2,6-Dichlorophenol → 6-[4-({[3-{[(2,6-Dichlorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid

HRID 2423463Notes

Reaction equation

HRID 2423463 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[OH:28].O[CH2:30][C:31]1[C:35]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[N:50]=[C:49]([C:54]([O:56]C)=[O:55])[CH:48]=[CH:47]4)=[CH:40][CH:39]=2)=[C:34]([CH:58]([CH3:60])[CH3:59])[O:33][N:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+]>O1CCCC1.CO>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[O:28][CH2:30][C:31]1[C:35]([CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[C:46]4[C:51](=[CH:52][CH:53]=3)[N:50]=[C:49]([C:54]([OH:56])=[O:55])[CH:48]=[CH:47]4)=[CH:40][CH:39]=2)=[C:34]([CH:58]([CH3:60])[CH3:59])[O:33][N:32]=1

Participants

7

Reactant 5

HCID 68992,6-DichlorophenolHCID 11776TriphenylphosphineHCID 14798Sodium HydroxideHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 59321462Methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate

Product 1

HCID 593215766-[4-({[3-{[(2,6-Dichlorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acidYield 24%

Reagents, catalysts & solvents 1

HCID 21899815MeOH tetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of triphenylphosphine (34 mg, 0.13 mmol), 2,6-dichlorophenol (21 mg, 0.13 mmol) and methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (56 mg, 0.13 mmol) was added diisopropyl azodicarboxylate (0.023 mL, 0.13 mmol). The solution was heated in a microwave reactor at 100° C. for 10 minutes. This heating was repeated again for 10 minutes. The mixture was adsorbed onto silica gel and purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution) to afford a solid that was dissolved in 2:1 tetrahydrofuran/methanol (1.5 mL). Then 1 N sodium hydroxide (0.13 mL, 0.13 mmol) was added. The solution was heated in a microwave reactor at 120° C. for 500 seconds. The mixture was concentrated and the residue was taken up with methanol. Then 10% aqueous citric acid was added and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with additional citric acid until the pH was approximately 2-3 and was extracted one more time with ethyl acetate. The combined organic layers were concentrated and the residue was taken up with ether which was removed under vacuum. The resulting solid was dissolved in ethyl acetate and the solution was washed with water and brine and then concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (12 mg, 24%). 1H-NMR (400 MHz, CDCl3) δ 8.36 (d, J=9 Hz, 1H), 8.24-8.19 (m, 2H), 8.02 (d, J=10 Hz, 2H), 7.66 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 6.99-6.97 (m, 1H) 5.15 (s, 4H), 3.27 (3.27 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). HRMS (ESI) C30H24Cl2N2O5 calculated: 563.1135 (M+H)+, found: 563.1130 (M+H)+.

Workup

  1. custompurified by chromatography (silica gel, 0-60% ethyl acetate in hexanes gradient elution)
  2. customto afford a solid
  3. temperatureThe solution was heated in a microwave reactor at 120° C. for 500 seconds
  4. concentrationThe mixture was concentrated
  5. additionThen 10% aqueous citric acid was added
  6. extractionthe mixture was extracted with ethyl acetate
  7. extractionwas extracted one more time with ethyl acetate
  8. concentrationThe combined organic layers were concentrated
  9. customwas removed under vacuum
  10. dissolutionThe resulting solid was dissolved in ethyl acetate
  11. washthe solution was washed with water and brine
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-c06f20e1b1524dc4b51116f91eb4d977
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

Loading…