Triethylamine → (+/-)-tert-Butyl 4-((1-(5-chloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

HRID 913888Notes

Reaction equation

HRID 913888 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 90495Di-tert-butyl dicarbonateHCID 57546145(+/-)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Product 1

HCID 57546106(+/-)-tert-Butyl 4-((1-(5-chloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (810 mg, 1.31 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 4 mL). The reaction was stirred at room temperature for 3 h and concentrated. The crude trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol and washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The crude amine was dissolved in dichloromethane (5 mL) and treated with di-tert-butyl dicarbonate (572 mg, 2.62 mmol) and triethylamine (0.27 mL, 2.0 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 400 mg (63%) as a viscous oil. 1H-NMR (CDCl3, 500 MHz) δ 9.90 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.22-7.25 (m, 2H), 7.02-7.06 (m, 2H), 6.96 (d, J=1.8 Hz, 1H, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.62-3.72 (m, 2H), 3.23-3.36 (m, 2H), 2.94-3.06 (m, 2H), 2.05-2.24 (m, 2H), 1.70-1.86 (m, 2H), 1.44 (m, 3H), 1.41 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 171.1, 161.7 (d, J=246.6 Hz), 155.0 135.7, 133.8, 128.7, 127.5, 126.2, 124.8, 124.2, 119.0, 115.7, 79.6, 78.6, 78.2, 60.4, 41.2, 28.5, 22.2, 14.3. Mass spec.: 488.39 (MH)+.

Workup

  1. concentrationconcentrated
  2. washwashed with several volumes of methanol which
  3. washThe product was eluted with 2 M ammonia in methanol
  4. concentrationconcentrated
  5. dissolutionThe crude amine was dissolved in dichloromethane (5 mL)
  6. stirringThe reaction was stirred at room temperature for 1 h
  7. customThe reaction was quenched by addition of 2 M ammonia in methanol
  8. concentrationconcentrated
  9. customThe residue was purified by column chromatography (30% ethyl acetate/hexanes)
  10. customto give 400 mg (63%) as a viscous oil

Sources & evidence

ORD record
ord-b8c483a1000f45119d8e419b87bc2881
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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