Formaldehyde → HCID 25160584, compound

HRID 914022Notes

Reaction equation

HRID 914022 reaction equation
[CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 57546182HCID 57546182, compound

Product 1

HCID 25160584HCID 25160584, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(2-(cyclopropylmethyl)-5-methyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (15 mg, 0.03 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 (9 mg, 0.14 mmol) and formalin (79 μL). 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 flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 5 mg (40%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.32-7.34 (m, 2H), 7.23 (m, 1H), 6.99-7.02 (m, 2H), 6.66 (m, 1H), 4.94 (q, J=6.4 Hz, 1H), 4.22-4.24 (m, 2H), 3.34-3.41 (m, 2H), 2.57 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.09-2.25 (m, 6H), 2.01-2.04 (m, 1H), 1.44 (d, J=6.4 Hz, 3H), 0.64 (m, 2H), 0.40-0.43 (m, 2H). Mass spec.: 436.53(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 flash chromatography on silica gel (10% methanolic ammonia/methylene chloride)
  13. customto afford 5 mg (40%) as a clear oil

Sources & evidence

ORD record
ord-32e3e11eceaa4b94b8f0a55dc7576b7d
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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