Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
5
[ 5327-32-2 ]
[ 6937-03-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 6, p. 1993 - 2004
[2] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2025 - 2034
[3] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 485,487
6
[ 5327-32-2 ]
[ 13362-30-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 23, p. 5978 - 5981
7
[ 5327-32-2 ]
[ 100367-40-6 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
8
[ 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
9
[ 5327-32-2 ]
[ 105250-17-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 23, p. 5978 - 5981
10
[ 5327-32-2 ]
[ 884495-14-1 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
11
[ 5327-32-2 ]
[ 884495-14-1 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
12
[ 5327-32-2 ]
[ 884495-14-1 ]
[ 228410-90-0 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
13
[ 5327-32-2 ]
[ 884495-14-1 ]
[ 228410-90-0 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 8, p. 1095 - 1109
Stage #1: 2-Amino-4-methylpyridine; acetic anhydride With acetic acid Reflux;
Stage #2: With ammonium hydroxide
II
A round-bottom flask was charged with Int-5 (10.8 g, 0.1 mol), AcOH (10 mL), and acetic anhydride (12 mL). The mixture was brought to reflux until the reaction was complete (as determined by TLC), and then poured into ice-water, basified to pH 9 with ammonium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give Int-6 (13.5 g, 90%).
87%
at 70℃; for 2h;
75%
With dmap for 5h; Heating;
75%
Stage #1: 2-Amino-4-methylpyridine; acetic anhydride With dmap for 5h; Heating / reflux;
Stage #2: With ammonia In water
a
a) 2-Acetamido-4-methylpyridine (2); 200.0 g of 2-aminopicoline (1) are mixed with 400 ml of acetic anhydride and with 100 mg of 4-dimethylaminopyridine and refluxed for 5 h. After cooling, the excess acetic anhydride is substantially distilled off, and the residue is poured onto ice and neutralized with aqueous ammonia solution. The precipitate of (2) which separates out during this is filtered off and dried in vacuo over P2O5. Yield: 209.0 g (75%)
75%
Stage #1: 2-Amino-4-methylpyridine; acetic anhydride With dmap for 5h; Heating / reflux;
Stage #2: With ammonia In water
a; 1
200.0 g of 2-aminopicoline (1) are mixed with 400 ml of acetic anhydride and with 100 mg of 4-dimethylaminopyridine and refluxed for 5 h. After cooling, the excess acetic anhydride is substantially distilled off, and the residue is poured onto ice and neutralized with aqueous ammonia solution. The precipitate of (2) which separates out during this is filtered off and dried in vacuum over P2O5. Yield: 209.0 g (75%)
62%
With triethylamine In dichloromethane at 0 - 40℃;
1.1
Synthesis Example 1; Synthesis of N-ethyl-N-methyl-N'[5-(4-t-butyl-phenyl)-4-methylpyridin-2- yl]formamidine (Compound No.1); (1); Triethylamine (101.7 mmol, 14 ml) and acetic anhydride (101.7 mmol, 9.6 ml) were added to a methylene chloride solution (250 ml) of 2-amino-4-picoline (92.5 mmol, 10 g) at 0°C, and the temperature was elevated to 40°C, followed by stirring for 2.5 hours. Water (200 ml) was added to the resulting reaction mixture to stop the reaction, and an aqueous layer was extracted with chloroform. An organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, followed by distilling away a solvent under reduced pressure. The resulting crude product was purified with column chromatography to obtain 8.6 g of 2-(acetylamino)-4- picoline (yield 62%). 1H NMR δ ppm (300 MHz, CDCl3) data of this compound are 8.21 (brs, IH), 8.10 (d, IH, J= 5.1Hz), 8.03 (s, IH), 6.86 (dd, IH, J= 0.9, 5.1Hz), 2.36 (s, 3H), 2.19 (s, 3H).
With acetic acid
for 3h; Heating;
With sodium hydrogencarbonate In tetrahydrofuran
With dmap
for 10h; Heating / reflux; Acidic aqueous solution;
10.A Example 10; Preparation of methyl [2-[[[3-(1,1-dimethylethyl)-1-ethyl-1H-pyrazol-5-yl]]carbonyl]amino]-4-pyridinecarboxylate (Compound 151); Step A; Preparation of N-(4-methyl-2-pyridinyl)acetamide
A solution of 2-amino-4-picoline (25 g, 231 mmol) in acetic anhydride (150 mL) was heated to reflux for 10 h. The reaction mixture was then cooled to room temperature and concentrated to give a thick oily residue. The residue was dissolved in dichloromethane (400 mL) and washed sequentially with 1 N hydrochloric acid (50 mL) and water (50 mL). The organic phase was dried and concentrated to give the title compound as a white solid (30 g).
With acetic acid at 85 - 95℃; for 5h; Large scale;
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 3-chloro-benzenecarboperoxoic acid In dichloromethane for 24h;
N-(4-Methyl-1-oxy-pyridin-2-yl)-acetamide:; 2-Acetamino-4-methylpyridine (30 g, 0.2 mol) was stirred with 57-80% m-CPBA (90 g, 0.3 mol) in dichloromethane (300 ml) in a water bath for 24 hr. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography(eluent, 1)ether, 2)methanol:chloroform (5:95)) to afford 26 g (78%) of N-(4-methyl-1-oxy-pyridin-2-yl)-acetamide. 1H NMR (200 MHz, CDCl3) δ 2.31(3H, s), 2.37 (3H, s), 6.80 (1H, dd, J=2.4 Hz, 6.6 Hz), 8.11 (1H, d, J=6.6 Hz), 8.26 (1H, d, J=2.4 Hz), 10.02 (1H, s).
