* 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 tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; acetonitrile at 75℃;
Finally, several additional analogues designed to evaluate replacement of the pyridazine in 1 with phenyl and pyridyl moieties, were prepared using the methodology outlined in Scheme 3. Suzuki coupling of 2-bromopyridine (18) with various boronic acids afforded 19 and 20 (Ghiron et al, J. Med. Chem. 2010, 53, 4379). Treatment of 20 with P2S5 in pyridine at 120 °C provided 21 in 71percent yield. Alkylation of 21 with 2- methylbenzyl bromide in the presence of K2C03 in DMF generated 22. Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 °C, 4- benzylthiophenylboronic acid (54percent); (b) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 °C, 6-hydroxypyridine-3-boronic acid pinacol ester (70percent>); (c) P2S5, pyridine, 120 °C (71percent>); (d) 2-methylbenzyl bromide, K2C03, DMF (76percent).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5774 - 5777
[2] Patent: WO2013/19938, 2013, A1, . Location in patent: Page/Page column 34; 35
3
[ 381725-49-1 ]
[ 381233-78-9 ]
Yield
Reaction Conditions
Operation in experiment
80.9%
at 95 - 100℃; for 4 h; Acidic conditions
The acid aqueous phase containing 2-methoxy-5-(pyridin-2-yl)pyridine obtained according to Example 3 is reintroduced into the reactor C. The mixture is heated to reflux (95-100°C) for at least 4 h. The conversion is monitored in HPLC. When the reaction is complete, it is cooled to 20-25°C, the acid aqueous phase is washed with 3.54 L (5.9 V) of MTBE (the product is in aqueous phase). Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. Once the phases are separated, the pH of the aqueous phase (containing the product) is adjusted to 12.5-13 with approximately 1.5 L of sodium hydroxide 30percent solution. The basic aqueous phase so obtained is washed with 3.54 L (5.9 V) of MTBE (the product is in aqueous phase). Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. The pH of the aqueous phase is adjusted to about 7-7.5 with approximately 0.3 L of concentrated hydrochloric acid. 7.26 L (12.1 V) of n-butanol and a solution of sodium chloride at 20percent, obtained by mixing 0.67 kg (1 . 12 W) of sodium chloride and 2.68 1 (4.47 V) of purified water, are added to the aqueous phase. Stirring is continued for 15 min, the mixture is left to decant and the phases are separated (the product passes into the organic phase). The aqueous phase is again extracted with 7.26 L (12.1 V) of n-butanol. Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. The organic phase so obtained are evaporated at 45-60°C under vacuum to a residue. The distillation residue is recovered with 2.4 L (4 V) of ethyl acetate. The mixture is heated to reflux and stirred for 15 min. It is cooled to 20-25 °C and stirred 30 min and then it is cooled to -10/-5°C and stirred for at least 2 h. The mixture is filtered and washed with 2x0.60 L (2x1 V) of cold ethyl acetate (-10/-5 °C). The product is dried at 45-50 °C under vacuum for at least 6 h. 736 g of product are obtained, equal to a molar yield of 80.9percent from starting 2-chloro-pyridine (HPLC purity A/Apercent 99.40).
