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c) (5-Cyano-pyridin-3-yl)-methanol A yellow solution of (5-bromo-pyridin-3-yl)-methanol (1.30 g, 6.91 mmol), anhydrous DMF (27.7 mL) and copper (1) cyanide (0.92 g, 10 mmol) was heated at 170 C. for 36 h. The reaction mixture was cooled to room temperature and additional copper (I) cyanide (0.058 g, 0.65 mmol) was added to the yellow solution. The reaction flask was then heated at 170 C. for an additional 12 h. The yellow solution was cooled to room temperature, quenched with NaHCO3 (120 mL), and extracted with EtOAc (3*100 mL). The combined organic extracts were dried over MgSO4, filtered through sintered glass and concentrated to yield 0.502 g (54%) of a brown oil residue. The residue was purified by column chromatography (elution with EtOAC:hexanes, 1:1) and yielded 0.225 g (24%) of the title compound as a white solid. 1H NMR (CDCl3): 8.80 (dd, J=2.20, 1.92 Hz, 2H), 8.03 (m, J=2.20, 1.92 Hz, 1H), 4.83 (d, J=4.7 Hz, 2H).
EXAMPLE 2 5-[[(5-Bromo-3,6-dihydro-2-methyl-6-oxo-4-pyrimidinyl)amino]methyl]-3-pyridinecarbonitrile A stirred mixture of 5-hydroxymethyl-3-bromopyridine (8.50 g, 45.2 mmol) and copper (I) cyanide (10.1 g, 11.3 mmol) in pyridine (50 mL) was heated in a sealed pressure reaction vessel at 165 C. for 20 hours. After cooling to 23 C., the mixture was diluted with concentrated ammonium hydroxide (15 mL) and saturated aqueous ammonium chloride (60 mL), after stirring for 2 hours, the mixture was treated with chloroform (50 mL) and allowed to set for 72 hours. The aqueous layer was then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 inch column, 4:1 EtOAc:hexane as eluant) followed by crystallization from diethyl ether to afford 5-hydroxymethyl-3-pyridinecarbonitrile (5.42 g, 40.4 mmol, 89% yield): Rf 0.49 (EtOAc); 1 H NMR (CDCl3, 200 MHz)delta8.80 (m, 2H), 8.03 (s, 1H), 4.83 (s, 2H).
19.2 5-(hydroxymethyl)pyridine-3-carbonitrile A mixture of 4.2 g (22.34 mmol) of (5-bromopyridin-3-yl)methanol and 5 g (55.84 mmol) of copper cyanide in 22 mL of pyridine is heated for 20 hours in a sealed tube at 160 C. After cooling to room temperature, the medium is taken up in 10 mL of concentrated aqueous ammonia and 30 mL of saturated NH4Cl solution and then stirred for 2 hours. The medium is then extracted with 200 mL of a DCM/iPrOH mixture (85/15), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 98/2 DCM/MeOH mixture. 2.13 g of 5-(hydroxymethyl)pyridine-3-carbonitrile are obtained in the form of a white solid. Yield=51% 1H NMR, CDCl3, 400 MHz, delta (ppm): 8.9 (d, 2H); 8.0 (s, 1H); 4.9 (s, 2H); 2.3 (bs, 1H)
42%
With pyridine; at 165℃; for 48h;Sealed tube;
The IIb-5-1 (5.00 g, 26.5 mmol, 1.0 equivalent weight) and CuCN (6.00 g, 65.0 mmol, 2.5 equivalent weight)were respectively weighted and dissolved in Py, and the mixture was disposed in a sealed tube and heated to 165C.After reacting for 48h, the end of the reaction was detected by TLC test. The reaction mixture was cooled to roomtemperature, diluted with aq. NH3 and aq. NH4Cl, and extracted with CHCl3 (150mL33). The organic phase was combinedand washed with water (100mL32), washed with saturated NaCl solution (100mL32), and dried with anhydrous Na2SO4.The organic phase was concentrated. The crude product was separated and purified by column chromatography, toobtain 1.50g solid IIb-5-2 (the yield was 42%).1H-NMR (400 MHz, CDCl3) delta ppm 8.81 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H), 4.83 (s, 2H).
With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 170℃; for 4h;Microwave irradiation;
To a stirred solution of (5-bromopyridin-3-yl)methanol (3.1 g, 16.57 mmol) in DMF (50 mL) at room temperature were added Zn(CN)2 (2 g, 16.57 mmol), dppf (460 mg, 0.828 mmol) and Pd2(dba)3 (307 mg, 0.335 mmol). The reaction mass was heated to 170 C. under microwave for 4 h. The reaction mass was filtered through celite pad, the filtrate was concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography (100-200) using CH2Cl2 in MeOH (90:10) as eluent and obtained 5-(hydroxymethyl)nicotinonitrile (800 mg, yield: 35% LC/MS: 88%) as a brown solid. NMR (CDCl3, 400 MHz): delta 8.81 (dd, J=9.6 Hz, 6.0 Hz, 2H), 8.03-8.02 (m, 1H), 4.83 (s, 2H), 2.11 (bs, 1H).
13.86%
With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; zinc; In 1,2-dimethoxyethane; at 130℃; for 15h;Inert atmosphere; Sealed tube;
A solution of (5-bromo-3-pyridyl)methanol (3 g, 15.96 mmol), Zn(CN)2(2.06 g, 17.55 mmol), DPPF (0.88g, 1.60 mmol), Zn (O. lg, 1.60 mmol) and Pd(dppf)Cl2(1.17 g, 1.60 mmol) in DME (40 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 130 C for 15 hr under N2atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (silica gel, Petroleum ether : Ethyl acetate=40: l to 0: 1) to give 5-(hydroxymethyl)pyridine-3-carbonitrile (1 g, 13.86% yield, 89% purity) as a black solid that can be used directly for next step. MS: m/z found 135.1 [M+H]+; 1H NMR (400 MHz, CDCl3): d 8.72 (s, 2H), 7.95 (s, 1H), 4.75 (s, 2H).
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