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

HRID 2200415Notes

Reaction equation

HRID 2200415 reaction equation
[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[N:18]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH:26]C(=O)OC(C)(C)C)[CH:16]=[N:15][C:14]=3[C:34]#[N:35])[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1>C(O)(C(F)(F)F)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:34]#[N:35])=[N:15][CH:16]=[C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[NH2:26])[N:18]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1

Participants

3

Reactant 1

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

Product 1

HCID 866855463-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrileYield 20.9%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

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. concentrationthe mixture was concentrated in vacuo
  2. customThe residue was purified by HPLC

Sources & evidence

ORD record
ord-2f9d0dba1b594520a66b66a35d753c5d
Source dataset
uspto-grants-2016_06
Patent number
US09359308B2

Reaction notes

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