Isopropyl Acetate → 3-Bromo-N-cyclopropyl-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzamide

HRID 337630Notes

Reaction equation

HRID 337630 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([OH:7])=O.C([N:20](CC)[CH:21]([CH3:23])[CH3:22])(C)C.C1(N)CC1.[NH4+].[Cl-].C(OC(C)C)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]#[C:13][CH2:14][O:15][CH3:16])[C:10]=1[CH3:11])[C:5]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:7]

Participants

6

Reactant 5

HCID 7915Isopropyl AcetateHCID 25517Ammonium ChlorideHCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 581709723-Bromo-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzoic acid

Product 1

HCID 581710363-Bromo-N-cyclopropyl-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzamide

Conditions

Temperature
5 °C

Procedure

To 3-bromo-5-(3-methoxy-prop-1-ynyl)-4-methyl-benzoic acid (0.38 M solution in THF) was added N,N-diisopropylethylamine (1.8 equiv.) and cyclopropylamine (1.35 equiv.) maintaining the internal temperature below 25° C. The mixture was cooled to 5° C. and 2-propanephosphoric acid anhydride (50 wt % in EtOAc, 1.5 equiv.) was added whilst maintaining the internal temperature below 25° C. The reaction mixture was aged for 1 h at ˜20° C. then cooled to 2° C. and 10 wt % aq. NH4Cl solution added, maintaining the internal temperature <30° C. Isopropyl acetate was added and the layers were allowed to settle. The lower aqueous layer removed. The organics were then washed with 1M HCl, followed by 10% NaHCO3 solution and finally 10% NaCl solution. The organic layer was concentrated to ˜1 M followed by the addition of toluene. The batch was then reconcentrated to ˜2 M and the resultant slurry aged for 18 h. Heptane was then added and the solids were filtered, washed with a mixture of 1:1 toluene/heptane and dried to give the title compound as an off-white solid. 1H NMR (500 MHz, Acetone-d6): δ 8.01 (s, 1 H), 7.92 (s, 1 H), 7.86 (s, 1 H), 4.37 (s, 2 H), 3.39 (s, 3 H), 2.95-2.89 (m, 1 H), 2.53 (s, 3 H), 0.76-0.67 (m, 2 H), 0.68-0.60 (m, 2 H). HRMS (ES, M+H) Calcd 322.0443. Found 322.0457.

Workup

  1. temperaturemaintaining the internal temperature below 25° C
  2. temperaturewhilst maintaining the internal temperature below 25° C
  3. temperaturethen cooled to 2° C.
  4. temperaturemaintaining the internal temperature <30° C
  5. customThe lower aqueous layer removed
  6. washThe organics were then washed with 1M HCl
  7. concentrationThe organic layer was concentrated to ˜1 M
  8. additionfollowed by the addition of toluene
  9. waitthe resultant slurry aged for 18 h
  10. additionHeptane was then added
  11. filtrationthe solids were filtered
  12. washwashed with a mixture of 1:1 toluene/heptane
  13. customdried

Sources & evidence

ORD record
ord-610a884fd4fa4484a65ff426ca55e43f
Source dataset
uspto-grants-2014_11
Patent number
US08889714B2

Reaction notes

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