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With tetrabutyl ammonium fluoride In tetrahydrofuran at -78 - 0℃; for 0.75 h;
To a solution of 2.389 g of 2-chloro-4-trimethylsilanylethynyl-pyridine (11.39 mmol) in THF (90 ml) were added 11.39 ml of a 1 M TBAF solution in THF at -78° C. and the reaction mixture was stirred for 45 min at 0° C. Then saturated NH4Cl solution was added and the THF was removed under reduced pressure. The aqueous mixture was extracted with diethylether and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The remaining residue was purified by column chromatography (pentane/diethylether 100:0 to 4:1) to give 2-chloro-4-ethynyl-pyridine (1.427 g, 91percent) as an off-white solid. 1H-NMR (CDCl3, 300 MHz: δ 3.36 (s, 1H), 7.27 (dd, J=5 and 1 Hz, 2H), 7.40 (br s, 1H), 8.37 (d, J=8 Hz, 2H).
91%
Stage #1: With tetrabutyl ammonium fluoride In tetrahydrofuran at -78 - 0℃; for 0.75 h; Stage #2: With water; ammonium chloride In tetrahydrofuran
b) Preparation of 2-chloro-4-ethynyl-pyridine:; To a solution of 2.389 g of 2-chloro-4-trimethylsilanylethynyl-pyridine (11.39 mmol) in THF (90 ml) were added 11.39 ml of a IM TBAF solution in THF at -780C and the reaction mixture was stirred for 45 min at O0C. Then saturated NH4Cl solution was added and the THF was removed under reduced pressure. The aqueous mixture was extracted with di- ethylether and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The remaining residue was purified by column chromatography (pentane/diethylether 100:0 to 4:1) to give 2-chloro-4-ethynyl- pyridine (1.427 g, 91percent) as an off-white solid. m-NMR (CDCl3, 300 MHz): δ 3.36 (s, IH), 7.27 (dd, J=5 and 1 Hz, 2H), 7.40 (br s, IH), 8.37 (d, J=8 Hz, 2H).
57.2%
With tetrabutyl ammonium fluoride In tetrahydrofuran for 0.05 h;
To a solution of 6(0.4g, I 9iminoi) in 10 mL THF was added IM TBAF over 3 minutes, TLC showed the starting material was consumed. The reaction mixture was then concentrated in vacuo. The crude product was purified by silica gel column chromatography to give product 7(0.15g. yield: 57.2 percent).LCMS: m/ i38(M+Hi.
Reference：
[1] Patent: US2007/185058, 2007, A1, . Location in patent: Page/Page column 12
[2] Patent: WO2007/90752, 2007, A1, . Location in patent: Page/Page column 30
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5270 - 5290
[4] Patent: WO2017/117708, 2017, A1, . Location in patent: Page/Page column 18
[5] Chemical Communications, 2013, vol. 49, # 20, p. 2037 - 2039
2
[ 153034-86-7 ]
[ 945717-09-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5270 - 5290
[2] Chemical Communications, 2013, vol. 49, # 20, p. 2037 - 2039
[3] Patent: WO2017/117708, 2017, A1,
With sodium cyanoborohydride; acetic acid In ethanol at 105℃; for 48h;
S4.C.c
A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65 ml of 4-tert-butyl-benzylamine (15.11 mmol), 0.58 ml of acetic acid (10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07 mmol) in ethanol (12 ml) were heated to 105° C. in a sealed tube for 2 d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOH solution and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. After column chromatography (heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound were isolated as a brown liquid. MS (ISP) 303.2 (M+H)+.
55%
Stage #1: 2-chloro-4-ethynylpyridine; 4-(1,1-dimethylethyl)-benzenemethanamine With sodium cyanoborohydride; acetic acid In ethanol at 105℃; for 48h; Heating in a sealed tube;
Stage #2: With sodium hydroxide; water In ethanol at 20℃;
S4-C.c
c) Preparation of (4-tert-butyl-benzyl)-[2-(2-chloro-pyridin-4-yl)-ethyl]-amine:; A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65 ml of 4-tert-butyl- benzylamine (15.11 mmol), 0.58 ml of acetic acid (10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07 mmol) in ethanol (12 ml) were heated to 1050C in a sealed tube for 2 d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOH solution and extracted with DCM. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. After column chromatography (heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound were isolated as a brown liquid. MS (ISP) 303.2 (M+H)+.
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