4-Methylmorpholine → CCR2 antagonist 3

Participants

Reaction Conditions

Reaction Steps

4-Fluoro-3-methylbenzoic acid (0.089 g, 0.58 mmol) and TBTU (0.196 g, 0.61 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.070 mL, 0.64 mmol) was dropwise added. After 40 min at 0° C. was (S)-1-(3-methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2) (0.1 g, 0.58 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. NaOH (aq., 3.8 M, 0.5 mL), water (0.5 mL) and dioxane (1 mL) was added and the resultant mixture was stirred at rt overnight. To the mixture was water (2 mL) and DMSO (4 mL) added. The residue was purified by preparative HPLC to give the title compound (121 mg, 68%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ 0.80-0.87, 0.94, 1.05, 1.68-1.93, 2.25-2.34, 2.54-3.00, 3.26-3.34, 3.39-3.46, 3.55-3.61, 3.62-3.75, 4.19-4.43, 7.02-7.49. Ratio major:minor:1:0.5. Total no of protons: 24. HRMS (M+H)+: calculated 309.1978. found 309.1949. XRPD pattern d (Å) 9.3 (vw), 7.8 (w), 7.6 (w), 6.5 (med), 5.7 (vs), 5.3 (str), 4.71 (str), 4.52 (str), 4.40 (med), 4.31 (med), 3.83 (med), 3.30 (med), 3.22 (med). The compound was found to be a hydrate (most likely a monohydrate).

Provenance & Evidence