Cesium carbonate → (R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate

HRID 1050514Notes

Reaction equation

HRID 1050514 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])=[CH:27][CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[N:7][C:2]=1[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])=[CH:29][CH:30]=1)#[N:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 5778154-(Morpholine-4-carbonyl)anilineHCID 634876Binap, (A+-)-HCID 118114972(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate

Product 1

HCID 118114741(R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamateYield 85%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

A mixture of (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (400 mg, 1.19 mmol), (4-aminophenyl)(morpholino)methanone (490 mg, 2.38 mmol), Pd(OAc)2 (54 mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol), fine powder Cs2CO3 (1.55 g, 4.76 mmol) in dioxane (40 mL) was degassed with nitrogen stream for 3 min. The mixture was stirred in a nitrogen atmosphere at 115° C. for 2.5 h. The mixture was cooled, diluted with 100 mL EtOAc, filtered through celite, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 65% EtOAc in DCM to give (R)-tert-butyl 1-(5-cyano-6-(4-(morpholine-4-carbonyl)phenylamino)pyrazin-2-yl)piperidin-3-ylcarbamate (88) (yield >85%).

Workup

  1. customwas degassed with nitrogen stream for 3 min
  2. temperatureThe mixture was cooled
  3. additiondiluted with 100 mL EtOAc
  4. filtrationfiltered through celite
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8af97c241bbb45e0975905107b060b5b
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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