80.9%
With hydrogenchloride In water at 80 - 100℃; for 4 h;
General procedure: The acid aqueous phase containing 2-methoxy-5-(pyridin-2-yl)pyridine obtained according to Example 3 was reintroduced into the reactor C. The mixture was heated to reflux (95-100° C.) for at least 4 h. The conversion was monitored in HPLC. When the reaction was complete, it was cooled to 20-25° C., the acid aqueous phase was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. Once the phases were separated, the pH of the aqueous phase (containing the product) was adjusted to 12.5-13 with approximately 1.5 L of sodium hydroxide 30percent solution. The basic aqueous phase so obtained was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The pH of the aqueous phase was adjusted to about 7-7.5 with approximately 0.3 L of concentrated hydrochloric acid. 7.26 L (12.1 V) of n-butanol and a solution of sodium chloride at 20percent, obtained by mixing 0.67 kg (1.12 W) of sodium chloride and 2.68 l (4.47 V) of purified water, were added to the aqueous phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated (the product passed into the organic phase). The aqueous phase was again extracted with 7.26 L (12.1 V) of n-butanol. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase so obtained were evaporated at 45-60° C. under vacuum to a residue. The distillation residue was recovered with 2.4 L (4 V) of ethyl acetate. The mixture was heated to reflux and stirred for 15 min. It was cooled to 20-25° C. and stirred 30 min and then it was cooled to −10/−5° C. and stirred for at least 2 h. The mixture was filtered and washed with 2×0.60 L (2×1 V) of cold ethyl acetate (−10-5° C.). The product was dried at 45-50° C. under vacuum for at least 6 h. 736 g of product were obtained, equal to a molar yield of 80.9percent from starting 2-chloro-pyridine (HPLC purity A/A percent 99.4percent).
60%
With hydrogenchloride In water for 4 h; Heating / reflux
Crude 6-methoxy-3,2'-bipyridine (55.0 kg, net: 42.6 kg) obtained in Example 2, 35percent hydrochloric acid (65 kg) and water (110 kg) were charged in a reactor vessel (inner volume 500 L) and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled and the aqueous layer was washed with methyl-tert-butyl ether (116 kgx4). A solution obtained by dissolving sodium hydroxide (35 kg) in water (102 kg) was added while maintaining the inside temperature at 25-35C to adjust its pH to 12, and the aqueous layer was washed again with methyl-tert-butyl ether (116 kg?2). 35percent Hydrochloric acid (40 kg) was added while maintaining the inside temperature at 25-40C to adjust its pH to 7. This mixture was transferred to a reactor vessel (inner volume 1000 L), n-butanol (175 kg) was added and sodium chloride (70 kg) was further added. The organic layer was separated and the aqueous layer was extracted with n-butanol (175 kg). The extract and the organic layer were combined and concentrated until n-butanol remaining in the reactor vessel became 69 kg. Ethyl acetate (84 kg) was added to the concentrate, and the mixture was dissolved by heating to 80C and cooled to 0C to allow recrystallization to give crude 5-(2'-pyridyl)-2-pyridone (32.1 kg, net: 29.1 kg). This was added to water (224 kg), dissolved by heating to 60C and cooled to 0C. The obtained slurry was filtered, washed with water (45 kg) and dried to give 5-(2'-pyridyl)-2-pyridone (23.56 kg, yield 60percent).1H-NMR spectrum (CDCl3) ?: 6.72(d,1H,J=9.9Hz), 7.19(dd,1H,J=4.9Hz,6.9Hz), 7.51(d,1H,J=7.9Hz), 7.70-7.76(m,1H), 8.15-8.23 (m,2H), 8.62(d,1H,J=4.0Hz), 13.30(brs, 1H)
Stage #1: With hydrogenchloride; water In toluene at 100℃; for 10 h; Stage #2: With potassium carbonate In water
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
With water; at 95 - 100℃; for 4h;Acidic conditions;
