Hydrochloric Acid → 4-Chloro-3,5-diethoxybenzoic acid ethyl ester

HRID 913310

Reaction equation

HRID 913310 reaction equation
[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8](N)=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2].[ClH:19].N([O-])=O.[Na+].[OH-].[Na+]>O.[Cu]Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([Cl:19])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)[CH3:2]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 123984444-Amino-3,5-diethoxybenzoic acid ethyl esterHCID 23668193Sodium Nitrite

Product 1

HCID 596847734-Chloro-3,5-diethoxybenzoic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 62652Cuprous chlorideCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g, 20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40 mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv). After 10 min, copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) was added, the reaction mixture stirred for an additional 5 h at 0° C. and then the ice bath removed. After stirring for 18 h, the crude reaction mixture was adjusted to pH=8 by addition of a solution of 1 M NaOH and the aqueous layer extraced with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J=7.0 Hz, 4H), 1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.18 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 13.33, 13.66, 60.29, 64.16, 105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]+.

Workup

  1. customprepared
  2. customthe ice bath removed
  3. stirringAfter stirring for 18 h
  4. customthe crude reaction mixture
  5. dry with materialThe combined organic phases were dried over MgSO4
  6. concentrationconcentrated by evaporation under reduced pressure
  7. customthe crude material purified by silica column chromatography
  8. washeluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%) of the title compound

Sources & evidence

ORD record
ord-f0342e38652441929a844400ad8547ca
Source dataset
uspto-grants-2011_09
Patent number
US08026365B2

Linked notes

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