(5-METHOXYPYRIDIN-2-YL)METHANOL

To a solution of compound 12 (1.40 g, 7.7 mmol) in MeOH (30 mL) was added an excess of KOH and the mixture was refluxed 2 h. The solvent was removed in vacuo, and the residue was partitioned between CH4) 5-methoxypyridine-2-carboxylic acid methyl ester 8 (6.2 g, 37.1 mmol) was dissolved in toluene (370 ml) under a nitrogen atmosphere and cooled to -78°C. 1.0 M diisobutylaluminum hydride in toluene (130 ml, 130.0 mmol) was added through a syringe and the mixture was stirred at 0°C for 90 minutes. The mixture was then quenched with 300 ml of saturated aqueous potassium sodium tartrate and warmed to 25 °C for 1 hour. The reaction mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous MgSOTo a mixture of 5-methoxypicolinaldehyde (326mgs, 2.36mmol) in MeOH (10 mL) was added NaBHTo a solution of compound 12 (1.40 g, 7.7 mmol) in MeOH (30 mL) was added an excess of KOH and the mixture was refluxed 2 h. The solvent was removed in vacuo, and the residue was partitioned between CH4) 5-methoxypyridine-2-carboxylic acid methyl ester 8 (6.2 g, 37.1 mmol) was dissolved in toluene (370 ml) under a nitrogen atmosphere and cooled to -78°C. 1.0 M diisobutylaluminum hydride in toluene (130 ml, 130.0 mmol) was added through a syringe and the mixture was stirred at 0°C for 90 minutes. The mixture was then quenched with 300 ml of saturated aqueous potassium sodium tartrate and warmed to 25 °C for 1 hour. The reaction mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous MgSOTo a mixture of 5-methoxypicolinaldehyde (326mgs, 2.36mmol) in MeOH (10 mL) was added NaBHPreparation 21(5-Methoxypyridin-2-yl)methanolTrifluoroacetic anhydride (28.2 mL, 203 mmol) was added dropwise to an ice cooled solution of the product from preparation 20 (-135 mmol) in dichloromethane (500 mL), the mixture was allowed to warm to room temperature and stirred overnight. TIc analysis indicated still largely starting material so a further portion of trifluoroacetic anhydride (15 mL, 108 mmol) was added dropwise and the mixture was allowed to stir for a further 27 hours. The reaction was quenched by the cautious addition of methanol (250 mL) and left to stir for 30 minutes before being concentrated in vacuo. 2.5 M sodium hydroxide (100 mL) was then added cautiously and the mixture was extracted with dichloromethane (4 x 100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired product (12 g, 64%) contaminated with recovered starting material (-15 mol%). 1H NMR (CDCI3, 400 MHz) delta 3.80 (3H, s), 4.40 (1 H, br), 4.66 (2H, s), 7.16 (1 H, dd), 7.20 (1 H, d), 8.17 (1 H, d).Preparation 22 5-Methoxypyridine-2-carbaldehvdeMnO2 (97.0 g, 360 mmol) was added in one portion to a solution of the alcohol from preparation 21 (12 g, 86 mmol) in dichloromethane (500 mL) and the resulting suspension was stirred at room temperature for64 hours. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give the desired product (8.6 g, 73%) contaminated with 5-methoxy-2-methylpyridine 1 -oxide (15 mol%) 5-methoxypyridine-2-carbaldehyde: To a solution of 5.7g (41 mmol) (5-methoxypyridin-2~ yl)methanol in 100 mL CHC I3 was added 15g MnO2 and the mixture heated to reflux for 2 hours, filtered, and washed with boiling CHCI3. The filtrate was washed with brine, dried over MgSO4, Preparation 22 5-Methoxypyridine-2-carbaldehvdeMnO2 (97.0 g, 360 mmol) was added in one portion to a solution of the alcohol from preparation 21 (12 g, 86 mmol) in dichloromethane (500 mL) and the resulting suspension was stirred at room temperature for64 hours. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give the desired product (8.6 g, 73%) contaminated with 5-methoxy-2-methylpyridine 1 -oxide (15 mol%) 5-methoxypyridine-2-carbaldehyde: To a solution of 5.7g (41 mmol) (5-methoxypyridin-2~ yl)methanol in 100 mL CHC I3 was added 15g MnO2 and the mixture heated to reflux for 2 hours, filtered, and washed with boiling CHCI3. The filtrate was washed with brine, dried over MgSO4, General procedure: Under the ice water bath, Diisopropyl azodicarboxylate (2.42 g, 12.0 mmol) was added dropwise to 3-hydroxy-4-methoxybenzaldehyde (1.35 g, 8.87 mmol), a solution of triphenylphosphine (3.14 g, 12.0 mmol) and compound 25 (1.50 g, 8.87 mmol) in THF (30 mL)After the addition was completed, the resulting mixture was stirred at room temperature overnight.Evaporate the solvent under reduced pressure.The product is purified by column chromatography (200-300 mesh silica gel, Ethyl acetate: petroleum ether = 1:20 to 1:2 elution), 4-methoxy-3-(5-methoxymethoxypyridin-2-ylmethoxy)benzaldehyde (26) (2.54 g) was obtained.The yield was 94.4%.A vial was charged with (S)-1-(1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)piperidin-3-amine (150 mg, 0.38 mmol), 1-hydroxy-2, 3-dihydro-1H-indene-5-carbonitrile (67 mg, 1.1 equiv), and CS2CO3 (150 mg, 1.2 equiv). The vial was fitted with a stirring bar, capped, and MeCN (1.3 ml) was added. The mixture was placed into a heating block set at 90C for 18h. The reaction was diluted with EtOAc and NH4Cl<3q), the mixture was extracted into EtOAc. The combined organic extracts were dried over MgS04, filtered, and concentrated to give the reaction crude. Crude material was purified on column chromatography (4g S1O2, 0-30% EtOAc in heptane) to afford tert-butyl ((3R, 4R)-4-fluoro-l-(1-((5-methoxypyridin-2-yl)methyl)-1H-benzo djimidazol-2-yl)piperidin-3~yl)carbamate as a colorless oil. (ESI, pos. ton) m/z: 456.2 [M+l].

Molecular Weight:139.15
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:139.063328530
Monoisotopic Mass:139.063328530
Topological Polar Surface Area:42.4
Heavy Atom Count:10
Complexity:97.6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes