Formaldehyde → HCID 68611705, compound

HRID 2095323Notes

Reaction equation

HRID 2095323 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:19][CH:20]=1.C=O.[CH3:33]C1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CC([O-])=O.[Na+].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:33][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:19][CH:20]=1

Participants

8

Reactant 6

HCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 6451Bromocresol GreenHCID 517045Sodium AcetateHCID 5003444Sodium cyanoborohydrideHCID 68611843HCID 68611843, compound

Product 1

HCID 68611705HCID 68611705, compoundYield 44%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of 3-[3-[5-[(2(S)-pyrrolidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol trifluoroacetate (C19H24N2O2.3.02CF3COOH.0.57H2O, 296 mg, 443 μmol) in ethanol (1.5 mL) in a 15 mL round bottom flask was added formalin (0.18 mL, 6.6 mmol, 15 equiv.). A small amount of bromocresol green was added to the reaction mixture to monitor the pH, which was adjusted to 4-5 by addition of NaOAc. The mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (42 mg, 0.67 mmol, 1.5 equiv.) was added, whereon the pH increased. Small amounts of CF3COOH were added over several hours to keep the pH between 4 and 5. The resulting mixture was stirred at room temperature for an additional 24 h. The solvents were evaporated, and the residue was purified by CC on silica gel (38×1.0 cm, CH2Cl2/methanol/saturated aqueous ammonia 20:1:0.1). The crude product was purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 8% to 25% CH3CN in water within 20 min, from 25% to 100% for another 20 min, then 100% CH3CN for 20 min, both solvents containing 0.1 vol % CF3COOH; tR 18.0-24.3 min) to give the methylation product as a trifluoroacetate (colorless oil, 131 mg, 44%). 1H NMR (CD3OD, 500 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.06 (d, 1H, J=1.9 Hz), 7.61 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.51-7.45 (m, 1H), 7.38 (d, 1H, J=7.8 Hz), 4.92-4.88 (m, 1H, overlapping with the CD3OH peak), 4.68 (dd, 1H, J=11.2, 3.0 Hz), 4.52 (dd, 1H, J=11.0, 6.8 Hz), 4.03-3.94 (m, 1H), 3.84-3.76 (m, 1H), 3.65-3.59 (m, 2H), 3.13 (d, 3H, J=3.7 Hz), 2.82 (t, 2H, J=7.8 Hz), 2.50-2.42 (m, 1H), 2.32-2.22 (m, 1H), 2.22-2.08 (m, 2H), 1.96-1.88 (m, 2H). Anal. Calcd. for C20H26N2O2.3.00CF3COOH (FW 668.5) C, 46.71; H, 4.37; N, 4.19; F, 25.58. Found: C, 46.93; H, 4.49; N, 4.26; F, 25.83.

Workup

  1. temperatureincreased
  2. stirringThe resulting mixture was stirred at room temperature for an additional 24 h
  3. customThe solvents were evaporated
  4. customthe residue was purified by CC on silica gel (38×1.0 cm, CH2Cl2/methanol/saturated aqueous ammonia 20:1:0.1)
  5. customThe crude product was purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 8% to 25% CH3CN in water within 20 min
  6. waitfrom 25% to 100% for another 20 min
  7. wait100% CH3CN for 20 min
  8. additionboth solvents containing 0.1 vol % CF3COOH

Sources & evidence

ORD record
ord-c2a94482e28943caada78631262f3994
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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