* 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 hydrogen bromide; bromine; sodium nitrite In water at 0 - 10℃; for 1.5 h;
Bromine (26 ml, 0.52 mol)was added to a solution of 2-amino-5-chloropyridine (2)(25.6 g, 0.2 mol) in 48percent HBr solution (100 ml, 1.2 mol),while maintaining the temperature at solution of sodium nitrite (32.4 g, 0.47 mol) in water(50 ml) was added over 1 h at the same temperature. Afterthe addition was complete, the reaction mixture was stirredfor additional 30 min and then treated with a solution ofNaOH (74.6 g, 1.86 mol) in water (100 ml) at such a ratethat the temperature did not exceed 20–25°C. The obtainedprecipitate was filtered off, washed with a saturatedsolution of NaHSO3 (~5 ml), several times with ice water(3×30 ml), and air-dried. Yield 35.6 g (93percent), beige powder,mp 67–68° (hexane) (mp 68–69°10). Rf -0.4 (CHCl3).1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.44 (1H, d,J = 8.4, H-3); 7.54 (1, dd, J = 8.4, J = 2.6, H-4); 8.35(1H, d, J = 2.6, H-6). 13C NMR spectrum (CDCl3), δ, ppm:128.7; 131.5; 138.1; 139.2; 148.6.
91%
Stage #1: With hydrogen bromide; bromine; sodium nitrite In water at 0℃; for 1 h; Stage #2: With sodium hydroxide In water; ethyl acetate
[Referential Example 25] 5-(5-Chloro-2-pyridyl)-1-(3-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] 1) 2-Bromo-5-chloropyridine Bromine (12 ml) was added to a solution of 2-amino-5-chloropyridine (5g) in 47percent hydrobromic acid (50 ml) at 0°C, and a solution of sodium nitrite (15 g) in water (20 ml) was added dropwise to this reaction liquid. After stirring the mixture for 1 hour, a solution of sodium hydroxide (32 g) in water (80 ml) and ethyl acetate to the reaction liquid, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 2-bromo-5-chloropyridine (6.8 g, 91percent) as a solid. 1H-NMR (400 MHz, CDCl3)δ: 7.44 (1H, d, J = 8.42 Hz), 7.54 (1H, m), 8.36 (1H, s).
91%
With hydrogen bromide; bromine; sodium nitrite In water at 0℃; for 1 h;
1) 2-Bromo-5-chloropyridine At 0°C, bromine (12 mL) was added to 2-amino-5-chloropyridine (5 g) in 47percent hydrobromic acid (50 mL), and then sodium nitrite (15 g) in water (20 mL) was added dropwise to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was partitioned between sodium hydroxide (32 g) in water (80 mL) and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, to thereby give 2-bromo-5-chloropyridine as a solid product (6.8 g, 91percent). 1H-NMR(400MHz,CDCl3)δ:7.44(1H,d,J=8.42Hz), 7.54(1H,m), 8.36(1H,s).
87%
With bromine; sodium nitrite In water; hydrogen bromide
(1) 2-Bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (15.0 g) in 47percent hydrobromic acid (18 ml) was gradually added dropwise bromine (18 ml) under ice-cooling. After the dropwise addition, a solution of sodium nitrite (20.1 g) in water (100 ml) was gradually added dropwise under ice-cooling, and the mixture was stirred for 1 hour. The solution was adjusted to pH 8 with a 5N aqueous sodium hydroxide solution and extracted with ether, washed with an aqueous sodium nitrite solution and water, and dried over magnesium sulfate. The solvent was distilled away under reduced pressure to give 19.5 g of a pale-brown solid (yield 87percent). IR (KBr): 3000, 1550 cm-1 1 H-NMR (CDCl3) δ: 7.43(1H, d, J=8.0 Hz), 7.54(1H, dd, J=8.0, 3.0 Hz), 8.35(1H, d, J=3.0 Hz)
85%
With hydrogen bromide; bromine; sodium nitrite In water at -5 - 15℃;
2-Amino-5-chloropyridine (3.86 g, 30.0 mmol) was dissolved in 48percent HBr (50 mL). To this solution was added bromine (4.61 mL), while the inside temperature was kept from -5 °C to 0 °C. After water (25 mL) containing sodium nitrite (5.18 g, 75.0 mmol) was slowly added to the mixture, inside temperature was slowly raised to 15 °C while stirring the mixture for 3 h. To the solution were added 5 M NaOH aqueous solution (150 mL), sodium thiosulfate aqueous solution (10 mL) and Et2O (150 mL). Organic layer was separated, washed with brine and dried over Na2SO4. Solvent was distilled off in vacuo to obtain the title compound (4.90 g, 25.5 mmol, 85percent) as a yellow solid. 1H NMR (CDCl3) δ: 7.44 (1H, dd, J = 8.5, 0.7 Hz), 7.53 (1H, dd, J = 8.3, 2.7 Hz), 8.35 (1H, dd, J = 2.7, 0.7 Hz).
Reference：
[1] Chemistry of Heterocyclic Compounds, 2017, vol. 53, # 2, p. 196 - 206[2] Khim. Geterotsikl. Soedin., 2017, vol. 53, # 2, p. 196 - 206,11
[3] Patent: EP1698626, 2006, A1, . Location in patent: Page/Page column 41
[4] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 24-25
[5] Patent: US5750545, 1998, A,
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642
[7] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[8] Patent: WO2005/99711, 2005, A1, . Location in patent: Page/Page column 22; 41-42
[9] Patent: US4457927, 1984, A,
[10] Patent: WO2005/100349, 2005, A2, . Location in patent: Page/Page column 49-50
[11] Patent: US2005/239800, 2005, A1, . Location in patent: Page/Page column 10; 19
[12] Patent: US2009/253708, 2009, A1, . Location in patent: Page/Page column 11-12
2
[ 1072-98-6 ]
[ 40473-01-6 ]
[ 2516-40-7 ]
Reference：
[1] Patent: US4510148, 1985, A,
3
[ 16110-09-1 ]
[ 40473-01-6 ]
Reference：
[1] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Inert atmosphere Stage #2: for 2 h;
Compound 17 (4.54 g, 23.6 mmol) was suspended in dried Et2O (100 mL) under argon atmosphere. To the suspension was added 1.54 M n-butyllithium solution in hexane (16.9 mL, 26.0 mmol) at -78 °C, and the mixture was stirred for 2 h to obtain a brown solution. Carbon dioxide gas (ca. 2 L) was blown into the solution, and the mixture was stirred for 2 h. After warming to room temperature, the solvent was distilled off in vacuo. Obtained brown solid was washed with hexane and suspended in water (50 mL). After 1 M HCl (30 mL) was added to this suspension, the mixture was concentrated in vacuo. Obtained yellow solid was washed with Et2O to obtain the title compound (358 mg, 2.27 mmol, 9.6percent) as a yellow solid. 1H NMR (DMSO-d6) δ: 8.05 (2H, d, J = 8.4 Hz), 8.12 (1H, dd, J = 8.4, 2.3 Hz), 8.76 (1H, d, J = 2.3 Hz). ESI-MS m/z: 158 [(M+H)+, 35Cl], 160 [(M+H)+, 37Cl].
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1623 - 1642
7
[ 1072-98-6 ]
[ 40473-01-6 ]
[ 2516-40-7 ]
Reference：
[1] Patent: US4510148, 1985, A,
8
[ 40473-01-6 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 132308-19-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 50℃; for 24 h;
To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3 H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
Intermediate 1 : methyl δ-chloro^-pyridinecarboxylateTo a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent): 1H NMR (400 MHz, CDCI3) δ ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
at 50℃; for 24 h;
I. methyl 5-chloro-2-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 50°C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue over silica gel, by using 10: 1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93percent yield): 1H NMR (400 MHz, CDC13) δ ppm 8.60 (d, J = 1.60 Hz, 1H), 8.01 (d, J= 8.40 Ηζ,ΙΗ), 7.75 (dd, J = 8.40, 2.40 Hz, 1H), 3.92 (s, 3H).
Stage #1: With acetyl chloride; sodium iodide In acetonitrile for 3 h; Heating / reflux Stage #2: With potassium carbonate In water; acetonitrile at 0℃;
Preparation 1 5-Chloro-2-iodopyridineAcetyl chloride (11.05 ml_, 0.155 mol) was added to a solution of 2-bromo-5-chloropyridine (20.0 g, 0.103 mol) in acetonitrile (120 ml.) followed by sodium iodide (23.3 g, 0.155 mol) and the mixture was heated at reflux with a drying tube fitted for 3 hours. The reaction was cooled in an ice bath, carefully basified with saturated aqueous potassium carbonate then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (200 mL), dried (MgSO4) and evaporated. The residue was then re-submitted to identical reaction and work-up conditions in order to ensure complete reaction and this gave the title compound (18.71 g, 75percent) as a brown solid. 1H NMR (CDCI3, 400 MHz) δ 7.30 (1H, dd), 7.65 (1H, d), 8.35 (1H, d); LRMS (APCI+) 240 [MH+].
75%
Stage #1: With acetyl chloride; sodium iodide In acetonitrile for 6 h; Heating / reflux Stage #2: With potassium carbonate In water; acetonitrile at 0℃;
Preparation 60; 5-Chloro-2-iodopyridine; Acetyl chloride (11.05 mL, 0.155 mol) was adde Xd to? a solution of 2-bromo-5-chloropyridine (20.0 g, 0.103 mol) in acetonitrile (120 mL) followed by sodium iodide (23.3 g, 0.155 mol) and the mixture was heated at reflux with a drying tube fitted for 3 hours. The reaction was cooled in an ice bath, carefully basified with saturated aqueous potassium carbonate then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (200 mL), dried (MgSO4) and evaporated. The residue was then re-submitted to identical reaction and work-up conditions in order to ensure complete reaction and this gave the title compound (18.71 g, 75percent) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 7.30 (1 H, dd), 7.65 (1 H, d), 8.35 (1 H, d); LRMS (APCI+) 240 [MH+].
Stage #1: With sec.-butyllithium In diethyl ether; hexane at -60℃; for 2 h; Stage #2: for 3 h; Stage #3: With hydrogenchloride; water In diethyl ether; hexane
2-Bromo-5-chloropyridine (5.8g, 30mmol) was added to dry diethyl ether (100ml). The mixture was cooled to-60°C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2hrs. A solution of N, N- dimethylacetamide (3. 1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgS04 and evaporated to give 1- (5-Chloro-pyridin-2-yl)-ethanone (4. 0g, 85percent).
59%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; Stage #2: for 0.5 h;
2) 1-(5-chloro-2-pyridyl)ethanone; A 1.56M solution of n-butyllithium in hexane (27 ml) was added dropwise to a solution of the 2-bromo-5-chloropyridine (6.8 g) in diethylether (45 ml) at-78°C, and thereafter, N,N-dimethyl acetamide (5 ml) was added dropwise to the solution. The mixture was stirred for 30 minutes. To the reaction liquid was added saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(5-chloro-2-pyridyl)ethanone (3.26 g, 59percent) as a solid. 1H-NMR (400 MHz, CDCl3)δ: 2.70 (3H, s), 7.80 (1H, dd, J = 8.42, 2.32 Hz), 8.00 (1H, d, J = 8.42 Hz), 8.62 (1H, d, J = 2.32 Hz).
59%
With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
2) 1-(5-Chloro-2-pyridyl)ethanone At -78°C, n-butyllithium (1.56M hexane solution, 27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise to the resultant mixture, followed by stirring for 30 minutes. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. Ethyl acetate was added for partitioning the resultant mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid product (3.26 g, 59percent). 1H-NMR(400MHz,CDCl3)δ:2.70(3H,s), 7.80(1H,dd,J=8.42,2.32Hz), 8.00(1H,d,J=8.42Hz), 8.62(1H,d,J=2.32Hz).
With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 10℃; for 1.5h;
Bromine (26 ml, 0.52 mol)was added to a solution of 2-amino-5-chloropyridine (2)(25.6 g, 0.2 mol) in 48% HBr solution (100 ml, 1.2 mol),while maintaining the temperature at solution of sodium nitrite (32.4 g, 0.47 mol) in water(50 ml) was added over 1 h at the same temperature. Afterthe addition was complete, the reaction mixture was stirredfor additional 30 min and then treated with a solution ofNaOH (74.6 g, 1.86 mol) in water (100 ml) at such a ratethat the temperature did not exceed 20-25C. The obtainedprecipitate was filtered off, washed with a saturatedsolution of NaHSO3 (~5 ml), several times with ice water(3×30 ml), and air-dried. Yield 35.6 g (93%), beige powder,mp 67-68 (hexane) (mp 68-6910). Rf -0.4 (CHCl3).1H NMR spectrum (CDCl3), delta, ppm (J, Hz): 7.44 (1H, d,J = 8.4, H-3); 7.54 (1, dd, J = 8.4, J = 2.6, H-4); 8.35(1H, d, J = 2.6, H-6). 13C NMR spectrum (CDCl3), delta, ppm:128.7; 131.5; 138.1; 139.2; 148.6.
