Diisopropylethylamine → quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide

HRID 63458

Reaction equation

HRID 63458 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:33]([C:24]4[CH:25]=[CH:26][C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[O:34])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 2760547Quinaldoyl chlorideHCID 670197065-(Aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

Product 1

HCID 57730490quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amideYield 86.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and quinoline-2-carbonyl chloride (0.57 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was isolated by filtration and dried in vacuo to give quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 76% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.08 min (96.58%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.93-2.16 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.74 (d, J=6.4 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.66-7.82 (m, 1H, Ar), 7.82-7.99 (m, 4H, Ar), 8.03-8.25 (m, 3H, Ar), 8.59 (d, J=8.1 Hz, 1H, Ar), 9.75 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.55, 48.99, 118.74, 122.24, 123.55, 128.15, 128.89, 129.15, 129.84, 130.60, 131.59, 133.67, 137.94, 146.05, 147.44, 149.89, 164.48, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C24H18N4O5: C, 65.15; H, 4.10; N, 12.68. Found: C, 65.05; H, 4.05; N, 12.58.

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionthe residue was dissolved in CH2Cl2 (100 mL)
  3. washThe organic layer was washed with water (100 mL), brine (100 mL)
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customThe crude product was purified by column chromatography (0-5% MeOH CH2Cl2)
  7. concentrationconcentrated
  8. customtriturated in Et2O for 18 h
  9. customThe product was isolated by filtration
  10. customdried in vacuo

Sources & evidence

ORD record
ord-8dd348fdd1764094839280d71eab5095
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Linked notes

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