Cesium carbonate → tert-butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate

HRID 1050561Notes

Reaction equation

HRID 1050561 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])[C@H:9]2[CH3:22])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].Cl.[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]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.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([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])[C@H:9]2[CH3:22])=[N:7][C:2]=1[NH:41][C:40]1[CH:42]=[CH:43][C:37]([CH:34]2[CH2:35][CH2:36][N:31]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[CH:38][CH:39]=1)#[N:24]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 1181146604-(1-Cyclopentylpiperidin-4-yl)aniline hydrochlorideHCID 118136131tert-butyl (2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate

Product 1

HCID 118136128tert-butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamateYield 68%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

tert-Butyl (2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (311) (390 mg, 1.1 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline HCl salt (304) (406 mg, 1.7 mmol), fine-powder Cs2CO3 (1.1 g, 3.3 mmol), BINAP (207 mg, 0.33 mmol), and Pd(OAc)2 (75 mg, 0.33 mmol) were combined and suspended in dioxane (30 mL) and water (1 mL). The mixture was sparged with nitrogen stream for 10 minutes, and then stirred under nitrogen atmosphere in 115° C. oil bath for 5 hours. The mixture was cooled to RT, diluted with EtOAc (100 mL), stirred, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica flash column chromatography (MeOH/DCM) to give tert-butyl (2R,3R)-1-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-ylcarbamate (312) (430 mg, 0.74 mmol, 68% yield).

Workup

  1. customThe mixture was sparged with nitrogen stream for 10 minutes
  2. temperatureThe mixture was cooled to RT
  3. additiondiluted with EtOAc (100 mL)
  4. stirringstirred
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-20d78b71306b4b1b9720c8765249679e
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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