Hexane → (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

HRID 1444550Notes

Reaction equation

HRID 1444550 reaction equation
[NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C[O:18][C:19](=O)[C:20]1[C:25]([NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:32]Br.C(N(CC)CC)C.CCCCCC>CN(C=O)C.CCOCC>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([C@H:2]([N:1]2[C:19](=[O:18])[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:32]2)[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]

Participants

7

Reactant 4

HCID 8058HexaneHCID 8471TriethylamineHCID 669203212-Bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl esterHCID 67175570(3R)-3-amino-3-(3-ethoxy-4-methoxyphenyl)propan-1-ol

Product 1

HCID 9845251(1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amideYield 64%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (1.1 g, 4.9 mmol), 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.5 g, 4.8 mmol) and triethylamine (0.75 mL, 5.4 mmol) in DMF (10 mL) was heated at 100° C. for 18 h. The solvent was removed in vacuo. The residue was extracted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with HCl (1N, 50 mL), brine (50 mL), and dried over MgSO4. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (5 mL) and hexane (5 mL) to give a suspension. The suspension was filtered to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (1.3 g, 64% yield): mp, 103-105° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, CH2), 1.08-1.12 (m, 2H, CH2), 1.44 (t, J=7 Hz, 3H, CH3), 1.64-1.73 (m, 1H, CH), 2.11-2.32 (m, 2H, CH2), 3.37 (dd, J=4, 9 Hz, 1H, OH), 3.50-3.59 (m, 1H, CHH), 3.74-3.79 (m, 2H, NCHH, CHH), 3.80 (s, 3H, CH3), 4.06 (q, J=7 Hz, 2H, CH2), 4.16 (d, J=18 Hz, 1H, NCHH), 6.65 (dd, J=4, 11 Hz, 1H, NCH), 6.83-6.99 (m, 4H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NH); 13C NMR (CDCl3) δ 8.35, 14.77, 16.22, 33.85, 46.23, 50.52, 55.98, 58.59, 64.55, 111.36, 112.99, 116.77, 116.99, 117.83, 119.77,130.73,133.37, 138.05,141.49, 148.62, 149.25,170.33, 172.76; Anal Calcd for C24H28N2O5: C, 67.91; H, 6.65; N, 6.60. Found: C, 67.92; H, 6.67; N, 6.37.

Workup

  1. customThe solvent was removed in vacuo
  2. extractionThe residue was extracted with ethyl acetate (50 mL) and water (50 mL)
  3. washThe organic layer was washed with HCl (1N, 50 mL), brine (50 mL)
  4. dry with materialdried over MgSO4
  5. customThe solvent was removed in vacuo
  6. customto give an oil
  7. filtrationThe suspension was filtered

Sources & evidence

ORD record
ord-f669ca23260b49558b701e589f9b7c9c
Source dataset
uspto-grants-2010_02
Patent number
US07662847B2

Reaction notes

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