Dimethylamine → HCID 10029737, compound

HRID 1785001Notes

Reaction equation

HRID 1785001 reaction equation
[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:32][CH2:33]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[N:38]([CH3:39])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]

Participants

6

Reactant 4

HCID 674DimethylamineHCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 10006005HCID 10006005, compound

Product 1

HCID 10029737HCID 10029737, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine in THF (0.8 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was taken up in ethyl acetate (30 ml) and washed with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC (CH3CN:Water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (200 mg, 50%): mp, 158-160° C.; 1H NMR (CDCl3): δ 0.86-0.92 (m, 2H, cyclopropyl ring CH2), 1.08-1.12 (m, 2H, cyclopropyl ring CH2), 1.66-1.70 (m, 1H, cyclopropyl ring CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CHHCO), 3.10 (s, 3H, NCH3), 3.64 (dd, J=8, 15 Hz, 1H, CHHCO), 4.13 (t, J=15 Hz, 2H, CHHN), 5.56-5.62 (m, 1H, CHN), 6.51 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=8 Hz, 1H, Ar), 7.23-7.36 (m, 3H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NHCO); 13C NMR (CDCl3): 8.22, 16.16, 35.58, 35.92, 37.27, 49.59, 53.83, 58.94, 111.0, 115.65, 117.64, 117.67, 119.90, 119.80, 121.66, 122.58, 125.64, 133.27, 138.05, 138.69, 141.49, 169.11, 169.81, 172.65; Anal. Calcd. for C25H25F4N3O5: C, 57.36; H, 4.81; N, 8.03; Found: C, 57.22; H, 4.76; N, 8.11.

Workup

  1. stirringThe resulted mixture was stirred at room temperature for 3 hours
  2. customThe solvent was removed in vacuo
  3. washwashed with water (20 ml)
  4. washThe organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml)
  5. dry with materialdried over magnesium sulfate
  6. customThe solvent was removed in vacuo
  7. stirringThe resulted oil was stirred with ether overnight
  8. filtrationThe suspension was filtered
  9. customto give a yellowish solid
  10. customThe solid was purified by HPLC (CH3CN:Water=45:55)

Sources & evidence

ORD record
ord-446fafb1ee064224abd7736ba3691682
Source dataset
uspto-grants-2009_03
Patent number
US07504427B2

Reaction notes

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