Formaldehyde → HCID 25160456, compound

HRID 914020Notes

Reaction equation

HRID 914020 reaction equation
[F:1][CH:2]([F:38])[CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[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[CH:12]=[C:11]2[C:6]([C:7]([CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH3:15])=[CH:8][C:9]([CH3:13])=[CH:10]2)=[N:5]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546138HCID 57546138, compound

Product 1

HCID 25160456HCID 25160456, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(2-(2,2-difluoroethyl)-5-methyl-2H-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 4.5 mg (54%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.83 (s, 1H), 7.30-7.34 (m, 2H), 7.22 (m, 1H), 6.99-7.02 (m, 2H), 6.67 (m, 1H), 6.05-6.29 (m, 1H), 4.86 (q, J=6.4 Hz, 1H), 4.64-4.71 (m, 2H), 3.33-3.38 (m, 2H), 2.57 (m, 2H), 2.28 (s, 3H), 2.20 (s, 3H), 2.15-2.24 (m, 6H), 1.44 (d, J=6.4 Hz, 3H). Mass spec.: 446.63(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 4.5 mg (54%) as a clear oil

Sources & evidence

ORD record
ord-4a449514ad4c489b8a0d24effcc0c2a8
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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