Formaldehyde → HCID 25160455, compound

HRID 914019Notes

Reaction equation

HRID 914019 reaction equation
[F:1][CH:2]([F:38])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH3:14])[CH:6]=[N:5]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:38][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH3:14])[CH:6]=[N:5]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546098HCID 57546098, compound

Product 1

HCID 25160455HCID 25160455, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(1-(2,2-difluoroethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. 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 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4 mg (47%) as a clear oil. LC/MS (HPLC method 1): tR=2.35 min, 446.56(MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customflushed with several volumes of methanol which
  3. washThe crude secondary amine was eluted in 2 M ammonia in methanol
  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. concentrationThe reaction was concentrated
  12. custompurified by column chromatography (10% methanolic ammonia/methylene chloride)
  13. customto afford 4 mg (47%) as a clear oil

Sources & evidence

ORD record
ord-e895dc3cfa604e0ca6ad198a7444a40a
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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