Acetic Acid → 2-(4-((2S)-2-((di-3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol

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Reaction Steps

To a solution of 2-(4-((2S)-2-(aminomethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.380 g, 0.845 mmol, Example 192, Step 1) in CH2Cl2 (8.0 mL) was added 3-oxetanone (0.20 mL, 2.5 mmol, Aldrich, St. Louis, Mo.), 4 molecular sieves (75 mg), acetic acid (0.015 mL, 0.17 mmol) and sodium triacetoxyborohydride (0.717 g, 3.38 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (2×15 mL) and the combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (80 g of silica gel, 2 to 5% MeOH in CH2Cl2) to afford 2-(4-((2S)-2-((di-3-oxetanylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.116 g) as a mixture of two isomers:

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