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tert-Butyl 4-nicotinoylpiperidine-1-carboxylate → tert-Butyl 4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate

HRID 1478527
Notes
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Reaction equation

HRID 1478527 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([Mg]Cl)(C)C.[C:28]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:28]([OH:35])([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 19698705tert-Butyl 4-nicotinoylpiperidine-1-carboxylate2×HCID 867160644-Chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline2×HCID 178418918HCID 178418918, compound

Product 1

HCID 118005527tert-Butyl 4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028
Tetrahydrofuran
Solvent

Conditions

Temperature
50 °C

Procedure

To a solution of 4-chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline (Intermediate 20: step b, containing about 13% molar of 4-chloro-3-phenyl-2-(trifluoromethyl)quinoline as impurity, 340 mg) in THF (4 mL) at −78° C. under N2 was added iPrMgCl (2.0 M in THF, 0.40 mL, 0.8 mmol). After stirring for 8 minutes, the cooling bath was removed, and stirring was continued for 20 minutes, then tert-butyl 4-nicotinoylpiperidine-1-carboxylate (225 mg, 0.770 mmol, Intermediate 21) was added in neat. After stirring at room temperature overnight, the mixture became clear brown and was heated at 50° C. for 1.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.17-9.35 (m, 1H), 8.50-8.88 (m, 2H), 8.29 (d, J=7.58 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 7.82-8.00 (m, 1H), 7.47-7.57 (m, 4H), 7.21-7.33 (m, 2H), 4.08-4.26 (m, 2H), 2.69-2.99 (m, 3H), 1.82-1.92 (m, 1H), 1.53-1.80 (m, 3H), 1.47 (s, 4.5H), 1.41 (s, 4.5H); MS m/e 598.3 [M+H]+.

Workup

  1. customthe cooling bath was removed
  2. stirringstirring
  3. waitwas continued for 20 minutes
  4. stirringAfter stirring at room temperature overnight
  5. customThe mixture was quenched with saturated NH4Cl aqueous solution
  6. extractionextracted with EtOAc
  7. dry with materialThe extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes)

Sources & evidence

ORD record
ord-997f79bbeb4d4884aa28f062fd3fec33
Source dataset
uspto-grants-2016_08
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09403816B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes