* 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.
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 70,73
2
[ 13466-38-1 ]
[ 100-39-0 ]
[ 83664-33-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With silver carbonate In benzene at 50℃; for 24 h;
To a solution of 5-bromopyridin-2 (1E-ONE (100 mmol, 17. 4 g, 1. 0 eq.) in benzene (170 mL) was added silver (I) carbonate (67. 0 mmol, 18. 5 g, 0. 67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20. 5 g, 1. 2 eq.) was added via syringe in a steady stream. The mixture was heated to 50 °C and stirred in the dark for approximately 24 hours. LC/MS of the reaction mixture indicates two peaks both with M+H = 265 corresponding to the desired molecular weight. On the basis of relative polarities, the more polar peak was thought to be the N-alkylated product and consisted of approximately 20 percent of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2percent sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i over a gradient of 5-95percent hexanes in ethyl acetate to afford the title compound as a golden oil (25. 1 g, 95percent). LRMS : 265 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 29 (1 H, s) 7. 72 (1 H, D, J=8. 5 Hz) 7. 31-7. 43 (5 H, m) 6. 54 (1 H, d, J=8. 5Hz) 5. 34 (2 H, s)
95%
With silver carbonate In toluene at 100℃;
To a solution of 5-bromopyridin-2(1 H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwiseand the reaction mixture was stirred at 100 °C over night. The reaction mixture was filteredthrough a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1 .8 g, 95percent).
95%
With silver carbonate In toluene at 100℃;
To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at 100° C. over night. The reaction mixture was filtered through a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1.8 g, 95percent).
85%
With silver carbonate In tetrahydrofuranReflux; Darkness
To a solution of 1 (1.4 g, 8 mmol) in dry THF (80 mL) was added benzyl bromide (1.14 mL, 9.6 mmol) and Ag2CO3 (1.32 g, 4.8 mmol) and subsequently refluxed in the dark overnight. The reaction mixture was filtered through celite and concentrated to provide brown solid which was flash chromatographed on silica gel eluting with 10percent EtOAc in hexanes to provide 1.8 g (85percent) of a white solid;1H NMR (CDCl3) δ (ppm) 5.34 (s, 2H), 6.71 (d, 1H, J = 8.7 Hz), 7.25-7.44 (m, 5H), 7.64 (dd, 1H, J = 8.8 Hz), 8.20 (d, 1H, J = 2.5 Hz); MS (ESI) m/z 289 (M+Na)+.
With potassium hydroxide In toluene for 1.5 h; Heating / reflux
A mixture of 2,5-dibromopyridine (20 g, 84.4 MMOL), DIBENZO-18-CROWN-6 (1.5 g, 4. 2mmol), benzyl alcohol (11. 9 g, 11.4 mL, 109.8 mmol), potassium hydroxyde (11. 4 g, 202.6 mmol) and toluene (200 mL) was atirred at reflux with a Dean-Stark apparatus for 1.5 hours. After removal of solvent in reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (hexane: ethyl acetate, 98: 2) followed by recrystallization from hexane, to give 2- (BENZYLOXY)-5- bromopyridine (20.6 g, 92percent) as a colorless solid.
92%
With potassium hydroxide In toluene for 1.5 h; Heating / reflux under azeotropic conditions
A mixture of 2,5-dibromopyridine (20.0 g, 84.4 mmol), dibenzo-18-crown-6 (1.5 g, 4.2 mmol), benzyl alcohol (11.9 g, 11.4 mL, 109.8 mmol) and KOH (11.4 g, 202.6 mmol) in toluene (200 mL) was refluxed with Dean-Stark for 1.5 hours. After removal of solvent under reduced pressure, the residue was diluted with water, and extracted with chloroform. The separated organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by column chromatography on silica-gel, (hexane:ethyl acetate, 98:2) followed by recrystallization from hexane, to give 2-benzyloxy-5-bromopyridine (20.6 g, 92 percent) as a colorless solid.
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1 h;
Manufacturing Example 12-1-1 2-Benzyloxy-5-bromopyridine; To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into is water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent).1H-NMR Spectrum (CDCl3) δ (ppm): 5.34 (2H, s), 6.71-6.73 (1H, m), 7.32-7.45 (5H, m), 7.64-7.67 (1H, m), 8.20-8.21 (1H, m).
90%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: at 0 - 20℃; for 1 h;
To a solution of phenyl-methanol (20.5 g, 190 mmol) in N,N-dimethylformamide (200 mL) was added sodium hydride (7.6 g, 190 mmol) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2,5-Dibromopyridine was then added thereto on the ice bath (0° C.), and stirred for 60 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:20 then 1:10) to obtain the title compound (15.1 g, 90percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 5.34 (2H, s), 6.71-6.73 (1H, m), 7.32-7.45 (5H, m), 7.64-7.67 (1H, m), 8.20-8.21 (1H, m).
