Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 23, p. 5978 - 5981
5
[ 5327-32-2 ]
[ 100367-40-6 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
6
[ 5327-32-2 ]
[ 54221-95-3 ]
Yield
Reaction Conditions
Operation in experiment
42%
Stage #1: With potassium permanganate In water at 50 - 90℃; for 2.5 h;
b) 2-Acetamidopyridine-4-carboxylic acid (3); 214.0 g of (2) are introduced in portions with stirring into an aqueous solution of 160 g of potassium permanganate at 500C. A further 360 g of potassium permanganate are added in portions over the course of one hour. The temperature of the reaction mixture should not exceed 9O0C during this. The mixture is then stirred for 1.5 h and filtered hot, and the filtrate is adjusted to pH 3-4 with cone. HCI. The white precipitate of (3) which separates out is filtered off and dried in vacuo overYield: 108.O g (42percent)
42%
With potassium permanganate In water at 50 - 90℃; for 2.5 h;
214.0 g of (2) are introduced in portions with stirring into an aqueous solution of 160 g of potassium permanganate at 50°C. A further 360 g of potassium permanganate are added in portions over the course of one hour. The temperature of the reaction mixture should not exceed 90°C during this. The mixture is then stirred for 1.5 h and filtered hot, and the filtrate is adjusted to pH 3-4 with conc. HCl. The white precipitate of (3) which separates out is filtered off and dried in vacuum over P2O5. Yield: 108.0 g (42percent)
25%
With hydrogenchloride; potassium permanganate In water
(A) 2-(Acetylamino)isonicotinic acid N1-(4-Methyl-2-pyridyl)acetamide (25 g, 0.168 mol) suspended in water (250 ml) was added with potassium permanganate (76.1 g, 0.50 mol) at 100° C. over 1 hour and then stirred for 40 minutes. The reaction solution was returned to room temperature, and black crystals were removed by filtration. The resulting filtrate was added with 12 N hydrochloric acid until pH of the solution became 3 to 4. After the reaction solution was stirred for about 15 minutes, the deposited white crystals were collected by filtration, washed with water, and dried by using a vacuum pump to obtain 7.65 g (25percent) of the title compound without purification. 1H-NMR (CD3OD) δ: 2.20 (3H, s), 7.59 (1H, dd, J=1.47, 5.13 Hz), 8.42 (1H, dd, J=0.73, 5.13 Hz), 8.63 (1H, s) EI/MS; m/z: 179 (M+)
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 11, p. 4527 - 4530
[2] Patent: WO2006/89798, 2006, A1, . Location in patent: Page/Page column 25
[3] Patent: EP1894925, 2008, A1, . Location in patent: Page/Page column 14; 41
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 6942 - 6990
[5] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 485,487
[6] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
[7] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 6, p. 1993 - 2004
[8] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 23, p. 5978 - 5981
[9] Patent: US2003/92720, 2003, A1,
[10] Patent: US2003/100567, 2003, A1,
[11] Patent: US2002/147203, 2002, A1,
[12] Patent: US5972975, 1999, A,
[13] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6305 - 6310
[14] Patent: US2004/23978, 2004, A1, . Location in patent: Page/Page column 13
[15] Patent: US2004/23980, 2004, A1, . Location in patent: Page/Page column 13
[16] Patent: US2004/23981, 2004, A1, . Location in patent: Page/Page column 15
[17] Biochemistry, 2010, vol. 49, # 49, p. 10421 - 10439
[18] Patent: WO2012/28106, 2012, A1, . Location in patent: Page/Page column 45
[19] Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5290 - 5305
7
[ 5327-32-2 ]
[ 105250-17-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 23, p. 5978 - 5981
8
[ 5327-32-2 ]
[ 884495-14-1 ]
[ 228410-90-0 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
b) 2-Acetamidopyridine-4-carboxylic acid (3); 214.0 g of (2) are introduced in portions with stirring into an aqueous solution of 160 g of potassium permanganate at 500C. A further 360 g of potassium permanganate are added in portions over the course of one hour. The temperature of the reaction mixture should not exceed 9O0C during this. The mixture is then stirred for 1.5 h and filtered hot, and the filtrate is adjusted to pH 3-4 with cone. HCI. The white precipitate of (3) which separates out is filtered off and dried in vacuo overYield: 108.O g (42percent)
