Dimethylformamide → 4-Methyl-2-((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carbonyl)benzonitrile

HRID 60927Notes

Reaction equation

HRID 60927 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:59][N:60](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:59]#[N:60])=[C:3]([C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([CH3:17])[C@H:12]2[CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][N:21]=2)=[O:10])[CH:4]=1

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 89739735(2-Bromo-5-methylphenyl)((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone

Product 1

HCID 1177277964-Methyl-2-((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carbonyl)benzonitrile

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
150 °C

Procedure

A mixture of (2-bromo-5-methylphenyl)((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (synthesized from Example A3, 0.35 g, 0.744 mmol), Zn(CN)2 (0.105 g, 0.818 mmol), Pd2(dba)3 (0.068 g, 0.074 mmol) and 2-dicyclohexylphophino-2′,6′-dimethoxybiphenyl (S-Phos; 0.076 g, 0.186 mmol) in wet DMF (DMF:H2O 10:1, 20 mL) was degassed and sealed and heated in a microwave reactor for 1 h at 150° C. The reaction was cooled to rt and the solvent was removed in vacuo. The crude was dissolved with EtOAc, washed with satd. aq. NaHCO3 and brine and dried over Na2SO4. The solvent was removed and the crude was purified in silica gel with 0˜100% EtOAc/Hex to obtain the title compound. ESI-MS (m/z): 417 [M+1]+.

Workup

  1. customwas degassed
  2. customsealed
  3. temperatureThe reaction was cooled to rt
  4. customthe solvent was removed in vacuo
  5. dissolutionThe crude was dissolved with EtOAc
  6. washwashed with satd
  7. dry with materialaq. NaHCO3 and brine and dried over Na2SO4
  8. customThe solvent was removed
  9. customthe crude was purified in silica gel with 0˜100% EtOAc/Hex

Sources & evidence

ORD record
ord-d492422dd2c14dcf9635045cacd804df
Source dataset
uspto-grants-2016_09
Patent number
US09440982B2

Reaction notes

Loading…