* 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.
Stage #1: at 0 - 20℃; for 1 h; Stage #2: With potassium carbonate In water; ethyl acetate
c) 2,6-Dibromopyridin-4-amine; Iron (1.26 g, 22.56 mmol) was added slowly to a stirred solution of 2,6-dibromo-4- nitropyridine 1 -oxide (preparation 22b, 1.68 g, 5.64 mmol) in acetic acid (16 mL) at 0 °C, and the mixture was stirred at room temperature. After 1 hour, water and ethyl acetate were added to the reaction mixture. The organic layer was washed with water, satured aqueous potassium carbonate solution and brine, and dried (MgS04) and evaporated to give the title compound (1.35 g, 96percent) as a white solid.LRMS (m/z): 251/253/255 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.33 (br. s., 2 H) 6.68 (s, 2 H)
96%
at 0 - 20℃; for 1 h;
Iron (1.26 g, 22.56 mmol) was added slowly to a stirred solution of 2,6-dibromo-4-nitropyridine 1-oxide (preparation 22b, 1.68 g, 5.64 mmol) in acetic acid (16 mL) at 0 title compound (1.35 g, 96percent) as a white solid.LRMS (m/z): 251/253/255 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.33 (br. s., 2 H) 6.68 (s, 2 H)
94%
at 100℃; for 1 h;
To a solution of 2,6-dibromo-4-nitropyridine 1-oxide (6.80 g, 22.82 mmol) in acetic acid (100 mL) at rt was added Fe powder (6.40 g, 114.13 mmol). The resulting reaction mixture was heated to 100° C. for 1 h. After completion of reaction (by TLC), acetic acid was distilled off under reduced pressure, the residue was basified with aqueous ammonia solution and extracted with EtOAc (3.x.250 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was treated with ether and hexane and filtered to obtain the desired product as an off white solid (5.40 g, 94percent).
90%
Stage #1: for 0.75 h; Stage #2: With potassium carbonate In water
2, 6-dibromo-4-nitro pyridine 1-oxide (14.5 g, 48.6 mmol) was taken up in 130 mL of acetic acid and iron powder (11.0g, 197 mmol) was added in portion-wise and the mixture was stirred at room temperature for 45 minutes. 500 mL of water was added and the product was extracted with EtOAc (50 mL). The organic layer was washed with 300mL of water then with 30 mL of a sat K2CO3 sol and then with 300mL of brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 11.1g of the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.1-4.4 (br. s, 2H), 6.65 (s, 2H). LRMS (ES+) m/z = 251, 253 (MH+).
Reference：
[1] Patent: WO2012/41476, 2012, A1, . Location in patent: Page/Page column 58-59
[2] Patent: EP2441755, 2012, A1, . Location in patent: Paragraph 0174
[3] Patent: US2012/88750, 2012, A1, . Location in patent: Page/Page column 22
[4] Tetrahedron Letters, 2011, vol. 52, # 44, p. 5728 - 5732
[5] Chemistry - A European Journal, 2013, vol. 19, # 41, p. 13745 - 13760
[6] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 343[7] Recueil des Travaux Chimiques des Pays-Bas, 1962, vol. 81, p. 124,127
[8] Journal fuer Praktische Chemie (Leipzig), 1988, vol. 330, # 1, p. 154 - 158
[9] Patent: US2007/197478, 2007, A1, . Location in patent: Page/Page column 51
2
[ 175422-04-5 ]
[ 39771-34-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: at 90℃; for 0.5 h; Heating / reflux Stage #2: With sodium hydroxide In water
To a solution of 2,6-dibromo-4-nitro-pyridine (1.0 g, 3.54 mmol) in glacial acetic acid (20 ml.) was added Fe-powder (1.0 g, 17.74 mmol) at room temperature. The reaction mixture was refluxed for 900C for 30 min. After completion of reaction (TLC monitoring), water was added (100 mL), basified with 2N NaOH (pH 12-14). The resulting mixture was filtered through celite-bed and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water, dried (Na2SO4), filtered and evaporated to dryness to get the desired product as an off white solid (0.80 g, 90percent). 1H NMR (DMSO-d6, 400 MHz): δ 6.67 (s, 2H) and 6.71 (br s, 2H).