The acid aqueous phase containing 2-methoxy-5-(pyridin-2-yl)pyridine obtained according to Example 3 is reintroduced into the reactor C. The mixture is heated to reflux (95-100C) for at least 4 h. The conversion is monitored in HPLC. When the reaction is complete, it is cooled to 20-25C, the acid aqueous phase is washed with 3.54 L (5.9 V) of MTBE (the product is in aqueous phase). Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. Once the phases are separated, the pH of the aqueous phase (containing the product) is adjusted to 12.5-13 with approximately 1.5 L of sodium hydroxide 30% solution. The basic aqueous phase so obtained is washed with 3.54 L (5.9 V) of MTBE (the product is in aqueous phase). Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. The pH of the aqueous phase is adjusted to about 7-7.5 with approximately 0.3 L of concentrated hydrochloric acid. 7.26 L (12.1 V) of n-butanol and a solution of sodium chloride at 20%, obtained by mixing 0.67 kg (1 . 12 W) of sodium chloride and 2.68 1 (4.47 V) of purified water, are added to the aqueous phase. Stirring is continued for 15 min, the mixture is left to decant and the phases are separated (the product passes into the organic phase). The aqueous phase is again extracted with 7.26 L (12.1 V) of n-butanol. Stirring is continued for 15 min, the mixture is left to decant and the phases are separated. The organic phase so obtained are evaporated at 45-60C under vacuum to a residue. The distillation residue is recovered with 2.4 L (4 V) of ethyl acetate. The mixture is heated to reflux and stirred for 15 min. It is cooled to 20-25 C and stirred 30 min and then it is cooled to -10/-5C and stirred for at least 2 h. The mixture is filtered and washed with 2x0.60 L (2x1 V) of cold ethyl acetate (-10/-5 C). The product is dried at 45-50 C under vacuum for at least 6 h. 736 g of product are obtained, equal to a molar yield of 80.9% from starting 2-chloro-pyridine (HPLC purity A/A% 99.40).
80.9%
With hydrogenchloride; In water; at 80 - 100℃; for 4h;
General procedure: The acid aqueous phase containing 2-methoxy-5-(pyridin-2-yl)pyridine obtained according to Example 3 was reintroduced into the reactor C. The mixture was heated to reflux (95-100 C.) for at least 4 h. The conversion was monitored in HPLC. When the reaction was complete, it was cooled to 20-25 C., the acid aqueous phase was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. Once the phases were separated, the pH of the aqueous phase (containing the product) was adjusted to 12.5-13 with approximately 1.5 L of sodium hydroxide 30% solution. The basic aqueous phase so obtained was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The pH of the aqueous phase was adjusted to about 7-7.5 with approximately 0.3 L of concentrated hydrochloric acid. 7.26 L (12.1 V) of n-butanol and a solution of sodium chloride at 20%, obtained by mixing 0.67 kg (1.12 W) of sodium chloride and 2.68 l (4.47 V) of purified water, were added to the aqueous phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated (the product passed into the organic phase). The aqueous phase was again extracted with 7.26 L (12.1 V) of n-butanol. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase so obtained were evaporated at 45-60 C. under vacuum to a residue. The distillation residue was recovered with 2.4 L (4 V) of ethyl acetate. The mixture was heated to reflux and stirred for 15 min. It was cooled to 20-25 C. and stirred 30 min and then it was cooled to -10/-5 C. and stirred for at least 2 h. The mixture was filtered and washed with 2×0.60 L (2×1 V) of cold ethyl acetate (-10-5 C.). The product was dried at 45-50 C. under vacuum for at least 6 h. 736 g of product were obtained, equal to a molar yield of 80.9% from starting 2-chloro-pyridine (HPLC purity A/A % 99.4%).