91%
[Referential Example 25] 5-(5-Chloro-2-pyridyl)-1-(3-pyridyl)-1H-pyrazole-3-carboxylic acid; [Show Image] 1) 2-Bromo-5-chloropyridine Bromine (12 ml) was added to a solution of 2-amino-5-chloropyridine (5g) in 47% hydrobromic acid (50 ml) at 0C, and a solution of sodium nitrite (15 g) in water (20 ml) was added dropwise to this reaction liquid. After stirring the mixture for 1 hour, a solution of sodium hydroxide (32 g) in water (80 ml) and ethyl acetate to the reaction liquid, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 2-bromo-5-chloropyridine (6.8 g, 91%) as a solid. 1H-NMR (400 MHz, CDCl3)delta: 7.44 (1H, d, J = 8.42 Hz), 7.54 (1H, m), 8.36 (1H, s).
91%
With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 1h;
1) 2-Bromo-5-chloropyridine At 0C, bromine (12 mL) was added to 2-amino-5-chloropyridine (5 g) in 47% hydrobromic acid (50 mL), and then sodium nitrite (15 g) in water (20 mL) was added dropwise to the reaction mixture, followed by stirring for 1 hour. The reaction mixture was partitioned between sodium hydroxide (32 g) in water (80 mL) and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, to thereby give 2-bromo-5-chloropyridine as a solid product (6.8 g, 91%). 1H-NMR(400MHz,CDCl3)delta:7.44(1H,d,J=8.42Hz), 7.54(1H,m), 8.36(1H,s).
87%
With bromine; sodium nitrite; In water; hydrogen bromide;
(1) 2-Bromo-5-chloropyridine To a solution of 2-amino-5-chloropyridine (15.0 g) in 47% hydrobromic acid (18 ml) was gradually added dropwise bromine (18 ml) under ice-cooling. After the dropwise addition, a solution of sodium nitrite (20.1 g) in water (100 ml) was gradually added dropwise under ice-cooling, and the mixture was stirred for 1 hour. The solution was adjusted to pH 8 with a 5N aqueous sodium hydroxide solution and extracted with ether, washed with an aqueous sodium nitrite solution and water, and dried over magnesium sulfate. The solvent was distilled away under reduced pressure to give 19.5 g of a pale-brown solid (yield 87%). IR (KBr): 3000, 1550 cm-1 1 H-NMR (CDCl3) delta: 7.43(1H, d, J=8.0 Hz), 7.54(1H, dd, J=8.0, 3.0 Hz), 8.35(1H, d, J=3.0 Hz)
85%
With hydrogen bromide; bromine; sodium nitrite; In water; at -5 - 15℃;
2-Amino-5-chloropyridine (3.86 g, 30.0 mmol) was dissolved in 48% HBr (50 mL). To this solution was added bromine (4.61 mL), while the inside temperature was kept from -5 C to 0 C. After water (25 mL) containing sodium nitrite (5.18 g, 75.0 mmol) was slowly added to the mixture, inside temperature was slowly raised to 15 C while stirring the mixture for 3 h. To the solution were added 5 M NaOH aqueous solution (150 mL), sodium thiosulfate aqueous solution (10 mL) and Et2O (150 mL). Organic layer was separated, washed with brine and dried over Na2SO4. Solvent was distilled off in vacuo to obtain the title compound (4.90 g, 25.5 mmol, 85%) as a yellow solid. 1H NMR (CDCl3) delta: 7.44 (1H, dd, J = 8.5, 0.7 Hz), 7.53 (1H, dd, J = 8.3, 2.7 Hz), 8.35 (1H, dd, J = 2.7, 0.7 Hz).
To a solution of 30.7 mmol of 11 and 5 mL of bromine in 48 mL of hydrobromic acid (48%) at 0 C was added 24 mL (25 M) of aqueous NaN02. The mixture was stirred for 1 h at rt before it was neutralized by 145 mL of 3M NaOH. The aqueous solution was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over MgS04, and concentrated under a reduced pressure. The crude product was purified by column chromatography to give 24.6 mmol of 12. 7.2 Results [0206] Analytical data for exemplary compounds of structure 12 are provided below. 7.2.a 2-Bromo-5-chloro-pyridine [0207] ¹H NMR (300 MHz, DMSO-d6) No. 8.47 (d, J = 2.8 Hz, 1H), 7.89 (dd, J1 = 8.5 Hz, J2 = 2.7 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H) ; MS m/z: 192 (M + 1). 7.2. b 2-Bromo-5-(4- uoro phenyl)-pyridine [0208] ¹H NMR (300 MHz, DMSO-d6) 8 8.68 (d, J = 2.4 Hz, 1H), 8.03 (dd, J1 = 8.3 Hz, J2 = 2.6 Hz, 1H), 7.80-7.70 (m, 3H), 7.34 (d, J = 6.6 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H); MS m/z: 252 (M + 1).
With sodium hydroxide; hydrogen bromide; bromine; sodium nitrite; In ethanol; water;
(b) The starting material 2-bromo-5-chloropyridine is prepared analogously to methods know from the literature as follows: 17 ml. of bromine is added to a solution of 14 g. of 2-amino-5-chloropyridine in 30 ml. of water and 45 ml. of hydrobromic acid (63% in water); the mixture is cooled to 0. Under temperature control, a solution of 21 g. of sodium nitrite in 30 ml. of water is added dropwise at such a rate that the temperature of the mixture does not exceed 5. Thereafter, the mixture is combined under cooling with a solution of 45 g. of sodium hydroxide in 115 ml. of water. The thus-precipitated crystals are vacuum-filtered, washed with water, and recrystallized first from acetone and then once again from ethanol. Yield: 10 g. of 2-bromo-5-chloropyridine, m.p. 68.
With hydrogen bromide; bromine; sodium nitrite; In water; at 0℃; for 1h;
To a solution of 30.7 mmol of 2 and 5 mL of bromine in 48 mL of hydrobromic acid (48%) at 0 C was added 24 mL (25 M) of aqueous NaN02. The mixture was stirred for 1 h at rt before it was neutralized by 145 mL of 3M NaOH. The aqueous solution was extracted with ethyl acetate. and the organic phase was washed with saturated NaCl, dried over MgS04, and concentrated under a reduced pressure. The crude product was purified by column chromatography to give 24.6 mmol of 12. ¹H NMR (300 MHz, DMSO-d6) No. 8.47 (d, J = 2.8 Hz, 1H), 7.89 (dd, Jl = 8.5 Hz, J2 = 2.7 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H); MS m/z: 192 (M + 1).
To a solution of 30.7 mmol of 11 and 5 mL of bromine in 48 mL of hydrobromic acid (48%) at 0 C. was added 24 mL (25 M) of aqueous NaNO2. The mixture was stirred for 1 h at rt before it was neutralized by 145 mL of 3M NaOH. The aqueous solution was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl, dried over MgSO4, and concentrated under a reduced pressure. The crude product was purified by column chromatography to give 24.6 mmol of 12. 7.2.a 2-Bromo-5-chloro-pyridine 1H NMR (300 MHz, DMSO-d6) delta 8.47 (d, J=2.8 Hz, 1H), 7.89 (dd, J=8.5 Hz, J2=2.7 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H); MS m/z: 192 (M+1).
A. 2-Bromo-5-chloropyridine A 1000 mL three necked round bottomed flask was fitted with an air driven stirrer, a thermometer, and an addition funnel. The addition funnel was capped with an inlet adapter connected to a one liter suck back trap which was vented to two scrubbing traps with 7% sodium sulfite solution. The flask was charged with 280 mL of concentrated HBr (48%). 2-Amino-5-chloropyridine (42.4 grams, 329 mmol) was added in small portions at such a rate that the temperature did not exceed 28 C. An ice/salt bath was used to cool the reaction to 5 C. and bromine (45 ml, d=3.1, g/ml, 87 5 mmol) was added in portions such that the temperature did not exceed 10 C. After five minutes of stirring the temperature was cooled to 5 C. and a solution of sodium nitrite (56.8 grams, 820 mmol) in approximately 130 mL of water was added dropwise over 90 minutes at such a rate that the reaction temperature did not exceed 10 C. Out-gassing of bromine and nitrogen was noted during the addition. The reaction was allowed to stir for one hour at 5-10 C. Then 50% aqueous NaOH (d=1.52 g/ml, about 160 ml) was added drop wise over 90 minutes at such a rate that the reaction temperature did not exceed 10 C. The basic reaction slurry was extracted with 600 mL of ether (some non crystalline solid did not dissolve and was removed with the drying agent by filtration). The ether extract was cooled in an ice water bath and was washed with 200 mL of saturated sodium bisulfite solution until neutral to starch iodide paper. The organic extract was washed with 100 mL of saturated sodium chloride solution, dried with MgSO4, and concentrated under reduced pressure to yield a volatile solid. The water bath was kept below 30 C. during the strip. The product can disappear if dried in a vacuum oven. The yield was 57.2 grams, and the purity was 95% by GC. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 7.20 (d, 1H); 7.80 (d, 1H); 8.45 (s, 1H).
Stage #1: 2-Bromo-5-chloro-pyridine With n-butyllithium In diethyl ether at -78℃; for 1h;
Stage #2: tropinone In diethyl ether
57%
Stage #1: 2-Bromo-5-chloro-pyridine With n-butyllithium In diethyl ether; hexane at -78℃; for 1h;
Stage #2: tropinone In diethyl ether; hexane at -78 - -50℃;
Preparation 1 5-Chloro-2-iodopyridineAcetyl chloride (11.05 ml_, 0.155 mol) was added to a solution of 2-bromo-5-chloropyridine (20.0 g, 0.103 mol) in acetonitrile (120 ml.) followed by sodium iodide (23.3 g, 0.155 mol) and the mixture was heated at reflux with a drying tube fitted for 3 hours. The reaction was cooled in an ice bath, carefully basified with saturated aqueous potassium carbonate then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (200 mL), dried (MgSO4) and evaporated. The residue was then re-submitted to identical reaction and work-up conditions in order to ensure complete reaction and this gave the title compound (18.71 g, 75%) as a brown solid. 1H NMR (CDCI3, 400 MHz) delta 7.30 (1H, dd), 7.65 (1H, d), 8.35 (1H, d); LRMS (APCI+) 240 [MH+].
75%
Preparation 60; 5-Chloro-2-iodopyridine; Acetyl chloride (11.05 mL, 0.155 mol) was adde Xd to? a solution of 2-bromo-5-chloropyridine (20.0 g, 0.103 mol) in acetonitrile (120 mL) followed by sodium iodide (23.3 g, 0.155 mol) and the mixture was heated at reflux with a drying tube fitted for 3 hours. The reaction was cooled in an ice bath, carefully basified with saturated aqueous potassium carbonate then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (200 mL), dried (MgSO4) and evaporated. The residue was then re-submitted to identical reaction and work-up conditions in order to ensure complete reaction and this gave the title compound (18.71 g, 75%) as a brown solid. 1H NMR (CDCl3, 400 MHz) delta 7.30 (1 H, dd), 7.65 (1 H, d), 8.35 (1 H, d); LRMS (APCI+) 240 [MH+].
With chloro-trimethyl-silane; sodium iodide; In acetonitrile;Reflux;
Step A 5-chloro-2-iodopyridine A solution of 2-bromo-5-chloropyridine (1 g, 5.21 mmol, 1.00 equiv) and NaI (2.3 g, 15.33 mmol, 3.00 equiv) in CH3CN (20 mL) in a 100-mL round-bottom flask was treated with chlorotrimethylsilane (570 mg, 5.23 mmol, 1.00 equiv) dropwise with stirring. The reaction mixture was stirred overnight at reflux. The reaction was then quenched by the addition of 50 mL of sodium hydroxide (aq, 2N). The resulting solution was extracted with 2*20 mL of ethyl acetate. The combined organic layers were washed with 50 mL brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography over a silica gel column with ethyl acetate/petroleum ether (1:40) to yield 5-chloro-2-iodopyridine as a yellow solid
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; In N,N-dimethyl-formamide; at 50℃; under 760.051 Torr;
Production Example 2-1 Ethyl 5-chloropyridin-2-carboxylate: Palladium acetate (117 mg), 1,1'-bis(diphenylphosphino)ferrocene (577 mg) and triethylamine (1.4 mL) were added to an ethanol-DMF mixed solvent (1/1, 30 mL) of 2-bromo-5-chloropyridine (1.0 g), and stirred overnight in a carbon monoxide atmosphere (1 atmospheric pressure) at 50C. Ethanol was evaporated off under reduced pressure from the reaction solution, water was added to the resulting residue, and extracted with hexane/ethyl acetate (2/3). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 9/1 to 4/1) to obtain the entitled compound (1.4 g).