85%
With potassium hydroxide In toluene for 3 h; Heating / reflux
A suspension of 2, 5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, . 05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide [(1. 1] g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85percent) which was used without purification. Mass spec.: 264.25 (MH) [+.]
71.2%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 20℃;
To a solution of sodium hydride (1.04 g, 26.0 mmol, 1.3 equiv)In N, N-dimethylformamide (30 ml) was added benzyl alcohol (2.59 g, 24.0 mmol, 1.2 equiv)The mixture was stirred at 0 ° C for 1 hour,Followed by the addition of 2,5-dibromopyridine (4.74 g, 20 mmol, 1.0 equiv)The reaction solution was allowed to react overnight at room temperature.The reaction was diluted with ethyl acetate (300 mL), washed with half-saturated brine (300 mL x 4) and the organic phase was dried over anhydrous sodium sulfate. The filtrate was chromatographed three times with petroleum ether and the residue was purified by column chromatography (Eluent: petroleum ether: ethyl acetate = 200: 1) to give 2- (benzyloxy) -5-bromopyridine (3.76 g, yield: 71.2percent).
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 5, p. 1408 - 1412
[2] Polyhedron, 2013, vol. 52, p. 755 - 760
[3] Patent: WO2004/43926, 2004, A1, . Location in patent: Page 150
[4] Patent: WO2004/69805, 2004, A1, . Location in patent: Page 55
[5] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 66
[6] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 62-63
[7] Patent: WO2003/104236, 2003, A1, . Location in patent: Page 168-169
[8] Patent: CN106588937, 2017, A, . Location in patent: Paragraph 0196
[9] Patent: WO2004/814, 2003, A1, . Location in patent: Page 61; 62
[10] Patent: US2004/102472, 2004, A1, . Location in patent: Page 38
4
[ 13466-38-1 ]
[ 100-39-0 ]
[ 83664-33-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.0833333 h; Inert atmosphere; Cooling with ice Stage #2: at 20℃; for 1 h;
Example 117; Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methylimidazolidine-2,4-dione; 117-a) Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-5-methylimidazolidine-2,4-dione; 117-a-1) Preparation of 5-bromo-2-(benzyloxy)pyridine; 2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N'-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50percent) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99percent) was obtained as a pale yellow solid.1H-NMR (CDCl3) δ: 5.10 (2H, s), 6.54 (1H, d, J=9.5 Hz), 7.28-7.39 (7H, m).
Reference：
[1] Patent: US2010/48610, 2010, A1, . Location in patent: Page/Page column 66
[2] European Journal of Organic Chemistry, 2007, # 24, p. 4038 - 4049
[3] Patent: WO2009/70869, 2009, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2007/84560, 2007, A2, . Location in patent: Page/Page column 158
5
[ 13466-38-1 ]
[ 100-44-7 ]
[ 83664-33-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-ethyl-N,N-diisopropylamine; zinc(II) oxide; zinc(II) chloride In 1,4-dioxane at 110℃; Inert atmosphere
General procedure: To a solution of substituted 2-oxo-1,2-dihydropyridines (3.36 mmol), zinc oxide (0.30 g, 3.70 mmol),zinc chloride (0.50 g, 3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 1,4-dioxane (15 mL)was added benzyl chloride (0.58 g, 4.04 mmol) under argon atmosphere. The mixture was heated in 110 °C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature,and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate(30 mL). The filtrate was washed with water (10 mL 2), once with brine (10 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:20) to yield thecorresponding compounds.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3565 - 3569
10
[ 39856-50-3 ]
[ 100-51-6 ]
[ 83664-33-9 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
11
[ 13466-38-1 ]
[ 100-39-0 ]
[ 83664-33-9 ]
Reference：
[1] Patent: US2005/187266, 2005, A1,
12
[ 83664-33-9 ]
[ 106984-91-2 ]
Reference：
[1] Polyhedron, 2013, vol. 52, p. 755 - 760
13
[ 83664-33-9 ]
[ 68-12-2 ]
[ 635712-99-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: for 0.5 h;
To a solution of [2-BENZYLOXY-5-BROMO-PYRIDINE] (1.64 g, 6.2 mmol) in tetrahydrofuran (25 [ML,-78°C)] was added n-butyllithium (2.5 M in hexane, 2.61 mL, 1.05 equiv). After 1 h [AT-78°C,] dimethylformamide (0.97 mL, 2 equiv) was added and the mixture stirred for 30 min. The reaction was quickly poured into a stirred solution of 5percent aqueous sodium bicarbonate (50 [ML)] and extracted with diethyl ether [(-3X).-THE ETHEREAL-WAS WASHED-WITH BRINE, DNeD-OVER MaGNESIUM~SULFATE, AND] concentrated to give 1.16 g (quant. ) which was used without purification. Mass spec.: 186.34 [(MH)] [+.]
