* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With iron; ammonium chloride In ethanol; water at 60℃; for 3 h;
To a solution of Compound 2 (36.2 g, 174 mmol) in ethanol (775 mL) and water (310 mL) were added iron (48.6 g, 870 mmol) and ammonium chloride (46.5 g, 870 mmol), and the reaction mixture was stirred at 60° C. for 3 hours. The reaction suspension was filtered with Celite, followed by washing with ethanol, and ethanol of the filtrate was removed under reduced pressure. The obtained residue was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. To the residue was added hexane, followed by filtration. The obtained residue was washed with hexane to obtain Compound 3 (28.46 g, 92percent) as a brown solid. [0625] Compound 3; 1H-NMR (DMSO-d6) δ: 5.10 (s, 2H), 6.02 (s, 2H), 6.82 (s, 1H).
92%
With iron; ammonium chloride In ethanol; water at 60℃; for 3 h;
To a solution of Compound 2 (36.2 g, 174 mmol) in ethanol (775 mL) and water (310 mL) were added iron (48.6 g, 870 mmol) and ammonium chloride (46.5 g, 870 mmol), and the obtained reaction mixture was stirred at 60° C. for 3 hours. The reaction suspension was filtered with Celite, followed by washing with ethanol, and ethanol of the filtrate was removed by distillation under reduced pressure. The reaction solution was extracted with ethyl acetate. The organic layer was then washed with water and brine and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue, hexane was then added, followed by filtration. The obtained residue was washed with hexane to obtain Compound 3 (28.46 g, 92percent) as a brown solid. Compound 3; 1H-NMR (DMSO-d6) δ: 5.10 (s, 2H), 6.02 (s, 2H), 6.82 (s, 1H).
Reference：
[1] Patent: US2013/184240, 2013, A1, . Location in patent: Paragraph 0621; 0624; 0625
[2] Patent: US9567330, 2017, B2, . Location in patent: Page/Page column 33
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2949 - 2961
[4] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2749 - 2754
[5] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 12, p. 2129 - 2132
2
[ 5409-39-2 ]
[ 97941-89-4 ]
Yield
Reaction Conditions
Operation in experiment
49%
With hydrogenchloride; tin(ll) chloride In water at 80 - 100℃; for 0.5 h;
5-Chloro-3-nitropyridin-2-amine (2000.0 mg, 11.52 mmol) and SnCl2 (8740.0 mg, 46.09 mmol) were added in conc. HCl (20.0 mL) and then stirred at 80-100° C. for 0.5 hour. The reaction mixture was neutralized with saturated 1N NaOH aqueous solution (pH=7), and it was then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=90:10) on silica. The fractions containing the product were collected and evaporated to obtain ivory solid compound of 5,6-dichloropyridin-2,3-diamine (1000.0 mg, 49percent). [0523] 1H-NMR (300 MHz, DMSO-d6); δ: 6.80 (s, 1H), 6.04 (s, 2H), 5.11 (s, 2H)
Reference：
[1] Patent: US2014/315888, 2014, A1, . Location in patent: Paragraph 0522-0523
[2] Journal of Organic Chemistry, 1959, vol. 24, p. 1455,1459
With aminosulfonic acid In methanol at 20℃; for 7.5 h;
To a solution of Compound 3 (28.1 g, 158 mmol) in methanol (840 mL) were successively added sulfamic acid (765 mg, 7.88 mmol) and ortho formic acid triethyl (39.3 mL, 236 mmol), and the reaction mixture was stirred at room temperature for 7.5 hours. The reaction suspension was filtered, followed by washing with methanol, and the solvent of the filtrate was removed under reduced pressure. To the residue was added hexane, followed by filtration. The obtained residue was washed with hexane to obtain Compound 4 (24.3 g, 82percent) as a gray solid. [0627] Compound 4; 1H-NMR (DMSO-d6) δ: 8.40 (s, 1H), 8.58 (s, 1H).