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
N-(5-chloro-4-methylpyridin-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97.3%
With chlorine In dichloromethane; water
23 Synthesis of 2-acetamido-4-methyl-5-chloropyridine (IIk)
Example 23 Synthesis of 2-acetamido-4-methyl-5-chloropyridine (IIk) In 300 ml of water, 15.0 g (0. lmol) of 2-acetamido-4-methylpyridine (Ia) was dissolved. To this solution, 35.5 g (0.25 mol) of disodium hydrogenphosphate and 100 ml of dichloromethane were added in this order. While this mixture was stirred, 8.0 g (0.11 mol) of chlorine was introduced thereto at 0° C. for one hour. After having further been stirred at the same temperature for 2 hours, the mixture was separated into a water layer and an extract layer. After the water layer was further extracted with 100 ml of dichloromethane, the newly-separated extract layer was combined with the previously-separated extract layer and washed with saturated brine. Then the washed mixture was desiccated with sodium sulfate anhydride. When the solvent was evaporated off, 18.0 g (yield: 97.3%) of 2-acetamido-4-methyl-5-chloropyridine (IIk) was obtained as a pale yellow crystal.
97.3%
With chlorine In dichloromethane; water
23 Synthesis of 2-acetamido-4-methyl-5-chloropyridine (IIk)
Example 23 Synthesis of 2-acetamido-4-methyl-5-chloropyridine (IIk) In 300ml of water, 15.0g (0.1mol) of 2-acetamido-4-methylpyridine (Ia) was dissolved. To this solution, 35.5g (0.25mol) of disodium hydrogenphosphate and 100ml of dichloromethane were added in this order. While this mixture was stirred, 8.0g (0.11mol) of chlorine was introduced thereto at 0°C for one hour. After having further been stirred at the same temperature for 2 hours, the mixture was separated into a water layer and an extract layer. After the water layer was further extracted with 100ml of dichloromethane, the newly-separated extract layer was combined with the previously-separated extract layer and washed with saturated brine. Then the washed mixture was desiccated with sodium sulfate anhydride. When the solvent was evaporated off, 18.0g (yield: 97.3%) of 2-acetamido-4-methyl-5-chloropyridine (IIk) was obtained as a pale yellow crystal.
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.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 0.5h;
(2); N-Bromosuccinimide (6.8 mmol, 1.2 g) was added to a N'N- dimethylformamide solution (20 ml) of 2-(acetylamino)-4-picoline (6.7 mmol, 1 g) at 0C, followed by stirring at the same temperature for 30 minutes. Water (20 ml) was added to the resulting reaction mixture on ice to stop the reaction, and an aqueous layer was extracted with diethyl ether five times. An organic layer was dried over anhydrous sodium sulfate, and filtered, followed by distilling away a solvent under reduced pressure. The resulting crude product was purified with column chromatography to obtain 1.25 g of 2-(acetylamino)-5-bromo-4-picoline (yield 82%). 1H NMR δ ppm (300 MHz, CDCl3) data of this compound are 8.27 (s, IH), 8.13 (s, IH), 7.85 (brs, IH), 2.41 (s, 3H), 2.20 (s, 3H).
With bromine; In CH3 CO2 Na; water;
Example 9 Single step synthesis of 2-acetamido-4-methyl-5-bromopyridine (IIa) by bromination of 2-acetamido-4-methylpyridine (Ia) in aqueous solution of sodium acetate (CH3 CO2 Na) Into a 300 ml three-neck flask, 155 ml of water was introduced and then a solution in which 12.3 g (0.15 mol) of CH3 CO2 Na has been dissolved in 25 ml of water was added thereto. The pH at this moment was 8.8. Then, 9.0 g (0.06 mol) of 2-acetamido-4-methylpyridine (Ia) was added thereto and dispersed therein. Thereafter, 9.6 g (0.06 mol) of bromine was added dropwise thereto for 12 minutes at 19-24 C. After being stirred overnight, the mixture was filtered under reduced pressure. The cake obtained by the filtration was washed with water.
2-acetamido-4-methylpyridinium hydrobromide perbromide[ No CAS ]
[ 142404-82-8 ]
[ 5327-32-2 ]
Yield
Reaction Conditions
Operation in experiment
In water;
While being stirred at room temperature, 97.1g of the above-obtained mixture of IIa and IIIa was added thereto. After being heated on a hot water bath and reacted for two hours at 38C, the reaction mixture was further reacted overnight at room temperature and then reacted for two hours on a hot bath at 45C. The color of the slurry gradually changed from orange to yellow. After being cooled to room temperature, the pH of the slurry was adjusted to 4.96 with 5% NaOH aqueous solution. Then, it was filtered under reduced pressure. The cake obtained by the filtration was washed with 40ml of water. When the washed cake was dried, 62.4g of IIa was obtained as pale brown powder.
1.1 Example 1
A 4-necked flask was charged with 4 g of 2-aminopyridine-4-methyl,4g glacial acetic acid,Stirring mixing evenly,While stirring, 4 g of acetyl chloride was added dropwise,After completion of the dropwise addition,Heating to 115-120 ° C,Refluxed for 10 h, cooled, crystallized, filtered and dried to give 2-acetamidopyridine-4-methyl
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