With N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); for 4h;Heating / reflux;
A mixture of 2-bromo-5-chloropyridine (4.35 g, 22.6 mmol), ethanol (15 mL), dilsopropylethylamine (5.0 mL, 28.7 mmol), and Pd(PPh3)4 (0.523 g) is heated at reflux under carbon monoxide for 4 h. After cooling, the mixture is concentrated and the residue purified by flash chromatography (7% EtOAc/1% NH4OH in hexane) to give ethyl 5-chloropyridine-2-carboxylate as a solid. 1H NMR (400 MHz, CDCl3) delta8.79, 7.97, 7.70, 4.35, 1.32.
With phosphorus(V) oxybromide; for 16h;Heating / reflux;
A mixture of <strong>[4214-79-3]5-chloro-2-pyridinol</strong> (7.00 g, 54.0 mmol) and phosphorus oxybromide (24.8 g) is stirred for 16 h at reflux. After cooling to rt, 100 mL of water is added and the mixture extracted with CH2Cl2, the organic layers dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (biotage; 10percent EtOAc/10percent CH2Cl2/1percent NH4OH in hexane) to give 2-bromo-5-chloropyridine. 1H NMR (400 MHz, CDCl3) delta8.40, 7.57, 7.48.
With hexamethyldistannane;Pd(PPh3)4; In hexane; dichloromethane; chloroform; ethyl acetate;
3-(5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile Pd(PPh3)4 (5 mg, 0.004 mmol) was added to a solution of hexamethylditin (160 mg, 0.49 mmol) and <strong>[40473-01-6]5-chloro-2-bromopyridine</strong> (76 mg, 0.395 mmol) in toulene (1 mL) under argon. The resulting solution was stirred at 80 C. for 16 h. After cooling to room temperature, a second portion of Pd(PPh3)4 (20 mg, 0.019 mmol) and 3-(5-bromofuran-2-yl)-benzonitrile (79 mg, 0.32 mmol) were added and the resulting solution was stirred at 110 C. for 14 h. After cooling to room temperature, the solvent was removed in vacuo. Chromatography (5g silica gel SPE tube, 25-50% chloroform in hexane to 2% ethyl acetate in 1:1 chloroform:hexane) followed by triturating with hexanes and purification by preparative TLC (90% dichloromethane in hexane) afforded 15.7 mg (17%) of 3-(5-(5-choro-2-pyridyl)-2-furyl)-benzonitrile (97.5% pure by GC/MS, contaminated with 2.5% dimer). 1H-NMR (CDCl3), delta (ppm): 8.55 (d, 1H), 8.03 (s, 1H), 7.94 (dd, 1H), 7.73 (s, 2H), 7.54 (m, 12), 7.16 (d, 1H), 6.88 (d, 1H).
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; diethyl ether; hexane; N,N-dimethyl acetamide; water;
a 2-Acetyl-5-chloropyridine To a suspension of 56 g of 2-bromo-5-chloropyridine in 560 ml of dry diethylether is added a solution of 179 ml of n-butyllithium (15% solution in hexane) at -78 and under argon at such a rate that the temperature never exceeds -72. Immediately thereafter the solution of 25.7 ml of N,N-dimethylacetamide in dry THF is added. The mixture is stirred for one hour at the same temperature and thereafter decomposed by careful addition of 100 ml of 3N hydrochloric acid, followed by 100 ml of water with vigorous cooling. Working up by process A (see Example 1) and purification by chromatogrphy over silica gel (toluene/ethyl acetate=20/1) yields the compound as white needles; m.p.: 58-65.
N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With water; sodium carbonate;C72H59P4PdPol; In 1,4-dioxane; at 90℃; for 3h;
Example31:A/-r(2S)-5-(5-chloro-2-pyridinvn-2.3-dihvdro-1H-inden-2-vl1-2-propanesulfonamideTo a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (1 g, 2.74 mmol) in dry 1,4 dioxane (15 ml), polymer supported Pd(PPh3)4 (54 mg, 0.5 mmol/g, 0.027 mmol) was added along with <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1.05 g, 5.48 mmol) and 3.5 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90 degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCI and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 682 mg of title compound were recovered as whitish solid (71%). Due to the use of chiral Intermediate 7, the final compound is believed to be A/-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.Mass spectrum (ES): Found 351 (MH+), C-i/H 1935(^2028 requires 350; 1H-NMR (500MHz, DMSO-d6): 1.25 (6H, d, J=7Hz), 2.90 (2H, m), 3.24 (3H, m), 4.14 (1H, m), 7.31 (1H, d, J=8Hz), 7.46 (1H, d, J=8Hz), 7.86 (1H, m), 7.90 (1H, m), 7.96 (2H, m), 8.66 (1H,m)
71%
With sodium carbonate;polymer supported Pd(PPh3)4; In 1,4-dioxane; water; at 90℃; for 3h;
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (1 g, 2.74 mmol) in dry 1,4 dioxane (15 ml), polymer supported Pd(PPh3)4 (54 mg, 0.5 mmol/g, 0.027 mmol) was added along with <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1.05 g, 5.48 mmol) and 3.5 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90 degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 682 mg of title compound were recovered as whitish solid (71%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.Mass spectrum (ES): Found 351 (MH+), C17H1935ClN2O2S requires 350; 1H-NMR (500 MHz, DMSO-d6): 1.25 (6H, d, J=7 Hz), 2.90 (2H, m), 3.24 (3H, m), 4.14 (1H, m), 7.31 (1H, d, J=8 Hz), 7.46 (1H, d, J=8 Hz), 7.86 (1H, m), 7.90 (1H, m), 7.96 (2H, m), 8.66 (1H, m)
PREPARATION 3 Preparation of 2-bromobenzothiazole 2-Bromo-5-chloropyridine was prepared from 2-amino-5-chloropyridine according to the method of L. C. Craig, J. Amer. Chem. Soc., 1934, 56, 231, to furnish a white crystalline solid in 70percent yield, m.p. 69°-70° C.
2-Bromo-5-chloropyridine (5.8g, 30mmol) was added to dry diethyl ether (100ml). The mixture was cooled to-60C and a solution of sec-BuLi (1.4M solution in hexanes, 22mL) was added dropwise and the mixture was stirred for 2hrs. A solution of N, N- dimethylacetamide (3. 1ml, 33mmol) in diethyl ether (20ml) was added slowly dropwise and the solution left to stir for 3hrs. The reaction was brought to room temperature, hydrolysed with 2N HC1 and extracted with DCM. The organic phase was washed with water, dried over MgS04 and evaporated to give 1- (5-Chloro-pyridin-2-yl)-ethanone (4. 0g, 85%).
59%
2) 1-(5-chloro-2-pyridyl)ethanone; A 1.56M solution of n-butyllithium in hexane (27 ml) was added dropwise to a solution of the 2-bromo-5-chloropyridine (6.8 g) in diethylether (45 ml) at-78C, and thereafter, N,N-dimethyl acetamide (5 ml) was added dropwise to the solution. The mixture was stirred for 30 minutes. To the reaction liquid was added saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 1-(5-chloro-2-pyridyl)ethanone (3.26 g, 59%) as a solid. 1H-NMR (400 MHz, CDCl3)delta: 2.70 (3H, s), 7.80 (1H, dd, J = 8.42, 2.32 Hz), 8.00 (1H, d, J = 8.42 Hz), 8.62 (1H, d, J = 2.32 Hz).
59%
With n-butyllithium; In diethyl ether; hexane; at -78℃; for 0.5h;
2) 1-(5-Chloro-2-pyridyl)ethanone At -78C, n-butyllithium (1.56M hexane solution, 27 mL) was added dropwise to 2-bromo-5-chloropyridine (6.8 g) in diethyl ether (45 mL), and then N,N-dimethylacetamide (5 mL) was added dropwise to the resultant mixture, followed by stirring for 30 minutes. Subsequently, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. Ethyl acetate was added for partitioning the resultant mixture. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 1-(5-chloro-2-pyridyl)ethanone as a solid product (3.26 g, 59%). 1H-NMR(400MHz,CDCl3)delta:2.70(3H,s), 7.80(1H,dd,J=8.42,2.32Hz), 8.00(1H,d,J=8.42Hz), 8.62(1H,d,J=2.32Hz).
B. 2-Acetyl-5-chloropyridine A two liter 4 neck flask was equipped with an overhead air-driven stirrer, a low temperature thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of s-butyllithium (222 ml, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-4-chloropyridine (57.72 g; 0.30 mol) and 600 mL of anhydrous ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76 C. The s-butyllithium was added dropwise at a rate to maintain the temperature at -74 C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of anhydrous ether, then charged with 30.7 mL of dimethylacetamide (0.330 mol) and 30 mL of anhydrous ether. Ten minutes after the completion of the s-butyllithium addition, the dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74 C. or less. This addition took about 40 minutes. The reaction mixture was held at -76 C. for one hour after the dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30 C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature. The ether layer was separated, washed with water and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in methylene chloride, slurried with one weight equivalent of silica gel, filtered through celite and concentrated under reduced pressure. The resultant solid was an orange color. The product was recrystallized from hexane to give 29.35 g of product as an orange/tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.70 (s, 3H); 7.85 (d, 1H); 7.95 (d, 1H); 8.63 (s, 1H).
To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at -5 C. was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at -5 C. The sol. was allowed to cool to -70 C., and a sol. of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (25.0 g, 130 mmol) in THF (100 mL) was added dropwise at -70 C. over 15 min such that the internal temperature did not exceed -65 C. The mixture was stirred at -70 C. for 30 min. DMF (10.52 mL, 136 mmol) was added dropwise over 20 min such that the internal temperature did not exceed -70 C. The orange mixture was stirred at -70 C. for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. 1M NaOH (50 mL). The mixture was extracted with EtOAc (2×), and the combined org. extracts were washed back with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9?1:8?1:6?1:4?1:2?1:1) yielded the title compound (21.55 g, 72%). LC-MS: tR=0.74 min; ES+: 295.01.
72%
To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at -5 C. was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at -5 C. The sol. was allowed to cool to -70 C., and a sol. of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (25.0 g, 130 mmol) in THF (100 mL) was added dropwise at -70 C. over 15 min, such that the internal temperature did not exceed -65 C. The mixture was stirred at -70 C. for 30 min. DMF (10.52 mL, 136 mmol) was added dropwise over 20 min such that the internal temperature did not exceed -70 C. The orange mixture was stirred at -70 C. for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. 1M NaOH (50 mL). The mixture was extracted with EtOAc (2×), and the combined org. extracts were washed back with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9?1:8?1:6?1:4?1:2?1:1) yielded the title compound (21.55 g, 72%). LC-MS: tR=0.74 min; ES+: 295.01.
72%
<strong>[40473-01-6]2-Bromo-5-chloro-pyridine</strong>-4-carbaldehyde To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at -5 C. was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at -5 C. The sol. was allowed to cool to -70 C., and a sol. of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (25.0 g, 130 mmol) in THF (100 mL) was added dropwise at -70 C. over 15 min such as the internal temperature did not exceed -65 C. The mixture was stirred at -70 C. for 30 min. DMF (10.5 mL, 136 mmol) was added dropwise over 20 min at such a rate that the internal temperature did not exceed -70 C. The orange mixture was stirred at -70 C. for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. 1M NaOH (50 mL). The mixture was extracted with EtOAc (2*), and the combined org. extracts were washed back with aq. 1M NaOH (2*). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9?1:8?1:6?1:4?1:2?1:1) yielded the title compound (21.6 g, 72%). LC-MS: tR=0.74 min; ES+: 295.01.
72%
<strong>[40473-01-6]2-Bromo-5-chloro-pyridine</strong>-4-carbaldehyde. To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at -5 0C was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at -5 0C. The sol. was allowed to cool to -70 0C, and a sol. of 2- bromo-5-chloropyridine (25.0 g, 130 mmol) in THF ( 100 mL) was added dropwise at -70 0C over 15 min such as the internal temperature did not exceed -65 0C. The mixture was stirred at -70 0C for 30 min. DMF (10.5 mL, 136 mmol) was added dropwise over 20 min <n="46"/>at such a rate that the internal temperature did not exceed -70 0C. The orange mixture was stirred at -70 0C for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. IM NaOH (50 mL). The mixture was extracted with EtOAc (2x), and the combined org. extracts were washed back with aq. IM NaOH (2x). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 1 :9 - > 1 :8 - > 1 :6 ? 1 :4 ? 1 :2 ? 1 :1) yielded the title compound (21.6 g, 72 %). LC-MS: tR = 0.74 min; ES+: 295.01.
a) 5-Chloro-pyridine-2-carbaldehyde To a solution of 2-bromo-5-chloropyridine (14.8 g, 77 mmol) in THF (38.5 mL) was added dropwise a a solution of i-PrMgCl.LiCl (14% in THF, 81 mL, 85 mmol) at 0-5 C. and the resulting mixture stirred at 0 C. for 1 h. Then DMF (7.7 mL, 100 mmol) was added dropwise at -5 C. and the temperature maintained at 0 C. for 2 h. The reaction mixture was then poured into ice cold saturated brine (500 mL) and then extracted with ethylacetate (2*300 mL). The combined organic layers were washed with saturated sodiumhydrogencarbonate solution, brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:0 to 9:1) afforded the title compound (6.24 g, 57%) which was obtained as a brown solid. MS: m/e=141.0 [M]+.
