Water → 6-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide

HRID 63441노트

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HRID 63441 반응식
[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=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>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([C:38]2([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:31]3=[O:47])=[O:10])=[CH:6][N:5]=1)[CH3:2]

참가 물질

6

반응물 4

HCID 962WaterHCID 682631,1'-CarbonyldiimidazoleHCID 64858176-Ethoxypyridine-3-carboxylic acidHCID 670232045-Aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)isoindole-1,3-dione hydrochloride

생성물 1

HCID 670232516-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide수율 86%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

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온도
40 °C

실험 절차

A stirred mixture of 6-ethoxy-nicotinic 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 solvent was removed in vacuo and the crude product was purified by column chromatography (80/20, EtOAc hexanes). The product fractions were combined, concentrated and the residue was triturated in Et2O. The product was isolated by filtration and dried in vacuo to give 6-ethoxy-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-nicotinamide as a white solid (0.77 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.56 min (99.14%); mp: 174-176° C.; 1H NMR (DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 1.89 (s, 3H), 2.02-2.08 (m, 1H), 2.54-2.73 (m, 3H), 4.34 (dd, J=7.2, 14.1 Hz, 2H), 4.62 (d, J=6.0 Hz, 2H), 6.88 (d, J=8.7 Hz, 1H), 7.77-7.83 (m, 3H), 8.14 (dd, J=2.4, 8.7 Hz, 1H), 8.70 (d, J=2.1 Hz, 1H), 9.20 (t, J=6.0 Hz, 1H), 11.01 (s, 1H); 13C NMR (DMSO-d6) δ 14.40, 21.00, 28.60, 29.10, 42.50, 58.70, 61.80, 110.30, 121.60, 123.00, 123.20, 129.60, 131.40, 133.40, 138.10, 147.10, 147.30, 164.70, 165.00, 167.70, 167.90, 172.10, 172.20; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.3H2O: C, 60.60; H, 5.00; N, 12.29. Found: C, 60.24; H, 4.86; N, 12.15.

후처리

  1. temperaturethe mixture was heated at 40° C. for 1.5 h
  2. temperatureThe mixture was cooled to rt
  3. customThe solvent was removed in vacuo
  4. customthe crude product was purified by column chromatography (80/20, EtOAc hexanes)
  5. concentrationconcentrated
  6. customthe residue was triturated in Et2O
  7. customThe product was isolated by filtration
  8. customdried in vacuo

출처 및 근거

ORD 기록
ord-beeac270b0654191bb3be9673013ee90
출처 데이터셋
uspto-grants-2016_09
특허 번호
US09447070B2

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