Acetic Acid → 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl ester

HRID 530632Notes

Reaction equation

HRID 530632 reaction equation
[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH:11]=O)[C:7]([F:10])([F:9])[F:8])[CH3:2].[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([C@H:22]2[O:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.FC(F)(F)C1C=C([C@@H]2CO2)C=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11][N:24]1[CH2:25][CH2:26][O:27][C@H:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=2)[CH2:23]1)[C:7]([F:10])([F:9])[F:8])[CH3:2]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 22823242(R)-2-[3-(Trifluoromethyl)phenyl]oxiraneHCID 76971764(R)-2-(3-(Trifluoromethyl)phenyl)morpholineHCID 901034654,4,4-Trifluoro-3-formyl-butyric acid ethyl ester

Product 1

HCID 1178708034,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl esterYield 66%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of the unpurified racemic 4,4,4-trifluoro-3-formyl-butyric acid ethyl ester from above (step b), 0.498 g (2.15 mmol) of (R)-2-(3-trifluoromethyl-phenyl)-morpholine [prepared from (R)-2-(3-trifluoromethyl-phenyl)oxirane in a similar manner to that described in Example 4 (steps b-e)], 0.162 g (2.7 mmol) of acetic acid and 8 mL of dichloromethane was stirred at room temperature. After 30 min, 0.913 g (4.3 mmol) of sodium triacetoxyborohydride was added. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate and washed successively with 0.5 M sodium carbonate solution, water and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexanes-ethyl acetate (90:10) to give 0.592 g (66%) of 4,4,4-trifluoro-3-[(R)-2-(3-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-butyric acid ethyl ester as an oil. Used as is in the next step

Workup

  1. stirringThe mixture was stirred overnight at room temperature
  2. washwashed successively with 0.5 M sodium carbonate solution, water
  3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by chromatography on silica gel
  7. washeluting with hexanes-ethyl acetate (90:10)

Sources & evidence

ORD record
ord-e99c3b2437dc45229ef197af5fda4132
Source dataset
uspto-grants-2016_05
Patent number
US09353096B2

Reaction notes

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