With triethylamine;palladium diacetate; 1,1'-bis(diphenylphosphino)ferrocene; at 50℃; under 775.743 Torr; for 24h;
To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3 H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With triethylamine;1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; at 50℃; under 775.743 Torr; for 24h;
Intermediate 1 : methyl delta-chloro^-pyridinecarboxylateTo a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 ml.) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 ml_, 312 mmol). The resulting mixture was stirred at 500C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 ml.) and water (300 ml_). The combined organic layers were dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, by using 10:1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93%): 1H NMR (400 MHz, CDCI3) delta ppm 8.60 (d, J = 1.60 Hz, 1 H), 8.01 (d, J = 8.40 Hz, 1 H), 7.75 (dd, J = 8.40, 2.40 Hz, 1 H), 3.92 (s, 3H).
93%
With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; triethylamine; at 50℃; under 775.743 Torr; for 24h;
I. methyl 5-chloro-2-pyridinecarboxylate To a solution of 2-bromo-5-chloropyridine (30.0 g, 155.9 mmol) in MeOH (280 mL) was added Pd(OAc)2 (3.5 g, 10.8 mmol), dppf (17.3 g, 37.96 mmol), Et3N (42.0 mL, 312 mmol). The resulting mixture was stirred at 50C under a CO atmosphere (15 psi) for 24 h, then concentrated under reduced pressure to give crude residue. This residue was partitioned between EtOAc (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SC>4) and evaporated. Flash chromatography of the residue over silica gel, by using 10: 1 petroleum ether/EtOAc, afforded the title compound as a pale yellow solid (25 g, 93% yield): 1H NMR (400 MHz, CDC13) delta ppm 8.60 (d, J = 1.60 Hz, 1H), 8.01 (d, J= 8.40 Etazeta,IotaEta), 7.75 (dd, J = 8.40, 2.40 Hz, 1H), 3.92 (s, 3H).
With diisopropylamine;palladium diacetate; trisodium tris(3-sulfophenyl)phosphine; In water; N,N-dimethyl-formamide; at 80℃; for 1h;
Step C: methyl 3-bromo-5-(5-chloropyridin-2-yl')benzoate; To a solution of methyl 3-bromo-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (0.10 g, 0.29 mmol) in DMF (1.5 mL) and water (0.49 mL) were added <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (0.17 g, 0.88 mmol), palladium(II) aceate (3.3 mg, 0.015 mmol), 3,3'3"-phosphinidynetris(benzenesulfonic acid) trisodium salt (25.0 mg, 0.044 mmol) and diisopropylamine (0.10 mL, 0.73 mmol). The mixture was heated to 80 C. After 1 h, the mixture was filtered and the filtrate was purified by reverse phase chromatography (C-18, 85% <n="177"/>water / acetonitrile ? 5% water / acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (78 mg). MS 326.0 (M).
With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Inert atmosphere;
23.A
To a degassed solution of 5-formyl-4-methylthiophen-2-ylboronic acid(2.21 g, 13.0 mmol, commercially available), 2-bromo-5-chloropyridine (2.00 g, 10.4 mmol, commercially available) and 2 N Na2CO3 (10.4 mL, 20.8 mmol) in DMF (70.2 mL) was added PdCl2dppf (0.380 g, 0.520 mmol); the flask degassed and heated to 80 0C for 2.0 h. Upon cooling, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 75 ml). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, CH2Cl2:Et0Ac, 100:0 to 0:100) to afford 2.01 g of the title compound as a yellow solid : 1H NMR (500 MHz, DMSO-d6) δ 9.96 (1 H, s), 8.57 (1 H, s), 7.98 (2 H, s), 7.75 (1 H, s), 2.49 (3 H, s).HPLC retention time: 3.158 min; LCMS (ES): m/z 238 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
Example 55C. Ethyl l-(5-chloropyridin-2-yl)-4-formyl-lH-pyrazole-3-carboxylate; [00259] To a solution Example 55B (0.96 g, 5.7 mmol) in DMF (4 mL) was added potassium carbonate (2.10 g, 16.0 mmol), followed by <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1.00 g, 5.2 mmol). The mixture was stirred at 100 0C for 2 h. After cooling to rt, 300 mL CH2Cl2 was added. The solid was filtered. The filtrate was concentrated to yield a residue which was purified by flash chromatography (0 to 20% ethyl acetate :hexanes) to afford Example 55C (1.3 g, 90 % yield). LC-MS, [M+H]+ = 280. 1H NMR(CDCl3, 400 MHz) delta 10.46 (s, 1 H), 9.09 (s, 1 H), 8.44 (d, J= 2.5 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 1 H), 7.87 (dd, J= 8.8, 2.5 Hz, 1 H), 4.53 (q, J= 7.2 Hz, 2 H), 1.48 (t, J = 7.2 Hz, 3 H).
Reference Example 22 (2-Bromo-5-chloropyridin-4-yl)(2,3,6-trifluorophenyl)methanol Under argon atmosphere, n-butyl lithium (1.58 M hexane solution, 23 ml, 36.4 mmol) was added at -75 C. to a tetrahydrofuran (50 ml) solution of diisopropylamine (5.5 ml, 39.0 mmol), and the mixture was stirred for 1 hour. A tetrahydrofuran (25 ml) solution of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (5.0 g, 26.0 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour. 2,3,6-Trifluorobenzaldehyde (3.34 ml, 28.6 mmol) was added dropwise to the reaction solution, and the mixture was stirred for 2.5 hours whilst raising the temperature to room temperature. Water was added to the reaction solution, followed by concentration under reduced pressure, and then extraction was carried out with ethyl acetate. The resulting organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography (hexane/ethyl acetate), and then washed with dichloromethane/hexane to give the title compound (5.08 g, 14.4 mmol, 55%) as a white powder. 1H-NMR (400 MHz, CDCl3) delta: 2.71 (1H, d, J=5.2 Hz), 6.28 (1H, d, J=5.2 Hz), 6.82-6.88 (1H, m), 7.12-7.21 (1H, m), 8.06 (1H, s), 8.25 (1H, s). MS (m/z): 352 (M++H).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 20℃; for 5h;
C. (5-Chloropyridin-2-yl)methyl benzoateTitle compound was prepared according to the procedure described in: Hasnik, Z.; Silhar, P.; Hocek, M. Synlett 2008, 4, 543. A solution of (benzoyloxymethyl)zinc(II) iodide Part B (2.11 mL, 1.949 mmol) was added to a solution of 2-bromo-5- chloropyridine (125 mg, 0.650 mmol) and Pd(PPh3)4 (37.5 mg, 0.032 mmol) in THF (1.30 mL). The reaction mixture was stirred at RT for 5 h at which point it was quenched with IM NaH2PO4 (30 mL). The solid formed was filtered and washed well with water. The filtrate was extracted with DCM (3 x 25 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product was subjected to flash chromatography (silica gel/hexanes -EtOAc 100:0 to 50:50 gradient) to afford (5-chloropyridin-2-yl)methyl benzoate 16C (101 mg, 63 % yield) as an off-white solid. LC-MS, [M + H]+ = 248. HPLC-Method 8; 3.30 min.
To a mixture of 2-bromo-5-chloropyridine (2.0 g, 10.4 mmol) and toluene (50 ml) was added a 1.6 M n-butyl lithium hexane solution (7.8 mL, 12.5 mmol) at -78 C., which was stirred for 1 hour. N,N-dimethylformamide (4.0 mL, 52.0 mmol) was then added dropwise into the mixture at the same temperature, which was then stirred for a further 15 minutes at room temperature. Water and tetrahydrofuran were added to this reaction solution, followed by vigorous stirring. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Sodium borohydride (1.18 g, 31.2 mmol) was added at 0 C. to the filtrate, and stirred for 1 hour at room temperature. This reaction solution was partitioned into water and tetrahydrofuran. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:diethyl ether=1:2) to obtain the title compound (706 mg, 47%). 1H-NMR Spectrum (CDCl3) delta (ppm): 4.75 (2H, s), 7.25 (1H, dd, J=0.8, 8.4 Hz), 7.68 (1H, dd, J=2.4, 8.4 Hz), 8.53 (1H, d, J=2.4 Hz).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
2-Bromo-5-chloropyridine (2.04 g, 10.6 mmol), <strong>[408502-23-8]2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (2.50 g, 10.6 mmol), K2CO3 (4.38 g, 31.8 mmol) and PdCl2 (dppf) (0.40 g, 0.53 mmol) were stirred in DMSO (20 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80 C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (810 mg, 34%) as a white solid: 1H NMR (300 MHz, CDCl3) delta 8.67 (d, J=2.0 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 7.79-7.75 (dd, J=8.8, 2.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.46-7.44 (dd, J=5.3, 1.5 Hz, 1H), 7.30 (s, 1H), 3.99 (s, 3H).
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 12h;
A mixture of 5-(chloromethyl)-l,3-oxazolidin-2-one (136 mg), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (192 mg), cesium carbonate (489mg), bispalladium tribenzylideneacetone (137 mg) and (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (260 mg) in 1 ml of dioxane was stirred at 850C for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (5 x 10 ml) eluting with ethyl acetate (50 ml). The eluent was concentrated in vacuo to provide a clear reddish-brown liquid, which was purified via column chromatography on a Biotage Horizon 4OM column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound (204 mg, 83 %).
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 12.0h;
A mixture of (5S)-5-(chloromethyl)-l,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 4), 2- bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium tribenzylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 850C for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2x) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volumes), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.44 g, 61%).
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 12h;
A mixture of (5R)-5-(chloromethyl)-l,3-oxazolidin-2-one (2.15 g, INTERMEDIATE 5), 2- bromo-5-chloropyridine (3.05 g), cesium carbonate (20.67 g), bispalladium triberi2ylideneacetone (2.18 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.07 g) in 16 ml of dioxane was stirred at 850C for 12 h. The sample was then cooled to room temperature, and purified was purified via column chromatography (2x) on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (2.32 g, 59%).
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 120℃; for 16h;
Intermediate 41 (1-41) tert-Butyl 4-(5-chloro-2-pyridyl)piperazine-l-carboxylate (1-41) A mixture of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1.5 g, 7.79 mmol), 1-BOC-piperazine (2.18 g, 11.69 mmol), sodium tert-butoxide (1.49 g, 15.59 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.451 g, 0.78 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.357 g, 0.390 mmol) in toluene (25 mL) was stirred at 120 C for 16 h. The mixture was poured into water, and extracted with EtOAc. The mixture was filtered through a short pad of diatomaceous earth. The organic layer was separated, washed with water and brine, dried (MgS04) and evaporated in vacuo. The crude product was purified by flash column chromatography (silica, EtOAc in DCM 0/100 to 20/80). The desired fractions were collected and evaporated in vacuo to yield intermediate compound 1-41 (0.888 g, 38%) as an orange solid.
37%
With triethylamine; In acetonitrile; at 150℃; for 2h;Microwave irradiation;
Example 85: Synthesis of 6-(4-(5-chloropyridin-2-yl)piperazin-1-yl)- N -(( E )-5-hydroxyadamantan-2-yl)picolinamide [251] [252] Step 1: Synthesis of tert-butyl 4-(5-chloropyridin-2-yl)piperazine-1-carboxylate [253] Tert-butyl piperazine-1-carboxylate (300 mg, 1.611 mmol) and <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (465 mg, 2.416 mmol) were dissolved in acetonitrile (3 ml), followed by addition of triethylamine (0.45 ml, 3.222 mmol), and then the resulting liquid was subjected to microwave irradiation at 150oC for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous ammonium chloride solution (10 ml) , and extracted with MC (15 ml x 2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 177 mg of colorless oil (37%).
