* 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 potassium phosphate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In toluene at 100℃; for 22 h;
A pressure vessel was charged with methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3- [(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 (6.4g, 15 mmol), 2,4- difluorobenzylamine (3.2g, 22.5 mmol), K3PO4 (9.45g, 45mmol), Pd(OCOCF3)2 (398mg, 1.2 mmol), Xantophos (694mg, 1.2 mmol) and toluene (200 mL). The mixture was purged by CO (4X) before being heated to 100 0C for 22 hours under CO atmosphere (60psi). After cooled down to the room temperature, the solids were filtered off through celite and washed with EtOAc. The filtrate was concentrated and the residual was purified by column chromatography ( silical gel, EtOAc/hexane 0~80percent) to afford methyl 1-[2,2- bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3- [(phenylmethyl)oxy]-1 ,4-dihydro-2-pyridinecarboxylate 25 as a light brown oil (4.7g, 61percent). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.4 (m, 1 H), 8.4 (s, 1 H), 7.4 (m, 6 H), 6.8 (d, J=9.3 Hz, 2 H), 5.3 (s, 2 H), 4.6 (d, J=5.7 Hz, 2 H), 4.5 (s, 1 H), 4.0 (d, J=4.8 Hz, 2 H), 3.8 (S, 3 H), 3.4 (s, 6 H). LC-MS (M+H+): calcd 517, obsd 517.
61%
With potassium phosphate; palladium(II) trifluoroacetate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In toluene at 100℃; for 22 h;
The pressure vessel, 1- [2,2-bis (methyloxy) ethyl] -5-bromo-4-oxo-3 - [(phenylmethyl) oxy] -1,4-dihydro-2-pyridinecarboxylic acid methyl ester 24 (6.4g, 15 mmol), 2,4- difluorobenzylamine (3.2g, 22.5 mmol), K3PO4 (9.45g, 45mmol), Pd (OCOCF3) 2 (398mg, 1.2 mmol), Xantphos (694mg, 1.2 mmol ) and was charged with toluene (200 mL). The mixture was purged with CO (4 times), for 22 hours at 100 , was under CO atmosphere (60psi) reaction. After cooling to room temperature, the solid was filtered through Celite, and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, EtOAc / hexanes 0-80percent) to give 1- [2,2-bis (methyloxy) ethyl] -5 - ([(2,4 difluorophenyl) methyl] amino} carbonyl) -4-oxo-3 - [(phenylmethyl) oxy] -1,4-dihydro-2-pyridinecarboxylic acid methyl esterTo give a 25 as an oil of pale brown (4.7g, 61percent)..
2,4-difluorobenzylamine (209 mg, 1.4 mmol) and acetic acid (88 mg, 1.4 mmol) were added to a toluene (5.4 mL) suspension of compound 12B (539 mg, 1.3 mmol) at room temperature, and the mixture was then heated to 90°C and stirred for 7 hours. After the completion of reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 3 : 7 (v/v)) to obtain 666 mg (yield: 97percent) of compound 13C as a pale yellow oil. 1H-NMR (CDCl3) δ: 3.37 (6H, s), 3.79 (3H, s), 4.01 (2H, d, J = 5.0 Hz), 4.47 (1H, t, J = 5.0 Hz), 4.65 (2H, d, J = 6.0 Hz), 5.26 (2H, s), 6.78-6.86 (2H, m), 7.30-7.42 (6H, m), 8.42 (1H, s), 10.41 (1H, t, J = 6.0 Hz).
