Water → HCID 86684919, compound

A solution of 4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenethiol (56.1 g, 196 mmol) in tetrahydrofuran (93 mL) was added at room temperature to a suspension of potassium tert-butoxide (22.8 g, 203 mmol) in tetrahydrofuran (370 mL). The orange-brown clear solution was stirred for 20 min and a solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (74.4 g, 178 mmol) in dimethylacetamide (240 mL) was added. The mixture was stirred for 15 h at room temperature. Water (550 mL) and ethyl acetate (500 mL) were added and phases were separated. The aqueous layer was extracted with ethyl acetate (500 mL), the combined organic solution of 4-(2,2,2-trifluoro-eth sodium chloride (124 g) in water (1.1 L) (2×600 mL) and concentrated in vacuo to a volume of ca. 260 mL. Toluene (600 mL) was added, the mixture again concentrated in vacuo to a volume of ca. 260 mL and further toluene (240 mL) was added. The warm mixture (internal temperature 45° C.) was filtered, the precipitate was washed with toluene (120 mL) and the combined filtrate was allowed to slowly cool to room temperature (within 60 min). Crystallization started at 26° C. internal temperature. The suspension was stirred for 1 h at 22° C., heptane (620 mL) was added within 45 min and the suspension was stirred for 17 h at room temperature before it was filtered. The precipitate was washed with toluene/heptane 1:1 (v/v, 240 mL) and heptane (120 mL) and dried in vacuo at 40° C. to provide the title compound as off-white crystals (87.7 g, 96.1% purity, 88%). MS (ESI & APCI): m/z=536.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ0.58-0.62 (m, 1H), 0.64-0.68 (m, 1H), 0.89-0.93 (m, 1H), 1.04-1.09 (m, 1H), 1.16-1.22 (m, 2H), 1.31 (s, 3H), 1.45-1.55 (m, 2H), 1.88-1.94 (m, 1H), 2.79-2.85 (m, 1H), 3.83-3.88 (m, 1H), 3.91-3.98 (m, 2H), 4.41 (q, J=7.9 Hz, 2H), 4.61 (dd, J=4.7 Hz, 8.0 Hz, 1H), 7.12 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.31 (d, J=2.8 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 8.04 (br s, 1H).

1. stirringThe mixture was stirred for 15 h at room temperature
2. customphases were separated
3. extractionThe aqueous layer was extracted with ethyl acetate (500 mL)
4. concentrationconcentrated in vacuo to a volume of ca. 260 mL
5. additionToluene (600 mL) was added
6. concentrationthe mixture again concentrated in vacuo to a volume of ca. 260 mL and further toluene (240 mL)
7. additionwas added
8. filtrationThe warm mixture (internal temperature 45° C.) was filtered
9. washthe precipitate was washed with toluene (120 mL)
10. customCrystallization
11. customstarted at 26° C.
12. stirringThe suspension was stirred for 1 h at 22° C.
13. additionheptane (620 mL) was added within 45 min
14. stirringthe suspension was stirred for 17 h at room temperature before it
15. filtrationwas filtered
16. washThe precipitate was washed with toluene/heptane 1:1 (v/v, 240 mL) and heptane (120 mL)
17. customdried in vacuo at 40° C.

ORD record

ord-3004e33042d642c4af3d7cb6e4a6fbbc

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796471B2