[(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidine-3-yl]-methanol[ No CAS ]
2-[(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidine-3-ylmethoxy]-5-chloro-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
To a stirred solution of [(3RS,4RS)-l-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]- methanol (4.0 g, 12.7 mmol) in DMF (60 niL) at RT was added NaH (608 mg, 60%, 15.2 mmol). The reaction mixture was heated at 50 C for 30 minutes, then cooled down to RT before 2- bromo-5-chloropyridine (3.66 g, 19.0 mmol) was added. The resulting brownish solution was stirred overnight at 60 C, then concentrated under high vacuum. The residues was taken up in EtOAc, and washed with water.. The organic phase was dried over Na2S04 and a purification by column chromatography gave 3.90 g (72%) of the title product as a viscous oil. ES-MS m/e: 427.2 (M+H+).
72%
c) 2-[(3RS,4RS)-1-Benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-ylmethoxy]-5-chloro-pyridine; To a stirred solution of [(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]-methanol (4.0 g, 12.7 mmol) in DMF (60 mL) at RT was added NaH (608 mg, 60%, 15.2 mmol). The reaction mixture was heated at 50 C. for 30 minutes, then cooled down to RT before <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (3.66 g, 19.0 mmol) was added. The resulting brownish solution was stirred overnight at 60 C., then concentrated under high vacuum. The residues was taken up in EtOAc, and washed with water. The organic phase was dried over Na2SO4 and a purification by column chromatography gave 3.90 g (72%) of the title product as a viscous oil. ES-MS m/e: 427.2 (M+H+).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 16h;Sealed tube; Inert atmosphere;
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate In a 10 mL seal tube, methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (100 mg, 213 mmol, Eq: 1.00), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (40.9 mg, 213 mumol, Eq: 1.00) and cesium carbonate (139 mg, 425 mumol, Eq: 2.0) were combined with 1,4 dioxane (2.00 ml) and water (400 muA) to give a light brown solution. It was degassed for 10 min and tetrakis(triphenylphosphine)palladium (0) (24.6 mg, 21.3 mumol, Eq: 0.1) was added. The reaction mixture was heated to 80 C. and stirred for 16 hr. It was diluted with EtOAc (6 ml), concentrated in vacuo and purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8%, 10% MeOH/CH2Cl2) to afford methyl (S)-1-((S)-2-(5-(5-chloropyridin-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a solid (86 mg, 88%). ESI-LRMS m/e calcd for C23H26ClN5O3 [M+] 455, found 456 [M+H+].
With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 120℃; for 0.25h;Inert atmosphere; Microwave irradiation;
1-((2S,4/?)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3dihydroquinolin-1 (2/-/)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (78 mg, 0.406 mmol), 2'-(dicyclohexylphosphino)-/V,/V- dimethyl-[1 ,1 '-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium ie f-butoxide (27.3 mg, 0.284 mmol) were combined in 1 ,4-dioxane (1 ml_). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120C for 15 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3x50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) to give 1 -((2S,4R)-4-((5-chloropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4- carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1 (2/-/)-yl)ethanone (54 mg, 0.107 mmol, 53 % yield). LCMS: (Formate, 2 min), Rt = 0.86 mins, MH+ = 506.
With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 120℃; for 0.833333h;Inert atmosphere; Microwave irradiation;
1-((2S,4/?)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4- dihydroquinolin-1 (2H)-yl) ethanone hydrochloride (for a preparation see Intermediate 65) (100 mg, 0.232 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (89 mg, 0.464 mmol), 2'- (dicyclohexylphosphino)-/V,/V-dimethyl-[1 ,1 '-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 .3 mg, 0.023 mmol) and sodium ie f-butoxide (44.6 mg, 0.464 mmol) were combined in 1 ,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120C for 25 mins. A further portion of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (89 mg, 0.464 mmol), 2'- (dicyclohexylphosphino)-/V,/V-dimethyl-[1 ,1 '-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol), sodium ie f-butoxide (44.6 mg, 0.464 mmol) and 1 ,4-dioxane (1 mL) were added and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120C for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3x50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1 -((2S,4R)-4-((5-chloropyridin-2-yl)amino)-2-methyl-6-(5- (morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1 (2H)-yl)ethanone (34 mg, 0.067 mmol, 29 % yield) LCMS: (Formate, 2 min), Rt = 0.83 mins, MH+ 506.
With sodium t-butanolate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 120℃; for 0.416667h;Inert atmosphere; Microwave irradiation;
Example 5l-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(l-(2-methoxyethyl)-lH-pyrazol-4- yl)-2-methyl-3,4-dihydroquin 1-((2S,4R)-4-amino-6-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone (for a preparation see Intermediate 11) (lOOmg, 0.304 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (117mg, 0.609 mmol), Davephos (23.97mg, 0.061 mmol), Pd2(dba)3 (27.9mg, 0.030 mmol) and sodium tert-butoxide (58.5mg, 0.609 mmol) were combined in 1,4-dioxane (3ml) and the mixture degassed over a period of 20min before being heated at 120C for 25min (microwave). The reaction mixture was partitioned between water (100ml) and DCM (3x 100ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil was dissolved in DMSO (2x 1ml) and purified by MDAP (HpH x2). The solvent was evaporated under vacuum to give l-((2S,4R)-4- ((5-chloropyridin-2-yl)amino)-6-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)-2-methyl-3,4- dihydroquinolin-l(2H)-yl)ethanone (51mg, 0.116 mmol, 38 % yield) as a yellow glass. LCMS (formate), Rt 0.87min, MH+ 440.
38%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 120℃; for 0.75h;Microwave irradiation;
EXAMPLE 5 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone 1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 11) (100 mg, 0.304 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (117 mg, 0.609 mmol), Davephos (23.97 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min before being heated at 120 C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3*100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil was dissolved in DMSO (2*1 ml) and purified by MDAP (HpH *2). The solvent was evaporated under vacuum to give 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (51 mg, 0.116 mmol, 38% yield) as a yellow glass. LCMS (formate), Rt 0.87 min, MH+440.
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 85℃; for 12h;
A mixture of 5-(chloromethyl)-5-methyl-l,3-oxazolidin-2-one (1.50 g, INTERMEDIATE 16), 2- bromo-5-chloropyridine (1.92 g), cesium carbonate (4.89 g), bispalladium tribenzylideneacetone (1.37 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.30 g) in 25 ml of dioxane was stirred at 850C for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (15 x 15 ml) of silica gel eluting with ethyl acetate. The eluent then was concentrated in vacuo and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (1.01 g, 39%).
With 2-Picolinic acid; copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 130℃; for 24h;
Cesium carbonate (71 g, 218 mmol) was added to <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (14 g, 73 mmol) and diethyl malonate (22 mL, 145 mmol) in dry 1 ,4-dioxane (280 mL) and the solution was degassed with argon for 30 minutes. Then copper (I) oxide (2.8 g, 14.55 mmol) and picolinic acid (3.6 g, 29 mmol) were added and the mixture was stirred in a sealed vessel at 130C for 24 hours. The mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc: Hexane 92: 8 to afford the title compound as a yellow oil (54%, 8.0 g). 1H NMR (400 MHz, DMSO-d6): delta ppm 1 .17 (t, 3H), 3.85 (s, 2H), 4.08 (q, 2H), 7.42 (d, 1 H), 7.90 (dd, 1 H), 8.54 (d, 1 H).
With potassium acetate; palladium diacetate; triphenylphosphine In 1-methyl-pyrrolidin-2-one at 110℃; for 2h; Schlenk technique; Inert atmosphere; chemoselective reaction;
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
rac-1-((2S,3R,4R)-4-((5-chloropyridin-2-yl)amino)-2-cyclopropyl-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46.6%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere;
rac- I -((2S,3R,4R)-4-Amino-2-cyclopropyl-3-methyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for apreparation see Intermediate 14, 205 mg, 0.839 mmol) was added to a reaction vessel in anhydrous1,4-dioxane (5 mL). <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (242 mg, 1.259 mmol), DavePhos (66.0 mg, 0.168mmol), sodium tert-butoxide (242 mg, 2.52 mmol) and Pd2(dba)3 (115 mg, 0.126 mmol) were added and the reaction left to stir at 100 C for I h under N2. The reaction mixture was filtered through celite and the celite washed with ethyl acetate (3x10 mL). The combined filtrates were washed with water (2x40 mL) and the layers separated. The organic phase was dried through a hydrophobic frit and concentrated in vacuo to give 665 mg of crude orange/brown solid. This was purified bychromatography on silica (25 g, eluting with 0-2.5% methanolic ammonia/DCM). The fractions containing product were combined and concentrated in vacuo to give 256 mg of product as an orange solid. This was still of insufficient purity so was purified by chromatography on silica (10 g, eluting with 0-25% ethyl acetate/cyclohexane). The fractions containing mainly product were combined and concentrated in vacuo to give 160 mg of product (160 mg, 0.450 mmol, 53.6%) as anorange solid. The fractions containing product with a substantial impurity were combined and concentrated in vacuo to give 139 mg of impure product (139 mg, 0.391 mmol, 46.6%) as an orange solid. LCMS (2 mm Formic): Rt = 1.06 mi [MH] = 356.
2-bromo-5-chloro-4-(triethylsilyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -20℃; for 1.25h;
To a solution of diisopropylamine (10.6 g) in THF (170 ml) was added at -20 C n-butyl lithium (1.6 M in hexane, 65.6 ml) over 30 mm and the solution was allowed to warm to 0 C and stirring was continued for 30 mm. The solution was cooled again to -78 C and treated with25 a solution of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (19.2 g) in THF (30 ml) over 15 mm and stirring was continued for 1 h. To the dark brown solution was added triethylchlorosilane (16.6 g) over 3 mm, the mixture was warm to -20 C and was poured into a mixture of aqueous HC1 (1 M, 110 ml) and half-saturated aqueous NH4C1 (110 ml) and extracted with t-butylmethyl ether (300 ml). The
5-chloro-2-(1H-1,2,4-triazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 16h;
To a stirred solution of compound <strong>[40473-01-6]2-bromo-5-chloropyridine</strong>(1.0 g, 0.0052 mol) inNMP (12.0 mL), potassium carbonate (2.1 g, 3.0 eq) and 1H-1,2,4-triazole (0.431 g,1 .2 eq) was added. The reaction mixture was heated at 10000 16 hours. After cooling, the reaction mixture was quenched with water and extracted with Diethyl ether. The organic layer was, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography to yield the titlecompound (0.6 g, 63 %) as a off white solid. 1H NMR: (CDCI3, 300MHz) 6 9.13(s,1H), 8.42(s 1H), 8.1(s, 1H), 7.87-7.86(d, 2H).
With 1H-imidazole; 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; ammonium chloride; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 3h;Sealed tube;
General procedure: To a stirred solution of aryl halide (Br/I) (1 mmol) in dry dioxane in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol%), dppf (6 mol %), DIPEA (2 mmol), imidazole (0.25 mmol), ammonium chloride (2 mmol) and then Co2(CO)8 (0.3 mmol). The seal tube was closed immediately and stirred at 90 C for 3h. After the reaction time the reaction mixture was cooled to room temperature. The reaction mixture was filtered through celite pad and washed with dioxane, the filtrate was concentrated under reduced pressure and the residue obtained was purified by column chromatography.
ethyl 1-isopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate[ No CAS ]
ethyl 3-(5-chloropyridin-2-yl)-1-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 105℃; for 3.5h;Inert atmosphere; Reflux;
To a solution of ethyl I -isopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(trifluoro- methyl)-1 H-pyrrole-2-carboxylate (2.05 g, 5.27 mmol) and <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1 .520 g, 7.90mmol) in DME (40 mL) was added Cs2CO3 (5.15 g, 15.8 mmol) and H20 (10 mL). The mixture was degassed by bubbling Argon for 30 mm. Pd(dppf)C12 (385 mg, 0.527 mmol) was added and the mixture was placed in a pre-heated oil-bath at 105 C. The mixture was heated to reflux for 3 h. More <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (0.052 g, 0.270 mmol) and Pd(dppf)C12 (0.1 g, 0.137 mmol) were added and?heating was continued for 30 mm. The mixture was cooled to RT and diluted with CH2CI2 (50 mL). Thesolution was filtered over Celite and the residue washed with CH2CI2. The combined filtrate wasconcentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was washed with saturated aqueous NaHCO3(2x50 mL) and brine (2x50 mL) before drying on Na2SO4 and concentration in vacuo. The crude product was purified using flash cc (silica, gradient heptane/EtOAc, 1:0 -> 9:1)to give the desired product (1.48 g,75%) as a white solid.
