Water → HCID 86613796, compound

HRID 2378116Notes

Reaction equation

HRID 2378116 reaction equation
Br[CH2:2][CH2:3][OH:4].[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:26]2[N:27]=[N:28][NH:29][N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH:5]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C@@H:14]([N:25]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=2)[C:26]2[N:27]=[N:28][N:29]([CH2:2][CH2:3][OH:4])[N:30]=2)[CH2:13][C@@H:12]1[CH2:46][CH3:47])=[O:10])([CH3:7])[CH3:6]

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 108982-BromoethanolHCID 86613797HCID 86613797, compound

Product 1

HCID 86613796HCID 86613796, compoundYield 7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

Add 2-bromoethanol (0.093 mL, 1.25 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzyl-(2H-tetrazol-5-yl)amino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (653 mg, 1.045 mmol) and cesium carbonate (749 mg, 2.30 mmol) in dry dimethylformamide under an atmosphere of nitrogen and stir the mixture at 50° C. for 24 h. Cool to room temperature, add water, and extract with ethyl acetate. Dry the organic solvent over sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate/hexanes to afford a mixture of two compounds. Separate by normal phase HPLC eluting with standard hexane/ethanol gradient to afford (+/−)-trans-4-[(3,5-bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1carboxylic acid isopropyl ester (48 mg, 7%). 1H NMR (CDCl3, 300 MHz): δ 0.95 (t, J=7.7 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H), 1.35 (d, J=6.3 Hz, 3H), 1.55-1.69 (m, 2H), 2.31-2.47 (m, 3H), 3.98-4.00 (m, 2H), 4.49-4.73 (m, 5H), 5.09 (septuplet, J=7.5 Hz, 1H), 5.41 (dd, J=11.9, 7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.81 (s, 2H), 8.39 (d, J=8.6 Hz, 1H). MS (ES+): 670 (M+H).

Workup

  1. temperatureCool to room temperature
  2. extractionextract with ethyl acetate
  3. dry with materialDry the organic solvent over sodium sulfate
  4. filtrationfilter
  5. customremove the solvent under reduced pressure
  6. customPurify the residue by silica gel chromatography
  7. washeluting with ethyl acetate/hexanes
  8. customto afford
  9. additiona mixture of two compounds
  10. customSeparate by normal phase HPLC
  11. washeluting with standard hexane/ethanol gradient

Sources & evidence

ORD record
ord-89c2438a92654ae8b5998f68f9168881
Source dataset
uspto-grants-2008_12
Patent number
US07470705B2

Reaction notes

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