42%
With potassium permanganate; In water; at 50 - 90℃; for 2.5h;
214.0 g of (2) are introduced in portions with stirring into an aqueous solution of 160 g of potassium permanganate at 50°C. A further 360 g of potassium permanganate are added in portions over the course of one hour. The temperature of the reaction mixture should not exceed 90°C during this. The mixture is then stirred for 1.5 h and filtered hot, and the filtrate is adjusted to pH 3-4 with conc. HCl. The white precipitate of (3) which separates out is filtered off and dried in vacuum over P2O5. Yield: 108.0 g (42percent)
7.65 g (25%)
With hydrogenchloride; potassium permanganate; In water;
(A) 2-(Acetylamino)isonicotinic acid N1-(4-Methyl-2-pyridyl)acetamide (25 g, 0.168 mol) suspended in water (250 ml) was added with potassium permanganate (76.1 g, 0.50 mol) at 100° C. over 1 hour and then stirred for 40 minutes. The reaction solution was returned to room temperature, and black crystals were removed by filtration. The resulting filtrate was added with 12 N hydrochloric acid until pH of the solution became 3 to 4. After the reaction solution was stirred for about 15 minutes, the deposited white crystals were collected by filtration, washed with water, and dried by using a vacuum pump to obtain 7.65 g (25percent) of the title compound without purification. 1H-NMR (CD3OD) delta: 2.20 (3H, s), 7.59 (1H, dd, J=1.47, 5.13 Hz), 8.42 (1H, dd, J=0.73, 5.13 Hz), 8.63 (1H, s) EI/MS; m/z: 179 (M+)
With potassium permanganate; In water;
2-Acetylamino-isonicotinic Acid (2-2) N-(4-Methyl-pyridin-2-yl)-acetamide, 70 g (466 mmol) was stirred in 400 mL water. The mixture was warmed to 80° C. KMnO4 (368 g, 2.33 mol, 5 equiv) was added dissolved in water over 45 minutes. The solution was heated to reflux for 3 hours. The reaction was then cooled and filtered. The filtrate was concentrated in vacuo to afford the desired product. 1H NMR (CD3OD) delta 8.62 (s, H), 8.42 (d, 1H, J=5.1 Hz), 7.59 (dd, 1H, J=5.1 Hz), 2.19 (s, 3H).
In water;
2-Acetylamino-isonicotinic acid (8-2) N-(4-Methyl-pyridin-2-yl)-acetamide, 70 g (466 mmol) was stirred in 400 mL water. The mixture was warmed to 80° C. KMnO4 (368 g, 2330 mmol, 5 equiv) was added dissolved in water over 45 min. The solution was heated to reflux for 3 h. The reaction was cooled and filtered. The filtrate was conc in vacuo to afford the desired product. 1H NMR (CD3OD) delta 8.62 (s, 1H), 8.42 (d, 1H, J=5.1 Hz), 7.59 (dd, 1H, J=5.1 Hz), 2.19 (s, 3H).
With potassium permanganate; In water;
Step B 4-Carboxy-2-acetylaminopyridine In a 500 mL beaker fitted with a large Teflon coated magnetic stirrer bar was added 200 mL of water and 20 g (133 mmol) of 4-methyl-2-acetylaminopyridine. The solution temperature was raised to 85° C. and 46 g (291 mmol, 2.2 eq) of potassium permanganate was added portionwise over 1 h at such a rate that the solution temperature remained between 85-90° C. After permanganate addition was completed, the mixture was stirred for 30 min at 90° C. The mixture was then filtered through a bed of celite while still hot and then the filtrate volume was reduced by two thirds in vacuo. After cooling to room temperature, the mixture was again filtered through celite. The pH of the filtrate was adjusted to 4.5 with concentrated HCl. The water was removed in vacuo and the product recrystallized from water/ethanol to give 3.4 g of the title compound. 1 H NMR (200 MHz, CD3 OD) delta 8.60 (d, 1H, J=2 Hz); 8.39 (d, 1H, J=5 Hz); 7.56 (dd, 1H, J=5 Hz, J=2Hz); 2.16 (s, 3H).
With potassium permanganate; In water; for 3h;Heating / reflux;
2-Acetylamino-isonicotinic Acid (2-2) N-(4-Methyl-pyridin-2-yl)-acetamide, 70 g (466 mmol) was stirred in 400 mL water. The mixture was warmed to 80° C. KMnO4 (368 g, 2.33 mol, 5 equiv) was added dissolved in water over 45 minutes. The solution was heated to reflux for 3 hours. The reaction was then cooled and filtered. The filtrate was concentrated in vacuo to afford the desired product. 1H NMR (CD3OD) delta 8.62 (s, 1H), 8.42 (d, 1H, J=5.1 Hz), 7.59 (dd, 1H, J=5.1 Hz), 2.19 (s, 3H).
