Formaldehyde → HCID 25160714, compound

HRID 914027Notes

Reaction equation

HRID 914027 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:29]4[N:30]([CH3:33])[N:31]=[N:32][C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546218HCID 57546218, compound

Product 1

HCID 25160714HCID 25160714, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (17 mg, 0.033 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., treated with sodium cyanoborohydride (4.1 mg, 0.065 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 10.4 mg (73%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.28 (s, 1H), 7.42 (s, 1H), 7.12 (m, 2H), 6.89 (m, 2H), 4.69 (s, 2H), 4.08 (s, 3H), 3.44 (s, 2H), 2.51 (m, 2H), 2.19 (s, 3H), 2.12 (m, 4H), 1.89 (m, 2H). Mass spec.: 437.14 (MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customflushed with several volumes of methanol which
  3. washThe crude secondary amine was eluted in 2M ammonia
  4. concentrationconcentrated
  5. dissolutionThe resulting residue was dissolved in acetonitrile (1 mL)
  6. temperaturecooled to 0° C.
  7. waitAfter 5 min
  8. customThe ice bath was removed
  9. stirringstirring
  10. waitcontinued for 1 h
  11. additionThe reaction was diluted with ether
  12. washwashed with 1M sodium hydroxide
  13. concentrationThe ethereal was concentrated
  14. customThe cartridge was flushed with several volumes of methanol which
  15. washThe product was eluted with 2 M ammonia
  16. concentrationconcentrated
  17. customto give 10.4 mg (73%) as a colorless film

Sources & evidence

ORD record
ord-99649c3ceeb24dd3a1e36a63ee36c16f
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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