73%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78℃; for 0.5 h;
n-Butyl lithium (2. 5M, 95. 9 mmol, 38. 4 mL, 1. 05 eq.) was added dropwise via syringe to a stirred solution OF 2- (BENZYLOXY)-5-BROMOPYRIDINE (91. 3 mmol, 24. 1 G, 1. 0 eq.) in THF (260 mL, c = 0. 35) cooled to-78 °C. Upon completion of addition, the solution was allowed to continue stirring at the same low temperature for 1 hour. At this point, NN-dimethylformamide (183 mmol, 13. 4 G, 2. 0 eq.) was added dropwise as a solution in 5 mL THF. Stirring was continued at the same low temperature for a further 30 minutes at which point the reaction was quenched by addition of 5percent sodium bicarbonate. The mixture was transferred to a separatory funnel and extracted with ether (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant yellow oil was purified on a Biotage Sp4 65i over a gradient OF 0-50percent hexanes in ethyl acetate to afford the title compound (14. 1 g, 73percent). LRMS : 214 (M+H) +. 'H NMR (DMSO-D6, 400 MHz) ; 10. 02 (1 H, s) 8. 86 (1 H, s) 8. 03 (1 H, d, J=9. 3 Hz) 7. 31-7. 43 (5 H, m) 6. 50 (1 H, d, J=9. 3 HZ) 5. 33 (2 H, s)
40%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 0.5 h;
Manufacturing Example 12-1-2 6-Benzyloxy-pyridin-3-carbaldehyde; To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Manufacturing Example 12-1-1 in anhydrous tetrahydrofuran (250 mL) were added dropwise n-butyl lithium (2.67 M n-hexane solution, 25.6 mL, 68.4 mmol) under nitrogen atmosphere on a dry ice-ethanol bath (-78° C.), which was stirred for 30 minutes at -78° C. N,N-Dimethylformamide (6.60 mL, 85.5 mmol) was then added thereto at -78° C, and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring for 10 minutes at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:7 then 1:5) to obtain the title compound (4.87 g, 40percent).1H-NMR Spectrum (CDCl3) δ (ppm): 5.49 (2H, s), 6.89-6.92 (1H, m), 7.34-7.48 (5H, m), 8.07-8.10 (1H, m), 8.64-8.65 (1H, m), 9.97 (1H, s).
40%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 0.5 h;
To a solution of 2-benzyloxy-5-bromopyridine (15.1 g, 57.0 mmol) described in Manufacturing Example 12-1-1 in anhydrous tetrahydrofuran (250 mL) were added dropwise n-butyl lithium (2.67 M n-hexane solution, 25.6 mL, 68.4 mmol) under nitrogen atmosphere on a dry ice-ethanol bath (-78° C.), which was stirred for 30 minutes at -78° C. N,N-Dimethylformamide (6.60 mL, 85.5 mmol) was then added thereto at -78° C., and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated after stirring for 10 minutes at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:7 then 1:5) to obtain the title compound (4.87 g, 40percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 5.49 (2H, s), 6.89-6.92 (1H, m), 7.34-7.48 (5H, m), 8.07-8.10 (1H, m), 8.64-8.65 (1H, m), 9.97 (1H, s).
Reference：
[1] Patent: WO2003/104236, 2003, A1, . Location in patent: Page 169
[2] Polyhedron, 2013, vol. 52, p. 755 - 760
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2536 - 2548
[4] Patent: WO2004/92145, 2004, A1, . Location in patent: Page 149
[5] Patent: US2009/82403, 2009, A1, . Location in patent: Page/Page column 66
[6] Patent: US2007/105904, 2007, A1, . Location in patent: Page/Page column 63
14
[ 83664-33-9 ]
[ 144-55-8 ]
[ 635712-99-1 ]
Reference：
[1] Patent: US2004/204397, 2004, A1,
15
[ 83664-33-9 ]
[ 73183-34-3 ]
[ 832735-54-3 ]
Yield
Reaction Conditions
Operation in experiment
59.5%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere
To a solution of 2- (benzyloxy) -5-bromopyridine (compound 204-9) (3.76 g, 14.2 mmol, 1.0 equiv)(Compound No. 205) (4.34 g, 17.1 mmol, 1.2 equiv) was added to a solution of 1,4-dioxane (50 mL)Potassium acetate (3.48 g, 35.5 mmol,2.5 equivalents) and [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (1.16 g, 1.4 mmol, 0.1 equiv)The reaction solution was heated under reflux with nitrogen under reflux to 100 ° C overnight.The reaction was taken dry and the residue was purified by column chromatography (eluent: petroleum ether: dichloromethane = 2: 1)To give 2- (benzyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine(2.63 g, yield: 59.5percent).
