Potassium Hydroxide → 1'-(5-Ethyl-3-methylpyridin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4'-bipiperidin-2-one

HRID 407972Notes

Reaction equation

HRID 407972 reaction equation
Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:15]1=[O:26].[OH-].[K+].Cl[C:30]1[C:35]([CH3:36])=[CH:34][C:33]([CH2:37][CH3:38])=[CH:32][N:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+]>CO.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH2:37]([C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([N:23]2[CH2:22][CH2:21][CH:20]([N:16]3[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:4]4[CH:5]=[CH:6][C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:15]3=[O:26])[CH2:25][CH2:24]2)=[N:31][CH:32]=1)[CH3:38]

Participants

10

Reactant 5

HCID 14797Potassium HydroxideHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl2×HCID 23676156Sodium t-butoxideHCID 66803550(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4'-bipiperidin-2-one hydrochlorideHCID 866880852-Chloro-5-ethyl-3-methylpyridine

Product 1

HCID 866881101'-(5-Ethyl-3-methylpyridin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4'-bipiperidin-2-oneYield 66.5%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (prepared according to the method of Example 45) (0.100 g, 0.246 mmol) in 5 mL MeOH was added KOH (0.014 g, 0.246 mmol). The mixture was stirred for 30 minutes at ambient temperature, cooled in an ice bath and filtered through a syringe filter, and the filtrate was concentrated and used directly. To the obtained residue was added 2-chloro-5-ethyl-3-methylpyridine (0.0460 g, 0.296 mmol), toluene (5 mL), Pd(OAc)2 (0.00830 g, 0.0370 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (also known as “DavePhos”) (0.0291 g, 0.0739 mmol), and NaOtBu (0.0710 g, 0.739 mmol) and the mixture was heated at 110° C. overnight. The reaction was cooled to ambient temperature, diluted with water and extracted with CH2Cl2. The organic layers were combined, dried over Na2SO4 and purified on silica gel eluting with 100% EtOAc to give 1′-(5-ethyl-3-methylpyridin-2-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.080 g, 66.5% yield) as a white solid. Mass spectrum (apci) m/z=489.3 (M+H).

Workup

  1. temperaturecooled in an ice bath
  2. filtrationfiltered through a syringe
  3. filtrationfilter
  4. concentrationthe filtrate was concentrated
  5. temperaturethe mixture was heated at 110° C. overnight
  6. temperatureThe reaction was cooled to ambient temperature
  7. extractionextracted with CH2Cl2
  8. dry with materialdried over Na2SO4
  9. custompurified on silica gel eluting with 100% EtOAc

Sources & evidence

ORD record
ord-f9fe753ac0a940efa7b65bf6796e94c2
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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