Formaldehyde → HCID 25160453, compound

HRID 914017Notes

Reaction equation

HRID 914017 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH:35]3[CH2:37][CH2:36]3)[N:7]=2)[CH:3]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546158HCID 57546158, compound

Product 1

HCID 25160453HCID 25160453, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(5-chloro-2-cyclopropyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (65 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 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 (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (38.7 mg, 0.62 mmol) and formalin (0.45 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 loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 16 mg (29%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.41 (m, 1H), 7.30-7.33 (m, 2H), 6.99-7.03 (m, 2H), 6.78 (m, 1H), 4.92 (q, J=6.4 Hz, 1H), 3.86-3.90 (m, 2H), 3.33-3.38 (m, 2H), 2.52-2.53 (m, 2H), 2.20 (s, 3H), 1.97-2.24(m, 6H), 1.41 (d, J=6.4 Hz, 3H), 1.25-1.28 (m, 2H), 1.13-1.17 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 161.3 (d, J=243.8 Hz), 145.4 135.2, 129.0, 128.9, 127.9, 122.3, 122.1, 117.0, 115.0, 114.9, 73.8, 52.1, 50.8, 46.4, 40.5, 34.7, 32.8, 22.8. Mass spec.: 442.44 (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 (2 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. customThe cartridge was flushed with several volumes of methanol which
  13. washThe product was eluted with 2 M ammonia in methanol
  14. concentrationconcentrated
  15. customto give 16 mg (29%) as a clear oil

Sources & evidence

ORD record
ord-99144c3ddac847099ad44bb2fe4cc39a
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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