trans-1,4-Cyclohexanedimethanol

white crystalline powder

Thionyl chloride (16.6g, 139.5mmol) was added dropwise to a stirred solution of trans-cyclohexane-1, 4-dicarboxylic acid (10.0g, 58.1mmol) in methanol (160mL) at 0'20°C. The resulting mixture was stirred at reflux for 4h. The resulting solution was evaporated in vacuo and the residue was partitioned between aqueous water (50mL) and dichloromethane (100mL). The organic layer was washed with aqueous NaHCO3 (40mL), brine (50mL) and dried (Na2SO4), and evaporated in vacuo to give a colorless solid (9.8g, 84.0percent). Next, a mixture of this solid (9.8g) and NaBH4 (18.5g, 488.2mmol) in THF (196mL) was stirred at reflux for 0.5h. Then methanol (69mL) was added to the resulting solution at room temperature. The resulting solution was stirred at reflux for 12h and quenched with 30percent hydrochloric acid (20mL) in and ice bath. The resulting mixture was stirred for 1h and alkalized with 50percent sodium hydroxide solution (30mL). The resultant mixture was extracted with dichloromethane (3×60mL). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to give 42 (2.4g, 28.6percent) as a colorless solid. Mp: 63'65°C. 1H NMR (CDCl3): delta 0.93'1.03 (m, 4H), 1.45'1.47 (m, 2H), 1.84'1.88 (m, 4H), 3.40'3.46 (m, 4H).To a 100 mL-flask containing 79 (4.0 g, 27.8 mmol) in DMF (40 mL) was added TBDMSCl (3.56 g, 23.6 mmol) and imidazole (3.79 g, 55.6 mmol). The reaction was allowed to stir at 25 C. for 16 hours after which time saturated aqueous LiBr (50 mL) was added and the reaction extracted with ether (2×50 mL). The ether layers were pooled and extracted again with LiBr (2×35 mL). The ether layer became clear. The ether layer was then concentrated in vacuo and the product purified by flash chromatography, on a silica gel column, eluting with 1:2 ether/petroleum ether to yield 83 (3.80 g, 62%) as a homogenous oil. 1H NMR (CDCl3) delta 3.46 (d, J=6.2 Hz, 2H), 3.39 (d, J=6.2 Hz, 2H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) delta 69.2, 69.1, 41.2, 41.1, 29.5, 26.5, 18.9, -4.8; APCI m/z (rel intensity) 259 (MH+, 100).To a 500-mL flask containing(lR, 4R)-cyclohexane-l, 4-diyldimethanol (80 g, 555 mmol) and 1H- imidazole (37.8 g, 555 mmol) in DMF (400 mL) was added to a solution of tert- butylchlorodimethylsilane (84 g, 555 mmol) in DMF (400 mL) at about 0C. After addition, the reaction was allowed to stir at about 25C for about 16 h. The solution was poured into ice water (200 mL) and extracted with MTBE (3x100 mL). The organics were combined, concentrated in vacuo, and purified by flash chromatography on silica gel (1 :2 EtOAc/petroleum ether) to afford the title compound (68 g, 45.1 %); lH NMR (400MHz, CDC13) delta 0.03 (s, 6 H) 0.86 - 0.96 (m, 13 H) 1.34 - 1.58 (m, 3 H) 1.81 (d, J=8.61 Hz, 4 H) 3.42 (dd, J=17.61, 6.26 Hz, 4 H)To a solution of trans-

Intermediate in the preparation of Apadenoson.