C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:14][C@H:13]([CH:15]1[CH2:16][CH2:17]1)[C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1(S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was dissolved in DMF (15 mL, 200 mmol). Washed and dried sodium hydride (298 mg, 12.4 mmol) was added carefully in three separate portions and the resulting mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorotoluene (749 μL, 6.2 mmol) was added, and the mixture was stirred overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chromatography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated and concentrated. The crude material was then treated with 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred overnight at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg, 99.4% purity). MS m/z: [M+H]+ calcd for C15H20ClNO, 266.12; found 266.0.
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