Methanol → (1S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-methoxy-acetamide

HRID 913188Notes

Reaction equation

HRID 913188 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].C[OH:36]>C1COCC1>[CH2:27]([O:26][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:7]2=[O:36])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25])[CH3:28]

Participants

5

Reactant 3

HCID 887MethanolHCID 96623Methoxyacetyl chlorideHCID 66718531(S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one

Product 1

HCID 67417838(1S)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-methoxy-acetamideYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of (1S)-7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-2,3-dihydro-isoindol-1-one (0.5 g, 1.2 mmol) and 2-methoxyacetyl chloride (0.3 mL, 3.2 mmol) in THF (6 mL) was heated to reflux for 17 hours. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid, which was purified with Prep HPLC to give (1S)—N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-2-methoxy-acetamide as an off-white solid (180 mg, 32% yield): mp 151-153° C.; 1H NMR (CDCl3) δ 1.47 (t, J=7 Hz, 3H, CH3), 2.84 (s, 3H, CH3), 3.56 (s, 3H, CH3), 3.77 (dd, J=5, 14 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.08 (s, 2H, CH2), 4.12 (q, J=7 Hz, 2H, CH2), 4.53 (dd, J=10, 15 Hz, 1H, CHH), 5.87 (dd, J=5, 10 Hz, 1H, NCH), 6.81-6.82 (m, 1H, Ar), 7.10-7.13 (m, 2H, Ar), 7.51 (d, J=7 HZ, 1H, Ar), 7.67 (t, J=8 Hz, 1H, Ar), 8.81 (d, J=8 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 14.69, 41.59, 48.80, 54.81, 55.96, 59.74, 64.55, 72.18, 111.49, 112.53, 116.06, 118.59, 120.49, 125.09, 129.39, 131.33, 136.02, 136.59, 148.62, 149.77, 167.57, 168.89, 169.16. Analy. calculated for C23H26N2O8S: C, 56.32; H, 5.34, N, 5.71. Found: C, 56.23; H, 5.30; N, 5.56.

Workup

  1. temperatureto reflux for 17 hours
  2. customThe solvent was removed in vacuo
  3. customto give a solid, which
  4. customwas purified with Prep HPLC

Sources & evidence

ORD record
ord-3e50522ce9904df69198ec08f646c7bb
Source dataset
uspto-grants-2011_09
Patent number
US08026269B2

Reaction notes

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