Sodium Bicarbonate → 2,4,6-Trifluoro-N-(6-{1-[2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl]-piperidin-4-yloxy}-pyridin-2-yl)-benzamide

HRID 1822039Notes

Reaction equation

HRID 1822039 reaction equation
[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].C([O-])(O)=O.[Na+].[CH:31]([N:34]1[CH:38]=[C:37]([CH2:39][CH2:40]OS(C)(=O)=O)[CH:36]=[N:35]1)([CH3:33])[CH3:32]>CN(C=O)C>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:40][CH2:39][C:37]3[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=3)[CH2:18][CH2:19]2)[N:8]=1)=[O:5]

Participants

5

Reactant 3

HCID 516892Sodium BicarbonateHCID 226115122-(1-isopropyl-1H-pyrazol-4-yl)-1-mesyloxyethaneHCID 578937702,4,6-Trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide

Product 1

HCID 578937332,4,6-Trifluoro-N-(6-{1-[2-(1-isopropyl-1H-pyrazol-4-yl)-ethyl]-piperidin-4-yloxy}-pyridin-2-yl)-benzamideYield 28%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), NaHCO3 (96 mg, 1.14 mmol), KI (24 mg, 0.14 mmol) and DMF (5 mL). Add methanesulfonic acid 2-(isopropyl-1H-pyrazol-4-yl)-ethyl ester (214 mg, 0.92 mmol) dropwise to the above mixture and then beat at 80° C. overnight. Quench the reaction with 0.1N NaOH solution, extract with ether/ethylacetate (8:1) three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3-4% methanol in methylene dichloride provides 96 mg (28%) of the title compound as a white solid: mass spectrum (ion spray): m/z=488.1 (M+1); 1H NMR (CDCl3, ppm): 8.04 (s, br, 1H), 7.86 (d, br, 1H), 7.65 (t, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 6.81 (m, 2H), 6.55 (d, 1H), 4.98 (m, 1H), 4.45 (hept, 1H), 2.81 (m 2H), 2.68 (m, 2H), 2.59 (m, 2H), 2.04 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H), 1.49 (d, 6H). Hydrochloride salt: Anal calcd for C25H28F3N5O2.HCl.0.5H2O: C, 56.34; H, 5.67; N, 13.14. Found: C, 56.35; H, 5.58; N, 12.96.

Workup

  1. customQuench
  2. customthe reaction with 0.1N NaOH solution
  3. extractionextract with ether/ethylacetate (8:1) three times
  4. dry with materialCombine the organic layers, dry over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate
  7. customto give a residue
  8. washChromatography (silica gel) eluting with 3-4% methanol in methylene dichloride

Sources & evidence

ORD record
ord-7d16dd3dbba7400b9275b0cda7501d0d
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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