Hydrochloric Acid → racemic cis-2-[1-(4-Bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]cyclohexanecarboxylic acid

HRID 1776719Notes

Reaction equation

HRID 1776719 reaction equation
[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:26])=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.Cl>C(#N)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:10][C:9]=3[N:26]=[C:31]2[C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]2[C:29]([OH:39])=[O:30])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 641660Hexahydrophthalic anhydride, cis-HCID 90414798N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine

Product 1

HCID 86281518racemic cis-2-[1-(4-Bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]cyclohexanecarboxylic acidYield 45.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
90 °C

Procedure

To a 100 mL round-bottomed flask was added N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.3 g, 2.9 mmol), cis-hexahydroisobenzofuran-1,3-dione (0.5 g, 2.9 mmol) and acetonitrile (27 mL). The resulting solution was heated to 90° C. After 3 h, the reaction was cooled to RT and HCl (15 mL, 6 N) was added and the mixture was heated to 90° C. for 15 h. The resulting mixture was cooled to RT and concentrated to dryness. The residue was partitioned between water (100 mL) and DCM (100 mL) and the mixture was stirred vigorously while the pH was adjusted to 4-5 using sat. NaHCO3. The organic layer was separated and the aqueous layer was further extracted with DCM (2×100 mL). The combine organic layers were dried with magnesium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (750 mg, 44%). MS (ESI): mass calcd. for C31H28BrN3O3, 569.13; m/z found, 570.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.36 (d, J=8.5, 1H), 8.05 (d, J=8.5, 1H), 7.93 (d, J=8.2, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4, 1H), 7.74 (d, J=8.5, 1H), 7.60 (ddd, J=8.1, 7.0, 1.1, 1H), 7.47-7.41 (m, 2H), 7.29 (d, J=2.3, 1H), 7.19 (d, J=8.8, 1H), 7.05 (d, J=8.5, 2H), 7.01 (dd, J=8.8, 2.4, 1H), 5.53-5.41 (m, 2H), 5.39 (s, 2H), 3.60-3.51 (m, 1H), 2.88-2.76 (m, 1H), 2.43-2.29 (m, 1H), 2.00-1.93 (m, 1H), 1.92-1.69 (m, 4H), 1.52-1.36 (m, 2H).

Workup

  1. temperaturethe reaction was cooled to RT
  2. temperaturethe mixture was heated to 90° C. for 15 h
  3. temperatureThe resulting mixture was cooled to RT
  4. concentrationconcentrated to dryness
  5. customThe residue was partitioned between water (100 mL) and DCM (100 mL)
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was further extracted with DCM (2×100 mL)
  8. dry with materialThe combine organic layers were dried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-bd05c43af660454c8fbdb8d07f90f224
Source dataset
uspto-grants-2016_02
Patent number
US09265770B2

Reaction notes

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