Acetic Acid → (R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid

HRID 41104

Reaction equation

HRID 41104 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C@H:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:36])[C:33]=1[CH:34]=O)[C:28]([OH:30])=[O:29].C(O)(=O)C>CO>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][O:16][C@H:11]([CH2:10][N:9]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=[C:34]2[C:33]2[C:32]([F:36])=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=2[F:24])[CH2:12]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 450736293,5-Difluoro-4-formylbenzoic acidHCID 67170278(R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate

Product 1

HCID 67169642(R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acidYield 82.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of (R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate (600 mg, 1.87 mmol), 3,5-difluoro-4-formylbenzoic acid (347 mg, 1.87 mmol) and acetic acid (0.534 ml, 9.33 mmol) in methanol (15.0 ml) was stirred for 1.5 hr at room temperature. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, eluting with mixtures of EtOAc and heptane, to afford (R)-4-(1-((4-(tert-butoxycarbonyl)morpholin-2-yl)methyl)-5-methyl-1H-benzo[d]imidazol-2-yl)-3,5-difluorobenzoic acid (750 mg, 82%) as an oil. The oil was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; particle size: 5 μm). MS m/z 488.4 [M+H]+ (ESI), Rt 1.56 min.

Workup

  1. concentrationThe mixture was then concentrated under reduced pressure
  2. customthe residue was purified by silica gel flash chromatography
  3. washeluting with mixtures of EtOAc and heptane

Sources & evidence

ORD record
ord-36aa6bd91acc4a919a71b1846cced277
Source dataset
uspto-grants-2013_09
Patent number
US08530467B2

Linked notes

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