Reference：
[1] Patent: CN106588937, 2017, A, . Location in patent: Paragraph 0197
With silver carbonate; In benzene; at 50℃; for 24h;
To a solution of 5-bromopyridin-2 (1E-ONE (100 mmol, 17. 4 g, 1. 0 eq.) in benzene (170 mL) was added silver (I) carbonate (67. 0 mmol, 18. 5 g, 0. 67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20. 5 g, 1. 2 eq.) was added via syringe in a steady stream. The mixture was heated to 50 C and stirred in the dark for approximately 24 hours. LC/MS of the reaction mixture indicates two peaks both with M+H = 265 corresponding to the desired molecular weight. On the basis of relative polarities, the more polar peak was thought to be the N-alkylated product and consisted of approximately 20 % of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2% sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i over a gradient of 5-95% hexanes in ethyl acetate to afford the title compound as a golden oil (25. 1 g, 95%). LRMS : 265 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 29 (1 H, s) 7. 72 (1 H, D, J=8. 5 Hz) 7. 31-7. 43 (5 H, m) 6. 54 (1 H, d, J=8. 5Hz) 5. 34 (2 H, s)
95%
With silver carbonate; In toluene; at 100℃;
To a solution of 5-bromopyridin-2(1 H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwiseand the reaction mixture was stirred at 100 C over night. The reaction mixture was filteredthrough a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1 .8 g, 95%).
95%
With silver carbonate; In toluene; at 100℃;
To a solution of 5-bromopyridin-2(1H)-one (1.28 g, 7.36 mmol) and Ag2CO3 (3 g, 11.04 mmol) in toluene (50 mL) was added (bromomethyl)benzene (1.25 g, 7.36 mmol) dropwise and the reaction mixture was stirred at 100 C. over night. The reaction mixture was filtered through a short pad of silica gel and washed with DCM. The filtrate was concentrated to yield the title compound as light yellow oil (1.8 g, 95%).
85%
With silver carbonate; In tetrahydrofuran;Reflux; Darkness;
To a solution of 1 (1.4 g, 8 mmol) in dry THF (80 mL) was added benzyl bromide (1.14 mL, 9.6 mmol) and Ag2CO3 (1.32 g, 4.8 mmol) and subsequently refluxed in the dark overnight. The reaction mixture was filtered through celite and concentrated to provide brown solid which was flash chromatographed on silica gel eluting with 10% EtOAc in hexanes to provide 1.8 g (85%) of a white solid;1H NMR (CDCl3) delta (ppm) 5.34 (s, 2H), 6.71 (d, 1H, J = 8.7 Hz), 7.25-7.44 (m, 5H), 7.64 (dd, 1H, J = 8.8 Hz), 8.20 (d, 1H, J = 2.5 Hz); MS (ESI) m/z 289 (M+Na)+.
Preparation d-3 2-(Benzyloxy)-5-bromopyridine To a solution of 5-bromopyridin-2(1H)-one (100 mmol, 17.4 g, 1.0 eq.) in benzene (170 mL) was added silver (I) carbonate (67.0 mmol, 18.5 g, 0.67 eq.). The flask was wrapped with aluminum foil and then benzyl bromide (120 mmol, 20.5 g, 1.2 eq.) was added via syringe in a steady stream. The mixture was heated to 50 C. and stirred in the dark for approximately 24 hours. LC/MS of the reaction mixture indicates two peaks both with M+H=265 corresponding to the desired molecular weight. On the basis of relative polarities, the more polar peak was thought to be the N-alkylated product and consisted of approximately 20% of the total. The reaction mixture was allowed to cool to room temperature and the silver salt was removed by filtration of the mixture through a pad of celite. The filter cake was washed with benzene and the organic layer was washed twice with 2% sodium bicarbonate and twice with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified on a Biotage Sp4 65i over a gradient of 5-95% hexanes in ethyl acetate to afford the title compound as a golden oil (25.1 g, 95%). LRMS: 265 (M+H)+.
