Ethyl bromoacetate → [2-(3-Ethoxy-phenoxymethyl)-3-isobutyl-3H-benzimidazol-5-yloxy]-acetic acid ethyl ester

HRID 537315Notes

Reaction equation

HRID 537315 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:11]=2[N:10]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:22][C:19]1[CH:20]=[CH:21][C:11]2[N:10]=[C:9]([CH2:8][O:7][C:6]3[CH:23]=[CH:24][CH:25]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]=2[CH:18]=1)[CH3:38]

Participants

5

Reactant 3

HCID 7748Ethyl bromoacetateHCID 11430Potassium CarbonateHCID 866892932-[(3-Ethoxyphenoxy)methyl]-1-isobutylbenzimidazol-6-ol

Product 1

HCID 71621623[2-(3-Ethoxy-phenoxymethyl)-3-isobutyl-3H-benzimidazol-5-yloxy]-acetic acid ethyl esterYield 100%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 66b (3.00 g, 8.81 mmol) and DMF (35 mL). To the resultant solution was added K2CO3 (1.83 g, 13.2 mmol) followed by ethyl bromoacetate (1.62 g, 1.07 mL, 9.69 mmol). The mixture was stirred at rt overnight. The solids were then filtered off and rinsed with EtOAc (2×50 mL). The filtrate was washed with saturated NH4Cl (2×75 mL), H2O (2×75 mL), and brine (75 mL) and filtered through phase separation paper. The organic phase was filtered through a plug of silica gel, rinsed with EtOAc (3×100 mL), and concentrated in vacuo to 4.0 g of a brown oil. 1 g of the crude oil was chromatographed on a Biotage MPLC 25+M silica gel column with the product eluting with 30-36% EtOAc in hexanes. The product fractions were concentrated to give 975 mg of Compound #13 as a yellow oil (100%). 1H NMR (300 MHz, CDCl3): δ 7.69 (d, 1H), 7.20 (t, 1H), 6.93 (dd, 1H), 6.88 (d, 1H), 6.67 (dd, 1H), 6.63 (t, 1H), 6.54 (dd, 1H), 5.32 (s, 2H), 4.70 (s, 2H), 4.29 (qt, 2H), 4.05 (qt, 2H), 4.04 (d, 2H), 2.34 (nonet, 1H), 1.41 (t, 3H), 1.32 (t, 3H), 0.97 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 99% with a retention time of 3.9 min.

Workup

  1. customA 100 mL flask fitted with a stir-bar
  2. filtrationThe solids were then filtered off
  3. washrinsed with EtOAc (2×50 mL)
  4. washThe filtrate was washed with saturated NH4Cl (2×75 mL), H2O (2×75 mL), and brine (75 mL)
  5. filtrationfiltered through phase separation paper
  6. filtrationThe organic phase was filtered through a plug of silica gel
  7. washrinsed with EtOAc (3×100 mL)
  8. concentrationconcentrated in vacuo to 4.0 g of a brown oil
  9. custom1 g of the crude oil was chromatographed on a Biotage MPLC 25+M silica gel column with the product
  10. washeluting with 30-36% EtOAc in hexanes
  11. concentrationThe product fractions were concentrated

Sources & evidence

ORD record
ord-e54214677bdc41a4a1adbb6ebead8a61
Source dataset
uspto-grants-2014_10
Patent number
US08859780B2

Reaction notes

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