Formaldehyde → HCID 21071654, compound

HRID 1666893Notes

Reaction equation

HRID 1666893 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[CH3:28][N:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]([F:25])[F:24])[CH:16]=1)[CH2:12][CH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 21071426HCID 21071426, compound

Product 1

HCID 21071654HCID 21071654, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 63651,1-DichloroethaneSolvent

Procedure

Combine (2-(6-chloro-1H-indol-3-yl)ethyl)-(3-(2,2-difluoroethoxy)benzyl)amine (276 mg, 0.76 mmol) and formaldehyde (55.5 μL of a 38% aqueous solution, 0.76 mmol) in dichloroethane (15 mL) and stir at room temperature for 10 minutes; add in two portions sodium triacetoxyborohydride (321 mg, 1.51 mmol) over 10 minutes and stir at room temperature overnight before diluting with methanol (10 mL) and quenching with one drop of glacial acetic acid. Remove in vacuo the solvent, and redissolve the crude residue in methanol and directly load onto a 10 g SCX column. After washing thoroughly with methanol, elute the column with 2 N ammonia in methanol. Concentrate in vacuo the eluant to give the free base of the title compound as a straw-colored oil. Dissolve the free base (239 mg, 0.64 mmol) in methanol (20 mL) and treat with a solution of ammonium chloride (36 mg, 0.67 mmol) in methanol (5 mL). Sonicate the mixture for 10 minutes before removal of the solvent in vacuo to give the hydrochloride salt as a tacky yellow oil. Dissolve the oil in 10 mL of 1:1 acetonitrile-water and lyophilize overnight, providing a fluffy white solid and triturate with diethyl ether (10 mL) and acetonitrile (2 drops). Filtration and drying of the resulting precipitate afforded the desired hydrochloride as a white amorphous solid: mp: 63.8-65.8° C.; 1H NMR (400 MHz, dmso-d6): 11.10 (br s, 1H), 7.52 (d, 1H) J=8.4 Hz) 7.36 (d, 1H, J=2.0 Hz), 7.40-7.26 (m, 2H), 7.22 (d, 1H, J=2.4 Hz), 7.20-7.11 (m, 1H), 7.04 (br d, 1H, J=7.6 Hz), 6.96 (dd, 1H, J=8.6, 1.4 Hz), 6.38 (tt, 1H, J=54.4, 3.6, Hz), 4.50-4.02 (br m, 2H), 4.30 (td, 2H, J=14.4, 3.2 Hz), 3.15 (br s, 4H), 2.68 (br s, 3H); MS (ES+): n/e 378.9 (M+1); CHN (for C20H21ClF2N2O.HCl.0.7H20) calcd: C, 56.14; H, 5.51; N, 6.55. found: C, 55.72; H, 5.32; N, 7.07.

Workup

  1. customquenching with one drop of glacial acetic acid
  2. customRemove in vacuo the solvent
  3. dissolutionredissolve the crude residue in methanol and directly load onto a 10 g SCX column
  4. washAfter washing thoroughly with methanol
  5. washelute the column with 2 N ammonia in methanol
  6. concentrationConcentrate in vacuo the eluant

Sources & evidence

ORD record
ord-263699c0fb0540a4839be8b67eedd338
Source dataset
uspto-grants-2011_10
Patent number
US08044090B2

Reaction notes

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