Diisopropylethylamine → (S)-tert-butyl (4-(5-amino-6-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyrazin-2-yl)cyclohexyl)carbamate

HRID 596051Notes

Reaction equation

HRID 596051 reaction equation
[NH2:1][C:2]1[C:3]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C@@H:42]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1)[CH2:43][OH:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[CH2:10][CH2:9]2)=[N:4][C:3]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:41][C@@H:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)[CH2:43][OH:44])=[C:24]([F:31])[CH:23]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59694427(S)-2-amino-2-(3-chlorophenyl)ethanolHCID 1180455274-(3-Amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid

Product 1

HCID 131734621(S)-tert-butyl (4-(5-amino-6-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyrazin-2-yl)cyclohexyl)carbamateYield 83.6%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To 4-(3-amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (222 mg, 0.516 mmol) was added DMSO (4 mL), Hünig's base (0.450 mL, 2.58 mmol), (S)-2-amino-2-(3-chlorophenyl)ethanol (133 mg, 0.774 mmol) and then HATU (392 mg, 1.031 mmol). The reaction was stirred for 1 h at room temperature. To the reaction was added 50 mL of ethyl acetate, washed with water twice, saturated salt solution, dried over sodium sulfate, filtered and concentrated to residue. The crude was purified by flash chromatography using 12 gram column (solid load) eluting with 10-95% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give 252 mg of product (which is 2:1 trans to cis ratio), used as is (83% over two steps). LCMS (m/z): 584.3 (MH+), 0.91 min for both.

Workup

  1. washwashed with water twice
  2. dry with materialsaturated salt solution, dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated to residue
  5. customThe crude was purified by flash chromatography
  6. washeluting with 10-95% ethyl acetate in heptane
  7. concentrationThe desired fractions were concentrated to constant mass

Sources & evidence

ORD record
ord-ae9791ec86154fe896c303b44f5b4135
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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