Formaldehyde → Trifluoroacetic acid

HRID 914033Notes

Reaction equation

HRID 914033 reaction equation
[C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[C:31]4[N:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:27]=4[CH:26]=[C:25]([C:40]([F:43])([F:42])[F:41])[CH:24]=3)[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].O.C=O.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:13][N:10]1[CH2:11][CH2:12][C:7]([CH2:20][O:21][CH2:22][C:23]2[C:31]3[N:30]=[CH:29][NH:28][C:27]=3[CH:26]=[C:25]([C:40]([F:42])([F:41])[F:43])[CH:24]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1.[C:46]([OH:48])([C:45]([F:50])([F:49])[F:44])=[O:47]

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 22392675Trifluoroacetic acid waterHCID 67405110HCID 67405110, compound

Product 2

HCID 6422Trifluoroacetic acidHCID 25160967HCID 25160967, compound

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

tert-Butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate was treated with trifluoroacetic acid: water (9:1, 3 ml) at ambient temperature for 15 min at which time LC-MS analysis revealed completion of the reaction (HPLC method 10: tR=2.5 min, 520(MH)+). The volatiles were evaporated and dried under vacuo. The residue was treated with formaldehyde (0.1 mL, 3.6 mmol), acetic acid (cat.) and sodium cyanoborohydride (25 mg, 0.4 mmol) at ambient temperature for 2 h. The reaction was complete by LC-MS analysis (HPLC method 9: tR=2.7 min, 534(MH)+). The solvent was evaporated and the residue was treated with trifluoroacetic acid /dichloromethane (1:1, 4 ml) at ambient temperature for 3 h. LC-MS analysis (HPLC method 1: tR=2.0 min, 404(MH)+). The solvent was evaporated and the residue was purified by Prep HPLC (HPLC method 15). Fractions containing required product were combined and evaporated to give the title compound as a TFA salt. (6 mg, yield for 5 steps from (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol, 13.2% yield). 1H-NMR (CD3OD, 500 MHz) δ 8.85 (s, 1H), 7.99 (s, 2H), 7.57 (s, 1H), 7.43-7.27 (m, 5H), 4.85 (s, 2H), 3.52 (s, 2H), 3.45 (m, 2H), 2.85 (m, 2H), 2.75 (s, 3H), 2.69-2.66 (m, 2H), 2.19 (m, 2H); 19F NMR (471 MHz, CD3OD) δ −62.9, −77.6; LC/MS (HPLC method 1): tR=2.1 min, 404(MH)+.

Workup

  1. customcompletion of the reaction (HPLC method 10: tR=2.5 min, 520(MH)+)
  2. customThe volatiles were evaporated
  3. customdried under vacuo
  4. customThe solvent was evaporated
  5. additionthe residue was treated with trifluoroacetic acid /dichloromethane (1:1, 4 ml) at ambient temperature for 3 h
  6. customThe solvent was evaporated
  7. customthe residue was purified by Prep HPLC (HPLC method 15)
  8. additionFractions containing required product
  9. customevaporated

Sources & evidence

ORD record
ord-0c669884f8ab4a50816a466cbcf558b8
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

Loading…