60%
With hydrogenchloride; In water; for 4h;Heating / reflux;
Crude 6-methoxy-3,2'-bipyridine (55.0 kg, net: 42.6 kg) obtained in Example 2, 35% hydrochloric acid (65 kg) and water (110 kg) were charged in a reactor vessel (inner volume 500 L) and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled and the aqueous layer was washed with methyl-tert-butyl ether (116 kgx4). A solution obtained by dissolving sodium hydroxide (35 kg) in water (102 kg) was added while maintaining the inside temperature at 25-35C to adjust its pH to 12, and the aqueous layer was washed again with methyl-tert-butyl ether (116 kg?2). 35% Hydrochloric acid (40 kg) was added while maintaining the inside temperature at 25-40C to adjust its pH to 7. This mixture was transferred to a reactor vessel (inner volume 1000 L), n-butanol (175 kg) was added and sodium chloride (70 kg) was further added. The organic layer was separated and the aqueous layer was extracted with n-butanol (175 kg). The extract and the organic layer were combined and concentrated until n-butanol remaining in the reactor vessel became 69 kg. Ethyl acetate (84 kg) was added to the concentrate, and the mixture was dissolved by heating to 80C and cooled to 0C to allow recrystallization to give crude 5-(2'-pyridyl)-2-pyridone (32.1 kg, net: 29.1 kg). This was added to water (224 kg), dissolved by heating to 60C and cooled to 0C. The obtained slurry was filtered, washed with water (45 kg) and dried to give 5-(2'-pyridyl)-2-pyridone (23.56 kg, yield 60%).1H-NMR spectrum (CDCl3) ?: 6.72(d,1H,J=9.9Hz), 7.19(dd,1H,J=4.9Hz,6.9Hz), 7.51(d,1H,J=7.9Hz), 7.70-7.76(m,1H), 8.15-8.23 (m,2H), 8.62(d,1H,J=4.0Hz), 13.30(brs, 1H)
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
Referential Example 4. 5- (2-Pyridyl)-1,2-dihydropyridin-2-one 2,5-Diboromopyridine [CAS No. 624-28-2] (400 g) was added to 3500 ml of a 28% methanolic solution of sodium methoxide, the mixture was stirred at 60C for 3 hours and allowed to cool, the reaction solution was poured into 3 liters of water, the mixture was extracted with 9000 ml of diethyl ether, the extract was washed with a saturated saline solution for three times and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo.The residue was dissolved in 2 liters of dimethylformamide, 900 g of tri-N-butyl-(2-pyridyl) tin [CAS No. 59020-10-9] and 20 g of tetrakistriphenylphosphine palladium and mixture was stirred at 120C in a nitrogen atmosphere for 3 hours. The reaction solution was allowed tocool and poured into 3 liters of water, the mixture was extracted with 10 liters of diethyl ether, the extract was successively washed with a saturated sodium bicarbonate solution and a saturated saline solution and the solvent was evaporated in vacuo.A 48% aqueous solution (800 ml) of hydrogen bromide was added to the residue and the mixture was stirred at 110C for 3 hours. After allowing to cool, the reaction solution was washed with 3 liters of diethyl ether, poured into 2 liters of ice, adjusted to pH 11.0 with a 5N sodium hydroxide solution and washed with 3 liters of diethyl ether again. The aqueous layer was adjusted to pH 7.0 and extracted with dichloromethane. The crude crystals prepared by evaporating the solvent in vauco were washed with a mixed solvent consisting of diethyl ether and hexane to give 201.5 g (yield: 69%) of the title compound.1H-NMR (400MHz, CDCl3); delta(ppm) 6.72 (d, 1H), 7.20 (ddd, 1H), 7.50-7.54 (m,1H), 7.73 (dt,1H), 8.12-8.15 (m,1H), 8.19 (dd, 1H), 8.60-8.64 (m, 1H).
With hydrogenchloride; In water; at 80 - 100℃; for 4h;
General procedure: The acid aqueous phase containing 2-methoxy-5-(pyridin-2-yl)pyridine obtained according to Example 3 was reintroduced into the reactor C. The mixture was heated to reflux (95-100 C.) for at least 4 h. The conversion was monitored in HPLC. When the reaction was complete, it was cooled to 20-25 C., the acid aqueous phase was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. Once the phases were separated, the pH of the aqueous phase (containing the product) was adjusted to 12.5-13 with approximately 1.5 L of sodium hydroxide 30% solution. The basic aqueous phase so obtained was washed with 3.54 L (5.9 V) of MTBE (the product was in aqueous phase). Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The pH of the aqueous phase was adjusted to about 7-7.5 with approximately 0.3 L of concentrated hydrochloric acid. 7.26 L (12.1 V) of n-butanol and a solution of sodium chloride at 20%, obtained by mixing 0.67 kg (1.12 W) of sodium chloride and 2.68 l (4.47 V) of purified water, were added to the aqueous phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated (the product passed into the organic phase). The aqueous phase was again extracted with 7.26 L (12.1 V) of n-butanol. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase so obtained were evaporated at 45-60 C. under vacuum to a residue. The distillation residue was recovered with 2.4 L (4 V) of ethyl acetate. The mixture was heated to reflux and stirred for 15 min. It was cooled to 20-25 C. and stirred 30 min and then it was cooled to -10/-5 C. and stirred for at least 2 h. The mixture was filtered and washed with 2×0.60 L (2×1 V) of cold ethyl acetate (-10-5 C.). The product was dried at 45-50 C. under vacuum for at least 6 h. 736 g of product were obtained, equal to a molar yield of 80.9% from starting 2-chloro-pyridine (HPLC purity A/A % 99.4%).
