Potassium Carbonate → tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate

HRID 2200414Notes

Reaction equation

HRID 2200414 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=1[C:23]#[N:24].[N:25]1[N:26]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[N:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].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>[N:25]1[N:26]([C:30]2[CH:31]=[C:32]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]4[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[N:4][C:3]=3[C:23]#[N:24])[CH:34]=[CH:35][CH:36]=2)[N:27]=[CH:28][CH:29]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 234387563-(2H-1,2,3-Triazol-2-yl)anilineHCID 86685544tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate

Product 1

HCID 86685545tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamateYield 157.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 634876Binap, (A+-)-CatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (123 mg, 0.574 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (3 mL) was stirred at room temperature for 20 h. HOAc (0.3 mL) was added. Then, water was added to induce precipitation. The precipitate was collected, dried on vacuum to give tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (165 mg). A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.312 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg). The crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg).

Workup

  1. customwas degassed with Ar
  2. additionWater and EtOAc were added
  3. customOrganic phase was separated
  4. extractionThe aqueous phase was extracted with EtOAc again
  5. dry with materialThe combined organic phases were dried over Na2SO4
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-778508a15d9440bbb8a0a862a9648d53
Source dataset
uspto-grants-2016_06
Patent number
US09359308B2

Reaction notes

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