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

HRID 913832Notes

Reaction equation

HRID 913832 reaction equation
ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)[CH3:6].[OH:28][CH2:29][C:30]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>ClCCl.C1CCCCC1>[Cl:24][C:9]1[CH:8]=[C:7]([CH:5]([O:28][CH2:29][C:30]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=2)[CH:10]=1

Participants

4

Reactant 2

HCID 9994433Tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylateHCID 57546188(+/-)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate

Product 1

HCID 57546128(+/-)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 21916607Dichloromethane cyclohexaneSolvent

Conditions

Temperature
0 °C

Procedure

(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (600 mg, 1.27 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.41 g, 1.40 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 (40 μL, 0.26 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×), 1M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 380 mg (50%) as a yellow film. 1H-NMR (CDCl3, 300 MHz) δ 7.96 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.28-7.35 (m, 4H), 7.17-7.23 (m, 1H), 6.86 (m, 1H), 5.62 (s, 2H), 4.93 (q, J=6.2 Hz, 1H), 3.72 (m, 2H), 3.55-3.60 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.34 (d, J=8.8 Hz, 1H), 2.97-3.08 (m, 2H), 2.10-2.21 (m, 2H), 1.91-1.97 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.41 (s, 9H), 0.82-0.87 (m, 2H), 0.08 (s, 9H). Mass spec.: 600.22 (MH)+.

Workup

  1. additionThe reaction was treated with tetrafluoroboric acid-diethyl ether complex (40 μL, 0.26 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×), 1M potassium bisulfate (2×), brine (2×)
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customColumn chromatography on silica gel (18% ethyl acetate/hexanes) gave 380 mg (50%) as a yellow film

Sources & evidence

ORD record
ord-afc48d3d45b94e95803ee7a93ab7bc33
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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