Hydrochloric Acid → n-(3,4,5-Trimethoxyphenyl)-3-(5-methyl(tetrahydropyran-2-yl)-3-(2-chloro-6-fluorophenyl)isoxazol-4-oyl)aminophenyl acetamide

HRID 434052Notes

Reaction equation

HRID 434052 reaction equation
CO[C:3]([C:5]1[CH:6]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+].Cl.[NH2:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36]([NH:38][C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=2)=[O:37])[CH:32]=[CH:33][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>ClCCl.CN(C1C=CN=CC=1)C.C1COCC1.CO>[CH3:46][O:45][C:43]1[CH:44]=[C:39]([NH:38][C:36](=[O:37])[CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([NH:28][C:3]([C:5]3[CH:6]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:24])[N:7]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[O:8][C:9]=3[CH3:10])=[O:4])[CH:30]=2)[CH:40]=[C:41]([O:49][CH3:50])[C:42]=1[O:47][CH3:48]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 181649HOAtHCID 187562602-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamideHCID 695610684-Methoxycarbonyl-5-methyl(tetrahydropyran-2-yl)-3-(2-chloro-6-fluoro-phenyl)isoxazole

Product 1

HCID 86759311n-(3,4,5-Trimethoxyphenyl)-3-(5-methyl(tetrahydropyran-2-yl)-3-(2-chloro-6-fluorophenyl)isoxazol-4-oyl)aminophenyl acetamideYield 51.1%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of 4-methoxycarbonyl-5-methyl(tetrahydropyran-2-yl)-3-(2-chloro-6-fluoro-phenyl)isoxazole (2.95 g, 7.98 mmol), 2N NaOH (8.0 ml, 16.0 mmol), MeOH (20 ml), and THF (10 ml) was heated to 55° C. for 4 h. After cooling to 0° C., HCl (1N) was added until pH 3. The mixture was extracted with ethyl acetate (3×), and the combined extracts were washed (brine), dried (MgSO4), filtered, and concentrated to give the crude acid. The crude acid was dissolved in dichloromethane (50 ml) along with 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (3.80 g, 12.0 mmol), EDCI (3.33 g, 17.4 mmol), HOAt (2.72 g, 20.00 mmol), and DMAP (0.10 g, 0.80 mmol) and stirred at room temperature overnight. The mixture was applied to a silica gel column and eluted with dichloromethane/acetone (gradient) to give the title compound (2.61 g, 41%).

Workup

  1. temperatureAfter cooling to 0° C.
  2. extractionThe mixture was extracted with ethyl acetate (3×)
  3. washthe combined extracts were washed (brine)
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give the crude acid
  8. washeluted with dichloromethane/acetone (gradient)

Sources & evidence

ORD record
ord-ac77a10443014053982eedc7cde20650
Source dataset
uspto-grants-2003_12
Patent number
US06670373B1

Reaction notes

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