4-Fluoroaniline → (R)-3-(1-(5-cyano-6-(4-fluorophenylamino)pyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea

HRID 1050534Notes

Reaction equation

HRID 1050534 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].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=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.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([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:19])[N:16]([CH3:18])[CH3:17])[CH2:9]2)=[N:7][C:2]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)#[N:21]

Participants

8

Reactant 4

HCID 97314-FluoroanilineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 118115329(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea

Product 1

HCID 118115113(R)-3-(1-(5-cyano-6-(4-fluorophenylamino)pyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
115 °C

Procedure

(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222, 40 mg, 0.13 mmol), 4-fluoroaniline (29 mg, 0.26 mmol), fine-powder cesium carbonate (170 mg, 0.52 mmol), Pd(OAc)2 (10 mg, 0.04 mmol), BINAP (25 mg, 0.04 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 mM It was then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. 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 7% MeOH in chloroform to isolate (R)-3-(1-(5-cyano-6-(4-fluorophenylamino)pyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (223). It was dissolved in 10 mL MeOH and 2 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 1.5 hour, diluted with 10 mL MeCN, stirred for 5 mM, concentrated in vacuo, acidified with 0.2 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide (224) as HCl salt (40 mg, 76%). MS found for C19H24FN7O2 as (M+H)+ 402.1, (M−H)− 400.1. UV: λ=264, 274, 300, 331, 372 nm. Proton NMR (CD3OD): δ 7.63 (1H, s), 7.59 (2H, m), 7.02 (2H, t, J=9.0 Hz), 4.34 (1H, m), 4.19 (1H, m), 3.74 (1H, m), 3.17 (1H, m), 3.05 (1H, m), 2.89 (6H, s), 2.02 (1H, m), 1.86 (1H, m), 1.70-1.61 (2H, m) ppm.

Workup

  1. temperatureThe mixture was cooled to RT
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-baab8f5e46b84591a6b5a3e9b8fcf2b2
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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