Tetrahydrofuran → 1-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-urea

HRID 509488Notes

Reaction equation

HRID 509488 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C([N:26]([CH2:29]C)[CH2:27][CH3:28])C.[C:31]1(C)[CH:36]=[CH:35]C=[C:33](C(N=C=O)=O)[CH:32]=1.C1C[O:46]CC1>>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:29]([NH:26][C:27]4[CH:28]=[C:36]([CH3:35])[CH:31]=[CH:32][CH:33]=4)=[O:46])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 126265343-Methylbenzoyl isocyanateHCID 687303673-(6-(aminomethyl)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 252358231-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-ureaYield 68%

Procedure

To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (12 mL) at 5˜10° C., was added m-toluoyl isocyanate (0.25 mL, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-m-tolyl-urea as an off-white solid (437 mg, 68% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.95 min (99.0%); mp, 200-202° C.; 1HNMR (DMSO-d6) δ 2.07-2.24 (m, 4H, ArCH3, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.40 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.70-7.95 (m, 8H, Ar and CH2NH), 8.54 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.92, 21.19, 23.39, 30.61, 42.30, 56.53, 114.93, 118.27, 120.00, 121.87, 123.63, 126.53, 128.44, 133.94, 137.70, 139.23, 140.26, 145.73, 154.50, 155.22, 160.46, 169.48, 172.61. LCMS MH=434; Anal Calcd For C23H23N5O4+1.4H2O: C, 60.23; H, 5.67; N, 15.27. Found: C, 60.18; H, 5.44; N, 15.09.

Workup

  1. customThe mixture was quenched with methanol (˜1 mL)
  2. customthe solvent was evaporated
  3. customThe residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%)

Sources & evidence

ORD record
ord-b6a0a4bd1beb45c49471545a149dc960
Source dataset
uspto-grants-2015_08
Patent number
US09096573B2

Reaction notes

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