Hydrochloric Acid → Ethyl 3-chloro-8-methoxynaphthalene-2-carboxylate

HRID 1968760Notes

Reaction equation

HRID 1968760 reaction equation
N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:19](N)=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+].[ClH:28]>O>[CH2:5]([O:7][C:8]([C:10]1[C:19]([Cl:28])=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6]

Participants

6

Reactant 4

HCID 313Hydrochloric Acid2×HCID 516892Sodium BicarbonateHCID 23668193Sodium NitriteHCID 66882606Ethyl 3-amino-8-methoxynaphthalene-2-carboxylate

Product 1

HCID 66882254Ethyl 3-chloro-8-methoxynaphthalene-2-carboxylate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

A solution of NaNO2 (884 mg, 12.81 mmol, 1.45 equiv) in water (20 ml) was added dropwise at 0° C. to a solution of 3-amino-8-methoxy-naphthalene-2-carboxylic acid ethyl ester (2.165 g, 8.83 mmol) in 18% aqueous HCl (50 ml). After it was stirred for 30 minutes at 0° C., this mixture was added dropwise at −20° C. to a solution of freshly prepared Cu(I)CI (2.62 g, 26.50 mmol, 3.0 equiv) in concentrated aqueous HCl (90 ml). After 1 hour at −10° C. and 1 hour at rt, solid NaHCO3 was carefully added to the reaction mixture until pH was >7.0. After dilution with water (200 ml), the aqueous phase was extracted with EtOAc (2 liters in total). The combined organic layers were washed with water (300 ml) and concentrated aqueous NH4Cl solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 10:0 to 9:1) afforded the title compound (1.36 g, 58%, inseparable ˜1:1 mixture of regioisomers A:B) as a slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.76 (s, 1H isomer A/B), 8.31 (s, 1H isomer A/B), 7.85 (s, 1H isomer A/B), 7.50-7.40 (m, 3H isomer A/B), 7.32 (d, J=8.6 Hz, 1H isomer A/B), 6.90 (dd, J=6.6/2.0 Hz, 1H isomer A/B), 6.83 (d, J=7.6 Hz, 1H isomer A/B), 4.44 (q, J=7.1 Hz, 2H), 4.01 (s, 3H isomer A/B), 4.00 (s, 3H isomer A/B). 1.44 (t, J=7.1 Hz, 3H isomer A/B), 1.44 (t, J=7.1 Hz, 3H isomer A/B). MS (ES+): 265 (M+H)+.

Workup

  1. waitAfter 1 hour at −10° C.
  2. extractionAfter dilution with water (200 ml), the aqueous phase was extracted with EtOAc (2 liters in total)
  3. washThe combined organic layers were washed with water (300 ml) and concentrated aqueous NH4Cl solution (100 ml)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification via flash chromatography (gradient of hexane/EtOAc 10:0 to 9:1)

Sources & evidence

ORD record
ord-04e05ffc92de4c06a5b211a7a70cbf66
Source dataset
uspto-grants-2013_04
Patent number
US08426440B2

Reaction notes

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