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 658144Notes

Reaction equation

HRID 658144 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-9ee1b29fcfed49228b359c30b978ed0b
Source dataset
uspto-grants-2011_12
Patent number
US08076369B2

Reaction notes

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