70%
With ammonia In tetrahydrofuran; water at 95℃; for 2.5 h;
P. 2, 6-Dibromo-pyridin-4-ylamine A solution of 15.3 G (54.3 MMOL) 2,6-dibromo-4-nitro-pyridine and 18.5 ml (271.5 MMOL) 25percent aq. ammonia in 40 mi tetrahydrofurane was transferred to an autoclave and heated at 95 C for 2.5 h. After cooling to room temperature, the reaction was poured into water (200 mi) and extracted with dichloromethane (3 x 200 ML). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was crystallized from ethyl acetate/petroleum ether to afford 9.6 G (70percent) of the title compound as a yellow solid. m. p. 184-186 C.
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
6
[ 25373-69-7 ]
[ 39771-34-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1958, vol. 77, p. 343[2] Recueil des Travaux Chimiques des Pays-Bas, 1962, vol. 81, p. 124,127
[3] Patent: WO2012/41476, 2012, A1,
[4] Patent: EP2441755, 2012, A1,
[5] Patent: US2012/88750, 2012, A1,
7
[ 2408-70-0 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1946, vol. 65, p. 129,136
[2] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
8
[ 2464-63-3 ]
[ 39771-34-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1946, vol. 65, p. 129,136
9
[ 2408-70-0 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
10
[ 2408-70-0 ]
[ 7664-41-7 ]
[ 71-36-3 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
11
[ 2408-70-0 ]
[ 39771-34-1 ]
[ 329974-09-6 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 1, p. 38 - 43
12
[ 2408-70-0 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1946, vol. 65, p. 129,136
[2] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
13
[ 2408-70-0 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
14
[ 2408-70-0 ]
[ 7664-41-7 ]
[ 71-36-3 ]
[ 39771-34-1 ]
[ 408352-48-7 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 44,47
c) 2,6-Dibromopyridin-4-amine; Iron (1.26 g, 22.56 mmol) was added slowly to a stirred solution of 2,6-dibromo-4- nitropyridine 1 -oxide (preparation 22b, 1.68 g, 5.64 mmol) in acetic acid (16 mL) at 0 C, and the mixture was stirred at room temperature. After 1 hour, water and ethyl acetate were added to the reaction mixture. The organic layer was washed with water, satured aqueous potassium carbonate solution and brine, and dried (MgS04) and evaporated to give the title compound (1.35 g, 96%) as a white solid.LRMS (m/z): 251/253/255 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.33 (br. s., 2 H) 6.68 (s, 2 H)
96%
With iron; acetic acid; at 0 - 20℃; for 1h;
Iron (1.26 g, 22.56 mmol) was added slowly to a stirred solution of 2,6-dibromo-4-nitropyridine 1-oxide (preparation 22b, 1.68 g, 5.64 mmol) in acetic acid (16 mL) at 0 title compound (1.35 g, 96%) as a white solid.LRMS (m/z): 251/253/255 (M+1)+.1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.33 (br. s., 2 H) 6.68 (s, 2 H)
94%
With iron; acetic acid; at 100℃; for 1h;
To a solution of 2,6-dibromo-4-nitropyridine 1-oxide (6.80 g, 22.82 mmol) in acetic acid (100 mL) at rt was added Fe powder (6.40 g, 114.13 mmol). The resulting reaction mixture was heated to 100 C. for 1 h. After completion of reaction (by TLC), acetic acid was distilled off under reduced pressure, the residue was basified with aqueous ammonia solution and extracted with EtOAc (3×250 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was treated with ether and hexane and filtered to obtain the desired product as an off white solid (5.40 g, 94%).
