(4S)-6a-(2,3-difluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole → ((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol

HRID 2195758Notes

Reaction equation

HRID 2195758 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH:13]1[CH2:12][O:11][NH:10]2>C(O)(=O)C.CCOC(C)=O.[Zn]>[NH2:10][C@@:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:16][O:15][C@H:14]([C:17]([F:19])([F:18])[F:20])[C@H:13]1[CH2:12][OH:11]

Participants

5

Reactant 1

HCID 70495269(4S)-6a-(2,3-difluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole

Product 1

HCID 70496186((2S,3R,4S)-4-amino-4-(2,3-difluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanolYield 98.1%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(4S)-6a-(2,3-difluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (3.16 g) was dissolved in acetic acid (20 mL) and the reaction mixture cooled to 0° C. Zinc (5.0 g) was added, and the reaction was allowed to warm and stir at RT for 20 h. The reaction mixture was then diluted with EtOAc (50 mL) and filtered through Celite®, washing with a further 100 mL of EtOAc. The combined organic portions were evaporated, dissolved in CHCl3 (20 mL), and ammonia (28% aq., 25 mL) was added slowly. The layers were separated, and the aqueous portion was further extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over anhydrous MgSO4 and evaporated to afford the title compound (3.12 g) which was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.93 (ddd, J=7.8, 5.1, 2.8 Hz, 1H), 3.85 (dd, J=12.4, 5.1 Hz, 1H), 4.03 (dd, J=9.1, 2.8 Hz, 1H), 4.14 (dd, J=12.3, 2.7 Hz, 1H), 4.35 (d, J=9.1 Hz, 1H), 4.68 (quin, J=7.3 Hz, 1H), 7.09-7.25 (m, 2H), 7.25-7.34 (m, 1H)

Workup

  1. temperatureto warm
  2. filtrationfiltered through Celite®
  3. washwashing with a further 100 mL of EtOAc
  4. customThe combined organic portions were evaporated
  5. dissolutiondissolved in CHCl3 (20 mL)
  6. additionammonia (28% aq., 25 mL) was added slowly
  7. customThe layers were separated
  8. extractionthe aqueous portion was further extracted with CHCl3 (2×25 mL)
  9. dry with materialThe combined organic extracts were dried over anhydrous MgSO4
  10. customevaporated

Sources & evidence

ORD record
ord-ea9a1fbc675b45ea8daac709b6f08f0a
Source dataset
uspto-grants-2012_12
Patent number
US08338407B2

Reaction notes

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