3
[ 381725-49-1 ]
[ 71-36-3 ]
[ 381233-78-9 ]
[ 28509-24-2 ]
Yield
Reaction Conditions
Operation in experiment
188g (66%)
With hydrogenchloride; sodium hydroxide;
5-Pyridin-2-yl-2(1H)-pyridone A mixture of 2-methoxy-5-pyridin-2-yl-pyridine (550g) and a 4mol/L aquesous solution of hydrochloric acid (2.4L) was heated under reflux for 3 hours. After cooling the reaction solution, and washed with tert-butylmethyl ether (2.2L). To the aqueous layer was added 8mol/L aqueous solution of sodium hydroxide (1.1L) under cooling with ice-water, and then the mixture was washed twice with tert-butylmethyl ether (2.2L). Then, it was adjusted to pH 8 with concentrated hydrochloric acid (310ml) and 8mol/L aqueous solution of sodium hydroxide (100ml), followed by partitioning between 1-butanol (4.5L) and brine (1.8L). The aqueous layer was extracted again with 1-butanol (4.5L), and the combined organic layer was evaporated at 45-50C. To the resulting residue was added tert-butylmethyl ether (2.2L), to give crystals. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60C. Then, water (1.6L) was added thereto to dissolve under heating. Then the mixture was water-cooled, and recrystallized. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60C, to give 188g (66%) of the title compound as grayish white crystals. 1H-NMR (DMSO-d6,400MHz): 6.42 (1H, d), 7.19-7.26 (1H, m), 7.74-7.81 (2H,m), 8.11 (1H,d), 8.17 (1H,dd), 8.52-8.55 (1H,m). MS: MH+173
1-phenyl-5-(pyridin-2-yl)-2(1H)-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
187g (68%)
With pyridine; ammonium hydroxide;Cu(OAc)2; In N,N-dimethyl-formamide;
1-Phenyl-5-pyridin-2-yl-2(1H)-pyridone While stirring 5-Pyridin-2-yl-2(1H)-pyridone (185g), PhB(OH)2(261g), Cu(OAc)2(19.4g), pyridine (173ml) and DMF (1480ml) at room temperature, air was blown at 2.0L/minute therein, to initiate the reactions. Since 26% of the reactant remained unreacted 7 hours after the initiation of the reaction, flow of air was stopped to suspend the reactions. On the next day, air was blown into the solution to restart the reactions, and the reactant was consumed to 0.57% of the initial weight in 5.5 hours. The reaction solution was poured into ice-cooled 10% aqueous ammonia (7.5L), to give MA045. The resulting precipitates were collected by filtration under reduced pressure, and washed with water (3L). The resulting crystals were suspended into 10% aqueous ammonia (3.6L) under stirring at room temperature for 1 hour. Then the crystals were collected by filtration under reduced pressure, and washed with water (2L). The resulting crystals were air-dried overnight, to give 187g (68%) of the title compound as brown crystals.1H-NMR (CDCl3, 400MHz): 6.77(1H,d), 7.19(1H,dd), 7.42-7.48(3H,m),7.49-7.55 (3H, m), 7.72 (1H, dt), 8.04 (1H, dd), 8.21 (1H, d), 8.57-8.59 (1H, m). MS: MH+249
1-phenyl-5-(pyridin-2-yl)-2(1H)-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
