Methyl 4-aminobenzoate → Methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate

HRID 62714Notes

Reaction equation

HRID 62714 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:17])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:17][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)=[O:7]

Participants

7

Reactant 4

HCID 12082Methyl 4-aminobenzoateHCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 670415553,5-Dichloro-4-(cyclopentyloxy)benzoic acid

Product 1

HCID 51035072Methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoateYield 20.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (100 mg, 363 μmol) in DCM (5 mL), cooled to 0° C., was treated with oxalyl chloride (63.6 μL, 727 μmol), followed by a drop of DMF. The resultant mixture was stirred for 1 h at RT. The solvent was evaporated in vacuo and the residue dissolved in DCM (5 mL), and then treated with a solution of methyl 4-aminobenzoate (54.9 mg, 363 μmol) and DIPEA (190 μL, 1.09 mmol) in DCM (5 mL). The reaction mixture was stirred for 12 h at RT and then partitioned between DCM (20 mL) and aqueous HCl (20 mL, 1 M). The phases were separated and the organic phase was washed successively with water (2×20 mL), and brine (20 mL), dried over MgSO4, filtered and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30 mg, 20%): m/z 406 (M−H)− (ES−). NMR (400 MHz, CDCl3) δ: 8.06 (2H, d), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d), 5.05 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m), 1.70-1.60 (2H, m).

Workup

  1. customThe solvent was evaporated in vacuo
  2. dissolutionthe residue dissolved in DCM (5 mL)
  3. custompartitioned between DCM (20 mL) and aqueous HCl (20 mL, 1 M)
  4. customThe phases were separated
  5. washthe organic phase was washed successively with water (2×20 mL), and brine (20 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customthe solvent was removed in vacuo
  9. customThe residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane)

Sources & evidence

ORD record
ord-9184e050c76049c8bea47e6b0b6ed2d1
Source dataset
uspto-grants-2016_09
Patent number
US09447028B2

Reaction notes

Loading…