Water → HCID 58034222, compound

Temperature

0 °C

(S)-3-[4-(6-Chloro-pyridazin-3-yl)phenoxy]-2-methylpropan-1-ol (3.0 g, 10.76 mmol) was dissolved in a mixture of pyridine (10 mL) and THF (90 mL), and the solution cooled to 0° C. Methanesulfonyl chloride (2.863 g, 25 mmol) was introduced dropwise, and the reaction mixture was stirred at ambient temperature for 20 h. EtOAc (100 mL) and H2O (150 mL) were added, separated, and the aqueous layer was extracted further with EtOAc (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to a solid which was purified by column chromatography on silica gel, eluting with a gradient of hexane/EtOAc to provide the intermediate methanesulfonic acid (R)-3-[4-(6-chloro-pyridazin-3-yl)-phenoxy]-2-methylpropyl ester (3.52 g, 91%). This intermediate (7 mmol) was treated with (R)-2-methylpyrrolidine, benzenesulfonic acid salt (3.65 g, 15 mmol) and dry, pulverized K2CO3 (4.15 g, 30 mmol) in dry CH3CN (200 mL). The reaction mixture was heated at reflux for 30 h and cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography, eluting with a gradient mixture of CH2Cl12 and EtOH containing 10% of aqueous ammonia solution, to provide the title compound (1.46 g, 60%), m.p. 152-155° C., 1H NMR (CDCl3) 1.18 (d, 3H, —CH3), 1.27 (d, 3H, —CH3), 3.98 (m, 2H, —CH2—), 7.02 (d, 2H, Ar—H), 7.52 (d, 1H, C—H), 7.78 (d, 1H, C—H), 8.02 (d, 2H, Ar—H); HPLC retention time 7.530 min. (elution solvents CH3CN w/0.1% TFA and H2O w/0.1% TFA); 10-100% CH3CN over 20 min.

1. customseparated
2. extractionthe aqueous layer was extracted further with EtOAc (2×100 mL)
3. dry with materialThe combined extracts were dried (MgSO4)
4. customevaporated to a solid which
5. customwas purified by column chromatography on silica gel
6. washeluting with a gradient of hexane/EtOAc

ORD record

ord-e1208da1a00f414dbc9c63f4ea6a0571

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08076331B2