After a reactor was purged with nitrogen, a mixture of <strong>[381233-78-9]5-(2-pyridyl)-1,2-dihydropyridin-2-one</strong> (7.33 kg: WO2004/009553), triphenylboroxine (9.0 kg), copper acetate (anhydrous) (0.80 kg), water (0.50 kg), pyridine (7.1 kg), and N,N-dimethylformamide (66.7 kg) was stirred in the reactor at an internal temperature of 28 C for 1 hour. While the air of which oxygen concentration was adjusted to 9% with nitrogen was blown into the reactor at a rate of 30 L/min, the reaction mixture was stirred at 39-40 C (internal temperature) for 16 hours to yield reaction mixture 1 A. Water (191 kg) and 25% aqueous ammonia (85.8 kg) were charged in a separate reactor and cooled with cold water to 8.7 C. The reaction mixture 1A was then added to the reactor over 3 minutes. The reaction mixture was stirred for 4 hours at cooling with cold water. The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 65 kg of water. The precipitates, water (97 kg), and 25% aqueous ammonia (43.5 kg) were poured in a reactor and stirred for 1 hour while the temperature was maintained with warm water (25 C). The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 32.6 kg of water. The precipitates were then dried under reduced pressure (60 C; 18 hours) to give 9.6 kg of 5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one. 1H NMR (400 MHz DMSO-d6): delta 8.61-8.50 (m, 1H), 8.36 (d, 1H), 8.29 (dd, 1H), 7.90 (d, 1H), 7.80 (ddd, 1H), 7.56-7.45 (m, 5H), 7.27 (dd, 1H), 6.62 (d, 1H).
After a reactor was purged with nitrogen, a mixture of <strong>[381233-78-9]5-(2-pyridyl)-1,2-dihydropyridin-2-one</strong> (7.33 kg: WO2004/009553), triphenylboroxine (9.0 kg), copper acetate (anhydrous) (0.80 kg), water (0.50 kg), pyridine (7.1 kg), and N,N-dimethylformamide (66.7 kg) was stirred in the reactor at an internal temperature of 28 C. for 1 hour.While the air of which oxygen concentration was adjusted to 9% with nitrogen was blown into the reactor at a rate of 30 L/min, the reaction mixture was stirred at 39-40 C. (internal temperature) for 16 hours to yield reaction mixture 1A.Water (191 kg) and 25% aqueous ammonia (85.8 kg) were charged in a separate reactor and cooled with cold water to 8.7 C. The reaction mixture 1A was then added to the reactor over 3 minutes. The reaction mixture was stirred for 4 hours at cooling with cold water. The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 65 kg of water.The precipitates, water (97 kg), and 25% aqueous ammonia (43.5 kg) were poured in a reactor and stirred for 1 hour while the temperature was maintained with warm water (25 C.). The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 32.6 kg of water. The precipitates were then dried under reduced pressure (60 C.; 18 hours) to give 9.6 kg of 5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one.1H NMR (400 MHz DMSO-d6): delta 8.61-8.50 (m, 1H), 8.36 (d, 1H), 8.29 (dd, 1H), 7.90 (d, 1H), 7.80 (ddd, 1H), 7.56-7.45 (m, 5H), 7.27 (dd, 1H), 6.62 (d, 1H).
