Ethyl Acetate → Methyl 3-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxycyclobutyl)benzoate

HRID 2280853Notes

Reaction equation

HRID 2280853 reaction equation
Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[O:32]=[C:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:34]1.CC(=O)OCC>C1COCC1>[Cl:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)[CH:24]=[CH:25][C:2]=1[C:33]1([OH:32])[CH2:34][CH:35]([C:37]2[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:36]1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 712054084-((4-Bromo-3-chlorophenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)-isoxazoleHCID 71205447Methyl 3-(3-oxocyclobutyl)benzoateHCID 178418339Butyllithium

Product 1

HCID 71205407Methyl 3-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxycyclobutyl)benzoateYield 81.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirring solution of compound 1a (1.67 g, 3.5 mmol) in dry THF (30 mL) was added n-BuLi (2.5 M in hexane, 1.2 eq, 1.69 mL) dropwise over 10 min at −78° C. under a nitrogen atmosphere. This was stirred for 1 h at this temperature before adding a solution of compound 1c (0.72 g, 1 eq) in dry THF (10 mL) dropwise and stirred for 1 h at this temperature. The reaction mixture was allowed to warm to rt slowly and left stirring overnight. The reaction was quenched with a solution of saturated ammonium chloride solution (50 mL) and EA (250 mL). The organic layer was separated and the aq. layer was washed with EA (2×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the crude product as a brown oil. The product was isolated following CC with PE/EA (19:1 to 3:1). The reaction and purification was repeated twice on the same scale and the combined product (3.13 g) was repurified under the same conditions to afford the final product 1 (1.7 g, 19%). 1H NMR (CDCl3): 7.93 (m, 1H), 7.90-7.85 (m, 1H), 7.50-7.30 (m, 5H), 6.88 (s, 1H), 6.75-6.72 (m, 1H), 4.80 (s, 2H), 3.88 (s, 3H), 3.20-3.10 (m, 1H), 3.00-2.91 (m, 2H), 2.60-2.49 (m, 2H), 2.15-2.08 (m, 1H), 1.30-1.25 (m, 2H), 1.15-1.10 (m, 2H).

Workup

  1. stirringstirred for 1 h at this temperature
  2. waitleft
  3. stirringstirring overnight
  4. customThe reaction was quenched with a solution of saturated ammonium chloride solution (50 mL) and EA (250 mL)
  5. customThe organic layer was separated
  6. washthe aq. layer was washed with EA (2×100 mL)
  7. dry with materialThe combined organic extracts were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give the crude product as a brown oil
  11. customThe product was isolated
  12. customThe reaction and purification
  13. customthe combined product (3.13 g) was repurified under the same conditions

Sources & evidence

ORD record
ord-5529109eff19465a91ce710d4dedec13
Source dataset
uspto-grants-2015_09
Patent number
US09139539B2

Reaction notes

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