Water → 5-Ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amide

HRID 63453Notes

Reaction equation

HRID 63453 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]

Participants

6

Reactant 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 231456135-Ethoxypicolinic acidHCID 670232045-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride

Product 1

HCID 1238463525-Ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-amideYield 77%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54 2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.

Workup

  1. temperaturethe mixture was heated at 40° C. for 1.5 h
  2. temperatureThe mixture was cooled to rt
  3. filtrationThe solids were filtered
  4. dissolutiondissolved in CH2Cl2 (10 mL)
  5. customThe crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient, product eluted at 3% MeOH)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-b2c887f6b54844a2a7c6abe67339a120
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

Loading…