Cesium carbonate → HCID 118114703, compound

HRID 1050551Notes

Reaction equation

HRID 1050551 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=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:21]([C:3]1[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:9]2)=[CH:5][N:4]=1)#[N:22]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 21940085tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylateHCID 118114932HCID 118114932, compound

Product 1

HCID 118114703HCID 118114703, compoundYield 80%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
115 °C

Procedure

The mixture of (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 390 mg, 1.21 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (670 mg, 2.42 mmol), fine-powder cesium carbonate (1600 mg, 4.84 mmol), Pd(OAc)2 (134 mg, 0.60 mmol), BINAP (374 mg, 0.60 mmol) in 60 mL dioxane was degassed with nitrogen stream for 5 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 20 to 100% EtOAc in DCM to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (295) in >80% yield. It was dissolved in 40 mL MeOH and 10 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 2 mL 30% H2O2. The mixture was stirred at RT for 3 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water ×2, concentrated, and subjected to silica flash column using 0 to 7% MeOh in DCM to give crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (296). It was treated with 30 mL commercial 4N HCl in dioxane for 90 min, and concentrated in vacuo to afford crude (R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (297) hydrochloride.

Workup

  1. customwas degassed with nitrogen stream for 5 min
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with 120 mL EtOAc
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-b45c32598a104e8a8e6c70ca3f3fdcd6
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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