Hydrochloric Acid → 7-[4-({[5-Cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid

HRID 2423423Notes

Reaction equation

HRID 2423423 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:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([O:38]C)=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[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:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([OH:38])=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 59321535Methyl 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate

Product 1

HCID 593214757-[4-({[5-Cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acidYield 60.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of methyl 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (39 mg, 0.070 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.10 mL, 0.10 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated under a nitrogen stream and 1 N aqueous hydrochloric acid (0.10 mL, 0.10 mmol) was added. The solution was concentrated further under an nitrogen stream and water was added followed by ethyl acetate. A solid precipitated. The water layer was removed and ether was added and the solid was isolated by filtration. The solid was dried under a nitrogen stream at 45° C. to afford 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (23 mg, 60%). 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.81 (s, 2H), 8.60 (s, 1H), 8.43 (s, 1H), 8.25-8.10 (m, 2H), 7.75 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.99 (m, 1H), 2.50-2.40 (m, 4H), 2.15-2.05 (m, 1H), 2.00-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4 calculated: 546.0982 [M+H]+, found: 546.0981 [M+H]+.

Workup

  1. additionwas added
  2. concentrationThe solution was concentrated further under an nitrogen stream and water
  3. additionwas added
  4. customA solid precipitated
  5. customThe water layer was removed
  6. additionether was added
  7. customthe solid was isolated by filtration
  8. customThe solid was dried under a nitrogen stream at 45° C.

Sources & evidence

ORD record
ord-d2e28583da1a4f51abc509604bf702bd
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

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