3-Acetamidophthalic Anhydride → Apremilast, (+-)-

HRID 1254155Notes

Reaction equation

HRID 1254155 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]

Participants

4

Reactant 2

HCID 2261213-Acetamidophthalic AnhydrideHCID 112887921-(3-Ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine

Product 1

HCID 10151715Apremilast, (+-)-Yield 59.3%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A stirred solution of 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.7 mmol) and 3-acetamidophthalic anhydride (751 mg, 3.66 mmol) in acetic acid (20 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded the product as a yellow solid (1.0 g, 59% yield): mp, 144° C.; 1H NMR (CDCl3) δ1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 8.74 (d, J=8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; Anal Calc'd. for C22H24NO7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.31; H, 5.34; N, 5.83.

Workup

  1. temperatureat reflux for 15 h
  2. customThe solvent was removed in vacuo
  3. customto yield an oil

Sources & evidence

ORD record
ord-49899cb328094e7f9da2d4b22f29e0c6
Source dataset
uspto-grants-2013_06
Patent number
US08455536B2

Reaction notes

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