(5-BROMO-PYRIDIN-3-YL)-METHANOL

Sodium borohydride (2.2 g, 59.1 mmol) was added to a suspension of 5-bromo-pyridine-3- carbaldehyde (10. O g, 53.7 mmol) in MeOH (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour before it was quenched by the addition of water (5.0 mL). Evaporation of solvents afforded a light yellowish oil which was re-dissolved in EtOAc and washed with water. The organic layer was dried over anhy. Na[A] To a solution of 5-bromonicotinaldehyde (XLV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHTo a solution of 5-bromonicotinaldehyde (XLVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1 Step 1 (0829) To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1 To a solution of 5-bromonicotinaldehyde (XXXIX) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XL VI) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. 1H NMR (CDClTo a solution of 5-bromonicotinaldehyde (XXXVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over Mg504, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLIV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘H NMR (CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘HNMR(CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over Mg504, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘H NMR (CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).j0664j To a solution of 5-bromonicotinaldehyde (LV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over Mg504, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (LXII) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘H NMR (CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDCi3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C[0664] To a solution of 5-bromonicotinaldehyde (LV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (LXII) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDC1To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBLL (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDCh, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for CTo a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBLL (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSC , filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDC1To a solution of 5-bromonicotinaldehyde (LV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHi (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/i, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (LXII) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. 'HNMR (CDCI3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for CTo a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘H NMR (CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of 5-bromonicotinaldehyde (LV) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (LXII) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDC1To a solution of 5-bromonicotinaldehyde (XXXVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLIV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. 'HNMR (CDCI3, 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for CStep 1 [0644] To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. 1H NMR (CDClStep 1 [0645] To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBLL (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDC1[0641] To a solution of 5-bromonicotinaldehyde (XXXVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaB (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLIV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. TiNMR iCDC , 500 MHz) δ ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for CTo a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBLL (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO/t, filtered and concentrated in vacuo to afford (5- bromopyridin-3-yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. NMR (CDC1To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over Mg504, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘HNMR(CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of 5-bromonicotinaldehyde (LIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1 Step 1 (0829) To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1 (0831) To a solution of 5-bromonicotinaldehyde (XXXVIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1 (0853) To a solution of 5-bromonicotinaldehyde (LIII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBHStep 1: 19.1Step l : Synthesis of (5-bromopyridin-3-yl)methanol5-Bromonicotinic acid (1.00 g; 4.95 mmol) is dissolved in 30 mL anhydrous THF and triethylamine (0.76 mL; 5.44 mmol ) is added by syringe, the flask is flushed with argon and cooled to 0 °C. Ethylchloroformate (0.52 mL; 5.44 mmol ) is then added dropwise by syringe and the mixture is stirred at RT for 60 min. The crude mixture is filtered and the residue is washed twice with 5 mL THF, the filtrate is transferred to a 100 mL RBF and cooled to 0 °C. Sodium borohydride (468 nig: 12.4 mmol) is added in portions, followed by 5 ml , 1 LO which is added dropwise via a syringe. The mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is extracted 6 times with EtOAc, the organic layers are combined and dried over anhydrous sodium sulfate, concentrated in vacuo and deposited on silica. Purification by column chromatography on silica gel (pre washed with 1percent NEtTo a solution of 5-bromonicotinic acid (20.00 g, 97.00 mmol) in anhydrous THF (250 mL) was added a solution of BH(5-bromopyridin-3-yl)methanol. To a cold (0° C.) solution of ethyl-5-bromonicotinate (1.0g, 4.3 mmoL) in MeOH (15mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3x). The extracts were combined, dried (MgSOTo a cold (0b) To a cold solution of ethyl 5-bromonicotinate (1.003 g, 4.36 mmol) in methanol (15 ml, 371 mmol) was added sodium borohydride (0.652 g, 17.23 mmol) portion wise on 10 min. The reaction was stirred for 30 min. at 0 °C. The reaction was quenched with water and extracted three times with CHA solution of 9 g (40 mmol) of ethyl 5-bromo- nicotinate in 25 ml of methanol is added dropwise, at room temperature, to a suspension of 14.8 g (400 mmol) of sodium borohydride in 75 ml of methanol. After addition, the reaction medium is refluxed for 2 hours. The reaction medium is evaporated to dryness, taken up in aqueous sodium hydroxide solution to pH 9, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. 3.7 g (50percent) of (5-bromopyrid-3-yl)- methanol are obtained.To a stirred solution of methyl 5-bromonicotinate (10 g, 43.47 mmol) in methanol (100 mL) NaBHA solution of 5-bromo-nicotinic acid methyl ester (3 g, 13.1 mmol) dissolved in absolute ethanol (50 ml) was added portionwise sodium borohydride (1.48 g, 39.1 mmol) Reaction at room temperature for 30min, and then heated to 60 ° C reaction, 5h after the reaction is complete. Adding water to quench the reaction, distilling the ethanol, adding ethyl acetate, shaking the liquid, drying with anhydrous sodium sulfate, filtering and evaporating the solvent. The residue was chromatographed on silica gel to give a pale yellow oil (1.1g, 45percent).j0641j To a solution of 5-bromonicotinaldehyde (XXXVII) (2.0 g, 10.8 mmol, 1 eq) in MeOH (20 mL) was added NaBH4 (2.4 g, 64.9 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was diluted in water (15 mL), the aqueous phase was extracted with DCM (10 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford (5-bromopyridin-3- yl)methanol (XLIV) (1.8 g, 9.57 mmol, 90.0percent yield) as a colorless oil. ‘H NMR (CDC13, 500 MHz) ppm 4.73 (s, 2H), 7.90 (s, 1H), 8.47 (s, 1H), 8.57 (s, 1H). ESIMS found for C6H6BrNO mlz 188.0 (M+H).To a solution of compound E6 (50 g, 0.25 mol) in 400 ml_ of anhydrous THF was added a solution of BHUnder a nitrogen atmosphere, a solution of 5-bromonicotinic acid (5.05 g, 25.0 mmol) and thionyl chloride (10 mL) was stirred and heated. Under a nitrogen atmosphere, a solution of 5-bromonicotinic acid (5.05 g, 25.0 mmol) and thionyl chloride (10 mL) was stirred and heated.

Pharmaceutical intermediates

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