Hydrochloric Acid → 6-[4-({[5-Cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid

HRID 2423417Notes

Reaction equation

HRID 2423417 reaction equation
[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[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)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[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]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 59321527Methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate

Product 1

HCID 593215066-[4-({[5-Cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acidYield 52%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of methyl 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (53 mg, 0.095 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.14 mL, 0.14 mmol). The mixture was heated in a microwave reactor at 120° C. for 500 seconds and 1 N hydrochloric acid (0.14 mL, 0.14 mmol) was added. The mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The combined organic layers were washed with brine and concentrated. The solid was washed with ether and dried overnight under a nitrogen stream at 45° C. to afford 6-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (27 mg, 52%). 1H-NMR (400 MHz, DMSO-d6) δ 8.81 (s, 2H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.17-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.97 (m, 1H), 2.44-2.33 (m, 4H), 2.14-2.04 (m, 1H), 1.99-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4: 546.0982 (M+H)+, found: 546.0982 (M+H)+.

Workup

  1. concentrationThe mixture was concentrated
  2. additionwater was added
  3. extractionthe mixture was extracted with ethyl acetate
  4. extractionThe aqueous layer was extracted one more time with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. concentrationconcentrated
  7. washThe solid was washed with ether
  8. customdried overnight under a nitrogen stream at 45° C.

Sources & evidence

ORD record
ord-0ba3581a5b2349daa1390c9a3679543c
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

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