With potassium permanganate; In water; at 80℃; for 3.75h;
2-Acetylamino-isonicotinic acid (2-2) N-(4-Methyl-pyridin-2-yl)-acetamide, 70 g (466 mmol) was stirred in 400 mL water. The mixture was warmed to 80° C. KMnO4 (368 g, 2.33 mol, 5 equiv) was added dissolved in water over 45 minutes. The solution was heated to reflux for 3 hours. The reaction was then cooled and filtered. The filtrate was concentrated in vacuo to afford the desired product. 1H NMR (CD3OD) delta8.62 (s, 1H), 8.42 (d, 1H, J=5.1 Hz), 7.59 (dd, 1H, J=5.1 Hz), 2.19 (s, 3H).
With potassium permanganate; In water; for 3h;Heating / reflux;
2-Acetylamino-isonicotinic acid (2-2) N-(4-Methyl-pyridin-2-yl)-acetamide, 70 g (466 mmol) was stirred in 400 mL water. The mixture was warmed to 80° C. KMnO4 (368 g, 2.33 mol, 5 equiv) was added dissolved in water over 45 minutes. The solution was heated to reflux for 3 hours. The reaction was then cooled and filtered. The filtrate was concentrated in vacuo to afford the desired product. 1H NMR (CD3OD) delta8.62 (s, 1H), 8.42 (d, 1H, J=5.1 Hz), 7.59 (dd, 1H, J=5.1 Hz), 2.19 (s, 3H).
Int-6 (10 g, 67 mmol) was added to a solution of potassium permanganate (15 g) in water (60 mL), and the mixture was heated to 60 °C, then another batch of potassium permanganate (34 g) was added to the mixture in portions. After addition, the temperature was brought to 90 °C and stirred until the reaction finished (by TLC). The mixture was filtered while hot, the filtrate was cooled to room temperature, neutralized and acidified with concentrated hydrochloric acid. The solids were collected by filtration to afford Int-7 (4.2 g, 35percent>), which was used directly in the next step without purification.
With potassium permanganate; cetyltrimethylammonium chloride; sodium carbonate; In water; at 55 - 60℃;
Into a four-necked flask, 15 g of 2-acetamidopyridine-4-methyl prepared in the step (1) and 150 ml of deionized water were added,After mixing and dissolving,Heating to 55-60 C,4 g of sodium carbonate was added,Stirring to dissolve,Then 0.45 g CTAC was added,Stirring mixing evenly,Potassium permanganate was then added dropwise at a rate of 2 ml / min,Dropping 1h after the stop dropping,And stirred for 10-20 min,And then continue to drop potassium permanganate,So repeated to the completion of potassium permanganate drop, and then reaction 1.5h, hot filter, and to the filtrate by adding 3.5g of sodium hydroxide, 90-100 C under reflux 1h, adjusted with concentrated hydrochloric acid pHTo 5-6, and cooling to 60 DEG C to obtain 2-aminopyridine-4-carboxylic acid
2-acetamido-4-methylpyridinium hydrobromide perbromide[ No CAS ]
[ 142404-82-8 ]
Yield
Reaction Conditions
Operation in experiment
88%; 83.1%
With bromine; In dichloromethane;
Into a 100 ml three-neck flask, 5.0 g (0.033 mol) of Ia was introduced. Then, 15 ml of dichloromethane was added thereto so as to dissolve Ia. Thereafter, 5.34 g (0.33 mol) of bromine was added dropwise thereto. An orange-colored slurry was formed. After being stirred overnight at room temperature, the slurry was filtered under reduced pressure. When the cake obtained by the filtration was dried, 5.5 g (yield: 88%) of IIIa was obtained. After the pH of the mother liquor after the filtration under reduced temperature was adjusted to 9-10 with 5% sodium hydroxide aqueous solution, an organic layer was separated therefrom. When the solvent was evaporated away, 3.14 g (yield: 83.1%) of IIa was obtained as a slightly brown crystal.
88%; 83.1%
With bromine; In dichloromethane;
Into a 100ml three-neck flask, 5.0g (0.033mol) of Ia was introduced. Then, 15ml of dichloromethane was added thereto so as to dissolve Ia. Thereafter, 5.34g (0.33mol) of bromine was added dropwise thereto. An orange-colored slurry was formed. After being stirred overnight at room temperature, the slurry was filtered under reduced pressure. When the cake obtained by the filtration was dried, 5.5g (yield: 88%) of IIIa was obtained. After the pH of the mother liquor after the filtration under reduced temperature was adjusted to 9-10 with 5% sodium hydroxide aqueous solution, an organic layer was separated therefrom. When the solvent was evaporated away, 3.14g (yield: 83.1%) of IIa was obtained as a slightly brown crystal.
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