反应详情

To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added cyclopropylmethyl-methyl-amine hydrochloride (61 mg, 0.51 mmol), triethylamine (0.18 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (71 mg, 29% yield). Rf=0.50 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29Cl N2 O2, 376.9, found, 377.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, diagnostic peaks, δ 3.75 (s, 2H), 3.02 & 3.01 (2 singlets, 3H total), 2.62-2.54 (m, 6H), 1.82-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, peak list δ 175.9, 175.7, 146.4, 146.3, 135.2, 134.0, 130.9, 130.8, 126.5, 126.4, 123.7, 73.7, 73.5, 56.7, 54.6, 54.3, 52.4, 41.3, 41.0, 35.5, 34.5, 29.0, 28.5, 23.7, 10.5, 9.5, 3.8, 3.6.

1. customThe resulting reaction mixture
2. customthe layers were separated
3. extractionThe aqueous layer was subjected to EtOAc extraction (2×60 ml) again
4. dry with materialthe combined organic layers were dried over MgSO4
5. customevaporated
6. customThe residue was purified by flash column chromatography
7. washeluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH
8. additionThe product containing fractions
9. customwere collected
10. concentrationconcentrated under reduced pressure