Ethyl oxoacetate → Ethyl 2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate

HRID 514103Notes

Reaction equation

HRID 514103 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[CH:7][C:6]([CH3:14])=[CH:5]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[O:17]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[C:7]([CH:16]([OH:17])[C:15]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:14])=[CH:5]2

Participants

5

Reactant 2

HCID 70211Ethyl oxoacetateHCID 671261486-Chloro-7-fluoro-3-methylnaphthalen-1-ol

Product 1

HCID 67126131Ethyl 2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetateYield 58.7%

Reagents, catalysts & solvents 2

HCID 24193Titanium TetrachlorideCatalystHCID 6344DichloromethaneSolvent3×

Procedure

To a mixture of 6-chloro-7-fluoro-3-methylnaphthalen-1-ol (2.24 g, 13.78 mmol) in anhydrous dichloromethane (100 mL) at −40° C. was added a 1 M titanium(IV) chloride solution in dichloromethane (13.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxylate (1.69 g, 16.54 mmol) dissolved in dichloromethane (5 mL) was added over 15 minutes and stirred for 1 hour at −40° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid (2.53 g). 1H-NMR: 400 MHz, (CDCl3) δ: 8.48 (s, 1H), 7.89 (d, J=10.5 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.11 (s, 1H), 5.67 (s, 1H), 4.30 (dq, J=10.8, 7.1 Hz, 1H), 4.15 (dq, J=10.8, 7.1 Hz, 1H), 3.61 (s, 1H), 2.52 (s, 3H), 1.20 (t, J=7.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13ClFO4: 311.7; found: 311.0.

Workup

  1. additionwas added over 15 minutes
  2. stirringstirred for 1 hour at −40° C
  3. customThe reaction was quenched by the addition of Rochelle's salt solution
  4. stirringstirred at room temperature for 2.5 hours
  5. washThe resulting mixture was washed with water and aqueous layer
  6. extractionback-extracted with dichloromethane (2×)
  7. dry with materialThe combined organic layer was dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-b226f3c8d0d8482fb7ca23d2ad179b7a
Source dataset
uspto-grants-2015_08
Patent number
US09102614B2

Reaction notes

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