Hydrochloric Acid → HCID 68469064, compound

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Reaction Conditions

Reaction Steps

1-Methanesulfonyl-4-methylsulfanyl-benzene (4.3 g) was dissolved in THF (40 ml) and cooled to −78° C. prior to the slow addition of 1.6 M n-BuLi in hexane (13.4 ml). After 0.5 h, BF3.Et2O (2.7 ml) was added followed by 3,4-epoxytetrahydropyran (2.2 g) (Berti et al. Tetrahedron 1974, 30, 4013) (2.3 g) in THF (20 ml). After an addition 1 h at −78° C., the solution was warmed to 0° C. After 2 h, the solution was cooled to −78° C. and 1N HCl solution (aq) was added. The solution was warmed to rt and EtOAc was added. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (3S*,4R*)-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran-3-ol (1.3 g) as the major product. MS found: (M+H)+=303.0. (23b) The above derivative (23a) (1.3 g) was dissolved in CH2Cl2 (15 ml) and cooled to 0° C. prior to the addition of Et3N (1.7 ml) and methanesulfonyl chloride (0.5 ml). After 1.5 h, the CH2Cl2 was removed and EtOAc was added. This was washed with 1N HCl, saturated NaHCO3, and brine. The organic layer was dried, filtered, and concentrated. This solid was dissolved in DMSO (10 ml) prior to the addition of NaN3 (1.3 g). This was heated at 85° C. for 18 h. After cooling to 0° C., water was added and it was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (3R*,4R*)-3-azido-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran (0.93 g). MS found: (M+H)+=328.0. (23c) The above derivative (23d)(0.9 g) was dissolved in MeOH (10 ml) prior to the addition of 5% Pd/BaSO4 (800 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to (3R*,4R*)-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran-3-ylamine (750 mg) as a major product. MS found: (M−H)−=300.5 (23d) A portion (66 mg) of the above derivative (23c) was dissolved in DMF (1.1 ml) prior to the addition of DIEA (0.14 ml) and example (1d)(50 mg). After cooling to 0° C., BOP reagent (97 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. 1N HCl was added. This was exacted with EtOAc. The organic layer was washed with NaHCO3(aq), dried, filtered and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (53 mg). MS found: (M+H)+=528.1.

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