Preparation of (5-cyanopyridin-3-yl)-methanol_Industrial additives

Background and overview^[1]

(5-Cyanopyridin-3-yl)-methanol is a pharmaceutical intermediate that can be prepared from 5-bromonicotinonitrile through a three-step reaction. It has been reported in the literature that (5-cyanopyridin-3-yl)-methanol can be used to prepare compound (S)-1-(((4-((5-cyanopyridin-3-yl)methoxy)-2- ((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidine-5-yl)methyl)piperidine-2-carboxylic acid, a PD1/PD -L1 inhibitor.

Preparation^[1]

Step 1: Synthesis of 5-vinylnicotinonitrile

A stirred solution of 5-bromonicotinonitrile (2 g, 0.12 mol) and tributylvinyltin (95.3 g, 300 mmol) in DMF (200 mL) was purged with nitrogen at room temperature. To the mixture, Pd(PPh₃)₄ (13.84g, 12mmol) was added and purged with nitrogen again for 20 minutes. The mixture was then heated at 80°C for 4 hours. Upon completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAC (3 × 200 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, 100-200#) using 10% EtOAc in hexanes to obtain 5-ethyl ink adhesion promoter alkenyl nicotinonitrile as an off-white solid (yield: 10.5 g , 67%). ¹H NMR (MHz, DMSO-d6): δ5.55 (d, J = 10.8 Hz, 1H), 6.17 (d, J = 17.6 Hz, 1H), 6.80 (m, 1H) , 8.52 (s, 1H), 8.90 (s, 1H), 9.03 (s, 1H).

Step 2: Synthesis of 5-formylnicotinonitrile

To a stirred solution of 5-vinylnicotinonitrile (10.5 g, 81 mmol) in acetone (200 mL) and water (40 mL) at 0°C, OsO₄ was added (82 mL, 2.5 wt% tert-butanol solution, 8.1 mmol) and N-methylmorpholine N-oxide (29 g, 242 m mol carbon black) and stirred for 3 h. NaIO₄ (60 g, 282 mmol) was added to the mixture, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (300 mL) and extracted with DCM (2 x mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give crude product. The crude product was purified on combiflash chromatography using 30% ethyl acetate in hexanes as eluent to afford 5-formylnicotinonitrile as a yellow solid (yield: 7.9 g, 74%). ¹ H NMR (MHz, DMSO-d6): δ8.77 (s, 1H), 9.29 (s, 1H), 9.31 (s, 1H), 10.12 (s, 1H).

Step 3: Synthesis of (5-cyanopyridin-3-yl)-methanol

To a stirred solution of 5-formylnicotinonitrile (12g, 91mmol) in methanol (100mL) at 0°C, sodium borohydride (5.12g, 136mmol) was added in portions over 30 minutes, and the mixture was heated at 0°C. The mixture was stirred for 2 hours. After TLC showed completion, the reaction mixture was concentrated and the residue was diluted with water (100 mL) and DCM (200 mL). The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 100-200#) using 1% MeOH in DCM to give (5-cyanopyridin-3-yl)-methanol as a yellow solid (yield: 7.4 g, 60.7 %). ¹ H NMR (MHz, DMSO-d6): δ4.50 (bs, 1H), 5.54 (s, 2H), 8.19 (s, 1H), 8.80 (s, 1H), 8.91 ( s, 1H).

References

[1] WO2019087214 – PYRIMIDINE DERIVATIVES AS INHIBITORS OF PD1/PD-L1 ACTIVATION