenylphosphene (4.6g, 0.1738mmol) were added and refluxed at 120°C for 4h. 20mL of 1N 89 HCl was added and the reaction was continued at 120°C for 2h. The mixture was cooled and neutralized by aqueous NaHCO3 solution and 131 product was extracted in ethyl acetate, dried with Na2SO4 which was then concentrated and dried with n-pentane to get 1.4g of compound 14 as yellow solid (yield 82.4percent). 1H NMR (400MHz, DMSO‑d6) δ 8.28–8.27 (m, 1H), 8.07 (s, 1H), 6.90 (s, 2H), 3.84 (s, 3H). C6H7N3O2 [M]: 153.14; MS (ESI) m/z: [M+H]+: 154.05
Reference：
[1] European Journal of Pharmaceutical Sciences, 2018, vol. 124, p. 165 - 181
5
[ 23611-75-8 ]
[ 23688-89-3 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: at 20℃; for 2 h; Stage #2: With hydrogenchloride; water In ethanol
Example 15; 6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-m-tolylpyrazine-2-carboxamide; Example 15A; 6-chloropyrazine-2-carboxylic Acid; The product from Example 1E (1.78 g, 10.3 mmol) was dissolved in EtOH (25 mL). 1M NaOH (25 mL) was added, and the reaction stirred at ambient temperature for 2 h. The reaction mixture was acidified to pH3 with 1M HCl (aq). The mixture was then diluted with water (150 mL) and extracted with EtOAc (4.x.100 mL). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a white solid (1.54 g, 94percent). MS (DCI/NH3) m/z 176 (M+NH4)+.
Reference：
[1] Patent: US2009/281118, 2009, A1, . Location in patent: Page/Page column 14
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7678 - 7692
6
[ 770-00-3 ]
[ 23611-75-8 ]
Yield
Reaction Conditions
Operation in experiment
67%
for 8 h; Reflux
Example 1E; Methyl 6-chloro-2-pyrazinecarboxylate; The product from Example 1D (7.18 g, 45.9 mmol) was dissolved in SOCl2 (50 mL, 687 mmol). The reaction was heated to reflux for 8 h and then allowed to cool to ambient temperature. The SOCl2 was removed under reduced pressure, and the residue was quenched with water (50 mL) at 0° C. The mixture was neutralized by the addition of 1M K2CO3 (aq) and extracted with CH2Cl2 (5.x.100 mL). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (5percent EtOAc in CH2Cl2, Rf=0.35) to afford the title compound as a thick oil that slowly solidified (7.16 g, 67percent). 1H NMR (DMSO-d6, 300 MHz) pp 3.94 (s, 3H), 9.07 (s, 1H), 9.19 (s, 1H). MS (DCI/NH3) m/z 190 (M+NH4)+.
Reference：
[1] Patent: US2009/281118, 2009, A1, . Location in patent: Page/Page column 10-11
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7816 - 7825
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7678 - 7692
A mixture of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (248 mg, 0.58 mmol) (as prepared in Example 26 Step (a)), <strong>[23611-75-8]methyl <strong>[23611-75-8]6-chloropyrazine-2-carboxylate</strong></strong> (100 mg, 0.58 mmol), dioxane (4.8 ml) and 2M aqueous Cs2CO3 solution (0.58 ml) was degassed with a stream of N2 for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.22 mol) was added and the stirred mixture was heated at reflux for 1.5 h. The reaction was then cooled, allowed to stand for 15 min and the supematent decanted off. The remaining salts were washed with further dioxane (5 ml) and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The pH was adjusted to 6 by dropwise addition of 2N aqueous HCl and the aqueous phase was extracted with further CH2Cl2 (220 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white amorphous solid (89.8 mg, 34%); 1H NMR (400 MHz, CDCl3) ? 9.63 (1H, s), 9.19 (1H, s), 8.81 (1H, s), 8.38 (1H, dd, J=8.2, 1.7 Hz), 7.75 (1H, d, J=8.2 Hz), 7.56-7.48 (5H, m), 4.67 (2H, s), 2.64 (3H, s); m/z (ES+) 437 (M+H)+.
With potassium carbonate; In acetonitrile; for 3h;Heating / reflux;
A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol of N-BOC-piperazine and 20 mmol of K2CO3 in 20 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to yield a colorless solid. MS (m/e): 323.4 (MH+, 100%)
With caesium carbonate; lithium chloride;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; for 2h;Heating / reflux;
To a solution of 0.10 g of <strong>[23611-75-8]methyl <strong>[23611-75-8]6-chloropyrazine-2-carboxylate</strong></strong> in 2.9 mL of dioxane, 65 mg of 2-furanboronic acid, 74 mg of lithium chloride, 0.57 g of cesium carbonate, 21 mg of 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and 24 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the mixture was heated under reflux for 2 hours. To the reaction mixture, water and ethyl acetate were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate = 87:13 to 83:17 to obtain 74 mg of methyl 6-(2-furyl)pyrazine-2-carboxylate as a white solid. 1H-NMR (CDCl3) delta: 4.05 (3H, s), 6.60 (1H, dd, J = 3.5, 1.8 Hz), 7.30-7.32 (1H, m), 7.62-7.65 (1H, m), 9.12 (1H, s), 9.12 (1H, s)
Example 12; 6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylbenzyl)pyrazine-2-carboxamide; Example 12A; 6-Chloro-pyrazine-2-carboxylic Acid 2-methyl-benzylamide; The product from Example 1E (1.00 g, 5.79 mmol) and MgCl2 (1.11 g, 11.7 mmol) were suspended in THF (25 mL) and stirred at ambient temperature for 5 min. 2-Methylbenzylamine (1.8 mL, 14.5 mmol) was added, and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (150 mL) and extracted with CH2Cl2 (4×100 mL). The organic extracts were combined and washed with 0.25M HCl (aq) (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography to afford the title compound as a white solid (1.35 g, 89%). 1H NMR (DMSO-d6, 300 MHz) delta ppm 2.33 (s, 3H), 4.48 (d, J=6.10 Hz, 2H), 7.12-7.26 (m, 4H), 9.02 (s, 1H), 9.15 (s, 1H) 9.33 (t, J=5.76, 1H). MS (DCI/NH3) m/z 262 (M+H)+.
Example 1E; Methyl 6-chloro-2-pyrazinecarboxylate; The product from Example 1D (7.18 g, 45.9 mmol) was dissolved in SOCl2 (50 mL, 687 mmol). The reaction was heated to reflux for 8 h and then allowed to cool to ambient temperature. The SOCl2 was removed under reduced pressure, and the residue was quenched with water (50 mL) at 0 C. The mixture was neutralized by the addition of 1M K2CO3 (aq) and extracted with CH2Cl2 (5×100 mL). The organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (5% EtOAc in CH2Cl2, Rf=0.35) to afford the title compound as a thick oil that slowly solidified (7.16 g, 67%). 1H NMR (DMSO-d6, 300 MHz) pp 3.94 (s, 3H), 9.07 (s, 1H), 9.19 (s, 1H). MS (DCI/NH3) m/z 190 (M+NH4)+.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 130℃; for 0.333333h;Microweve irradiation;
Step 1. Methyl 6-(5-chloro-l-[f4-methylphenyl)sulfonyll-lH-pyrrolo[2 -&]pYridin-3-Yl}- pyrazine-2-carboxylateA solution of <strong>[23611-75-8]methyl <strong>[23611-75-8]6-chloropyrazine-2-carboxylate</strong></strong> (0.1 g, 0.579 mmol), 5- chloro- 1 -[(4-methylphenyl)sulfonyl]-3-(4s4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1H- pyrrolo[2,3-&]pyridine (0.276 g, 0.637 mmol), PdCl2(dppf) (0.085 g, 0.116 mmol) and Na2C(¾(0.87 mL, 2 M in water, 1.74 mmol) in DMF (6 mL) was microwaved at 130 C for 20 min. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was then washed with 1/2 brine and brine before dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of ethyl acetate: hexane 10:90 to 80:20 to afford the title compound. MS APCI: [M + H]+ m/z = 443.0.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃;Microwave irradiation; Inert atmosphere;
Example 66Methy[ 6- ({4-[(3,4-dif[uoropheny[)carbamoy[]-3-methy[- 1 ,2-thiazo[-5-y[lamino)-pyrazine-2-carboxy[ate A mixture of 5-amino-N-(3,4-dif[uoropheny[)-3-methy[-1 ,2-thiazo[e-4-carboxamide [Intermediate 3] (150 mg, 0.56 mmo[, 1.0 eq), methy[ 6-ch[oropyrazine-2- carboxy[ate [CAS RN: 23611-75-8] (120 mg, 0.56 mmo[, 1.0 eq) and cesiumcarbonate (417 mg, 1.28 mmo[, 2.3 eq) in 5.4 mL dioxane/DMF (7/1) was p[aced ina microwave via[ and f[ushed with argon. Then, pa[[adium(II) acetate (13 mg,0.06 mmo[, 0.1 eq) and Xantphos (32 mg, 0.06 mmo[, 0.1 eq) were added. The via[was capped and the reaction mixture was stirred at an environmenta[ temperatureof 110 C overnight. On coo[ing, the vo[ati[e components were removed in vacuo.The crude materia[ was disso[ved in a sma[[ amount DM50 and fi[tered. Purificationwas conducted via preparative HPLC (method A) to give 10 mg (4 % yie[d of theory) of the tit[e compound.UPLC-MS (Method 1): R = 1.20 mm; MS (ESIneg) m/z = 404 [M-H].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 3.98 (s, 3H), 7.38-7.53 (m, 2H), 7.95 (m,1H), 8.73 (s, 1H), 8.84 (s, 1H), 10.48 (s, 1H), 11.22 (s br, 1H), 1xCH3 not assigned.
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