With palladium diacetate; cesium fluoride; In ethylene glycol; at -10℃; for 6h;
synthesis of 3-(3-chloro-6-pyridyl)phenol (19-C) The sequentially 1.66g (12mmol) 3-hydroxy-phenylboronic acid (19-A), 1.92g (10mmol) 2-chloro-5-bromo pyridine (19-B), 3.80g (25mmol) cesium fluoride, 45 mg (0.2mmol) palladium acetate, 50 ml of ethylene glycol added to the 250 ml three port in the reaction bottle, controls heats to -10 C reaction 6 hours. After the reaction is complete, add 40 ml × 3 ethyl acetate extraction, with 40 ml × 3 saturated salt water extraction, anhydrous magnesium sulphate drying 2 hours, filtering, desolvation, crystallization, the drying of 1.67g strawcoloured solid, i.e. compound 19-C, content 99.2% (HPLC), the yield is 80.4%.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 75℃; for 12h;Inert atmosphere;
In a three-neck flask, 9.62 g (50.0 mmol) of 2-bromo-5- chioropyridine, 12.0 g (60.0 mmol) of 2-bromophenylbo- ronic acid, 1.44 g (1.25 mmol) of tetrakis(triphenylphosphine)palladium (0), 70 mL of tetrahydroffiran and 70 mL ofa 2M aqueous sodium carbonate solution were placed. The resulting mixture was stirred at 75 C. for 12 hours in anitrogen atmosphere.Afier completion of the reaction, 50 ml of water was added to the reaction solution. The resulting mixture was transferred to a separating funnel, and extracted with ethyl acetate several times. The extracted product was dried with anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by silica gel chromatography (hexane:dichloromethane=1:1), whereby compound (1-a) was obtained as white solids.The yield was 9.00 g (67%).
methyl 2-(5-chloropyridin-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48.2%
With copper; In dimethyl sulfoxide; at 50℃; for 2h;
a9.1) methyl 2-(5-chloropyridin-2-yl)propanoate <strong>[40473-01-6]2-Bromo-5-chloropyridine</strong> (1 g, 5.20 mmol) was added to a suspension of methyl 2-bromopropanoate (0.955 g, 5.72 mmol) and copper (0.759 g, 11.95 mmol) in dimethyl sulfoxide (5 mL). The mixture was stirred at 50 C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). An aqueous solution of potassium dihydrogenphosphate (0.707 g, 5.20 mmol, 15 mL) was added, and the mixture stirred for 30 minutes before filtering. The copper salts were washed with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuum. Purification by flash chromatography (petroleum ether/ethyl acetate) provided the titled compound (500 mg, 48.2%). MS (ESI+) m/z 200.0 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.55 (d, 3H), 3.69 (s, 3H), 3.95 (q, 1H), 7.25 (d, 1H), 7.65 (d, 1H), 8.51 (s, 1H).
With [Pd(N-(3-chloro-2-quinoxalinyl)-N'-(2,6-diisopropylphenyl)imidazolium)(PPh3)Cl2]; potassium carbonate In water at 70℃; for 3h;
82%
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; for 14h; Inert atmosphere;
4.1.1. General procedures for the synthesis of compounds 18a-18e,18j, 18k, 18m-18p, 18r, 18s
General procedure: Reactions were carried out with Phenylboronic acid (146 mg,1.2 mmol), 2-bromo-pyridine derivatives (234 mg, 1.0 mmol, 2-bromo-4-phenylpyridine for 18a; 172 mg, 1.0 mmol, 2-bromo-4-methylpyridine for 18b; 192 mg, 1.0 mmol, 2-bromo-4-chloropyridine for 18c; 183 mg, 1.0 mmol, 2-bromoisonicotinonitrilefor 18d; 186 mg, 1.0 mmol, 2-bromoisonicotinaldehyde for 18e;176 mg, 1.0 mmol, 2-bromo-5-fluoropyridine for 18j; 192 mg,1.0 mmol, 2-bromo-5-chloropyridine for 18k; 183 mg, 1.0 mmol, 6-bromonicotinonitrile for 18m; 186 mg, 1.0 mmol, 6-bromonicotinaldehyde for 18n; 236 mg, 1.0 mmol, 2-bromo-5-(methylsulfonyl)pyridine for 18o, 200 mg, 1.0 mmol, 1-(6-bromopyridin-3-yl)ethan-1-one for 18p, 234 mg, 1.0 mmol, 2-bromo-5-phenylpyridine for 18r; 263 mg, 1.0 mmol, N-benzyl-6-bromopyridin-3-amine for 18s), Pd(PPh3)2Cl2 (3.5 mg, 0.5 mol %),K2CO3 (387 mg, 2.8 mmol) in DME/H2O (8 mL, 3:1) under nitrogenatmosphere. The mixture was stirred at 80 C for about 14 h and thecompletion of the reaction was monitored by TLC. After cooling toroomtemperature, themixturewas extracted with ethyl acetate. Thecombined organic layers were washed with brine and the organicphase was dried with anhydrous sodium sulfate and concentrated invacuo. The crude compound was purified by silica gel column chromatographyto give corresponding intermediates.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 12h; Reflux; Inert atmosphere;
With potassium phosphate tribasic heptahydrate; palladium diacetate In water; isopropyl alcohol at 80℃;
Procedure A
General procedure: A mixture of 2-bromopyridines (2 mmol), boronic acids (3 mmol), Pd(OAc)2 (6.8 mg, 1.5 mol%), K3PO4·7H2O (1.35 g, 4 mmol) in mixture of isopropanol (10 mL) and water (10 mL) was stirred at 80°C overnight. The mixture was added brine (40 mL) and extracted four times with ethyl acetate (4 x 25 mL), the solvent was evaporated under reduced pressure and the product was isolated by short column chromatography using ethyl acetate and petroleum as eluent.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 2h; Schlenk technique; Inert atmosphere; Reflux;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 120℃; for 12h;
6-8 Synthesis Example 6: Synthesis of compound LEM-6
100mmol of 2-bromo-5-chloropyridine, 100mmol of phenylboronic acid, 41.4g of potassium carbonate (300mmol), 800ml of THF and 200ml of water were added to the reaction flask, and 1mol% of Pd(PPh3)4 was added. React at 120°C for 12h. After the completion of the reaction, the reaction was stopped, and the reactant was cooled to room temperature, water was added, and the organic phase was concentrated to obtain a white solid, which was filtered and washed with water. The obtained solid was recrystallized and purified with toluene to obtain a white powder M1. Wherein, the amount of Pd(PPh3)4 added is 1 mol% of 2-bromo-5-chloropyridine.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 120℃; for 12h;
1-5 Synthesis Example 1: Synthesis of Compound A1
Add 100mmol of 2-bromo-5-chloropyridine, 100mmol of phenylboronic acid, 41.4g of potassium carbonate (300mmol), 800ml of tetrahydrofuran (THF) and 200ml of water into the reaction flask, and add 1mol% of tetrakis(triphenylphosphine) ) Palladium (Pd(PPh3)4). React at 120°C for 12h. After the completion of the reaction, the reaction was stopped, the reactant was cooled to room temperature, water was added, and the organic phase was concentrated to obtain a white solid, which was filtered and washed with water. The obtained solid was recrystallized and purified with toluene to obtain a white powder M1. Wherein, the amount of Pd(PPh3)4 added is 1 mol% of 2-bromo-5-chloropyridine.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 20h; Inert atmosphere; Reflux;
tert-butyl 3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 14h;Inert atmosphere;
A mixture of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro- lH-pyrrole-l-carboxylate (106 mg, 0.360 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (76 mg, 0.40 mmol), cesium carbonate (350 mg, 1.10 mmol) and PdCl2(dppf)-CH2Cl2 (18 mg, 0.022 mmol) in dioxane (2.4 mL) and water (0.5 mL) was degassed and heated at 90C for 14 h. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-100% EtOAc/hexane to give 74a (50 mg, 0.18 mmol, 50 % yield) as a yellow solid. 1H MR (400MHz, CHLOROFORM-d) delta 8.62 - 8.41 (m, 1H), 7.82 - 7.57 (m, 1H), 7.40 - 7.16 (m, 1H), 6.60 - 6.32 (m, 1H), 4.60 - 4.49 (m, 2H), 4.41 - 4.27 (m, 2H), 1.52 - 1.45 (m, 9H).
50%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 14h;
A mixture of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (commercially available, 106 mg, 0.360 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (76 mg, 0.40 mmol), cesium carbonate (350 mg, 1.10 mmol) and PdCl2(dppf)-CH2C12 (18 mg, 0.022 mmol) in dioxane (2.4 mL) and water (0.5 mL) was degassed and heated at 90 C. for 14 h. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-100% EtOAc/hexane to give 1d (50 mg, 0.18 mmol, 50% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) delta 8.62-8.41 (m, 1H), 7.82-7.57 (m, 1H), 7.40-7.16 (m, 1H), 6.60-6.32 (m, 1H), 4.60-4.49 (m, 2H), 4.41-4.27 (m, 2H), 1.52-1.45 (m, 9H).
50%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 14h;
mixture of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH- pyrrole-l -carboxylate (106 mg, 0.360 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (76 mg, 0.40 mmol), cesium carbonate (350 mg, 1.10 mmol) and PdCl2(dppf)-CH2Cl2 (18 mg, 0.022 mmol) in dioxane (2.4 mL) and water (0.5 mL) was degassed and heated at 90C for 14 h. The mixture was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-100% EtOAc/hexane to give Example 199 A (50 mg, 0.18 mmol, 50 % yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) delta 8.62 - 8.41 (m, 1H), 7.82 - 7.57 (m, 1H), 7.40 - 7.16 (m, 1H), 6.60 - 6.32 (m, 1H), 4.60 - 4.49 (m, 2H), 4.41 - 4.27 (m, 2H), 1.52 - 1.45 (m, 9H).
(3-bromophenyl)(5-chloropyridin-2-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-Bromo-5-chloro-pyridine With n-butyllithium In hexane; toluene at -78℃; for 2.5h;
Stage #2: N-methoxy-N-methyl-3-bromobenzamide In hexane; toluene at -78℃; for 2.5h;
2.B Step B: (3-Bromophenyl)(5-chloropyridin-2-yl)methanone:
To a stirred solution of 2-bromo-5- chloropyridine (21.68 g, 113 mmol) in anhydrous toluene (512 mL) at -78°C was added n- butyllithium (2.5 M in hexane) (49.0 mL, 123 mmol) dropwise over a period of 1 h by a syringe pump. The mixture was stirred at -78°C for 90 min. A solution of 3-bromo-N-methoxy-N- methylbenzamide (25 g, 102 mmol) in anhydrous toluene (80 mL) was added to the mixture over a period of 30 min by a syringe pump. The resulting mixture was stirred at -78°C for another 2 h and was warmed to 0°C. A solution of hydrochloric acid (1 M, 100 mL) was added to the reaction and stirred for 20 min. The pH of the mixture was adjusted to about 9 by addition of aqueous sodium bicarbonate (saturated). The mixture was extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc/hexane = 9:1 v/v) to afford the title compound. MS (ES+) m/z: 296, 298 (M+H).
(2-bromopyridin-4-yl)(5-chloropyridin-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of 2-bromo-5- chloropyridine (3.41 g, 17.74 mmol) in 10 mL of anhydrous THF at -78°C under nitrogen was added to a solution of n-butyllithium (2.5 M in hexane, 7.10 mL, 17.74 mmol) in anhydrous THF (50 mL) dropwise. The reaction mixture was stirred for 15 min and a solution of 2- bromopyridine-4-carboxaldehyde (3.0 g, 16.13 mmol) in 20 mL of THF was added in one portion. It was stirred for 10 min and the dry ice-acetone bath was replaced with an ice-water batch. The reaction was stirred at 0°C for 30 min and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 0-100percent ethyl acetate in hexane) to afford the title compound. MS (ES+) m/z: 299, 301 (M+H).
5-chloro-2-(2,7-dimethylocta-2,6-dien-4-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: A dry and nitrogen-flushed 25 ml Schlenk tube equipped with a magnetic stirrer and a septum was charged with a solution of 2-bromopyridine (1 mmol, 1.0 equiv) in dry THF (3 mL). i-PrMgClLiCl (2.1 mmol, 1.0 S3 M in THF, 2.1 equiv) was then added dropwise at 0 C. After the reaction mixture was continuously stirred at 0 C for 3 h, a complete Br/Mg exchange was observed as indicated by thin layer chromatography (TLC). Allylic chloride (3.0 mmol, 3.0 equiv) was added at 0 C and the resulting mixture was gradually raised to room temperature, and stirred overnight. The resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 30 mL). The organic fractions were dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography.
4-{3-[4-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}pyrrolidin-2-one[ No CAS ]
1-(5-chloropyridin-2-yl)-4-[3-{4-(difluoromethoxy)phenyl}-1,2,4-oxadiazol-5-yl]pyrrolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 2h;Inert atmosphere;
(62-4) Synthesis of 1-(5-chloropyridin-2-yl)-4-{3-[4-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}pyrrolidin-2-one (Compound 62) To a mixture of 4-{3-[4-(difluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}pyrrolidin-2-one (148 mg, 0.50 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (96 mg, 0.50 mmol), palladium (II) acetate (11 mg, 0.05 mmol), BINAP (47 mg, 0.08 mmol), cesium carbonate (244 mg, 0.75 mmol) was added toluene (5 mL) under a nitrogen atmosphere, and the mixture was stirred at 120 C for 20 hours. After cooling to room temperature, the mixture was filtered through Celite, washed with ethyl acetate, and the solvent was evaporated off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 160 mg (yield 81%) of the title compound. The obtained compound was recrystallized from ethanol.
