Ammonium Chloride → 4-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide

HRID 1038979Notes

Reaction equation

HRID 1038979 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][C@H:54]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:55][O:56][C:57]1[CH:66]=[CH:65][C:60]2[NH:61][C:62](=[O:64])[NH:63][C:59]=2[CH:58]=1.[NH4+].[Cl-]>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:53][C@H:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH2:55][O:56][C:57]2[CH:66]=[CH:65][C:60]3[NH:61][C:62](=[O:64])[NH:63][C:59]=3[CH:58]=2)=[O:14])[C:7]1=[O:15]

Participants

8

Reactant 5

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 584430534-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acidHCID 67395993(R)-5-(2-Amino-2-phenylethoxy)-1H-benzo[d]imidazol-2(3H)-one

Product 1

HCID 462348434-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

4-(3,4-Difluorobenzyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (48 mg, 0.18 mmol) was placed in a 25-mL RBF under a nitrogen atmosphere followed by HATU (82 mg, 0.22 mmol), then NMP (1.0 mL) and finally N,N-diisopropylethylamine (0.11 mL, 0.63 mmol). The reaction was stirred for five minutes at room temperature, and was added to a solution of 5-[(2R)-2-amino-2-phenylethoxy]-1,3-dihydro-2H-benzimidazol-2-one (55 mg, 0.18 mmol) in NMP (1.0 mL). The reaction was allowed to stir at room temperature for forty minutes, then was added to a separatory funnel containing ethyl acetate (75 mL) and dilute aqueous NH4Cl (50 mL); the phases were separated and the organic layer was washed with saturated aqueous NaHCO3 (50 mL), followed by brine (50 mL) and dried over anhydrous Na2SO4, then concentrated in vacuo. The crude product was purified by silica gel chromatography (10-gram column) using 0-10% CH3OH in CH2Cl2, with the product eluting at 8% CH3OH in CH2Cl2, to afford 4-(3,4-difluorobenzyl)-3-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-3,4-dihydropyrazine-2-carboxamide as a light yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.51 (s, 1H), 10.38 (s, 1H), 9.82 (d, 1H), 8.05 (d, 1H), 7.57 (d, 1H), 7.50 (m, 1H), 7.43 (m, 3H), 7.35 (t, 2H), 7.27 (t, 1H), 7.24 (m, 1H), 6.75 (d, 1H), 6.51 (d, 2H), 5.34 (m, 1H), 5.16 (s, 2H), 4.09 (m, 2H). LRMS (ESI) calc'd for (C27H23F2N5O4) [M+H]+, 518.2; found 518.2.

Workup

  1. stirringto stir at room temperature for forty minutes
  2. additionwas added to a separatory funnel
  3. customthe phases were separated
  4. washthe organic layer was washed with saturated aqueous NaHCO3 (50 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by silica gel chromatography (10-gram column)
  8. washwith the product eluting at 8% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-34d0131ebbdf4b6e84b30f491e99bc5b
Source dataset
uspto-grants-2013_10
Patent number
US08552019B2

Reaction notes

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