1,2-Dichloroethane → 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide

HRID 596024Notes

Reaction equation

HRID 596024 reaction equation
[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=1)[CH2:29][OH:30].C(Cl)CCl.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=3)[CH2:29][OH:30])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 118045792(S)-2-Amino-2-(3-bromo-5-fluorophenyl)ethan-1-OL hclHCID 1180458424-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid

Product 1

HCID 1180460264-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamideYield 41%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (20 mg, 0.057 mmol) in DMF (573 μL) was added (S)-2-amino-2-(3-bromo-5-fluorophenyl)ethanol HCl salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69 mg, 0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 μl, 0.172 mmol). The reaction mixture was stirred for 15 h. Water was added, and the reaction mixture was extracted with EtOAc three times. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were lyophilized to provide 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (16.1 mg, 0.023 mmol, 41%) as a TFA salt. LCMS (m/z): 565.1/567.1 (MH+), 0.72 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.69 (m, 2H), 7.65-7.47 (m, 2H), 7.40-7.30 (m, 1H), 7.22-7.06 (m, 2H), 5.08 (t, J=5.7 Hz, 1H), 4.41-4.14 (m, 1H), 3.85-3.67 (m, 2H), 3.63-3.48 (m, 1H), 2.74 (t, J=11.5 Hz, 1H), 2.17 (td, J=3.1, 6.3 Hz, 1H), 2.04-1.89 (m, 1H), 1.84-1.66 (m, 2H), 1.65-1.30 (m, 2H). The absolute stereochemistry was determined based on the information of X-ray co-structure in ERK2 of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide.

Workup

  1. extractionthe reaction mixture was extracted with EtOAc three times
  2. dry with materialThe organic layers were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by HPLC

Sources & evidence

ORD record
ord-7d608cbe301f4a4b9f9b323500062308
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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