With tris-(dibenzylideneacetone)dipalladium(0); triphenylphosphine; sodium t-butanolate; In toluene; at 100℃; for 24h;Inert atmosphere;
The diphenylamine 16.9 g (0.1 muM), tertiary butyl alcohol sodium 28 g (0.3 muM) with toluene 400 ml is added to the reaction flask, stirring 30 minutes, nitrogen protection, adding 5 - chloro -2 bromo - pyridine 23 g (0.12 muM) with three (two inferior bian ji acetone) two palladium 1.5 g, finally adding tri-[...] 4 g, raising the temperature to 100 C reaction 24 h. The post-treatment process: cooling, adding water to stop the reaction, filtration, liquid, turns on lathe does toluene, adding dichloromethane dissolved solids, column separation (petroleum ether: dichloromethane=3:1), obtaining the solid (A - 8) 15.4 g, yield 55%.
Taking 4 - hydroxy pyridine 10 g (0.1 muM) dissolved in 100 ml anhydrous in tetrahydrofuran, stirring, accurate weighing NaH 0.96 g (0.4 muM) added to the reaction flask in batches (should not be too fast, to prevent too much bubble generating), after adding solution to appear yellow, then adding 5 - chloro -2 - bromo pyridine 21.1 g (0.11 muM, added in batches), reaction at room temperature overnight.The post-treatment process: filtering, for removing solid material, turns on lathe does, adding dichloromethane dissolved, column with petroleum ether: ethyl acetate=1:5 ([...]) [...], to get the solid (A - 9) 15 g, yield 71%.
9-chloro-6H-pyrido[1,2-a]pyrido[2',3':4,5]thieno[3,2-d]pyrimidin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With caesium carbonate; In toluene; at 150℃;Inert atmosphere; Molecular sieve;
General procedure: General Procedure for Synthesis of 6H-pyrido[1,2-a]pyrido[20,30:4,5]thieno[3,2-d]pyrimidin-6-ones(2-8 and 10-13). A solution of compound 1 or 9 (100 mg; 0.480 mmol), 2-bromo pyridine (2 equiv.,0.960 mmol) and Cs2CO3 (2.62 equiv., 1,258 mmol) was heated at 150 C in dry toluene (2 mL) for 24-36 h. The reaction was followed by TLC. After completion, the mixture was concentrated under vacuum. The solid obtained was submitted to a column chromatography. The increase of polarityin solvent gradient was made from neat petroleum ether to mixture of AcOEt/petroleum ether (9:1).
methyl 7-aminothieno[2,3-b]pyrazine-6-carboxylate[ No CAS ]
9-chloro-6H-pyrazino[2',3':4,5]thieno[3,2-d]pyrido[1,2-a]pyrimidin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With caesium carbonate; In toluene; at 150℃;Inert atmosphere; Molecular sieve;
General procedure: General Procedure for Synthesis of 6H-pyrido[1,2-a]pyrido[20,30:4,5]thieno[3,2-d]pyrimidin-6-ones(2-8 and 10-13). A solution of compound 1 or 9 (100 mg; 0.480 mmol), 2-bromo pyridine (2 equiv.,0.960 mmol) and Cs2CO3 (2.62 equiv., 1,258 mmol) was heated at 150 C in dry toluene (2 mL) for 24-36 h. The reaction was followed by TLC. After completion, the mixture was concentrated under vacuum. The solid obtained was submitted to a column chromatography. The increase of polarityin solvent gradient was made from neat petroleum ether to mixture of AcOEt/petroleum ether (9:1).
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); triethylamine In tetrahydrofuran; water at 20℃; for 2h; Inert atmosphere; chemoselective reaction;
methyl (R)-3-(5-amino-6-(isobutyl((1s,4s)-4-methoxycyclohexyl)amino)pyridin-3-yl)butanoate[ No CAS ]
methyl (R)-3-(5-((5-chloropyridin-2-yl)amino)-6-(isobutyl((1s,4s)-4-methoxycyclohexyl)amino)pyridin-3-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;
A mixture of methyl (R)-3-(5-amino-6-(isobutyl((1 s,4S)-4-methoxycyclohexyl)amino)pyridin-3-yl)butanoate (1 00 mg, 0.265 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1 00 mg,0.53 mmol), Pd2(dba)3 (50 mg, 0.053 mmol), Xantphos (75 mg, 0.106 mmol) andCs2C03 (175 mg, 0.53 mmol) in toluene (3 ml) was stirred at 100C under N2atmosphere overnight. The resulting mixture was partitioned between EtOAc and10 H20. The organic layer was washed with brine, dried over Na2S04, filtered andconcentrated to give the crude product which was purified by flash chromatography(silica gel, 0-30% EtOAc in PE) to afford the title compound (83 mg, 64% yield).LCMS (ESI) m/z calcd for C25H37CIN403: 488.26. Found: 489.42/491.39 (M/M+2t.
methyl (R)-3-(5-amino-6-(isobutyl((1r,4r)-4-methoxycyclohexyl)amino )pyridin-3-yl)butanoate[ No CAS ]
methyl (R)-3-(5-((5-chloropyridin-2-yl)amino)-6-(isobutyl((1r,4r)-4-methoxycyclohexyl)amino)pyridin-3-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 130℃;Inert atmosphere;
A mixture of methyl (R)-3-(5-amino-6-(isobutyl((1r,4R)-4-methoxycyclohexyl)amino)pyridin-3-yl)butanoate (1 00 mg, 0.27 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (1 04 mg, 0.54mmol), Pd(OAc)2 (2.6 mg, 0.0043 mmol), BINAP (3.1 mg, 0.0049 mmol) and K2C03(112 mg, 0.81 mmol) in toluene (2 ml) was stirred at 130C under N2 atmosphere10 overnight. The resulting mixture was partitioned between EtOAc and H20. The15organic layer was washed with brine, dried over Na2S04, filtered and concentrated togive the crude product which was purified by flash chromatography (silica gel, 0-30%EtOAc in PE) to afford the title compound (80 mg, 62% yield). LCMS (ESI) m/z calcdfor C25H37CIN403: 488.26. Found: 489.38/491.10 (M/M+2t
(R)-ethyl 3-(5-amino-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate[ No CAS ]
(R)-ethyl 3-(5-((5-chloropyridin-2-yl)amino)-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 1.5h;Inert atmosphere;
A degassed solution of (R)-ethyl 3-(5-amino-6-(isobutyl(tetrahyd ro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate (15.9 g, 43.7 mmol) in toluene (437 ml) was treatedwith <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (10.1 g, 52.5 mmol), Pd(Oac)2 (1.96 g, 8.75 mmol), rac-BINAP (7.63 g, 12.2 mmol), and C2CO3 (25.7 g, 79.0 mmol). The mixture was sparged with nitrogen for 10 mm, and then stirred at 100 C (internal temperature). After 1 .5 hours LCMS indicated complete reaction. The mixture was cooled to RTand filtered to remove solids, washing with EtOAc. The filtrate was concentrated to a syrup at reduced pressure. This material was dissolved in EtOAc and the solution concentrated in the presence of silica gel, and the material subjected to flash chromatography (750 g silica gel column, dry loading, 0-100% EtOAc/hexanes, gradient elution)to afford 10.7 g of pure product and 3.39 g of impure material. Theimpure product was subjected to a second chromatography (120 g silica gel column,0-50% EtOAc/DCM, gradient elution) to give an additional 2.75 g of pure material fora total yield of 13.5 g (65%) of the title compound. LCMS (ESI) mlz calcd forC25H35C1N403: 474.24. Found: 364.38 (M+1). 1H NMR (400 MHz, CDCI3) O 8.54 (brs, 1 H), 8.23 (d, J = 2.4 Hz, 1 H), 7.90 (d, J = 1.8 Hz, 1 H), 7.84 (br s, 1 H), 7.50 (dd, J =8.8, 2.6 Hz, 1H), 6.66 (d, J= 8.8 Hz, 1H), 4.11 (q, J= 7.1 Hz, 2H), 3.94 (d, J= 11.0Hz, 2H), 3.20 - 3.37 (m, 3H), 2.94 - 3.06 (m, 3H), 2.53 - 2.70 (m, 2H), 1.62 - 1.80 (m, 4H), 1.31 - 1.46 (m, 4H), 1.20 (t, J = 7.1 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H).
(R)-ethyl 3-(5-amino-6-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate[ No CAS ]
(R)-ethyl 3-(5-((5-chloropyridin-2-yl)amino)-6-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.7%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 2h;Inert atmosphere;
A degassed solution of (R)-ethyl 3-(5-amino-6-((cyclopropylmethyl)(tetrahydro-2Hpyran-4-yl)amino)pyridin-3-yl)butanoate (.143g, 0.396 mmol) in toluene (7.91 ml) was15 treated with <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (0.084 g, 0.435 mmol), PdOAc2 (1.776 mg,7.91 IJmol), BINAP (0.069 g, 0.111 mmol), and Cs2C03 (0.232 g, 0.712 mmol). Themixture was purged with nitrogen and then heated at 100 oc for 2 hour. The reactionwas cooled and diluted with EtOAc and water. The combine extracts were washedwith brine, dried Na2S04, and concentrated onto silica gel. The residue was purified20 by silica gel chromatography (0-50% EtOAc/hexanes) to give (R)-ethyl 3-(5-((5-chloropyridin-2-yl)amino)-6-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)butanoate (0.145 g, 62.7% yield). LCMS m/z calcd forC2sH33CIN403: 472.22. Found: 473.2 (M+H)+.
methyl (R)-3-(3-amino-4-(isobutyl((1s,4S)-4-methoxycyclohexyl)amino)phenyl)butanoate[ No CAS ]
methyl (R)-3-(3-((5-chloropyridin-2-yl)amino)-4-(isobutyl((1s,4S)-4-methoxycyclohexyl)amino)phenyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; tert-butyl alcohol; at 100℃;Inert atmosphere;
A mixture of methyl (R)-3-(3-amino-4-(isobutyl((1 s,4S)-4-methoxycyclohexyl)amino)phenyl)butanoate (100 mg, 0.32 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (104 mg, 0.54 mmol), Pd2(dba)3 (24 mg, 0.027 mmol), Xantphos (31 .2 mg, 0.054 mmol) and t-BuOK (60 mg, 0.54 mmol) in dioxane (2 ml_) was stirred at 100C under N2 atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to afford the title compound (78 mg, 60% yield). LCMS (ESI) m/z calcd for C^HseCINsOs: 487.26. Found: 488.47/490.41 (M/M+2)+.
methyl (R)-3-(3-amino-4-(isobutyl((1r,4R)-4-methoxycyclohexyl)amino)phenyl)butanoate[ No CAS ]
methyl (R)-3-(3-((5-chloropyridin-2-yl)amino)-4-(isobutyl((1r,4R)-4-methoxycyclohexyl)amino)phenyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 130℃; for 5h;Inert atmosphere;
A mixture of methyl (R)-3-(3-amino-4-(isobutyl((1 r,4R)-4-methoxycyclohexyl)amino) phenyl)butanoate (100 mg, 0.27 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (104 mg, 0.54 mmol), Pd(OAc)2 (2.6 mg, 0.0043 mmol), BINAP (3.1 mg, 0.0049 mmol) and K2C03 (112 mg, 0.81 mmol) in toluene (2 mL) was stirred at 130C under N2 atmosphere for 5 hr. The resulting mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to afford the title compound (60 mg, 46% yield). LCMS (ESI) m/z calcd for C27H38CIN3O3: 487.26. Found: 488.53/490.49 (M/M+2)+.
methyl (R)-3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate[ No CAS ]
methyl (R)-3-(3-((5-chloropyridin-2-yl)amino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of methyl (R)-3-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl) butanoate (150 mg, 0.431 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (165 mg, 0.86 mmol), Pd2(dba)3 (78 mg, 0.086 mmol), Xantphos (99 mg, 0.172 mmol) and t-BuOK (96 mg, 0.86 mmol) in dioxane (6 mL) was stirred at 100C under N2 atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the title compound (135 mg, 68% yield). LCMS (ESI) m/z calcd for 459.23. Found: 460.44/462.40 (M/M+2)+.
