Hydrochloric Acid → 4-Amino-3-fluoro-2-(2-methyl-4-trifluoromethoxy-phenylamino)-5-nitro-benzoic acid methyl ester

HRID 504179Notes

Reaction equation

HRID 504179 reaction equation
[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[CH3:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[NH2:29].Cl>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:29][C:19]1[CH:20]=[CH:21][C:22]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:23][C:18]=1[CH3:17]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2759749Benzoic acid, 4-amino-2,3-difluoro-5-nitro-, methyl esterHCID 27755462-Methyl-4-(trifluoromethoxy)aniline

Product 1

HCID 866216094-Amino-3-fluoro-2-(2-methyl-4-trifluoromethoxy-phenylamino)-5-nitro-benzoic acid methyl ester

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
140 °C

Procedure

4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (0.50 g, 2.15 mmol) is suspended in xylenes (3 mL) and 2-methyl-4-trifluoromethoxy-phenylamine (1.00 g, 5.23 mmol) is added. The reaction mixture is stirred at 140° C. under N2. After stirring for 7 days, the reaction is a mixture of starting material and product. The reaction mixture is cooled to room temperature. The reaction mixture is poured into a separatory funnel and diethyl ether and 10% aqueous HCl are added and the layers separated. The aqueous phase is extracted with three portions of diethyl ether. The combined diethyl ether layers are dried (MgSO4) and concentrated under reduced pressure. The residue is redissolved in methylene chloride and flushed through a plug of silica gel eluting with methylene chloride. The filtrate is concentrated under reduced pressure to give a bright yellow solid. The solid is washed with diethyl ether and the filtrate is concentrated under reduced pressure and the residue is further purified by FCC (eluting with 100% methylene chloride) to yield 0.39 g (45%) of the desired pure product as a yellow solid. MS APCI (−) m/z 402 (M−1) detected.

Workup

  1. stirringAfter stirring for 7 days
  2. additiona mixture of starting material and product
  3. temperatureThe reaction mixture is cooled to room temperature
  4. additionThe reaction mixture is poured into a separatory funnel
  5. customthe layers separated
  6. extractionThe aqueous phase is extracted with three portions of diethyl ether
  7. dry with materialThe combined diethyl ether layers are dried (MgSO4)
  8. concentrationconcentrated under reduced pressure
  9. dissolutionThe residue is redissolved in methylene chloride
  10. customflushed through a plug of silica gel eluting with methylene chloride
  11. concentrationThe filtrate is concentrated under reduced pressure
  12. customto give a bright yellow solid
  13. washThe solid is washed with diethyl ether
  14. concentrationthe filtrate is concentrated under reduced pressure
  15. customthe residue is further purified by FCC (eluting with 100% methylene chloride)

Sources & evidence

ORD record
ord-482e6934a1514bb0ad7bdda4f7594c89
Source dataset
uspto-grants-2010_08
Patent number
US07777050B2

Reaction notes

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