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Hydrochloric Acid → 3-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

HRID 240678
Notes
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Reaction equation

HRID 240678 reaction equation
Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.O>[C:24]([NH:28][C:29](=[O:30])[N:20]([CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[N:9]([CH:8]1[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]1=[O:2])[C:10]2=[O:22])[CH3:21])([CH3:27])([CH3:26])[CH3:25]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 62412tert-Butyl isocyanateHCID 81531DiisopropylethylamineHCID 670266492-(2,6-Dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride

Product 1

HCID 248958983-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-ureaYield 76.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and t-butyl-isocyanate (0.26 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added water (40 mL) and 1N HCl (40 mL). The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.59 g, 76%): mp 188-190° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.14 (96%); 1H NMR (DMSO-d6): δ 1.28 (s, 9H), 2.08 (m, 1H), 2.64-2.50 (m, 2H), 2.85 (s, 3H), 2.87-2.95 (m, 1H), 4.87 (s, 2H), 5.14-5.18 (dd, J=5.3, 12.6 Hz, 1H), 5.71 (s, 1H), 7.50-7.52 (m, 1H), 7.79-7.88 (m, 2H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 29.13, 30.90, 34.81, 47.02, 48.82, 50.07, 121.70, 127.45, 131.73, 132.49, 134.78, 139.63, 157.40, 166.95, 167.61, 169.80, 172.73. Anal Calcd for C20H24N4O5: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.87; H, 6.01; N, 13.83.

Workup

  1. customThe mixture was quenched with MeOH
  2. extractionextracted with H2O (40 mL)
  3. washThe organic layer was washed with brine (40 mL)
  4. concentrationconcentrated on rota-vap
  5. customThe resulting oil was purified on silica gel column

Sources & evidence

ORD record
ord-7c9a9b45b7624086a7654b9aae4cfd00
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08648096B2

Reaction notes

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