Example 117; Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-3-(3-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)benzyl)-5-methylimidazolidine-2,4-dione; 117-a) Preparation of 5-(2-(benzyloxy)pyridin-5-yl)-5-methylimidazolidine-2,4-dione; 117-a-1) Preparation of 5-bromo-2-(benzyloxy)pyridine; 2-Hydroxy-5-bromopyridine (1.00 g, 5.75 mmol) was dissolved in N,N'-dimethylformamide (23 mL), and the resultant mixture was added with sodium hydride (purity 50%) (253 mg, 6.32 mmol) under an argon atmosphere under ice-cold conditions. Five minutes later, the resultant mixture was added with benzyl bromide (6.82 mL, 6.90 mmol) at the same temperature, and stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=1/1). 5-Bromo-2-(benzyloxy)pyridine (1.51 g, yield 99%) was obtained as a pale yellow solid.1H-NMR (CDCl3) delta: 5.10 (2H, s), 6.54 (1H, d, J=9.5 Hz), 7.28-7.39 (7H, m).
95%
With silver carbonate; In toluene; at 110℃; for 20h;Inert atmosphere;
To a solution of compound B-i_2 (10.40 g, 59.77 mmol) in anhydrous toluene (400 mE) at room temperature under N2 was added silver carbonate (24.72 g, 89.66 mmol) and benzyl bromide (10.22 g, 59.77 mmol), and the mixture was stirred for 20 hat 110 C. After the reaction finished, the mixture was filtered with kieselguhr, the filter cake was washed with dichioromethane (20 mE*5), and the filtrate was concentrated in vacuo. The residue was purified by flash colunm chromatography eluted with Pet. Ether/EtOAc (10/1) to give compound B-i_3 as white solid (15.00 g, 95%).?H NMR (400 MHz, CDC13) oe: 8.22 (d, J=2.0 Hz, iH), 7.66(dd, J=2.5, 8.5 Hz, iH), 7.48-7.42 (m, 2H), 7.39 (btt., J=7.3Hz, 2H), 7.34 (btd., J=7.0 Hz, iH), 6.73 (d, J=8.5 Hz, iH),5.35 (s, 2H).
With silver carbonate; In benzene; at 50℃;Absence of light;
Example 24; ralphac-(3S,4i?)-iV-cyclopropyl-4-hydroxy-iV- [3 -(2-methoxyethoxy)-5 -(3 -methoxypropyl)benzyl] -4- ( 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3 -yl)piperidine-3 -carboxamide; Step 1: 2-(benzyloxy)-5-bromopyridine; A flame-dried round bottom was charged with 5-bromopyridin-2-ol (1 eq.), benzene (0.19 M), Ag2CO3 (0.6 eq.) and benzyl bromide (1.2 eq.) under N2. The reaction was heated to 50 0C overnight in the dark. The reaction was then cooled and filtered, washing with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (2-4% Et2O in hexanes) to afford the title compound as a white solid.
With silver carbonate; In benzene; at 50℃; for 18h;
3-Bromopyridone (5.00 g, 28.7 mmol), silver carbonate (5.30 g, 19.2 mmol) and benzyl bromide (5.89 g, 34.4 mmol) was stirred in benzene (50 mL) at 50 0C for 18 hours. The reaction mixture was filtered through Celite and partitioned between ethyl acetate and water. The organic layer was separated and concentrated to give a residue which was treated with n-butyl lithium and DMF by literature method to give 3-pyridyl-4-benzyloxy-aldehyde (3.00 g, 49%). MS m/z calculated for (M + H)+ 213, found 213.
To a solution of benzyl alcohol (11.4g, 0.105 mol) in N, N-dimethylformamide (250 ml) was added 70% oily sodium hydride (4.2 g, 0.123 mol) at 0C, followed by stirring as it was for 1.5 hours. Then, 2, 5-dibromopyridine (25 g, 0.106mol) was added thereto, followed by stirring at 70C for 2 hours. After cooling as it was, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous ammonium chloride solution twice, dried over anhydrous magnesium sulfate and concentrated, to give a crude product of the title compound (29.5 g) as a pale yellow liquid.1H NMR (400 MHz, DMSO-d6) delta ppm; 5.33 (2H, s), 6.90 (1H, d, J = 9.0 Hz), 7.30-7.41 (3H, m), 7.41-7.46 (2H, m), 7.92 (1H, dd, J = 2.8, 9.0 Hz), 8.30 (1H, d, J = 2.8 Hz).
