Trifluoroacetic acid → tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

HRID 58442Notes

Reaction equation

HRID 58442 reaction equation
[F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=[O:27].C([N:36]([CH2:40]C)C(C)C)(C)C.[C:42]([O:46][C:47](C1NCC2NN=C(C(O)=O)C=2C1)=[O:48])([CH3:45])([CH3:44])[CH3:43].CN(C(ON1[N:77]=[N:76][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][C:70]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:74]([C:73]3[C:72]4[CH2:40][N:36]([C:47]([O:46][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:48])[CH2:75][CH2:70][C:71]=4[NH:76][N:77]=3)=[O:27])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1184833185-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acidHCID 118483363Tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 118483436tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylateYield 80%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of tert-butyl 4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (9, 41.1 g, 113 mmol) in CH2Cl2 (50 mL) was added TFA (50 mL). The mixture was stirred at ambient temperature for 1 h and was concentrated under reduced pressure. The residue was dissolved in DMF (240 mL) and to this solution was added N,N-diisopropylethylamine (72.4 g, 560 mmol), followed by 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (30.1 g, 113 mmol), and HBTU (74.7 g, 169 mmol). The mixture stirred at ambient temperature for 16 h, was diluted with EtOAc (1 L) and washed with H2O (1.4 L). The organic layer was washed with brine (3×600 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (30-80% EtOAc in hexanes) to give tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (35) as a white solid (0.068 g, 80%): 1H NMR (300 MHz, CDCl3) δ10.23 (br, 1H), 7.36-7.28 (m, 1H), 7.15 (m, 1H), 4.86 (br, 2H), 4.62 (s, 2H), 3.72 (br, 2H), 3.27-2.74 (m, 5H), 1.90-1.64 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 515 [M+H]+.

Workup

  1. concentrationwas concentrated under reduced pressure
  2. dissolutionThe residue was dissolved in DMF (240 mL) and to this solution
  3. stirringThe mixture stirred at ambient temperature for 16 h
  4. washwashed with H2O (1.4 L)
  5. washThe organic layer was washed with brine (3×600 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe resulting residue was chromatographed over silica gel (30-80% EtOAc in hexanes)

Sources & evidence

ORD record
ord-4c5d9198e51245228ebe35c1ccdb9354
Source dataset
uspto-grants-2016_09
Patent number
US09434727B2

Reaction notes

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