Cesium fluoride → 1-(2-{4-[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-piperidine

HRID 1513911Notes

Reaction equation

HRID 1513911 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1

Participants

5

Reactant 3

HCID 25953Cesium fluoride2×HCID 2734335(2,5-Difluorophenyl)boronic acidHCID 57552542Trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-yl-ethoxy)-benzyl]-naphthalen-2-yl ester

Product 1

HCID 575525571-(2-{4-[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-piperidineYield 46.2%

Reagents, catalysts & solvents 1

HCID 178418476HCID 178418476, compoundCatalyst

Conditions

Temperature
75 °C

Procedure

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol) and add 20 mL degassed acetonitrile. To this solution add 2,5-difluorophenyl boronic acid (0.6 g, 3.82 mmol), transdichlorobis(triphenylphosphine) palladium II, (270 mg, 0.38 mmol) and cesium fluoride (2.61 g, 17.2 mmol). Sonicate the mixture briefly and heat to 75° C. After 3 hours add an additional small amount of the acid, the catalyst and the cesium fluoride and heat overnight. In the morning filter the mixture and run through and SCX column eluting with 2N ammonia in methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Concentrate to give 430 mg (46%) of the title compound: 1H-NMR (CDCl3, 300 MHz) δ7.85 (d, J=9.3 Hz, 1H); 7.73 (d, J=8.7 Hz, 1H); 7.33 (d, J=8.4 Hz, 1H); 7.18 (d, J=2.7 Hz, 1H); 7.11-6.89 (m, 4H); 6.86-6.82 (m, 2H); 6.73-6.69 (m, 2H); 4.34-4.19 (d, H); 4.04-3.99 (t, 2H); 3.93 (s, 3H); 2.72 (t, J=6.3 Hz, 2H); 2.47 (t, J=5.1 Hz, 4H); 1.58 (qui, J=5.4 Hz, 4H); 1.46-1.41 (m, 2H).

Workup

  1. additionadd 20 mL
  2. customdegassed acetonitrile
  3. customSonicate the mixture briefly
  4. additionAfter 3 hours add an additional small amount of the acid
  5. filtrationIn the morning filter the mixture
  6. washeluting with 2N ammonia in methanol
  7. customPurify further on a silica gel column
  8. washeluting with a 0-10% methanol/methylene chloride gradient
  9. concentrationConcentrate

Sources & evidence

ORD record
ord-316d05fbab2b4f928e0810ec34069b80
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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