Diisopropylamine → 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid

HRID 1506500Notes

Reaction equation

HRID 1506500 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]1.[C:21]1([N:27]2[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]3[O:40][N:39]=[C:38]4[C:41]5[C:46]([CH2:47][CH2:48][C:37]=34)=[CH:45][C:44]([CH:49]=[O:50])=[CH:43][CH:42]=5)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[OH:50][CH:49]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:38]1=[N:39][O:40][C:36]([C:30]3[CH:29]=[N:28][N:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:31]=3[C:32]([F:35])([F:34])[F:33])=[C:37]1[CH2:48][CH2:47]2)[C:14]1[O:13][CH:17]=[CH:16][C:15]=1[C:18]([OH:20])=[O:19]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 102683-Furoic acidHCID 866699303-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 671711812-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acidYield 108.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of diisopropylamine (0.072 mL, 0.508 mmol) in anhydrous THF (0.5 mL) was added a 2.5 M THF solution of n-BuLi (0.203 mL, 0.508 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at the same temperature for 15 min. before being cooled to −78° C. A solution of furan-3-carboxylic acid (28.5 mg, 0.254 mmol) in anhydrous THF (1 mL) was added. The reaction mixture was stirred at −78° C. for 30 min. before a solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 89B, 80 mg, 0.195 mmol) in anhydrous THF (1 mL) was added at the same temperature. The mixture was then allowed to warm to room temperature over 30 min. The reaction was quenched with water (3 mL). The mixture was concentrated and the aqueous residue was acidified with 10% aqueous citric acid solution to pH=3. The mixture was extracted with ethyl acetate (2×3 mL). The combined organic solutions were dried (sodium sulfate) and concentrated to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid (110 mg, 0.211 mmol, 108% yield) as green foam solid. Next, 48 mg of the solid was purified by reverse phase preparative HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) to give 2-(hydroxy(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)furan-3-carboxylic acid, TFA (32 mg) as white solid. The compound had an HPLC retention time=3.42 min. (condition C); LC/MS M+1=522.2; 1H NMR (400 MHz, MeOD) δ ppm 8.14 (1H, s), 7.88 (1H, d, J=7.9 Hz), 7.54-7.63 (6H, m), 7.48-7.52 (2H, m), 7.47 (1H, d, J=7.9 Hz), 6.72 (1H, d, J=2.0 Hz), 6.56 (1H, s), 3.03 (2H, t, J=6.9 Hz), 2.89 (2H, t, J=6.9 Hz).

Workup

  1. additionwas added at the same temperature
  2. temperatureto warm to room temperature over 30 min
  3. customThe reaction was quenched with water (3 mL)
  4. concentrationThe mixture was concentrated
  5. extractionThe mixture was extracted with ethyl acetate (2×3 mL)
  6. dry with materialThe combined organic solutions were dried (sodium sulfate)
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-eea696b4b6194ada980ca20b30d5486a
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

Loading…