* 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] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 822 - 839
[3] Patent: US2005/54654, 2005, A1, . Location in patent: Page/Page column 36
2
[ 66572-56-3 ]
[ 118289-16-0 ]
Yield
Reaction Conditions
Operation in experiment
75.21%
With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 20℃; for 3 h;
To a solution of 215.1 (2g, 9.9mmol, l .Oeq) in tetrahydrofuran (30mL) at 0°C, boron trifluoride etherate (4.18g, 29.7mmol, 3.0eq) was added dropwise. Reaction mixture was stirred at room temperature for 3h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 1.1 (1.4g, 75.21percent). MS(ES): m/z 189.65 [M]+
Reference：
[1] Patent: WO2018/71794, 2018, A1, . Location in patent: Paragraph 00983; 00984
[2] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2866 - 2875
[4] Patent: US2005/54654, 2005, A1, . Location in patent: Page/Page column 36
[5] Patent: EP2098517, 2009, A1, . Location in patent: Page/Page column 32
3
[ 118289-17-1 ]
[ 118289-16-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 1 h; Inert atmosphere
To a solution of 2-bromopyridine-4-carbaldehyde (20 g, 107.52 mmol) in MeOH (150 mL) was added portion wise sodium borohydride (12.0 g, 322.56 mmol) at 0° C. under inert atmosphere. The mixture was stirred at RT for 1 h. Saturated NH4Cl solution was added followed by extraction with EtOAc (3*200 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to obtain i (18.0 g, 90percent). 1H NMR (DMSO-d6, 400 MHz): δ 8.30 (d, J=4.8 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J=4.8 Hz, 1H), 5.55 (t, J=6.0 Hz, 1H) and 4.53-4.54 (d, J=5.6 Hz, 2H).
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 18, p. 2866 - 2875
5
[ 695-34-1 ]
[ 118289-16-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
6
[ 4926-28-7 ]
[ 118289-16-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2446 - 2458
7
[ 118289-16-0 ]
[ 83004-14-2 ]
Yield
Reaction Conditions
Operation in experiment
50%
With phosphorus tribromide In toluene at 0 - 100℃; for 0.5 h; Inert atmosphere
To the solution of i (18 g, 95.74 mmol) in toluene (180 mL) was added dropwise phosphorous tribromide (13.4 mL, 143.62 mmol) at 0° C. under inert atmosphere. The mixture was heated at 100° C. for 30 min. The reaction was cooled at 0° C. and NaHCO3 solution added followed by extraction with EtOAc (2*500 mL). The combined organic layer were dried (Na2SO4) and evaporated in vacuo. The residue was purified over silica eluting with 15percent EtOAc:Hexane to obtain ii (12.0 g, 50percent). 1H NMR (CDCl3, 400 MHz): δ 8.35 (d, J=4.8 Hz, 1H), 7.51 (s, 1H), 7.26 (d, J=6.0 Hz, 1H) and 4.34 (s, 2H). MS 251.80 [M+H]+.
With manganese(IV) oxide; In dichloromethane; at 20℃; for 54h;
149 g (1714 mmol) of manganese dioxide is added in measured quantities to 28.0 g (148.9 mmol) of 2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane within 6 hours. Then, stirring is continued at room temperature for 48 hours. It is suctioned off over Celite and concentrated by evaporation. 16.4 g of solidifying white oil accumulates.
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a solution of 215.1 (2g, 9.9mmol, l .Oeq) in tetrahydrofuran (30mL) at 0C, boron trifluoride etherate (4.18g, 29.7mmol, 3.0eq) was added dropwise. Reaction mixture was stirred at room temperature for 3h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 1.1 (1.4g, 75.21%). MS(ES): m/z 189.65 [M]+
Production of 2-Bromo-4-hydroxymethyl-pyridine 30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol) of <strong>[66572-56-3]2-bromo-isonicotinic acid</strong> in 1.2 1 of THF. Then, it is cooled to -10 C. and mixed drop by drop with 38.2 ml (295 mmol) of isobutyl chloroformate. After stirring has been continued for one hour at -10 C., it is cooled to -70 C. and mixed drop by drop with 590 ml (590 mmol) of LiAlH4 solution (1 M in THF). After stirring is continued for one hour at -70 C., it is allowed to reach -40 C. 600 ml of 50% acetic acid is added. It is stirred overnight at room temperature. The insoluble components are suctioned off, and the filtrate is concentrated by evaporation. The residue is purified on silica gel with hexane and hexane/ethyl acetate 1:1. 28.0 g of white solidifying oil accumulates.
1) Production of (2-bromopyridin-4-yl)methanol To a solution of <strong>[66572-56-3]2-bromoisonicotinic acid</strong> (678 mg) in tetrahydrofuran (30 ml), 8.4 ml of borane-tetrahydrofuran complex (1.17M tetrahydrofuran solution) was added, and the reaction solution was stirred overnight at room temperature. To the reaction solution was added 7.9 ml of 1N aqueous sodium hydroxide, and the mixture was stirred for 2 hours. The reaction solution was diluted with a saturated aqueous sodium chloride solution, extracted with diethyl ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: chloroform/(chloroform/methanol (9:1)) (100:0-0:100)) to afford the title compound as a white crystal.