Step 1 2-Benzyloxy-5-Bromopyridine A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3 eq), potassium hydroxide pellets (2.4 eq) and dibenzo-18-crown-6 (0.05 eq) in toluene (4 ml/mmol) was refluxed with azeotropic removal of water for 3 hours. After evaporation of the toluene, the resulting mixture was partitioned between chloroform and water. The crude product from the organic phase was recrystallized from ether-hexane to afford the 2-Benzyloxy-5-bromopyridine compound as a solid.
1.9 g (85%)
2-Benzyloxy-5-bromo-pyridine A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, 0.05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spec.: 264.25 (MH)+.
General procedure: A mixture of 2-cyclopropyl-ethanol (4.1 g) and DMF (15 mL) under argon was treated with NaH (60% in oil, 0.45 g). After 4 hours 5-bromo-2-fluoro-pyridine (3.0 g) was added at 0C. After 4 hours at room temperature, the mixture was distributed between water and EA. The organic phase was washed twice (water), dried (Na2SO4) and concentrated. The residue was purified by chromatography (S1O2; EA/heptane 1 :4) to provide the subtitle compound.
46
hexamethyldistannate[ No CAS ]
[ 83664-33-9 ]
argon[ No CAS ]
2-(phenylmethoxy)-5-(trimethylstannyl)-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; dichloromethane; water;
(a) (alpha) A solution of 10.62 g (40.2 mmol) of <strong>[83664-33-9]2-benzyloxy-5-bromopyridine</strong> [J.Org.Chem. 60, 1408 (1995)] and 10.0 ml (15.8 g, 48.2 mmol) of hexamethyldistannate in 100 ml of absolute dioxane was flushed with argon and treated with 2.32 g (2.0 mmol) of tetrakis-(triphenylphoshine)-palladium(IV). The mixture was boiled under reflux for 15 hours. For the working-up, the dark solution was filtered over Speedex and the solvent was distilled off under reduced pressure. The residue was dissolved in 300 ml of methylene chloride, washed twice with 100 ml of water each time, dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product was purified by flash chromatography on silica gel with a 3:1 mixture of hexane and methylene chloride as the eluent. There were obtained 10.4 g (74% of theory) of 2-benzyloxy-5-trimethylstannyl-pyridine as a colourless oil; MS: 349 (M+H+).
(1) Synthesis of 1-[6-(benzyloxy)pyridin-3-yl]propan-1-ol: In a nitrogen atmosphere at -78C, 2.71 M n-BuLi/hexane solution (18.8 mL) was dropwise added to a THF solution of <strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> (12.2 g, 46.2 mmol) synthesised according to the method described in a reference (), and stirred at -78C for 1 hour. At -78C, propionaldehyde (4.3 mL) was dropwise added, and stirred at -78C for 30 minutes and then at room temperature for 3 hours. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried with magnesium sulfate and concentrated. This was purified by silica gel column chromatography to obtain the intended compound (7.15 g, 64 %) as a yellow oil. 1H-NMR (400 MHz, CDCl3, delta): 0.91 (3H, t, J=7.6 Hz), 1.64-1.90 (2H, m), 4.57 (1H, t, J=6.8 Hz), 5.36 (2H, s), 6.78-6.84 (1H, m), 7.29-7.41 (3H, m), 7.43-7.48 (2H, m), 7.59-7.64 (1H, m), 8.07-8.10 (1H, m) ESI-MS (m/e): 244.2 [M+H]+
To a solution of phenylmethanol (12 g, 110.97 mmol) in THF (100 mL) was added NaH (4.88 g, 122.06 mmol) in portions at 0 C over 0.5 hour.After the addition, the mixture was stirred at 20 C for another 1 hour. Then 5-bromo-2- fluoro-pyridine (18.55 g, 105.4 2mmol) was added to the mixture. The resulting mixture was stirred at 20 C for 3 hours. The mixture was poured into saturated aqueous NfL (150 mL) and extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na3S04,filtered and concentrated to give the crude product (27 g, 95.62 mmol, 86% yield) as an oil. LCMS Rt= 0.96 min in 1.5 minchromatography, 5-95AB, MS ESI calcd. for Ci2HnBrNO[M+H+2]+266.0, found 265.8.
rac-tert-butyl (3S,4R)-4-[6-(benzyloxy)pyridin-3-yl]-3-({cyclopropyl[3-(2-methoxyethoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 2: ralphac-tert-butyl (35l,4i?V4-r6-rbenzyloxy)pyridin-3-yll-3-r{cvclopropyir3-(2- methoxyethoxy)-5-(3-methoxypropyl)benzyllamino}carbonyl)-4-hydroxypiperidine-l- carboxylate; To a solution of <strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> from step 1 (2.26 eq.) in THF (0.1M) at -78 0C was added n-butyllithium (2.5 M in hexanes, 2.3 eq.). The mixture was stirred for 30 min at -78 0C and MgBr2 (0.5 M in Et2O, 2.5 eq.) was added. After 30 min at -78 0C, the mixture was added dropwise via syringe to a -78 0C solution of ketoamide 3.1 in THF (0.05 M, 1 eq.) and warmed to 0 0C over 14 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with 2 x EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude was then purified by automated flash chromatography (10-80% EtOAc in hexanes) to afford the title compound.
