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HCID 71014126, compound → HCID 71014159, compound

HRID 1430081
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Reaction equation

HRID 1430081 reaction equation
Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:36])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:24]4[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:26]([NH:28][C@H:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]4[OH:35])=[O:27])[CH:16]=3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:37][Zn]C>C1COCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[C:17]([C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[OH:35])=[O:27])[CH:16]=[C:15]2[CH2:14][N:11]1[CH2:12][CH2:13][C:8]([F:36])([C:4]2[CH:3]=[C:2]([CH3:37])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 2

HCID 71014126HCID 71014126, compoundHCID 178477796HCID 178477796, compound2×

Product 1

HCID 71014159HCID 71014159, compound

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent
HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 4-{[4-(4-chloropyridin-2-yl)-4-fluoropiperidin-1-yl]methyl}-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (Example C) (0.022 g, 0.043 mmol) in THF (3 mL) under an atmosphere of nitrogen was added dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 90° C., cooled to RT, and retreated with additional dimethyl zinc (2.0 M in THF, 0.043 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0011 mg, 0.00090 mmol). The reaction was heated to 100° C. for 5 h, then at 50° C. for an additional 16 h. The mixture was cooled to RT, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-5% MeOH in dichloromethane to provide the title compound (Example D) as a white solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 495.1 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.36 (m, 2H), 8.30-8.20 (m, 2H), 7.69-7.38 (m, 3H), 7.00 (br s, 1H), 4.03 (s, 2H), 3.89 (br s, 1H), 3.59-3.49 (m, 1H), 3.48-3.14 (m, 1H), 2.85-2.81 (m, 2H), 2.61-2.57 (m, 2H), 2.44-2.37 (m, 2H), 2.37 (s, 3H), 2.18-2.13 (m, 2H), 1.87-1.79 (m, 4H), 1.50-1.14 (m, 4H).

Workup

  1. temperaturecooled to RT
  2. temperatureThe reaction was heated to 100° C. for 5 h
  3. temperatureThe mixture was cooled to RT
  4. washwashed with saturated aqueous sodium bicarbonate and brine
  5. dry with materialThe organic solution was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resultant residue was purified via silica gel chromatography
  9. washeluting with 0-5% MeOH in dichloromethane

Sources & evidence

ORD record
ord-69a2dc7f56ff48b7a543de2ed4568672
Source dataset
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08940765B2

Reaction notes

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