(Production Example 1) Synthesis of 5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one [Show Image] After a reactor was purged with nitrogen, a mixture of <strong>[381233-78-9]5-(2-pyridyl)-1,2-dihydropyridin-2-one</strong> (7.33 kg: WO2004/009553), triphenylboroxine (9.0 kg), copper acetate (anhydrous) (0.80 kg), water (0.50 kg), pyridine (7.1 kg), and N,N-dimethylformamide (66.7 kg) was stirred in the reactor at an internal temperature of 28 C for 1 hour. While the air of which oxygen concentration was adjusted to 9% with nitrogen was blown into the reactor at a rate of 30 L/min, the reaction mixture was stirred at 39-40 C (internal temperature) for 16 hours to yield reaction mixture 1 A. Water (191 kg) and 25% aqueous ammonia (85.8 kg) were charged in a separate reactor and cooled with cold water to 8.7 C. The reaction mixture 1A was then added to the reactor over 3 minutes. The reaction mixture was stirred for 4 hours at cooling with cold water. The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 65 kg of water. The precipitates, water (97 kg), and 25% aqueous ammonia (43.5 kg) were poured in a reactor and stirred for 1 hour while the temperature was maintained with warm water (25 C). The precipitates in the reaction mixture were collected by filtration with a centrifuge and the filtrated residue was washed with 32.6 kg of water. The precipitates were then dried under reduced pressure (60 C; 18 hours) to give 9.6 kg of 5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one. 1H NMR (400 MHz DMSO-d6): delta 8.61-8.50 (m, 1H), 8.36 (d, 1H), 8.29 (dd, 1H), 7.90 (d, 1H), 7.80 (ddd, 1H), 7.56-7.45 (m, 5H), 7.27 (dd, 1H), 6.62 (d, 1H).
Thereafter, 10 ml of an aqueous 35% hydrochloric acid solution was added to the collected aqueous layer and the reaction was allowed to proceed at 100C for 10 hours. Subsequent to the completion of reaction, the reaction solution was neutralized with potassium carbonate to a pH of 7 to 8 and 150 ml of THF and 5 g of brine were added thereto, followed by stirring. After liquid separation, 150 ml of THF and 10 g of brine were added to the aqueous layer and liquid separation was again performed. The obtained organic layers were combined, concentrated, dissolved by adding 100 ml of ethyl acetate, cooled to 0 to 5C and crystallized. The crystals were collected by filtration and dried to obtain 17.5 g of the objective compound (yield: 63.2%). As a result of measurement by HPLC, the purity was 99.8%.
A toluene solution of the obtained crude 6'-chloro-2,3'-bipyridyl was extracted two times with 125 ml of an aqueous 2 mol/l hydrochloric acid solution. Thereafter, 10 ml of an aqueous 35% hydrochloric acid solution was added to the collected aqueous layer and the reaction was allowed to proceed at 100 C. for 10 hours. Subsequent to the completion of reaction, the reaction solution was neutralized with potassium carbonate to a pH of 7 to 8 and 150 ml of THF and 5 g of brine were added thereto, followed by stirring. After liquid separation, 150 ml of THF and 10 g of brine were added to the aqueous layer and liquid separation was again performed. The obtained organic layers were combined, concentrated, dissolved by adding 100 ml of ethyl acetate, cooled to 0 to 5 C. and crystallized. The crystals were collected by filtration and dried to obtain 17.5 g of the objective compound (yield: 63.2%). As a result of measurement by HPLC, the purity was 99.8%.
With sodium hydroxide; In water; at 70 - 80℃; for 1h;Large scale;
BL03 compound is added to polyphosphoric acid, was added Compound BL-b, warmed to 90 , followed by slow addition of ammonium formate, the reaction was continued for 4-5 hours.After the reaction was cooled to room temperature, ice water was added 30L, stirring, 8kg sodium hydroxide was added, the reaction was heated to 70-80 deg.] C for 1 hour.After the reaction was cooled to room temperature.Filtration, the solid was washed with water 40-50 deg.] C for 20-24 hours blast drying, to obtain a gray powder 998g.