To a solution OF 2- (BENZYLOXY)-5-BROMOPYRIDINE (10. 0 g, 37.9 mmol) in diethyl ether (200 ML) was added n-butyllithium (1.56 M in n-hexane, 29.1 ML, 45.4 mmol) at - 78C. After the stirring at-78C for 30 minutes, tributyltin chloride was added. The reaction mixture was stirred at-78C for further 1 hour, and quenched with aqueous potassium fluoride slution. The solution was extracted with ethyl ether, and the extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced-pressure. The residue was purified by column chromatography on silica-gel (hexane: ethyl acetate, 98: 2) to give 2- (BENZYLOXY)-5- (TRIBUTYLSTANNYL)- pyridine (15. 4 g, 86%) as a colorless oil.
86%
To a cold (-78 C) solution of <strong>[83664-33-9]2-benzyloxy-5-bromopyridine</strong> (10.0 g, 37.9 mmol) in ether (200 mL) was added n-butyllithium (1.56 M in n-hexane, 29.1 mL, 45.4 mmol). After 30 min, Bu3SnCl was added and the reaction mixture was stirred at -78 C for further 1 hour and quenched with aqueous potassium fluoride solution. The solution was extracted with ether. The separated organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (hexane:ethyl acetate, 98:2) to give 2-benzyloxy-5-tributylstannanylpyridine (15.4 g, 86 %) as a colorless oil.
tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃;Inert atmosphere;
117-a-2) Preparation of 1-(2-(benzyloxy)pyridin-5-yl)ethanone; Under an argon atmosphere, 5-bromo-2-(benzyloxy)pyridine (100 mg, 0.38 mmol) and tetrakis triphenylphosphine palladium (46 mg, 0.04 mmol) were dissolved in toluene (1.5 mL). The resultant mixture was added with 1-ethoxyethenyl tri-n-butyltin (140 mL, 0.42 mmol) and stirred at 100 C. overnight. The reaction solution was cooled down to room temperature, added with 3N hydrochloric acid, and added with saturated sodium bicarbonate water to adjust to pH8. The reaction solution was filtered using celite, added with ethyl acetate, and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using preparative thin-layer chromatography (n-hexane/ethyl acetate=1/1).1-(2-(Benzyloxy)pyridin-5-yl)ethanone (51 mg, yield 59%) was obtained as a pale yellow oil.1H-NMR (CDCl3) delta: 2.39 (3H, s), 5.19 (2H, s), 6.61 (1H, d, J=9.7 Hz), 7.30-7.39 (5H, m), 7.86 (1H, dd, J=2.7, 9.7 Hz), 8.09 (1H, d, J=2.7 Hz).
With triethylamine;tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; at 20 - 100℃;Inert atmosphere;
To a solution of <strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> (600 mg) in DMF (12 mL) were added 3-buten-2-one (400 mg), tris(dibenzylidene acetone) dipalladium(0) (74 mg), triethylamine (460 mg), and tris(o-tolyl)phosphine (70 mg) at room temperature under nitrogen flow, and the mixture was stirred at 100C for 24 hours. The reaction liquid was allowed to cool, and insolubles were filtered through Celite. Water was added to the filtrate, followed by three times extractions with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1-3/2) to obtain (3E)-4-[6-(benzyloxy)pyridin-3-yl]but-3-en-2-one (220 mg).
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 85℃;Inert atmosphere;
General procedure: Compound 8 (7.5 mmol), 9a-c (10.5 mmol), Pd2dba3 (0.19 mmol), 2'-(dicyclohexyl phosphino)-N,N-dimethylbiphenyl-2-amine (0.75 mmol) and NaOtBu (10.5 mmol) were weighed in a 50 mL RB flask and dry toluene (20 mL) was added and flushed with argon for 15 min. Subsequently the reaction mixture was stirred at 85 C overnight, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite and concentrated to obtain a dark brown solid which was flash chromatographed on silica gel eluting with 30% EtOAc in hexanes.
