Hydrochloric Acid → 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea

HRID 331630

Reaction equation

HRID 331630 reaction equation
[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([CH3:31])[CH:23]=1.Cl>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:30])=[C:24]([CH3:31])[CH:23]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 1421574-Chloro-2-methylphenyl isocyanateHCID 594432803-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Product 1

HCID 577304911-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureaYield 90%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-chloro-1-isocyanato-2-methyl-benzene (0.17 mgl, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(4-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (380 mg, 90%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.6 min (99%); mp. 256-258° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H, CH—H), 2.19 (s, 3H, CH3), 2.31-2.47 (m, 1H, CH—H), 2.63 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CuI), 4.27-4.51 (m, 4H, CH2, CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 7.09-7.24 (m, 3H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 7.87 (d, J=3.4 Hz, 1H, Ar), 7.90 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 17.61, 22.49, 31.20, 42.83, 47.12, 51.58, 121.64, 121.98, 122.99, 125.36, 125.77, 126.97, 129.04, 129.46, 130.36, 137.14, 142.42, 144.58, 155.22, 167.92, 170.99, 172.85; LCMS MH=441. Anal Calcd for: C22H21ClN4O4+0.2H2O: C, 59.45; H, 4.85; N, 12.60; Cl, 7.98. found: C, 59.21; H, 4.71; N, 12.46; Cl, 8.21.

Workup

  1. stirringthe mixture was stirred for 10 minutes
  2. customThe solid was isolated by filtration
  3. washthe solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)

Sources & evidence

ORD record
ord-189a67c0c8d54fd984e9af310fcd3a34
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Linked notes

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