90%
2, 6-dibromo-4-nitro pyridine 1-oxide (14.5 g, 48.6 mmol) was taken up in 130 mL of acetic acid and iron powder (11.0g, 197 mmol) was added in portion-wise and the mixture was stirred at room temperature for 45 minutes. 500 mL of water was added and the product was extracted with EtOAc (50 mL). The organic layer was washed with 300mL of water then with 30 mL of a sat K2CO3 sol and then with 300mL of brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 11.1g of the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.1-4.4 (br. s, 2H), 6.65 (s, 2H). LRMS (ES+) m/z = 251, 253 (MH+).
PREPARATION 38; 2,6-dibromo pyridin-4-ylamine; 2,6-dibromo-4-nitro pyridine 1-oxide (14.5 g, 48.6 mmol) was taken up in 130 mL of acetic acid and iron powder (11 g, 196.9 mmol) was added in portionwise and the mixture was stirred at room temperature for 45 minutes. 500 mL of water was added and the product was extracted with EtOAc (500 mL). The organic layer was washed with 300 mL of water then with 300 mL of a sat K2CO3 sol and then with 300 mL of brine. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 11.1 g of the title compound as a white solid.1H NMR (CDCl3) 6.65 (s, 2H), 4.4-4.1 (s broad, 2H).LRMS (ES+) m/z 251,253 [MH]+
[[1-(6-{3-[(bis-carboxymethyl-amino)-methyl]-pyrazol-1-yl}-4-phenyl-pyridin-2-yl)-1<i>H</i>-pyrazol-3-ylmethyl]-(2,5-dioxo-pyrrolidin-1-yloxycarbonylmethyl)-amino]-acetic acid[ No CAS ]
Q. 2, 6-Dibromo-3-nitro-pyridin-4-ylamine A solution of 9.5 G (37.7 MMOL) 2, 6-dibromo-pyridin-4-ylamine in 15.3 ml concentrated sulphuric acid was cooled to 0 C and CONC. nitric acid (6.1 ml) was cautiously added. The mixture was cooled to room temperature and stirred for 45 min.. The reaction was poured into ice-water (150 ML), the precipitate filtered off and washed with ethyl acetate. 8.2 G (27.6 MMOL) of the yellow solid were carefully added to 82 ml conc. sulphuric acid and the reaction. heated at 100 C for 45 min.. The reaction mixture was cooled to room temperature and poured into ice. The precipitate was collected by filtration and dried in vacuo at 40 C to afford 7.3 G (91 %) of the title compound as a yellow solid. m. p. 140 C.
Example 6; -amino-l-benzyl-7-butoxypyrido[3,4-blpyrazine-2,3(lH,4 )-dionePreparation of 2,6-dibromo-3-nitropyridin-4-amine (6)[000404] 2,6-Dibromopyridin-4-amine (8.84 g, commercially available) was dissolved in 80mL of sulfuric acid at room temperature and then it was cooled at -5C. Nitric acid (4.8 mL) was added dropwise. The mixture was stirred at -5 C for 30 minutes, before it was poured onto 320 mL of crushed ice. The solid formed was filtered off and then dissolved in EtOAc. The organic layer was washed with saline, dried over magnesium sulfate and the solvent was removed in vacuo to give crude product as a yellow solid. Concentrated sulphuric acid (80ml) was heated in an oil bath until the temperature of the acid reached 47 C. Crude from the first step was added in portions until the temperature of the mixture reached 56C. The mixture was stirred at 53-55C for 1 hour before it was cooled in an ice-bath and poured onto 600 mL of crushed ice with stirring. The product precipitated and was filtered off. The crude was dissolved in EtOAc and was washed with water, aq. NaHC03, and saline, dried (Na2S04) and concentrated under reduced pressure to give 2,6-dibromo-3- nitropyridin-4- amine (6).
f 4-amino-2 6-diethoxypyridine <strong>[39771-34-1]4-amino-2,6-dibromopyridine</strong> (500 mg) was mixed with solid sodium hydroxide (508 mg) and ethanol (15 ml) in a bomb. The bomb was then heated at 160 C. for 6 hrs, allowed to cool, water added and solvent reduced under vacuum. The mixture was then extracted with water and ether. Removal of the ether left an oil of 4-amino-2,6-diethoxypyridine (220 mg, 61%).