With hydrogenchloride; tin(ll) chloride; In water; at 80 - 100℃; for 0.5h;
5-Chloro-3-nitropyridin-2-amine (2000.0 mg, 11.52 mmol) and SnCl2 (8740.0 mg, 46.09 mmol) were added in conc. HCl (20.0 mL) and then stirred at 80-100 C. for 0.5 hour. The reaction mixture was neutralized with saturated 1N NaOH aqueous solution (pH=7), and it was then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=90:10) on silica. The fractions containing the product were collected and evaporated to obtain ivory solid compound of 5,6-dichloropyridin-2,3-diamine (1000.0 mg, 49%). [0523] 1H-NMR (300 MHz, DMSO-d6); delta: 6.80 (s, 1H), 6.04 (s, 2H), 5.11 (s, 2H)
5,6-Dichloropyridin-2,3-diamine (1000.0 mg, 5.62 mmol) was added to diethyl oxalate (20.0 mL), and the mixture was stirred at 120 C. for 12 hours and then cooled to room temperature. Et2O was added thereto to form a solid, and the formed solid was filtered and dried under reduced pressure to obtain brown solid compound of 6,7-dichloropyrido[2,3-b]pyrazin-2,3(1H,4H)-dione. The mixture of unpurified 6,7-dichloropyrido[2,3-b]pyrazin-2,3(1H,4H)-dione and POCl3 (20.0 mL) was stirred at 130 C. for 48 hours and then cooled to room temperature. The reaction mixture was poured into ice water to form a solid, and the formed solid was filtered and then dried under reduced pressure to obtain brown solid compound of 2,3,6,7-tetrachloropyrido[2,3-b]pyrazine (1200.0 mg, 72% in 2 steps).
With iron; ammonium chloride; In ethanol; water; at 60℃; for 3.0h;
To a solution of Compound 2 (36.2 g, 174 mmol) in ethanol (775 mL) and water (310 mL) were added iron (48.6 g, 870 mmol) and ammonium chloride (46.5 g, 870 mmol), and the reaction mixture was stirred at 60 C. for 3 hours. The reaction suspension was filtered with Celite, followed by washing with ethanol, and ethanol of the filtrate was removed under reduced pressure. The obtained residue was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. To the residue was added hexane, followed by filtration. The obtained residue was washed with hexane to obtain Compound 3 (28.46 g, 92%) as a brown solid. [0625] Compound 3; 1H-NMR (DMSO-d6) delta: 5.10 (s, 2H), 6.02 (s, 2H), 6.82 (s, 1H).
92%
With iron; ammonium chloride; In ethanol; water; at 60℃; for 3.0h;
To a solution of Compound 2 (36.2 g, 174 mmol) in ethanol (775 mL) and water (310 mL) were added iron (48.6 g, 870 mmol) and ammonium chloride (46.5 g, 870 mmol), and the obtained reaction mixture was stirred at 60 C. for 3 hours. The reaction suspension was filtered with Celite, followed by washing with ethanol, and ethanol of the filtrate was removed by distillation under reduced pressure. The reaction solution was extracted with ethyl acetate. The organic layer was then washed with water and brine and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue, hexane was then added, followed by filtration. The obtained residue was washed with hexane to obtain Compound 3 (28.46 g, 92%) as a brown solid. Compound 3; 1H-NMR (DMSO-d6) delta: 5.10 (s, 2H), 6.02 (s, 2H), 6.82 (s, 1H).
Example 2 Preparation of 6,7-Dichloro-8-aza-1,4-dihydroquinoxaline-2,3-dione (6) A mixture of 15 mg (0.084 mmol) of <strong>[97941-89-4]2,3-diamino-5,6-dichloropyridine</strong> (4) and 10 mg (0.11 mmol) of oxalic acid in 1 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid (8 mg, 41%) mp >250 C. 1 H NMR (DMSO-d6), 7.556 (s,1), 12.100 (s,1), 12.640 (s,1).
With aminosulfonic acid; In methanol; at 20℃; for 7.5h;
To a solution of Compound 3 (28.1 g, 158 mmol) in methanol (840 mL) were successively added sulfamic acid (765 mg, 7.88 mmol) and ortho formic acid triethyl (39.3 mL, 236 mmol), and the reaction mixture was stirred at room temperature for 7.5 hours. The reaction suspension was filtered, followed by washing with methanol, and the solvent of the filtrate was removed under reduced pressure. To the residue was added hexane, followed by filtration. The obtained residue was washed with hexane to obtain Compound 4 (24.3 g, 82%) as a gray solid. [0627] Compound 4; 1H-NMR (DMSO-d6) delta: 8.40 (s, 1H), 8.58 (s, 1H).