Reference：
[1] Patent: EP2602260, 2013, A1, . Location in patent: Paragraph 0184
[2] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1461 - 1468
3
[ 1229006-20-5 ]
[ 72235-52-0 ]
[ 1229006-21-6 ]
Reference：
[1] Patent: US9242986, 2016, B2,
4
[ 1246616-66-9 ]
[ 1229006-21-6 ]
Reference：
[1] Patent: EP2602260, 2013, A1,
[2] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1461 - 1468
With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium(II) trifluoroacetate; In toluene; at 100℃; under 3102.97 Torr; for 22h;
A pressure vessel was charged with methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3- [(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 (6.4g, 15 mmol), 2,4- difluorobenzylamine (3.2g, 22.5 mmol), K3PO4 (9.45g, 45mmol), Pd(OCOCF3)2 (398mg, 1.2 mmol), Xantophos (694mg, 1.2 mmol) and toluene (200 mL). The mixture was purged by CO (4X) before being heated to 100 0C for 22 hours under CO atmosphere (60psi). After cooled down to the room temperature, the solids were filtered off through celite and washed with EtOAc. The filtrate was concentrated and the residual was purified by column chromatography ( silical gel, EtOAc/hexane 0~80%) to afford methyl 1-[2,2- bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3- [(phenylmethyl)oxy]-1 ,4-dihydro-2-pyridinecarboxylate 25 as a light brown oil (4.7g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.4 (m, 1 H), 8.4 (s, 1 H), 7.4 (m, 6 H), 6.8 (d, J=9.3 Hz, 2 H), 5.3 (s, 2 H), 4.6 (d, J=5.7 Hz, 2 H), 4.5 (s, 1 H), 4.0 (d, J=4.8 Hz, 2 H), 3.8 (S, 3 H), 3.4 (s, 6 H). LC-MS (M+H+): calcd 517, obsd 517.
61%
With potassium phosphate; palladium(II) trifluoroacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; under 3102.97 Torr; for 22h;
The pressure vessel, 1- [2,2-bis (methyloxy) ethyl] -5-bromo-4-oxo-3 - [(phenylmethyl) oxy] -1,4-dihydro-2-pyridinecarboxylic acid methyl ester 24 (6.4g, 15 mmol), 2,4- difluorobenzylamine (3.2g, 22.5 mmol), K3PO4 (9.45g, 45mmol), Pd (OCOCF3) 2 (398mg, 1.2 mmol), Xantphos (694mg, 1.2 mmol ) and was charged with toluene (200 mL). The mixture was purged with CO (4 times), for 22 hours at 100 , was under CO atmosphere (60psi) reaction. After cooling to room temperature, the solid was filtered through Celite, and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, EtOAc / hexanes 0-80%) to give 1- [2,2-bis (methyloxy) ethyl] -5 - ([(2,4 difluorophenyl) methyl] amino} carbonyl) -4-oxo-3 - [(phenylmethyl) oxy] -1,4-dihydro-2-pyridinecarboxylic acid methyl esterTo give a 25 as an oil of pale brown (4.7g, 61%)..
Methyl 1-[2,2-bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo- 3-[(phenylmethyl)oxy]-1 ,4-dihydro-2-pyridinecarboxylate 25 (11.6 g ) was treated with 90% formic acid (250 mL) at 40 0C for -12 hours (monitored by LC-MS). After the solvents were evaporated at <40 0C, the residue was re-dissolved in EtOAc (~ 1 L) and the resulting solution was washed with NaHCO3 and brine. The organic phase was then dried over Na2SO4. After evaporation of solvents, the titled compounds 26 and 27 were obtained as an approximate 80/20 equillibrium mixture (10.57g). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.3 (m, 1 H)1 9.47 (s, aldehyde-H. -0.2 H)), 8.4 (m, 1 H), 7.3 (s, 6 H), 7.2 (m, 1 H), 7.0 (m, 1 H), 6.3 (m, 2 H), 5.1 (s, 3 H), 4.9 (m, 1 H), 4.5 (m, 3 H), 3.9 (m, 2 H), 3.8 (s, 3 H). LC-MS, for 26 (M+H+), calcd 503, obsd 503; for 27 (M+H2O+H+), cald 489, obsd 489.
With formic acid; at 40℃; for 12.0h;
<strong>[1229006-21-6]1-[2,2-bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid methyl ester</strong> 25 (11.6 g) was treated with 90% formic acid (250 mL) at 40 C. for 12 hours (monitored by LC-MS). After the solvents were evaporated at <40 C., the residue was re-dissolved in EtOAc (1 L) and the resulting solution was washed with NaHCO3 and brine. The organic phase was then dried over Na2SO4. After evaporation of solvents, the titled compounds 26 and 27 were obtained as an approximate 80/20 equilibrium mixture (10.57 g).
