Trifluoroacetic acid → ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidine]-1'-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

HRID 251481Notes

Reaction equation

HRID 251481 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(#N)C>[N:14]1([CH:9]2[CH2:10][CH:11]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([CH2:13][CH2:12]3)[CH2:8]2)[CH2:19][CH2:18][C:17]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][NH:21][CH2:20]2)[CH2:16][CH2:15]1

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 58089822tert-butyl 1'-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4'-piperidine]-2(3H)-carboxylate

Product 1

HCID 58089661ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidine]-1'-yl)-8-azabicyclo[3.2.1]octane-8-carboxylateYield 88.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

The crude tert-butyl 1′-(8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H -spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 5b (3.641 g) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 45 min, then concentrated under reduced pressure. The oil obtained was re-dissolved in acetonitrile, re-concentrated under reduced pressure, treated with 2 N NaOH (25 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were washed with saturated NaHCO3, saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 2.55 g crude ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate 5c as a pale yellow oil, which solidified upon standing overnight at room temperature. LC/MS m/z [M+H]+ 384.2 retention time 1.34 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min). 1H-NMR (400 MHz, CDCl3) δ 7.60 (d, J=8.0 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.06 (br s, 2H), 4.37 (br s, 2H), 4.25 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.47 (m, 3H), 3.24 (m, 2H), 2.93 (m, 2H), 2.53 (m, 2H), 1.96 (m, 8H), 1.71 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).

Workup

  1. concentrationconcentrated under reduced pressure
  2. customThe oil obtained
  3. concentrationre-concentrated under reduced pressure
  4. additiontreated with 2 N NaOH (25 mL)
  5. extractionextracted with dichloromethane (2×50 mL)
  6. washThe combined extracts were washed with saturated NaHCO3, saturated brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-2329f4a275df4db0b76072d8532dcfcb
Source dataset
uspto-grants-2011_01
Patent number
US07863449B2

Reaction notes

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