Triethylamine → (3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol

To a pale yellow, homogeneous mixture of (Z)—N-hydroxybenzimidoyl chloride (Intermediate I-3B, 5.50 g, 35.4 mmol) and 4,4,4-trifluorobut-2-yn-1-ol (Intermediate I-3A, 5.46 g, 39.6 mmol) in dichloroethane (85 mL) in a 250 mL round bottom flask at 70° C. was added triethylamine (9.85 mL, 70.7 mmol) in 22 mL of dichloroethane over 2.5 h via an addition funnel (the first ˜50% over 2 h and the remaining 50% over 0.5 h). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane (100 mL), washed with water (100 mL), and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Analysis indicated that the product mixture was composed of a 86:14 mixture of the desired regioisomer, (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol, and the undesired regioisomer, (3-phenyl-5-(trifluoromethyl)isoxazol-4-yl)methanol. The mixture was purified by silica gel chromatography using a mixture of ethyl acetate and hexane to afford (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.34 g, 21.96 mmol, 62.1% yield) as a pale yellow oil. The compound had an HPLC ret. time=1.91 min. (condition A); LC/MS M+1=244.2; 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 4.97 (s, 2H), 7.47-7.56 (m, 3H), and 7.65 (d, J=6.60 Hz, 2H).

1. washwashed with water (100 mL)
2. customthe organic layer was collected
3. extractionThe aqueous layer was extracted with dichloromethane (2×50 mL)
4. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
5. customThe solvent was removed under reduced pressure
6. additionwas composed of a 86:14 mixture of the desired regioisomer, (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol
7. customThe mixture was purified by silica gel chromatography
8. additiona mixture of ethyl acetate and hexane

ORD record

ord-0a5b00c884824a19a14f2ecbddfc307f

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216972B2