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;Inert atmosphere;
To a solution of <strong>[118289-17-1]2-bromopyridine-4-carbaldehyde</strong> (20 g, 107.52 mmol) in MeOH (150 mL) was added portion wise sodium borohydride (12.0 g, 322.56 mmol) at 0° C. under inert atmosphere. The mixture was stirred at RT for 1 h. Saturated NH4Cl solution was added followed by extraction with EtOAc (3*200 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to obtain i (18.0 g, 90percent). 1H NMR (DMSO-d6, 400 MHz): delta 8.30 (d, J=4.8 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J=4.8 Hz, 1H), 5.55 (t, J=6.0 Hz, 1H) and 4.53-4.54 (d, J=5.6 Hz, 2H).
With sodium tetrahydroborate; In methanol; at 0 - 25℃;Inert atmosphere;
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), <strong>[118289-17-1]2-bromo-pyridine-4-carbaldehyde</strong> (904 mg, 4.86 mmol) was dissolved in MeOH (10 mL). NaBH4 (236 mg, 5.99 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted <n="85"/>with EA (3 x 20 ml_). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. TLC: rf (1 :1 hept-EA) = 0.22. LC-MS-conditions 02: tR = 0.63 min; [M+H]+ = 188.33.
With dibromo sulfoxide; In dichloromethane; at 0℃;
(2-Bromo-4- pyridyl)methanol (2.00 g, 10.6 mmol) was dissolved in dry CH2Cl2 (10 mL) and then SOBr2 (0.90 mL, 11.7 mmol) was added at 00C. The reaction mixture was stirred overnight, then the solvent was evaporated and the residue crystallised from MeOH-Et2O to give the title compound (2.81 g, 79 %) as a white solid. APCI MS m/z 252.2 (M + H). 1H-NMR (400 MHz, (CD3)2SO) delta 8.39 (d, J= 5.0 Hz, IH), 7.74 (d, J= 0.9 Hz, IH), 7.51 (dd, J- 5.0, 1.4 Hz, IH), 4.66 (s, 2H).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; toluene; at 80℃; for 5h;Inert atmosphere;
16.5 ml (0.3 mmol) of an aqueous solution of potassium carbonate having a concentration of 2M and 0.4 g (0.1 mmol) of 1,1'- bis (diphenylphosphino) ferrocene palladium ( I I ) dihydro- chloride are added under a stream of nitrogen to a solution containing 2.0 g (0.1 mmol) of 2- bromopyridine-4-methanol and 2.2 g (0.1 mmol) of 2- (trifluoromethyl) phenylboronic acid in 30 ml of toluene. The mixture is stirred at 80C for 5 hours then 20 ml of water are added. After extraction with ethyl acetate, the organic phase is dried over sodium sulphate, filtered and evaporated. The residue obtained is purified by chromatography over silica gel eluted with a 60/40 heptane/ethyl acetate mixture. 2.3 g (85%) of [2- (2-trifluoromethylphenyl) pyridin-4-yl] methanol are obtained in the form of a yellow oil.
With phosphorus tribromide; In toluene; at 0 - 100℃; for 0.5h;Inert atmosphere;
To the solution of i (18 g, 95.74 mmol) in toluene (180 mL) was added dropwise phosphorous tribromide (13.4 mL, 143.62 mmol) at 0 C. under inert atmosphere. The mixture was heated at 100 C. for 30 min. The reaction was cooled at 0 C. and NaHCO3 solution added followed by extraction with EtOAc (2*500 mL). The combined organic layer were dried (Na2SO4) and evaporated in vacuo. The residue was purified over silica eluting with 15% EtOAc:Hexane to obtain ii (12.0 g, 50%). 1H NMR (CDCl3, 400 MHz): delta 8.35 (d, J=4.8 Hz, 1H), 7.51 (s, 1H), 7.26 (d, J=6.0 Hz, 1H) and 4.34 (s, 2H). MS 251.80 [M+H]+.
Stage #1: (2-bromopyridin-4-yl)methanol With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h;
Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 3h;
215 Synthesis of compound 215.3
To a solution of 215.2 (1.4g, 7.4mmol, l .Oeq) in tetrahydrofuran (15mL) at 0°C, sodium hydride (0.35g, 14.8mmol, 2.0eq) was added. Reaction mixture was stirred at 0°C for 20 min. Then, methyl iodide (1.57g, 11.2mmol, 1.5eq) was added. Reaction mixture was stirred at room temperature for 3h. After completion of reaction, reaction mixture was transferred in ice-water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain 215.3 (0.7g, 46.53%). MS(ES): m/z 203.58 [M]+
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