Hydrochloric Acid → Trifluoroacetic acid

HRID 1891225Notes

Reaction equation

HRID 1891225 reaction equation
[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:37])([F:36])[F:35])=[C:32]([C:38]([OH:40])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-:43].[Li+].Cl.[O:46]1CCOCC1>C(#N)C>[C:33]([OH:46])([C:34]([F:37])([F:36])[F:35])=[O:43].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:42]=[CH:41][C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:35])([F:37])[F:36])=[C:32]([C:38]([OH:40])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 312751,4-DioxaneHCID 59452056HCID 59452056, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 59452056HCID 59452056, compound

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of the title compound from Example 12 Step F (24 mg, 0.035 mmol) in DCM (1 mL) were added DIEA (62 μL, 0.35 mmol) and acetyl chloride (8.3 mg, 0.104 mmol), and the resulting mixture was allowed to stir at room temperature. After 18 h, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude amide, which was used without further purification: LCMS m/z 606.9 [M+1-1]+. To a solution of the amide in dioxane (1.5 mL) was added lithium hydroxide (0.75 mL, 2N aqueous, 1.5 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (40 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 578.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.29 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.23-7.21 (m, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 5.16 (s, 2H), 4.52-4.49 (m, 1H), 3.91-3.87 (m, 1H), 3.12-3.07 (m, 1H), 2.77-2.70 (m, 1H), 2.58-2.53 (m, 1H), 2.27 (s, 3H), 2.01 (s, 3H), 1.78-1.72 (m, 2H), 1.59-1.51 (m, 1H), 1.44-1.35 (m, 1H).

Workup

  1. customthe reaction mixture was quenched by addition of sat aq NaHCO3
  2. extractionthe aqueous phase was extracted with DCM
  3. customThe organic phase was separated
  4. concentrationconcentrated in vacuo
  5. customto provide the crude amide, which
  6. customwas used without further purification
  7. stirringthe mixture was stirred at 50° C
  8. waitAfter 1 h
  9. custompurified by reverse phase HPLC (40 to 100% acetonitrile/water

Sources & evidence

ORD record
ord-d374dca2c9634cfcbd786b3a1147d7e0
Source dataset
uspto-grants-2013_08
Patent number
US08507512B2

Reaction notes

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