2-Hydroxymethyl-5-bromopyridine

Light yellow Cryst

To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol) dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was added sodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45 minutes 0.5 mL water was added and the mixture and evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g, 86percent) as pale-yellow oil.Example 14.1: (5-Bromo-pyridin-2-vl)-methanolA mixture of 5-bromo-pyridine-2-carbaldehyde (0.5 g, 2.68 mmol) in ethanol (30 ml_) was cooled in an ice bath. Sodium borohydride (0.41 g, 10.75 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, dried, the residue dissolved in dichloromethane (30 ml.) and quenched with a saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted further with dichloromethane (2 x 10 ml_). The combined organic phase was dried over sodium sulfate and concentrated to give the product as an off- white solid (426 mg, 84 percent). To a stirred solution of 5-bromopicolinaldehyde (0.5 g, 2.68 mmol, 1.0 eq) in methanol (10 mL) was added NaBHStep 2 In the 0 °C ice bath, add NaBH4 (1.220 g) to a solution of 5-bromopyridinecarboxaldehyde (2.010 g) in methanol (30 mL). After adding NaBH4, remove the water bath and naturally warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was quenched with EtOAc. Extracted with EA (50 mL × 2), the combined organic phases were washed with a saturated NaCl solution. Drying over anhydrous Na2SO4 and concentrated to afford 1.940 g (5-bromopyridin-2-yl)methanol.To a flask containing 5-Bromo-2-methyl-pyridine 1-oxide (1.14g, 6.20mmol) purged with argon was slowly added trifluoroacetic acid (lOmL). The mixture stirred for 0.5hrs at room temperature and 0.5hrs at 53°C. The mixture was cooled and diluted with saturated sodium bicarbonate. The aqueous solution stirred overnight at room temperature and was extracted with ethyl acetate, and concentrated to afford the title compound (895mg, 77percent) as a brown solid. *H NMR (300 MHz, CDCI3): 8 8.64 (s, 1H), 7.83 (d, 1H), 7.22 (d, 1H), 4.75 (s, 2H).A-3: 6-Methoxymethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64percent) of the title compound.MS: M=188.0 190.0 (M+H)+A-3: 6-Methoxymethyl-3-fpyrimidin-5-ylamino)-pyridine-2-carboxylic acid methyl esterStep 1: 5-Bromo-pyridin-2-yl-methanolTo a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0°C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0°C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 percent) of the title compound.+MS: M = 188.0 190.0 (M+H)To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64percent) of the title compound. MS: M=188.0 190.0 (M+H)+To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0°C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0°C, quenched with MeOH and refluxed for lh. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64 percent) of the title compound. MS: M = 188.0 190.0 (M+H)+5-bromo-2-pyridinecarboxylic acid, methyl ester (648mg, 3mmol) was dissolved in a solution of methanol (10ml) was slowly added sodium borohydride (340mg, 9mmol) in an ice bath after complete addition the ice bath was removed, warmed to at room temperature, the reaction was stirred for 12 hours; then 1N HCl was added to adjust PH 1, again was added saturated sodium bicarbonate solution to adjust PH 8, and then extracted with ethyl acetate, the organic phase was dried over anhydrous magnesium sulfate and filtered , concentrated under reduced pressure to give 5-bromo-2-pyridinemethanol (535 mg of the, white solid), yield: 94.8percent.Intermediate 5, 4 (5 -Bromopyridin-2-y] (methanol Methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.27 mmol) was dissolved in ethanol (20.0 mL). Sodium borohydride (1 .05 g, 27.8 mmol) was added at 0°C, and the mixture was stirred at room temperature for 18 h. The mixture was then concentrated under reduced pressure, quenched with 1 N hydrochloric acid, neutralized with solid potassium carbonate and extracted with dichloro- methane. The organic layer was dried over magnesium sulfate and evaporated to give 1.57 g (90percent of th.) of the title compound. LC-MS (method 6): Rt = 0.56 min; MS (ESIpos): m/z (percent) = 188.0 (100) [M+H]+.Manufacturing Example 54-1-1 (5-Bromo-pyridin-2-yl)-methanol; To a toluene (300 mL) solution of 2, 5-dibromopyridine (10.0 g, 42.2 mmol) was added dropwise n-butyl lithium (2.55 M n-hexane solution, 18.2 mL, 46.4 mmol) on a dry ice-ethanol bath (-78° C.) under nitrogen atmosphere, which was stirred for 2 hours at -78° C. N, N-dimethylformamide (3.7 g, 50.6 mmol) was then added dropwise thereto and stirred for 10 minutes at -78° C. Sodium borohydride (3.20 g, 84.4 mmol) and methanol (20.0 mL) were then added and stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1-->2:1) to obtain the title compound (4.70 g, 59.2percent).Step II; A slurry of compound 36 (10.0 g, 33.1 mmol) in TBME (100 ml) was treated with 20percent potassium carbonate (20 ml) solution and stirred at room temperature for 1 h. The layers were separated and the organic layer was washed with water. The solution thus obtained was concentrated to 10 mL volume and 20 mL heptanes was added at 45-50 C. Solution was cooled to 20-25 C and additional 20 mL heptanes was charged. Reaction was agitated at 20-25 C for 2 hours and filtered. Product was dried overnight under vacuum at 15-25 C to give 5.0 g (80percent) of product. Part A: Compound 413 (3.5 g, 20.7 mmol) was dissolved in methylene chloride (100 ml) and m-CPBA (4.95 g, 28.9 mmol) was added. The reaction mixture was stirred for two hours and then quenched with saturated sodium carbonate and stirred overnight. The organic layer was dried over sodium sulfate and the concentrated to provide a yellow solid (3.8 g). The solid was placed under argon and trifluoroacetic anhydride (15 mL) was added slowly. The reaction was stirred for 30 minutes at room temperature and then refluxed for 30 minutes. The reaction was cooled to room temperature and quenched slowly with saturated sodium bicarbonate. Methylene chloride was added and the organic layer was washed dried over sodium sulfate and concentrated. Column chromatography (2 to 1 ethyl acetate/hexanes) provided the desired product (3.O g, 78percent).Example 593-(((5-(l-(4-(2, 3-Dimethylphenoxy)butanoyl)-l, 2, 3, 4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBHTo a solution of 5-bromo-pyridine-2-carbaldehyde (0.30 g, 1.62 mmol) in DCM (15 ml.) was added morpholine (0.1O g, 1.13 mmol) and glacial acetic acid (2 mL) and stirred the resulting reaction mixture for 30 min. followed by addition of sodium triacetoxyborohydride (0.86 g, 4.05 mmol). The resulting reaction mixture was stirred for 4 h at room temperature. After completion of reaction (TLC monitoring), the reaction mixture was diluted with DCM, added water and extracted the organic layer. The organic layer was dried over Na

Molecular Weight:188.02
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:186.96328
Monoisotopic Mass:186.96328
Topological Polar Surface Area:33.1
Heavy Atom Count:9
Complexity:89.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes