Tetrahydrofuran → Racemic 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl-)ethanamine trifluoroacetic acid salt

HRID 1177487Notes

Reaction equation

HRID 1177487 reaction equation
[F:1][C:2]([F:31])([F:30])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:22][CH2:21]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)=[O:4].C[Si]([N-:36][Si](C)(C)C)(C)C.[Li+].[O:42]1CCCC1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.C(Cl)Cl>[F:1][C:2]([F:31])([F:30])[C:3]([OH:42])=[O:4].[F:1][C:2]([F:31])([F:30])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:18]([N:19]=2)=[CH:17][CH:16]=[C:15]([C:20]2([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:22][CH2:21]2)[N:14]=3)=[C:7]([F:29])[CH:6]=1)[NH2:36]

Participants

8

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 14798Sodium HydroxideHCID 2733832Lithium HexamethyldisilazideHCID 67111563HCID 67111563, compound

Product 1

HCID 87273677Racemic 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl-)ethanamine trifluoroacetic acid salt

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
0 °C

Procedure

To a slurry of 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)ethanone (0.300 g, 0.68 mmol) in 2.2 mL toluene under nitrogen was added slowly dropwise lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.75 mL, 0.75 mmol) over 2-3 min. The reaction mixture became clear and yellow. After 15 min, borane-methyl sulfide complex, 2.0 M sol in THF (0.68 mL, 1.4 mmol) was added dropwise. The reaction mixture became dark red, and was allowed to stir 40 min. The reaction mixture was cooled to 0° C. and 1 mL 2 N NaOH was added very cautiously dropwise via syringe (gas evolution). The resulting yellow mixture was allowed to stir overnight, and then the reaction mixture was partitioned between water and EA. The organic layer was washed with sat'd aq. Sodium bicarbonate, 1× brine, dried over sodium sulfate, filtered, and purified in vacuo to give a yellow oil. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-100% EtOAc/hexane. Product-containing fractions were combined and concentrated in vacuo, and the resulting material was purified by RPHPLC, 10-100% TFA/ACN in TFA/H2O. The purified fractions were combined and concentrated in vacuo to give racemic 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl-)ethanamine trifluoroacetic acid salt as a white solid. MS (ESI) m/z: calculated: 443.1; Observed: 444.1 (M++1).

Workup

  1. stirringto stir overnight
  2. customthe reaction mixture was partitioned between water and EA
  3. washThe organic layer was washed with sat'd aq. Sodium bicarbonate, 1× brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. custompurified in vacuo
  7. customto give a yellow oil
  8. concentrationconcentrated in vacuo
  9. customthe resulting material was purified by RPHPLC, 10-100% TFA/ACN in TFA/H2O
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1b80d8325fc2498ca671278c9dadea1e
Source dataset
uspto-grants-2010_11
Patent number
US07842685B2

Reaction notes

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