2-Chloroaniline → 5-(Benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acid

HRID 928966Notes

Reaction equation

HRID 928966 reaction equation
[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20](F)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:9]([O:16][C:17]1[C:18]([F:28])=[C:19]([F:27])[C:20]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1

Participants

5

Reactant 3

HCID 72402-ChloroanilineHCID 2733832Lithium HexamethyldisilazideHCID 897049155-Benzoxy-2,3,4-trifluorobenzoic acid

Product 1

HCID 897049035-(Benzyloxy)-2-((2-chlorophenyl)amino)-3,4-difluorobenzoic acidYield 89.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 2-chloroaniline (13.91 ml, 137.00 mmol) and 5-benzyloxy-2,3,4-trifluorobenzoic acid (19.33 g, 68.50 mmol) in THF (120 mL) at −78° C. was added LiHMDS (205.5 mL, 1 M in THF, 205.5 mmol) dropwisely under nitrogen atmosphere. The mixture was slowly warmed to room temperature and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and acidified to pH 2-3 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product (pale yellow solid, 23.80 g, 89.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.80 (s, 1H), 8.66 (s, 1H), 7.64 (m, 1H), 7.34 (m, 7H), 6.92 (m, 1H), 6.78 (m, 1H), 5.26 (s, 2H).

Workup

  1. customThe reaction was quenched with water (100 mL)
  2. extractionThe mixture was extracted with ethyl acetate (100 mL×3)
  3. washThe combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e5749811485d4b2f8bb989b6bb571a4d
Source dataset
uspto-grants-2016_03
Patent number
US09290468B2

Reaction notes

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