EXAMPLE 38 4-Amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide 5.1 g (0.02 mol) of 4-amino-2,6-dibromo-pyridine were dissolved in 100 ml of pyridine, treated with 7.1 g (0.03 mol) of 4-acetamino-benzenesulfochloride and stirred at 60 C. for 16 hours. After removal of the solvent the residue was taken up in 100 ml of 1N HCl, extracted twice with 100 ml of ethyl acetate each time, the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. Then, the mixture was freed from solvent and the residue was dried in a high vacuum. There were obtained 7.2 g (79%) of N-[4-(2,6-dibromo-pyridin-4-ylsulfamoyl)-phenyl]-acetamide as yellow crystals; m.p.: >260 C. (dec.). 6.2 g (0.0138 mol) of N-[4-(2,6-dibromo-pyridin-4-yl-sulfamoyl)-phenyl]-acetamide were dissolved in 138 ml of 1N NaOH and boiled at reflux for 2 hours. After cooling the mixture was adjusted to pH 6 with 2N HCl and the precipitate which separated was filtered off. The material on the suction filter was washed well with water and dried. It was subsequently chromatographed on silica gel with ethyl acetate/hexane 1:2 ->1:1. There were obtained 4.86 g (86%) of 4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 220-222 C.
e) 4-amino-2,6-dibromopyridine (Van Ammers and Den Hertog, 1958) A mixture of 4-nitro-2,6-dibromopyridine-N-oxide (1.2 g), iron powder (1.2 g) and acetic acid (15 ml) were stirred and heated to 100 C. for 1 hour. Upon cooling the mixture was basified with 3 molar sodium hydroxide and continuously extracted with ether. Removal of the ether under reduced pressure left a white crystalline product of 4-amino-2,6-dibromopyridine (1.0 g, 99%), m.p. 212-214 C.
With sulfuric acid; nitric acid; at -10 - -5℃; for 0.5h;
2,6-dibromo pyridin-4-ylamine (11.0 g, 43.6 mmol) was dissolved in 100 mL of sulfuric acid at room temperature and then cooled at -5 C. Concentrated nitric acid (6 mL) was added dropwise keeping the temperature between -10 C to -5 C then the mixture was stirred at -5 C for 30 minutes. The mixture was then poured onto ~400 mL of crushed ice. The solid formed was filtered off then dissolved in EtOAc. The residual water was removed and the organic layer was washed with 300 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 12. 5 g of the title product as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 5.4-5.7(br. s, 2H), 6.85 (s 1H).
With sulfuric acid; nitric acid; at -10 - -5℃; for 0.5h;
PREPARATION 39; 2,6-dibromo pyridin-4-yl-N-nitroamine2,6-dibromo pyridin-4-ylamine (11 g, 43.6 mmol) was dissolved in 100 mL of sulfuric acid at room temperature and then cooled at -5 C. 6 mL of nitric acid was added dropwise keeping the temperature between -10 C. to -5 C. and the mixture was stirred at -5 C. for 30 minutes. The mixture was then poured onto 400 mL of crushed ice. The solid formed was filtered off then dissolved in EtOAc. The residual water was removed and the organic layer was washed with 300 mL of brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 12.5 g of the title product as a yellow solid.1H NMR (CDCl3) 6.85 (s 1H), 5.7-5.4(s broad, 2H).
To a solution of 2,6-dibromo-pyridin-4-ylamine (0.80 g, 3.17 mmol) in THF (50 mL) was added benzoylisothiocyanate (0.47 mL, 3.49 mmol). The reaction mixture was heated to 650C overnight. After completion of reaction (TLC monitoring), THF was <n="17"/>distilled off and the crude solid was filtered and washed with hexane (2 x 50 mL) to get the desired product as a pale-yellow solid (1.20 g, 91%).1H NMR (DMSO-dbeta, 400 MHz): delta 7.55 (m, 2H), 7.68(m, 1 H), 7.96 (d, J=1.20 Hz1 2H), 8.27 (s, 2H), 11.93 (br s, 1 H) and 12.75 (br s, 1 H).
