Hydrochloric Acid → 1-(ethylamino)-2-[(3 S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol hydrochloride

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Reaction Steps

To a 25-mL round-bottom flask was added 24.1 (165 mg, 0.34 mmol, 1.00 equiv) and hydrochloric acid (12 M, 2 mL) in dichloromethane (12 mL). The reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford 1-(ethylamino)-2-[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol hydrochloride (105 mg, crude) as a yellow oil that was used in the next step without further purification. To a solution of this compound (105 mg, crude) in methanol (10 mL) was added HCHO (37%, 2 mL) and the reaction was stirred for 1 h at room temperature. Then NaBH3CN (50 mg, 63%) was added and the reaction stirred for another 2 h at ambient temperature. The resulting mixture was concentrated under reduced pressure and the crude product (85 mg) purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3OH NMR (6.0% CH3OH up to 50.0% in 25 min); UV detection at 254 nm. The fractions were collected and evaporated under reduced pressure to give the desired Compound I-36 (43 mg) as a white solid. An enantiomeric excess of 100% was measured by chiral HPLC analysis. 1H NMR (400 MHz, CD3OD): δ 8.48 (s, 1H), 5.30 (m, 1H), 3.84 (m, 1H), 2.94-3.32 (m, 5H), 2.73 (m, 1H), 2.20-2.68 (m, 11H), 1.50-1.72 (m, 4H), 1.15 (t, 3H). MS: m/z 403 (M+H)+.

Provenance & Evidence