Fusaric Acid → 5-Butylpyridine-2-carboxylic acid [2-(2,6-dioxo piperidin-3-YL)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]amide

HRID 448440

Reaction equation

HRID 448440 reaction equation
[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.S(Cl)(Cl)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:39])[N:24]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:25]2=[O:30].C(N(CC)CC)C>C1COCC1>[O:38]=[C:32]1[CH:31]([N:24]2[C:23](=[O:39])[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20][NH:19][C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=3)=[O:13])[C:25]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1

Participants

6

Reactant 4

HCID 3442Fusaric AcidHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 588273525-Butylpyridine-2-carboxylic acid [2-(2,6-dioxo piperidin-3-YL)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]amideYield 64.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of fusaric acid (0.36 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 95:5 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.58 g of the purified product in 64% yield: mp 137-139° C.; 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.24-1.39 (m, 2H), 1.54-1.65 (m, 2H), 2.06-2.10 (m, 2H), 2.51-2.72 (m, 4H), 2.84-2.97 (m, 1H), 4.94 (d, J=6.4 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.66-7.71 (m, 1H), 7.77-7.86 (m, 3H), 7.97 (d, J=8.0 Hz, 1H), 8.54 (d, J=1.7 Hz, 1H), 9.43 (t, J=6.4 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 13.7, 21.6, 22.0, 31.0, 31.7, 32.6, 38.5, 48.9, 121.8, 121.9, 127.2, 131.6, 133.0, 134.8, 137.3, 139.2, 141.2, 147.5, 148.5, 164.5, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H24N4O5.0.3H2O: C, 63.51; H, 5.46; N, 12.34. Found: C, 63.52; H, 5.55; N, 12.05.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 1 hour
  3. customExcess thionyl chloride was removed under vacuum
  4. customThe solvent was evaporated
  5. customthe crude residue was chromatographed
  6. washeluting the product with 95:5 methylene chloride-methanol
  7. customThis material was further purified by preparative HPLC
  8. washeluting with 1:1 acetonitrile-water

Sources & evidence

ORD record
ord-fafd4deeaeec4d47b531d557a42350ee
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Linked notes

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