85%
In tetrahydrofuran; at 70℃; for 16h;
To a solution of <strong>[39771-34-1]2,6-dibromopyridin-4-amine</strong> in THF (250 mL) was added benzoylisothiocyanate (3.50 mL, 26.0 mmol)) and the resulting reaction mixture heated to 70 C. for 16 h. A further 1.50 mL (11.20 mmol) of benzoylisothiocyanate was added to complete the reaction and the reaction stirred at 70 C. for 16 h. After completion (by TLC), the solvent was distilled under reduced pressure, the residue treated with 10% MeOH-ether solution then filtered to obtain the desired product as a yellow solid (7.60 g, 85%).
PREPARATION 23; /V-(2,6-Dibromopyridin-4-yl)benzamide; A solution of <strong>[39771-34-1]2,6-dibromopyridin-4-amine</strong> (0.15 g, 0.59 mmol), benzoyl chloride (0.21 mL, 1.78 mmol) and pyridine (0.14 mL, 1.73 mmol) in dichloromethane (3.7 mL) was stirred at room temperature. After overnight, water and dichloromethare were added to the mixture, the organic layer washed with water, dried (Na2S04) and evaporated. Purification of the residue by flash chromatography (100% hexanes to 1 :1 hexanes/ethyl acetate) gave the title compound (0.21 g, 98%) as a white solid.LRMS (m/z): 355/357/359 (M+1)+.
98%
With pyridine; In dichloromethane; at 20℃;
<strong>[39771-34-1]2,6-dibromopyridin-4-amine</strong> (0.15 g, 0.59 mmol), benzoyl chloride (0.21 mL, 1.78 mmol) and pyridine (0.14 mL, 1.73 mmol) in dichloromethane (3.7 mL) was stirred at room temperature. After overnight, water and dichloromethare were added to the mixture, the organic layer washed with water, dried (Na2SO4) and evaporated. Purification of the residue by flash chromatography (100% hexanes to 1:1 hexanes/ ethyl acetate) gave the title compound (0.21 g, 98%) as a white solid.LRMS (m/z): 355/357/359 (M+1)+.
With pyridine;dmap; In tetrahydrofuran; at 20 - 65℃; for 136h;
Step 1: To a solution of <strong>[39771-34-1]2,6-dibromopyridin-4-amine</strong> (1.0 g, 3.97 mmol), DMAP (0.048 g, 0.397 mmol), and pyridine (0.482 mL, 5.95 mmol) in THF (7.94 mL) at rt was slowly added acetic anhydride (0.412 mL, 4.37 mmol), and the mixture was stirred at rt for 16 h, after which time the reaction was heated to 65 C for a period of 5 days. After cooling to rt, MeOH (5 mL) was added and the reaction was concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient solvent system of 0-100%EtOAc/Hexanes. The product-containing fractions were collected and concentrated under reduced pressure to give N-(2,6-dibromopyridin-4-yl)acetamide (1.10g, 94%) as a yellow solid. MS ESI calcd for C7H6Br2N20 [M + H]+ 293, found 293.
With pyridine; dmap; In tetrahydrofuran; at 20 - 65℃;Inert atmosphere;
Preparative Example 2.15 N-(2,6-dibromopyridin-4-yl)acetamide 2,6-Dibromopyridin-4-amine, DMAP (0.048 g, 0.397 mmol) and pyridine (0.48 ml, 5.95 mmol) were taken-up in THF (7.9 ml) under argon. Acetic anhydride (0.41 ml, 4.37 mmol) was slowly added and the mixture was stirred overnight at room temperature. The reaction was then heated to 65 C for 5 days and cooled to room temperature, diluted with methanol, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-100% EtOAc/hexanes) to afford N-(2,6-dibromopyridin-4- yl)acetamide as a light yellow solid.. MS ESI calc'd. for C7H6Br2N20 [M+H]+ 294, found 294.
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