Tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate → (+/-)-tert-Butyl 4-((1-(3-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

HRID 913877Notes

Reaction equation

HRID 913877 reaction equation
ClC(Cl)(Cl)C(=N)[O:4][CH:5]([C:7]1[CH:8]=[C:9]([Cl:25])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:13]=[C:12]2[Br:24])[CH3:6].[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([CH2:49]O)[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>ClCCl.C1CCCCC1>[Br:24][C:12]1[C:11]2[C:15](=[C:7]([CH:5]([O:4][CH2:49][C:36]3([C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:40][CH2:41]3)[CH3:6])[CH:8]=[C:9]([Cl:25])[CH:10]=2)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[N:13]=1

Participants

4

Reactant 2

HCID 19084679Tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylateHCID 57546223HCID 57546223, compound

Product 1

HCID 57546087(+/-)-tert-Butyl 4-((1-(3-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 21916607Dichloromethane cyclohexaneSolvent

Conditions

Temperature
0 °C

Procedure

(±)-1-(3-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.69 g, 3.07 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.05 g, 3.38 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (86 μL, 0.61 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 1.2 g (56%) as a white film. 1H-NMR (CDCl3, 500 MHz) δ 7.48 (d, J=1.84 Hz, 1H), 7.19-7.21 (m, 2H), 7.08 (m, 1H), 6.97-7.00 (m, 2H), 5.49-5.56 (m, 2H), 5.01 (q, J=6.1 Hz, 1H), 3.70 (m, 2H), 3.43-3.47 (m, 2H), 3.22 (m, 2H), 3.00-3.05 (m, 2H), 2.04-2.14 (m, 2H), 1.76-1.87 (m, 2H), 1.43 (s, 9H), 1.42 (m, 3H), 0.72-0.82 (m, 2H), 0.08 (s,9H). Mass spec.: 720.42 (MNa)+.

Workup

  1. additionThe reaction was treated with tetrafluoroboric acid-diethyl ether complex (86 μL, 0.61 mmol)
  2. customquenched by addition of saturated sodium bicarbonate
  3. additiondiluted with diethyl ether
  4. customThe layers were separated
  5. washThe ethereal was washed with water (2×), brine (2×)
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customColumn chromatography on silica gel (18% ethyl acetate/hexanes) gave 1.2 g (56%) as a white film

Sources & evidence

ORD record
ord-34176bb58c674688b915c53d5606af45
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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