Formaldehyde → HCID 178434309, compound

HRID 914010Notes

Reaction equation

HRID 914010 reaction equation
[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.C=O.[C:33]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20][CH2:21][N:22]([CH3:33])[CH2:23][CH2:24]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[NH:4][N:3]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 178434308HCID 178434308, compound

Product 1

HCID 178434309HCID 178434309, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

(±)-3-Methyl-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole (32 mg, 0.08 mmol) and formaldehyde (37 wt. % solution in water, 120 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (24 mg, 0.38 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% ammonia/8% methanol/methylene chloride) to afford 20 mg (61%). 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.30-7.40 (m, 5H), 7.21-7.44 (m, 1H), 4.40 (q, J=6.7 Hz, 1H), 3.39 (q, J=9.2 Hz, 1H), 3.33 (d, J=9.2 Hz, 1H), 2.59 (s, 3H), 2.54 (m, 2H), 2.19-2.26 (m, 4H), 2.03-2.07 (m, 2H), 1.46 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.7, 139.0, 128.7, 127.3, 127.2, 126.7, 124.9 (q, J=272 Hz), 122.9, 122.6 (q, J=32.6 Hz), 119.7, 117.4, 78.4, 52.0, 51.9, 46.6, 40.7, 32.6, 22.0, 11.9. Mass spec.: 418.19 (MH)+. Mass spec.: 432.09 (MH)+.

Workup

  1. customThe solvent was removed in vacuo
  2. washAfter washing the column with several volumes of methanol
  3. washthe product was eluted
  4. washby washing the column with 2 M ammonia in methanol
  5. customThe solvents were evaporated
  6. customthe compound purified by flash chromatography on silica gel (1% ammonia/8% methanol/methylene chloride)
  7. customto afford 20 mg (61%)

Sources & evidence

ORD record
ord-c84ad1a5bf5f406abc8f317376ef6ed8
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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