Pyridine → 4-Chloro-3-[2-(4-isopropyl-3-methyl-phenoxy)-acetylamino]-benzoic acid

HRID 2358285Notes

Reaction equation

HRID 2358285 reaction equation
[CH:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][C:5]=1[CH3:15])([CH3:3])[CH3:2].[C:16]([Cl:21])(=O)[C:17](Cl)=O.[NH2:22][C:23]1C=C[C:26](Cl)=[C:27]([CH:31]=1)[C:28]([OH:30])=[O:29].N1C=CC=CC=1>CN(C)C=O.ClCCl.C1COCC1>[Cl:21][C:16]1[CH:17]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][C:23]=1[NH:22][C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([CH3:15])[CH:6]=1

Participants

8

Reactant 4

HCID 1049PyridineHCID 378795-Amino-2-chlorobenzoic acidHCID 65578Oxalyl chlorideHCID 23038202-(3-Methyl-4-(propan-2-yl)phenoxy)acetic acid

Product 1

HCID 104737744-Chloro-3-[2-(4-isopropyl-3-methyl-phenoxy)-acetylamino]-benzoic acidYield 100%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A suspension of 2-(4-isopropyl-3-methylphenoxy)acetic acid (1.50 g, 7.2 mmol) and catalytic dimethylformamide (3 drops) in dichloromethane (100 mL) was treated with a solution of oxalyl chloride (1.80 mL, 21.9 mmol) in dichloromethane (10 mL) dropwise over 20 min. After stirring for an additional 4 h, the solution was evaporated and taken up in THF (60 mL). One-half of this solution (ca. 3.6 mmol acid chloride) was added dropwise to an ice-cooled solution of 5-amino-2-chlorobenzoic acid (0.62 g, 3.6 mmol) and pyridine (0.87 mL, 11 mmol) in THF (5 mL). The resulting solution was stirred for 20 h, then partitioned between water and ethyl acetate (100 mL each). The organic layer was washed with 1 N aq. HCl and brine, and the aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid was triturated with 1:1 ethyl acetate, refiltered and dried under vacuum to afford the title product (1.20 g, 3.6 mmol, 100%). m.p. 174-175° C. 1H NMR (d6-DMSO): δ 10.28 (1H, s), 8.13 (1H, t, J=1.8 Hz), 7.79 (1H, dt, J=8, 2 Hz), 7.46 (1H, dd, J=8, 2 Hz), 7.13 (1H, dd, J=8, 1.6 Hz), 6.79-6.71 (2H, m), 4.62 (2H, s), 3.00 (1H, m, J=6.6 Hz), 2.25 (3H, s), 1.12 (6H, d, J=6.6 Hz). Mass spectrum (ES+): m/z 364 (33), 362 (100). Elemental analysis: calculated for C19H20ClNO4 C 63.07, H 5.57, N 3.87; observed C 62.87, H 5.58, N 3.67.

Workup

  1. customthe solution was evaporated
  2. stirringThe resulting solution was stirred for 20 h
  3. custompartitioned between water and ethyl acetate (100 mL each)
  4. washThe organic layer was washed with 1 N aq. HCl and brine
  5. extractionthe aqueous phases were back-extracted in sequence with ethyl acetate
  6. dry with materialdried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. customevaporated
  9. customThe resulting solid was triturated with 1:1 ethyl acetate
  10. customdried under vacuum

Sources & evidence

ORD record
ord-ff7e4e3384fd4a76a97499f2e1aaaf39
Source dataset
uspto-grants-2010_07
Patent number
US07763656B2

Reaction notes

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