Hydrochloric Acid → 6-(4-{[(5-(1-Methylethyl)-3-{[(2,4,6-trifluorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acid

HRID 2423462Notes

Reaction equation

HRID 2423462 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].O[CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:40]([CH3:42])[CH3:41])[O:15][N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+].Cl>ClCCl.O1CCCC1.O.CO>[CH3:42][CH:40]([C:16]1[O:15][N:14]=[C:13]([CH2:12][O:10][C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1)[CH3:41]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 5199742,4,6-TrifluorophenolHCID 59321462Methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate

Product 1

HCID 593214906-(4-{[(5-(1-Methylethyl)-3-{[(2,4,6-trifluorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acidYield 36.5%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2,4,6-trifluorophenol (18 mg, 0.12 mmol), methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinoline carboxylate (52 mg, 0.12 mmol) and triphenylphosphine (35 mg, 0.13 mmol) in dichloromethane (2 mL) was added diisopropyl azodicarboxylate (0.024 mL, 0.13 mmol) slowly. The solution was heated in a microwave reactor at 100° C. for 10 minutes. The solution was adsorbed onto silica gel and purification was done by chromatography (0-70% ethyl acetate in hexanes) to afford a solid which was dissolved in 2:1 tetrahydrofuran:methanol (1.5 mL). Then 1 N sodium hydroxide (0.19 mmol, 0.19 mmol) was added. The solution was subjected to microwave radiation at 120° C. for 500 seconds. The solution was concentrated then diluted with water before the addition of 1 N hydrochloric acid (0.19 mmol, 0.19 mmol). The resulting solid was extracted with ethyl acetate twice and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting solid was washed with methanol and dried to afford 6-(4-{[(5-(1-methylethyl)-3-{[(2,4,6-trifluorophenyl)oxy]methyl}-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylic acid (24 mg, 35%). 1H-NMR (400 MHz, DMSO-d6) δ 8.44-8.06 (m, 5H), 7.69 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 6.65 (t, J=9 Hz, 2H), 5.23 (s, 2H), 5.12 (s, 2H), 3.29 (septet, J=7 Hz, 1H), 1.37 (d, J=7 Hz, 6H). HRMS (ESI) C30H23F3N2O5 calculated: 549.1632 (M+H)+, found: 549.1631 (M+H)+.

Workup

  1. customThe solution was adsorbed onto silica gel and purification
  2. customto afford a solid which
  3. customat 120° C.
  4. customfor 500 seconds
  5. concentrationThe solution was concentrated
  6. extractionThe resulting solid was extracted with ethyl acetate twice
  7. dry with materialthe combined organic layers were dried over magnesium sulfate
  8. concentrationconcentrated
  9. washThe resulting solid was washed with methanol
  10. customdried

Sources & evidence

ORD record
ord-5c4ffeb39ba1428e8a389e7ced810504
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

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