With aminosulfonic acid; In methanol; at 20℃; for 7.5h;
To a solution of Compound 3 (28.1 g, 158 mmol) in methanol (840 mL) were successively added sulfamic acid (765 mg, 7.88 mmol) and ortho formic acid triethyl (39.3 mL, 236 mmol), and the obtained reaction mixture was stirred at room temperature for 7.5 hours. The reaction suspension was filtered, followed by washing with methanol, and the solvent of the filtrate was removed by distillation under reduced pressure. To the residue, hexane was added, followed by filtration. The obtained residue was washed with hexane to obtain Compound 4 (24.3 g, 82%) as a gray solid. Compound 4; 1H-NMR (DMSO-d6) delta: 8.40 (s, 1H), 8.58 (s, 1H).
5,6-dichloro-1,3-dihydroimidazo[4,5-b]pyridine-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 20℃; for 2.0h;Cooling with ice;
Step 1: 5,6-Dichloro-1,3-dihydro-imidazo[4,5-b]pyridine-2-thione Thiophosgene (4.0 mL) is added drop wise to an ice-cooled mixture of 5,6-dichloro-pyridine-2,3-diamine (9.18 g) and triethylamine (14.4 mL) in tetrahydrofuran (170 mL). After 1 h the ice bath is removed and the reaction mixture is stirred for 1 h at room temperature. Ethyl acetate (500 mL) and hydrochloric acid (1 N, 200 mL) are added. The organic phase is separated, washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound, which is used for the next reaction step without further purification. LC (method 1): tR=0.77 min; Mass spectrum (ESI+): m/z=220 [M+H]+.
With triethylamine; In tetrahydrofuran; for 2.0h;Cooling with ice;
Thiophosgene (4.0 mL) is added drop wise to an ice-cooled mixture of 5,6-dichloro- pyridine-2,3-diamine (9.18 g) and triethylamine (14.4 mL) in tetrahydrofuran (170 mL). After 1 h the ice bath is removed and the reaction mixture is stirred for 1 h at room temperature. Ethyl acetate (500 mL) and hydrochloric acid (1 N, 200 mL) are added. The organic phase is separated, washed with brine, dried over MgS04, and concentrated in vacuo to give the title compound, which is used for the next reaction step without further purification. LC (method 1 ): tR = 0.77 min; Mass spectrum (ESI): m/z = 220 [M+H]+
4-chloro-2-(5,6-dichloro-3H-imidazo[4,5-b]pyridin-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium metabisulfite; In N,N-dimethyl-formamide; at 170℃; for 0.25h;Microwave irradiation;
General procedure: A mixture of an appropriate 1,2-phenylenediamine (1.0 eq), appropriate aldehyde (1.0 eq), and sodium metabisulfite (1.0 eq) in 8 mL of DMF was heated in a CEM microwave at 170 C. for 15 min. Reaction mixture was concentrated and purified on ISCO purification system using 10-50% hexanes and ethylacetate.
5,6-dichloro-N-isopropyl-3H-imidazo[4,5-b]pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 5,6-dichloropyridine-2,3-diamine; isopropyl isothiocyanate In tetrahydrofuran for 36h; Reflux; Inert atmosphere;
Stage #2: With mercury(II) oxide In tetrahydrofuran for 0.666667h; Reflux;
5,6-Dichloro-N-ethyl-3H-imidazo[4,5-b]pyridin-2-amine(7a)
General procedure: Ethylisothiocyanate (1 mL, 11.24mmol) was added to a solution of diamine 6 (500 mg, 2.81 mmol) in anhydrous THF (10 mL) and thereaction mixture was reuxed under argon for 36 h. The mixture was then cooled to room temperatureand HgO (1.22 g, 5.65 mmol) was added, leading to an orange suspension. Refluxing the reactionmixture resulted progressively in a black coloured suspension and within 40 min the reaction was completed. The mixture was filtered warm through a celite pad, which was thoroughly washed withwarm MeOH. The solvent was then vacuum-evaporated and the residue was purified by columnchromatography using a mixture of CHCl3/MeOH (95/5 to 85/15, v/v) as the eluent, to result in 340 mgof 7a (52% overall yield).
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