Cesium carbonate → (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

HRID 1050539Notes

Reaction equation

HRID 1050539 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:19])[N:16]([CH3:18])[CH3:17])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:20]#[N:21].[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([C:3]1[C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([N:16]([CH3:18])[CH3:17])=[O:19])[CH2:9]2)=[CH:5][N:4]=1)#[N:21]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27281520tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylateHCID 118115329(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea

Product 1

HCID 118114862(R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

The mixture of (R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222, 330 mg, 1.07 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (275, 426 mg, 1.60 mmol), fine-powder cesium carbonate (1.05 g, 3.21 mmol), Pd(OAc)2 (72 mg, 0.32 mmol), BINAP (200 mg, 0.32 mmol) in 60 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 60 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in chloroform to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (276). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 2 hours, diluted with 10 mL MeCN, stirred for 5 min, concentrated in vacuo, diluted with EtOAc 150 mL, washed with water ×3, dried, concentrated in vacuo to afford crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277).

Workup

  1. customwas degassed with nitrogen stream for 3 min
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with 60 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-f8acdc60320c42e18c9d14a62c160c5b
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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