1,1,1,3,3,3-Hexafluoro-2-propanol → HCID 89682779, compound

Temperature

0 °C

A 25 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with triphosgene (55.0 mg, 0.190 mmol, 0.35 equiv), 1,1,1,3,3,3-hexafluoropropan-2-ol (133 mg, 0.790 mmol, 1.51 equiv) and dichloromethane (3 mL). N,N-diisopropylethylamine (204 mg, 1.58 mmol, 3.00 equiv) was added dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. 1-[[2-Fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine (150 mg, 0.530 mmol, 1.00 equiv) in dichloromethane (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 3 h at 0° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (320 mg) was purified by preparative HPLC using the following gradient conditions: 30% CH3CN/70% Phase A increasing to 70% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 30% CH3CN over 0.1 min, and holding at 30% 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 102 mg (40% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate as a white solid. 1H NMR 400 MHz (CDCl3) δ 7.73-7.76 (m, 2H), 7.65-7.69 (m, 1H), 7.47-7.53 (m, 2H), 7.15 (d, J=7.6 Hz, 1H), 5.74-5.80 (m, 1H), 3.60-3.69 (m, 6H), 2.65 (s, 3H), 2.49 (br, 4H). LCMS (ESI, m/z): 480 [M+H]+.

1. customA 25 mL round-bottom flask was purged with and
2. temperaturemaintained under an inert atmosphere of nitrogen
3. stirringThe resulting solution was stirred for 3 h at 0° C
4. customThe reaction was then quenched by the addition of water (10 mL)
5. extractionThe resulting solution was extracted with dichloromethane (3×10 mL)
6. washwashed with brine (2×10 mL)
7. dry with materialdried over anhydrous sodium sulfate
8. concentrationconcentrated under reduced pressure
9. customThe crude product (320 mg) was purified by preparative HPLC
10. wait30% CH3CN/70% Phase A increasing to 70% CH3CN over 10 min
11. waitto 100% CH3CN over 0.1 min
12. waitholding at 100% CH3CN for 1.9 min
13. waitreducing to 30% CH3CN over 0.1 min
14. waitholding at 30% for 1.9 min, on a Waters 2767-5 Chromatograph
15. customPurification

ORD record

ord-c8740d9577a148399a059d83ddcd56a2

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133148B2