Trifluoroacetic acid → 2-[(4-Ethoxyphenyl)methyl]-N,N-diethyl-1-[[(2R)-1-methyl-2-pyrrolidinyl]methyl]-1H-benzimidazole-5-carboxamide

HRID 1796506Notes

Reaction equation

HRID 1796506 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(O[C:33]([N:35]1[CH2:41][CH2:40][CH2:39][C@@H:36]1[CH:37]=O)=O)(C)(C)C.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:1]([CH2:37][C@H:36]3[CH2:39][CH2:40][CH2:41][N:35]3[CH3:33])[C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=3[N:15]=2)=[CH:19][CH:20]=1)[CH3:26]

Participants

5

Reactant 4

HCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 7009153N-(tert-Butoxycarbonyl)-D-prolinalHCID 22181390HCID 22181390, compound

Product 1

HCID 695958332-[(4-Ethoxyphenyl)methyl]-N,N-diethyl-1-[[(2R)-1-methyl-2-pyrrolidinyl]methyl]-1H-benzimidazole-5-carboxamideYield 36%

Procedure

N-[2-Amino-5-[(diethylamino)carbonyl]phenyl]-4-ethoxy-benzeneacetamide (85 mg, 0.230 mmol) and N-(tert-butoxycarbonyl)-D-prolinal (0.06 mL, 1.5 eq) were coupled and cyclized following the procedure in example 40E. The solvent was then concentrated. The residue was dissolved in MeOH and 37% formaldehyde in water (formalin) (few drops, excess) was added, followed by sodium cyanoborohydride (43 mg, 3 eq). The solution was then stirred at rt for 1 h. The crude product was directly purified by reversed-phase chromatography (C-18 column) using a gradient of 15–65% CH3CN/H2O and then lyophilized affording the title compound (46 mg, 36% yield) as the corresponding TFA salt; 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 4.85 (m, 1H), 4.66 (m, 1H), 4.49 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.78 (br s, 2H), 3.56 (br s, 2H), 3.27 (br s, 3H), 2.95 (s, 3H), 2.02 (m, 3H), 1.85 (m, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.25 (br s, 3H), 1.11 (br s, 3H); MS (ESI) (M+H)+=449.45; Anal. Calcd for C27H36N4O2+2.4 TFA+1.1H2O: C, 51.47; H, 5.51; N, 7.55. Found: C, 51.46; H, 5.43; N, 7.67.

Workup

  1. concentrationThe solvent was then concentrated
  2. dissolutionThe residue was dissolved in MeOH
  3. addition37% formaldehyde in water (formalin) (few drops, excess) was added
  4. customThe crude product was directly purified by reversed-phase chromatography (C-18 column)

Sources & evidence

ORD record
ord-09f5851809d34324b815a4711aea2797
Source dataset
uspto-grants-2006_04
Patent number
US07030139B2

Reaction notes

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