Acetic Acid → 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl ester

HRID 1161769Notes

Reaction equation

HRID 1161769 reaction equation
C([BH3-])#N.[Na+].C([O:7][C:8](=O)[C:9]([CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][C:20]=1[Cl:34])([CH2:15][CH:16]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.Cl.Cl.[N:38]1[C:42]2[CH2:43][CH2:44][CH:45]([NH2:47])[CH2:46][C:41]=2[NH:40][CH:39]=1.C(O)(=O)C>CO>[CH2:13]([O:12][C:10]([C:9]1([CH2:18][C:19]2[C:20]([Cl:34])=[CH:21][C:22]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][C:24]=2[Cl:25])[CH2:15][CH2:16][N:47]([CH:45]2[CH2:44][CH2:43][C:42]3[N:38]=[CH:39][NH:40][C:41]=3[CH2:46]2)[C:8]1=[O:7])=[O:11])[CH3:14]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 686481735-Amino-4,5,6,7-tetrahydrobenzimidazole dihydrochlorideHCID 866291152-(4-Benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester

Product 1

HCID 686483313-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl esterYield 38.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
60 °C

Procedure

Add sodium cyanoborohydride (3.6 g, 57.4 mmol) portion wise to a solution of 2-(4-benzyloxy-2,6-dichloro-benzyl)-2-(2-oxo-ethyl)-malonic acid diethyl ester (6.7 g, 14.4 mmol) (Preparation 10) and 4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylamine dihydrochloride salt (6.0 g, 28.7 mmol) (Preparation 1) in 70 ml of Methanol. After 3 h, add 4 ml of acetic acid and warm to 60° C. for 16 h. Most of the Methanol is removed via rotovap. Quench the resulting mixture with saturated bicarbonate and extract with ethyl acetate. Dry extracts over sodium sulfate, concentrate, and purify by normal phase column chromatography (0-10% methanol in ethyl acetate) to afford 3-(4-Benzyloxy-2,6-dichloro-benzyl)-2-oxo-1-(4,5,6,7-tetrahydro-3H-benzoimidazol-5-yl)-pyrrolidine-3-carboxylic acid ethyl ester as a white solid (3 g).

Workup

  1. customMost of the Methanol is removed via rotovap
  2. customQuench the resulting mixture with saturated bicarbonate
  3. extractionextract with ethyl acetate
  4. customDry
  5. concentrationconcentrate
  6. custompurify by normal phase column chromatography (0-10% methanol in ethyl acetate)

Sources & evidence

ORD record
ord-fd5d213a2d9e4d92b66a91f6a3698800
Source dataset
uspto-grants-2010_10
Patent number
US07820659B2

Reaction notes

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