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 85℃;Inert atmosphere;
General procedure: Compound 8 (7.5 mmol), 9a-c (10.5 mmol), Pd2dba3 (0.19 mmol), 2'-(dicyclohexyl phosphino)-N,N-dimethylbiphenyl-2-amine (0.75 mmol) and NaOtBu (10.5 mmol) were weighed in a 50 mL RB flask and dry toluene (20 mL) was added and flushed with argon for 15 min. Subsequently the reaction mixture was stirred at 85 C overnight, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite and concentrated to obtain a dark brown solid which was flash chromatographed on silica gel eluting with 30% EtOAc in hexanes.
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 85℃;Inert atmosphere;
General procedure: Compound 8 (7.5 mmol), 9a-c (10.5 mmol), Pd2dba3 (0.19 mmol), 2'-(dicyclohexyl phosphino)-N,N-dimethylbiphenyl-2-amine (0.75 mmol) and NaOtBu (10.5 mmol) were weighed in a 50 mL RB flask and dry toluene (20 mL) was added and flushed with argon for 15 min. Subsequently the reaction mixture was stirred at 85 C overnight, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite and concentrated to obtain a dark brown solid which was flash chromatographed on silica gel eluting with 30% EtOAc in hexanes.
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 0.333333h;Microwave irradiation;
5To a solution of <strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> (1.5 g, 5.6 mmol), piperidin-4-yl 4- isopropylpiperazine-1-carboxylate (2.15 g, 8.4 mmol) in toluene (30 mL) was added Pd2(dba)3 (1.57 g, 2.2 mmol), BINAP (2.79 g, 4.4mmol) and t-BuQK (3.78 g, 33.8 mmol). The reaction was stirred under the microwave irradiation at 120 t for 20 mm. The mixture was10 diluted with EA (lOOmL) and washed with water (3x50 mL). The organic phase was separated, dried and concentrated to dryness. The residue was taken into dilute HCI (pH=1, l0OmL) and the mixture was extracted with DCM (3x100 mL) to remove impurities. The aqueous phase was made basic (pH=9-10) with solid Na2CQ3 and extracted with DCM (3xlOOmL). The combined organic layers were dried, concentrated and purified by silica gel15 chromatography (EAIMeQH5O1) to give the title compound as a white solid (500 mg, 20%). [LCMS: Rt=2.09 mim, m/z 439.3 (M÷H7j.
20%
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 0.333333h;Microwave irradiation;
To a solution of <strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> (1.5 g, 5.6 mmol), piperidin-4-yl 4-isopropylpiperazine-1-carboxylate (2.15 g, 8.4 mmol) in toluene (30 mL) was added Pd2(dba)3 (1.57 g, 2.2 mmol), BINAP (2.79 g, 4.4 mmol) and t-BuOK (3.78 g, 33.8 mmol). The reaction was stirred under the microwave irradiation at 120 C. for 20 min. The mixture was diluted with EA (100 mL) and washed with water (3×50 mL). The organic phase was separated, dried and concentrated to dryness. The residue was taken into dilute HCl (pH=1, 100 mL) and the mixture was extracted with DCM (3×100 mL) to remove impurities. The aqueous phase was made basic (pH=9-10) with solid Na2CO3 and extracted with DCM (3×100 mL). The combined organic layers were dried, concentrated and purified by silica gel chromatography (EA/MeOH=50/1) to give the title compound as a white solid (500 mg, 20%). [LCMS: Rt=2.09 mim, m/z 439.3 (M+H)+].
(S)-1-(6-(benzyloxy)pyridin-3-yl)pyrrolidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 16h;Inert atmosphere;
To a solution of<strong>[83664-33-9]2-(benzyloxy)-5-bromopyridine</strong> (2.0 g, 7.60 mmol) in 25 mL of DME was added Cul (290 mg, 1.52 mmol), K2C03 (2.1 g, 15.21 mmol) and L-prolinemethyl ester hydrochloride (1.5 g, 9.12 mmol) at rt under argon. The reaction mixture was heated at 140 C for 16 h. TLC indicated presence of some SM and formation of a polar spot. The reaction mixture was cooled to rt, poured in to ice coid water (500 mL) and extracted with EtOAc (2 100 mL) to remoye staring material. The aqueous layer was acidifed with sat. KHSO4 solution and then extracted with EtOAc (2 X 250 mL). The combined organic layer was washed with water, brine, dried oyer Na2SO4, filtered and concentrated under reduced pressure to afford 1.7 g of (S)-1 -(6-(benzyloxy)pyridin-3 -yl)pyrrolidine-2-carboxylic acid (45%, LC-MS 84%).
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