1,1,1,3,3,3-Hexafluoro-2-propanol → HCID 71657081, compound

A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (126 mg, 0.750 mmol, 1.00 equiv), triphosgene (74.0 mg, 0.250 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (290 mg, 2.24 mmol, 2.99 equiv) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. 1-[[5-Chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine (210 mg, 0.750 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with H2O (3×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The crude product (150 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 51.5 mg (14% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.42 (d, J=2.4 Hz, 1H), 7.09-7.13 (m, 1H), 6.85 (d, J=8.9 Hz, 1H), 5.69-5.82 (m, 1H), 3.52-3.58 (m, 6H), 3.10-3.14 (m, 4H), 2.46-2.49 (m, 4H), 1.86-1.96 (m, 4H). LCMS (ESI, m/z): 474 [M+H]+.

1. stirringThe resulting solution was stirred for 2 hours at room temperature
2. extractionThe resulting solution was extracted with dichloromethane (3×10 mL)
3. washwashed with H2O (3×5 mL)
4. dry with materialdried over anhydrous sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customThe residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3)
8. customThe crude product (150 mg) was purified by preparative HPLC
9. wait20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min
10. waitto 100% CH3CN over 0.1 min
11. waitholding at 100% CH3CN for 1.9 min
12. waitreducing to 20% CH3CN over 0.1 min
13. waitholding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph
14. customPurification

ORD record

ord-3467e044e82f468ea396f9be34b5cbfd

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133148B2