Formic Acid → 2,2,2-Trifluoro-N-((1S,4R)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

HRID 60620Notes

Reaction equation

HRID 60620 reaction equation
[F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]

Participants

5

Reactant 2

HCID 284Formic Acid2×HCID 866866732,2,2-Trifluoro-N-((S)-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

Product 1

HCID 866866722,2,2-Trifluoro-N-((1S,4R)-4-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

A solution of Intermediate Ab (161 g, 624 mmol) in DMF (2 L) was vacuum degassed with Argon. [N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (CAS: 192139-92-7, 9.95 g, 15.6 mmol) was then added. Formic acid (57.5 g, 1.25 mol) was added slowly to ice cold triethylamine (126 g, 1.25 mol) with stirring, this was then added to the DMF solution. The resulting reaction mixture was heated to 50° C. (internal temperature) for 41 h with stirring. LCMS analysis of the reaction indicated it was incomplete, therefore a solution of formic acid (14.4 g, 313 mmol) was added slowly to ice cold triethylamine (31.6 g, 312 mmol), this was then added to the reaction mixture. Heating was continued for an additional 22 h. After cooling, the mixture was concentrated in vacuo to give an orange residue. The residue was diluted with ethyl acetate (1.5 L) and the solution washed with brine (2×0.5 L). The organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Silica, 3 Kg, 0-50% ethyl acetate in cyclohexane) gave Intermediate Ac (118 g, 73%). 97.5 d.e. % determination by LCMS (Method 4): Rt 3.37 min, M-H=258 (93.7%, desired); Rt 3.25 min, M-H=258 (1.2%, trans isomer). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J=4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).

Workup

  1. customdegassed with Argon
  2. customThe resulting reaction mixture
  3. stirringwith stirring
  4. additionthis was then added to the reaction mixture
  5. temperatureHeating
  6. temperatureAfter cooling
  7. concentrationthe mixture was concentrated in vacuo
  8. customto give an orange residue
  9. washthe solution washed with brine (2×0.5 L)
  10. dry with materialThe organics were dried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customPurification by column chromatography (Silica, 3 Kg, 0-50% ethyl acetate in cyclohexane)
  14. customgave Intermediate Ac (118 g, 73%)
  15. custom97.5 d

Sources & evidence

ORD record
ord-3c83ec4544494cbe9bcaff71812579a9
Source dataset
uspto-grants-2016_09
Patent number
US09440974B2

Reaction notes

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