A 62% aqueous sulfuric acid solution (306 mg, 1.9 mmol) was added to a toluene (2.7 mL)-formic acid (6.7 mL) solution of compound 13C (666 mg, 1.3 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After the completion of reaction, the solution was cooled to 5C and neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (37.0 g), followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure. Then, toluene (6.7 mL) was added to the obtained residue, and methanol (124 mg, 3.9 mmol), (R)-3-amino-butan-1-ol (138 mg, 1.6 mmol), and acetic acid (85 mg, 1.4 mmol) were further added dropwise thereto in this order at room temperature. The mixture was heated to 90C, stirred for 2 hours, and then allowed to cool to room temperature. Then, water (7 mL) was added thereto, followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure, and toluene was added to the residue. Then, the solvent was distilled off under reduced pressure to bring the contents to approximately 4.0 g. The residue was concentrated and crystalized. The obtained yellow slurry solution was filtered to obtain 429 mg (yield: 65%) of compound 12D as pale yellow crystals.
<strong>[72235-52-0]2,4-difluorobenzylamine</strong> (209 mg, 1.4 mmol) and acetic acid (88 mg, 1.4 mmol) were added to a toluene (5.4 mL) suspension of compound 12B (539 mg, 1.3 mmol) at room temperature, and the mixture was then heated to 90C and stirred for 7 hours. After the completion of reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate = 3 : 7 (v/v)) to obtain 666 mg (yield: 97%) of compound 13C as a pale yellow oil. 1H-NMR (CDCl3) delta: 3.37 (6H, s), 3.79 (3H, s), 4.01 (2H, d, J = 5.0 Hz), 4.47 (1H, t, J = 5.0 Hz), 4.65 (2H, d, J = 6.0 Hz), 5.26 (2H, s), 6.78-6.86 (2H, m), 7.30-7.42 (6H, m), 8.42 (1H, s), 10.41 (1H, t, J = 6.0 Hz).
Example 2e Methyl 5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate (in equilibrium with the corresponding aldehyde) Methyl 1-[2,2-bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 25 (11.6 g) was treated with 90% formic acid (250 mL) at 40 C. for ?12 hours (monitored by LC-MS). After the solvents were evaporated at <40 C., the residue was re-dissolved in EtOAc (?1 L) and the resulting solution was washed with NaHCO3 and brine. The organic phase was then dried over Na2SO4. After evaporation of solvents, the titled compounds 26 and 27 were obtained as an approximate 80/20 equillibrium mixture (10.57 g). 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.3 (m, 1H), 9.47 (s, aldehyde-H. ?0.2H)), 8.4 (m, 1H), 7.3 (s, 6H), 7.2 (m, 1H), 7.0 (m, 1H), 6.3 (m, 2H), 5.1 (s, 3H), 4.9 (m, 1H), 4.5 (m, 3H), 3.9 (m, 2H), 3.8 (s, 3H). LC-MS, for 26 (M+H+), calcd 503, obsd 503; for 27 (M+H2O+H+), cald 489, obsd 489.
Example 2d Methyl 1-[2,2-bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate A pressure vessel was charged with methyl 1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 24 (6.4 g, 15 mmol), 2,4-difluorobenzylamine (3.2 g, 22.5 mmol), K3PO4 (9.45 g, 45 mmol), Pd(OCOCF3)2 (398 mg, 1.2 mmol), Xantophos (694 mg, 1.2 mmol) and toluene (200 mL). The mixture was purged by CO (4*) before being heated to 100 C. for 22 hours under CO atmosphere (60 psi). After cooled down to the room temperature, the solids were filtered off through celite and washed with EtOAc. The filtrate was concentrated and the residual was purified by column chromatography (silical gel, EtOAc/hexane 0-80%) to afford methyl 1-[2,2-bis(methyloxy)ethyl]-5-([(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 25 as a light brown oil (4.7 g, 61%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.4 (m, 1H), 8.4 (s, 1H), 7.4 (m, 6H), 6.8 (d, J=9.3 Hz, 2H), 5.3 (s, 2H), 4.6 (d, J=5.7 Hz, 2H), 4.5 (s, 1H), 4.0 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calcd 517, obsd 517.
(4R,12aS)-N-(5-benzyl-2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide[ No CAS ]
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