With ammonium acetate; acetic acid; In isopropyl alcohol; at 100℃; for 11h;Product distribution / selectivity;
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
Examples 37 to 41: 2,3'-Bipyridyl-6'-one was synthesized by the same operation as in Example 1 and Example 23 except for using the nicotinic acid derivative shown in Table 4. In Example 37, 2,3'-bipyridyl-6'-one could be directly synthesized and therefore, the operation of hydrolysis in Example 23 was omitted.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 75℃;
Finally, several additional analogues designed to evaluate replacement of the pyridazine in 1 with phenyl and pyridyl moieties, were prepared using the methodology outlined in Scheme 3. Suzuki coupling of 2-bromopyridine (18) with various boronic acids afforded 19 and 20 (Ghiron et al, J. Med. Chem. 2010, 53, 4379). Treatment of 20 with P2S5 in pyridine at 120 C provided 21 in 71% yield. Alkylation of 21 with 2- methylbenzyl bromide in the presence of K2C03 in DMF generated 22. Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 C, 4- benzylthiophenylboronic acid (54%); (b) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 C, <strong>[1054483-78-1]6-hydroxypyridine-3-boronic acid pinacol ester</strong> (70%>); (c) P2S5, pyridine, 120 C (71%>); (d) 2-methylbenzyl bromide, K2C03, DMF (76%).
With tetraphosphorus decasulfide; In pyridine; at 120℃;
Finally, several additional analogues designed to evaluate replacement of the pyridazine in 1 with phenyl and pyridyl moieties, were prepared using the methodology outlined in Scheme 3. Suzuki coupling of 2-bromopyridine (18) with various boronic acids afforded 19 and 20 (Ghiron et al, J. Med. Chem. 2010, 53, 4379). Treatment of 20 with P2S5 in pyridine at 120 C provided 21 in 71% yield. Alkylation of 21 with 2- methylbenzyl bromide in the presence of K2C03 in DMF generated 22. Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 C, 4- benzylthiophenylboronic acid (54%); (b) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 C, 6-hydroxypyridine-3-boronic acid pinacol ester (70%>); (c) P2S5, pyridine, 120 C (71%>); (d) 2-methylbenzyl bromide, K2C03, DMF (76%).
1-phenyl-5-(pyridin-2-yl)-2(1H)-pyridone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.5 g
With pyridine; copper(II) acetate monohydrate; In N,N-dimethyl-formamide; at 20 - 30℃;
90 ml of dimethyl formamide was added to a RBF, to this 10 gm of 5-(2-pyridyl)- l,2-dihydropyridine-2-one, 12.4 gm of phenyl boronic acid, 1.042 gm of copper (II) acetate monohydrate and 9.18 gm of pyridine were added. Reaction mixture was stirred at 20-30C and the reaction was monitored by HPLC. After completion of reaction the reaction mixture was added to 400 ml of ammonia solution [(Aq. Ammonia (40 ml) mixed in purified water (360 ml)], followed by addition of 1.3 ml of dimethyl formamide. Reaction mixture was stirred for 15-25 minutes at 25-35C, filtered and the residue was washed with purified water (50.0 ml). The solid thus obtained was dried under vacuum at below 70C for 24 hrs to give 11.5 gm of title compound
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 25 - 30℃;
In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 201.5 g <strong>[381233-78-9]5-(2-pyridyl)-1,2-dihydropyridin-2-one</strong>, 208.3 g N-bromosuccinimide and 1300 mL N,N-dimethylforamide were stirred at 25-30 C. for 2-3 hours. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 min. The precipitate was filtered, washed with N,N-dimethylforamide and dried at 50 C. to obtain 230 g title compound.
In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 188.80 g 5-bromo-2-methoxypyridine in 190 mL tetrahydrofuran and 12.92 g pyridine-2-yl boronic acid were added and refluxed. The reaction mixture was cooled to 25-30 C. and aqueous solution of hydrochloric acid was added and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydroxide and extracted with tetrahydrofuran. The organic layer was washed with saline water, dried over anhydrous magnesium sulfate, and then evaporated to obtain the titled compound.
Chemistry
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Material Science
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110K+ Compounds
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