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

HRID 913971Notes

Reaction equation

HRID 913971 reaction equation
ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[CH:8]=[C:9]([Cl:26])[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])[CH:13]=[C:12]2[C:24]#[N:25])[CH3:6].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([CH2:50][OH:51])[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>ClCCl>[Cl:26][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([CH:5]([O:51][CH2:50][C:37]3([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=4)[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:41][CH2:42]3)[CH3:6])[CH:8]=1)[N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[C:12]2[C:24]#[N:25]

Participants

4

Reactant 2

HCID 19084679Tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylateHCID 57546157(+/-)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate

Product 1

HCID 57546180(+/-)-tert-butyl 4-((1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylateYield 38.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Fluoroboric acid diethylether complex (0.015 g, 0.095 mmol) was added to a 0° C. solution of (±)-1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethyl 2,2,2-trichloroacetimidate (0.945 g, 1.907 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.59 g, 1.907 mmol) in Dichloromethane (10 mL) and was stirred for 20 min at 0° C. TLC indicated the reaction was complete, and the reaction was quenched with aqueous sodium bicarbonate (10 mL). The reaction was extracted with ethyl acetate (3×10 mL) and the organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 15%-20% ethyl acetate/hexanes to give (±)-tert-butyl 4-((1-(5-chloro-3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (466 mg, 0.726 mmol, 38.0% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.60 (d, J=2.0 Hz, 1H), 7.49 (s, 1H), 7.15 (m, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.94 (app t, J=8.6 Hz, 2H), 5.22 (m, 2H), 5.07 (m, 1H), 3.66 (m, 2H), 3.33 (app t, J=8.3 Hz, 2H), 3.22 (d, J=8.8 Hz, 1H), 3.11 (d, J=8.8 Hz, 1H), 3.02 (m, 2H), 2.07 (m, 2H), 1.79 (m, 2H), 1.42 (d, J=6.3 Hz, 3H), 0.65-0.90 (m, 2H), −0.08 (s, 9H).

Workup

  1. customthe reaction was quenched with aqueous sodium bicarbonate (10 mL)
  2. extractionThe reaction was extracted with ethyl acetate (3×10 mL)
  3. dry with materialthe organic phase was dried with MgSO4
  4. customevaporated
  5. customThe residue was purified by chromatography on SiO2 with 15%-20% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-e3342672e1954e16bb45a8a1538f796b
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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