methyl 2-(6-amino-5-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-2-methylpropanoate[ No CAS ]
methyl 2-(6-((5-chloropyridin-2-yl)amino)-5-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of methyl 2-(6-amino-5-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)-2-methylpropanoate (560 mg, 1.60 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (544 mg, 3.2mmol), Pd2(dba)3 (140 mg, 0.16 mmol), Xantphos (196 mg, 0.32 mmol) and C52CO3 (1.11g, 0.16 mmol) in dioxane (6 mL) was stirred at 100C under N2 atmosphere overnight. Theresulting mixture was partitioned between EtOAc and H20. The organic layer was washedwith brine, dried over Na2SO4, filtered and concentrated to give the crude product whichwas purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the titlecompound (400 mg, 49% yield). LCMS (ESI) m/z calcd for C24H33C1N403: 460.22. Found: 461.12/463.14 (M/M+2).
methyl 1-(4-amino-5-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)cyclopropane-1-carboxylate[ No CAS ]
methyl 1-(4-((5-chloropyridin-2-yl)amino)-5-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of ethyl 1 -(5-amino-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3- yl)cyclopropane-1 -carboxylate (170 mg, 0.49 mmol), 2-bromo-5-ch loropyridine (153 mg, 0.80 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), Xantphos (64 mg, 0.11 mmol) and C52CO3(460 mg, 1 .41 mmol) in dioxane (4 mL) was stirred at 100C under N2 atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the title compound (110 mg, 49% yield). (ESI) mlz calcd for C24H31C1N403:458.21. Found: 459.34/461 .33(M/M+2).
methyl 2-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylpropanoate[ No CAS ]
methyl 2-(3-((5-chloropyridin-2-yl)amino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of methyl 2-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)-2-methylpropanoate (550 mg, 1 .59 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong>(460 mg, 2.39 mmol), Pd2(dba)3 (146 mg, 0.159 mmol), Xantphos (185 mg, 0.318 mmol)and Cs2CO3 (1.04 g, 3.18 mmol) in dioxane (12 mL) was stirred at 100C under N2atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20.The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated togive the crude product which was purified by flash chromatography (silica gel, 0-50%EtOAc in PE) to afford the title compound (650 mg, 89% yield). LCMS (ESI) mlz calcd forC25H34C1N303: 459.23. Found: 460.05/462.42 (M/M+2).
methyl 2-(3-amino-4-(diisobutylamino)phenyl)-2-methylpropanoate[ No CAS ]
methyl 2-(3-((5-chloropyridin-2-yl)amino)-4-(diisobutylamino)phenyl)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;
A mbdure of methyl 2-Q-amlno-4-(dllsobutylamlno)phenyl)-2-methylpropanoate(250 mg, 0.78 mmoD, 2-bromo-5-chloropyrldlne (301 mg, 1.56 mmoD, Pd2(dba)3 (71 mg,0.156 mmol), Xantphos (90 mg, 0.158 mmol) and C52CO3 (588 mg, 1.58 mmol) In toluene(10 mL) was stirred at 100C under N2 atmosphere overnIght The resulting mbcture waspartitioned between EtOAc and 1120. The organIc layer was washed with brine, dried overNa2SO4, filtered and concentrated to gIve the crude product whIch was purified by flashchromatography (sIlIca gel, 0-50% EtOAc In PE) to afford the title compound (180 mg, 53% yIeld). LCMS (ESI) mlz calcd for CUHMCIN3O2: 43123. Found:432.841434.81 (MiM+2).
methyl 1-(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)cyclopropane-1-carboxylate[ No CAS ]
methyl 1-(3-((5-chloropyridin-2-yl)amino)-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of methyl 1 -(3-amino-4-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)cyclopropane-1-carboxylate (550 mg, 1.59 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (460 mg, 2.39 mmol), Pd2(dba)3 (146 mg, 0.159 mmol), Xantphos (185 mg, 0.318 mmol) and Cs2CO3 (1.04 g, 3.18 mmol) in dioxane (12 mL) was stirred at 100C under N2 atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2SO4, filtered andconcentrated to give the crude product which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the title compound (566 mg, 71% yield). LCMS (ESI) mlz calcd for C25H32C1N303: 457.21. Found: 458.33/460.26 (M/M+2).
ethyl 2-(5-amino-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-2-methylpropanoate[ No CAS ]
ethyl 2-(5-((5-chloropyridin-2-yl)amino)-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of ethyl 2-(5-amino-6-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)pyridin-3- yl)-2-methylpropanoate (620 mg, 1.71 mmol), <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (657 mg, 3.42 mmol), Pd2(dba)3 (312 mg, 0.342 mmol), Xantphos (395 mg, 0.683 mmol) and C52CO3(1.11 g, 3.42 mmol) in dioxane (8 mL)was stirred at 100C under N2 atmosphere overnight. The resulting mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to afford the title compound (400 mg, 49% yield). LCMS (ESI) m/z calcd for C25H35C1N403:474.24. Found: 475.63/477.70 (M/M+2).
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78℃; for 0.75h;Inert atmosphere;
Under a nitrogen atmosphere, diisopropylamine (4 mL) was added to a reaction flask containing anhydrous THF (45 mL), cooled to -5 C, and n-butyllithium solution (12.5 mL) was slowly added dropwise.23% n-hexane solution). After the addition was continued, the mixture was stirred for 0.5 hours and then cooled to -78 C.A solution of <strong>[40473-01-6]2-bromo-5-chloropyridine</strong> (5.0 g, 26.00 mmol) in tetrahydrofuran (45 mL) was added dropwise. After the addition is continued for 15 minutes, the dry carbon dioxide gas is introduced.After stirring for 30 minutes, the reaction solution was allowed to warm to room temperature.Slowly add dropwise to saturated sodium bicarbonate solution (100 mL).The resulting mixture was extracted with diethyl ether (50 mL).The aqueous phase was adjusted to pH 2-3 with 1N hydrochloric acid, and the precipitated white solid was filtered and dried.2-Bromo-5-chloroisonicotinic acid (4.3 g, yield: 73%) was obtained.
6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one[ No CAS ]
6-(2,4-dimethylphenyl)-2-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.56%
With potassium phosphate; copper(l) iodide; N,N-dimethylethylenediamine; In N,N-dimethyl-formamide; at 110℃; for 12h;Inert atmosphere;
According to Scheme 1 Step viii: To a solution of intermediate 7a (100.00 mg, 353.87 umol, 1.00 eq) in DMF (5.00 mL) was added <strong>[40473-01-6]5-chloro-2-bromopyridine</strong> (204.30 mg, 1.06 mmol, 3.00 eq), DMEDA (18.72 mg, 212.32 umol, 22.82 uL, 0.60 eq), Cul (33.70 mg, 176.94 umol, 0.50 eq), K3PO4 (187.79 mg, 884.68 umol, 2.50 eq) at 20C under N2 atmosphere. Then the mixture was heated to 110C and stirred for 12 hours. The reaction was filtered and the filtrate was acidified to pH=5 with aqueous 12 M HCl and filtered. The filtrate was purified by prep-HPLC to provide Example 6 (71.93 mg, 196.61 umol, 55.56% yield as an off-yellow solid.
methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzoate[ No CAS ]
methyl 3-(5-chloro-2-pyridyl)-4-[4-(trifluoromethyl)anilino]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 1.5h;
To a solution of methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4-((4- (trifluoromethyl)phenyl)amino)benzoate (109 mg, 0.26 mmol, 1 eq) and 2-bromo-5- chloropyridine (55 mg, 0.29 mmol, 1.1 eq) in dioxane (2 mL) and H20 (0.5 mL) were added Pd(dppf)Cl2 (9.5 mg, 13 umol, 0.05 eq) and Na2C03 (55 mg, 0.52 mmol, 2 eq). The mixture was stirred at 90C for 1.5 hr. The reaction mixture was concentrated in vacuum. The residue was diluted with EA (20 mL), washed with brine (5 mL). The organic phase was dried over Na2S04, filtered and concentrated in vacuum. The crude product was purified by column chromatography (Si02) to give methyl 3-(5-chloro-2-pyridyl)-4-[4-(trifluoromethyl)anilino]benzoate (62 mg, 0.15 mmol, 57% yield).
With triethylamine; In acetonitrile; at 160℃; for 1.66667h;Microwave irradiation;
2-bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 mL), to this (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (211 mg, 1.559 mmol) and triethylamine (0.362 mL, 2.60 mmol) were added and the suspension was irradiated in the microwave to 160C for 1 h20. The sample was then extracted between water (20 mL) and dichloromethane (20 mL). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified on a silica gel column using a Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0 -> 90/10) to get the product as a beige solid (57 mg, 26 %). (0876) MS: 21 1.03 (M+H)+. (0877) 1H-NMR (400 MHz, DMSO -d6) d = 8.06 (d, J = 2.6 Hz, 1 H), 7.56 (dd, J = 9.0, 2.7 Hz, 1 H), 6.57 (d, J = 9.0 Hz, 1 H), 4.80 (d, J = 2.3 Hz, 1 H), 4.65 (d, J = 2.4 Hz, 1 H), 3.76 (dd, J = 7.3, 1.5 Hz, 1 H), 3.61 (d, J = 7.3 Hz, 1 H), 3.43 (dd, J = 10.1 , 1.5 Hz, 1 H), 3.20 (d, J = 10.3 Hz, 1 H), 1.90 (dd, J = 9.7, 2.3 Hz, 1 H), 1.87 - 1.81 (m, 1 H).
With triethylamine In acetonitrile at 160℃; for 1.66667h; Microwave irradiation;
75.A Step A
2-bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 mL), to this (1 R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (21 1 mg, 1.559 mmol) and triethylamine (0.362 mL, 2.60 mmol) were added and the suspension was irradiated in the microwave to 160°C for 1 h20. The sample was then extracted between water (20 mL) and dichloromethane (20 mL). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude was purified on a silica gel column using a Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0 -> 90/10) to get the product as a beige solid (51 mg, 23 %). (0882) MS: 21 1.04 (M+Hf. 1H-NMR (400 MHz, DMSO-cfe) d = 8.06 (dd, J = 2.7, 0.7 Hz, 1 H), 7.56 (dd, J = 9.0, 2.7 Hz, 1 H), 6.63 - 6.50 (m, 1 H), 4.80 (s, 1 H), 4.64 (s, 1 H), 3.75 (dd, J = 7.3, 1.5 Hz, 1 H), 3.61 (d, J = 7.3, 0.9 Hz, 1 H), 3.43 (dd, J = 10.1 , 1.6 Hz, 1 H), 3.20 (d, J = 10.1 , 1.1 Hz, 1 H), 1.94 - 1.78 (m, 2H).
2-(5-Chloropyridin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
Stage #1: 2-Bromo-5-chloro-pyridine; Triisopropyl borate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2.5h;
Stage #2: N-methyliminodiacetic acid In tetrahydrofuran; hexane; dimethyl sulfoxide at 115 - 125℃;
General Synthetic Method 1
Synthesis of MIDA Boronates MIDA boronates were synthesised according to the method described in the literature: G.R. Dick, D.M. Knapp, E.P. Gillis, M.D. Burke, Org. Lett.2010, 12, 2314-2317. On a scale of approximately 100 mmol (calculated on the basis of the 2-bromopyridine derivative), the procedure worked as described here. A 2-bromopyridine derivative (1 equivalent) and tripropan-2-yl borate (1.4 equivalents) were dissolved in THF (200 mL) and this solution was cooled to -78 °C. n- Butyllithium (2.5 M in hexanes, 1.2 equivalents) was slowly added over 90 min. Stirring at -78 °C was maintained for another 60 min, then the cooling bath was removed and the mixture was left to warm to ambient temperature. In a separate 3-neck round bottom flask with a distillation device and an internal thermometer mounted, a solution of 2,2'-(methylimino)diacetic acid (1.6 equivalents) in DMSO (dried over 3 molecular sieves, 150 mL) was heated to 125-130 °C. The suspension of the boronate in THF was slowly added over approximately 2 h distilling off the THF and keeping the temperature in a range between 115-125 °C. Eventually, the mixture was stirred another 20 min and then left sitting over night. The DMSO was distilled under vacuum and the residue was adsorbed onto diatomaceous earth and chromatographed over 340 g of silica using a ternary gradient of dichloromethane-ethyl acetate and then etyl acetate-THF.
7-chloro-2-phenyl-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidin-10-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; at 120℃;
General procedure: A mixture of methyl anthranilate (50 mg, 1 equiv.), 2-bromopyridine (2 equiv.),Pd(OAc)2 (0.03 equiv.), Xantphos (0.04 equiv.), and Cs2CO3 (2.5 equiv.) in eucalyptol(1.5 mL) was stirred at 120 C for 18-24 h. The reaction was followed by TLC. After completion,the reaction was then cooled to room temperature, and the mixture was concentratedunder vacuum. The solid obtained was purified by flash chromatography using a mixtureof ethyl acetate/petroleum ether.
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