Formaldehyde → HCID 67356504, compound

HRID 1407848Notes

Reaction equation

HRID 1407848 reaction equation
[ClH:1].[F:2][C:3]1[C:4]([F:28])=[CH:5][C:6]2[O:27][CH2:26][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:10]3=[O:25])[C:7]=2[CH:8]=1.[CH2:29](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[ClH:1].[F:2][C:3]1[C:4]([F:28])=[CH:5][C:6]2[O:27][CH2:26][C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:29])[CH2:23][CH2:24]4)[C:10]3=[O:25])[C:7]=2[CH:8]=1

Participants

7

Reactant 4

HCID 712FormaldehydeHCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 68601461HCID 68601461, compound

Product 1

HCID 67356504HCID 67356504, compoundYield 90%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride (0.240 g, 0.590 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.08 mL, 1.18 mmol), formaldehyde (37% w/w in water, 0.18 mL, 2.24 mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol), and acetic acid (3 drops). The reaction mixture was stirred at ambient temperature for 3.5 h and concentrated in vacuo Water (10 mL) was added to the residue and the mixture was extracted with dichloromethane (3×75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with dichloromethane/methanol/ammonium hydroxide (10/1/0.2) to afford 5,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride (0.205 g, 90%) as a colorless solid: mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ7.40 (dd, J=7.5, 7.5 Hz, 1H), 7.23-7.12 (m, 3H), 6.92 (dd, J=10.7, 6.4 Hz, 1H), 6.69 (dd, J=9.4, 8.0 Hz, 1H), 4.91 (d, J=9.4 Hz, 1H), 4.76 (d, J=9.4 Hz, 1H), 3.76 (t, J=7.0 Hz, 2H), 3.55-3.48 (m, 2H), 3.02-2.92 (m, 2H), 2.86 (s, 3H), 2.30-1.92 (m, 3H), 1.65-1.56 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.0, 158.5 (d, JC-F=10.3 Hz), 152.3 (d, JC-F=247.1 Hz), 146.7 (d, JC-F=238.3 Hz), 143.9, 132.5, 131.1, 125.4, 125.0, 113.6 (d, JC-F=19.8 Hz), 112.3, 100.8 (d, JC-F=22.2 Hz), 83.1, 59.0, 57.0, 56.7, 46.7, 34.0, 29.6, 29.5; MS (ES+) m/z 385.3 (M+1). Anal. Calcd for C22H22F2N2O2.2.4HCl: C, 55.99; H, 5.21; N, 5.94. Found: C, 55.75; H, 5.19; N, 5.97.

Workup

  1. concentrationconcentrated in vacuo Water (10 mL)
  2. additionwas added to the residue
  3. extractionthe mixture was extracted with dichloromethane (3×75 mL)
  4. dry with materialThe combined organic extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography
  8. washeluted with dichloromethane/methanol/ammonium hydroxide (10/1/0.2)

Sources & evidence

ORD record
ord-86710d31eb29414784263bd5995fb506
Source dataset
uspto-grants-2014_12
Patent number
US08916580B2

Reaction notes

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