Hydrochloric Acid → 4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridine

HRID 717871Notes

Reaction equation

HRID 717871 reaction equation
[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)[CH:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

6

Reactant 2

HCID 313Hydrochloric Acid2×HCID 69673501tert-Butyl 4-{[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate

Product 1

HCID 696736304-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridine

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent3×HCID 516892Sodium BicarbonateSolvent

Procedure

To a solution of tert-butyl 4-{[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.19 g, 0.23 mmol, from Step C) in 1,4-dioxane (2.0 mL) was added 4.0 M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol). The reaction mixture was stirred for one hour. Additional 4.0 M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol) was added and stirring was continued for two hours. The mixture was diluted with water, saturated sodium bicarbonate was used to adjust the pH to between 7 and 8, and then the product was extracted with two portions of DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% MeOH in DCM afforded product as an oil (62 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 4H), 7.48-7.34 (m, 6H), 7.14-7.11 (m, 1H), 6.91 (s, 1H), 5.17 (tt, J=8.7, 4.0 Hz, 1H), 4.71 (s, 2H), 3.13 (dt, J=12.7, 4.5 Hz, 2H), 2.78 (ddd, J=12.7, 9.7, 3.0 Hz, 2H), 2.07 (dq, J=12.2, 4.1 Hz, 2H), 1.67 (dtd, J=13.0, 9.4, 3.9 Hz, 2H), 1.11 (s, 9H); LCMS (M+H)+: 515.2.

Workup

  1. stirringstirring
  2. waitwas continued for two hours
  3. extractionthe product was extracted with two portions of DCM
  4. washThe combined extracts were washed with brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. washFlash chromatography on silica gel, eluting with a gradient from 0-15% MeOH in DCM afforded product as an oil (62 mg, 52%)

Sources & evidence

ORD record
ord-6ee84e350e9f4355a70250b49030b6dc
Source dataset
uspto-grants-2015_11
Patent number
US09193733B2

Reaction notes

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