Urea → 2-Chloro-4-(8-hydroxy-1,3-dioxohexahydroimidazo[1,5-a]pyridin-2-yl)-3-methylbenzonitrile

HRID 501595Notes

Reaction equation

CO[C:3]([C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].NC(N)=O.N1CC(=O)NC1=O>C(Cl)Cl>[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]2[C:3](=[O:4])[CH:5]3[CH:10]([OH:11])[CH2:9][CH2:8][CH2:7][N:6]3[C:32]2=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]

Participants

Conditions

Temperature: 0 °C

Procedure

To a suspension of compound 53B (0.20 g, 0.77 mmol) in CH2Cl2 (3 mL) cooled to 0° C. was added i-Pr2EtN (0.178 mL, 1.00 mmol). After stirring at 0° C. for 20 min, compound 23E (0.095 g, 0.59 mmol) in CH2Cl2 (1 mL) solution was added, along with 4 Å molecular sieves (0.5 g), and the resulting mixture stirred at rt until urea formation was completed (˜2 b). The mixture was then stirred at rt until hydantoin formation was complete (˜15 h). The reaction mixture was loaded on a silica gel column, eluted with 40% EtOAc/hexane, and 5% MeOH in EtOAc/hexane (1:1) to afford 0.11 g of the title compound as an off-white powder. HPLC: 99% at 1.67-1.79 min; Conditions: Phenom. Luna C18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient (A=90% H2O-10% ACN-0.1% H3PO4 and B=10% H2O-90% ACN-0.1% H3PO4), Flow rate at 4 mL/min., UV detection at 220 nm). The compound was further loaded on a Chiral AD column, eluted with 25% isopropanol in hexane isocratic to afford 50 mg each of enantiomer 53a (isomer A; retention time=14.2 min; 100% e.e.) and enantiomer 53b (isomer B; retention time=20 min; 100% e.e) of the title compound as white powders. Chiral HPLC Conditions: (CHIRALPAK® AD column 4.6×250 mm; 25% isopropanol in hexane over 30 min at flow rate 1.0 mL/min, UV detection at 220 nm); MS (ES) m/z 320 [M+1]+.

Workup

custom(˜15 h)
washeluted with 40% EtOAc/hexane, and 5% MeOH in EtOAc/hexane (1:1)

Sources & evidence

ORD record: ord-95fa51ce69e04b788081ad0bf8f09b31
Source dataset: uspto-grants-2010_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07772267B2

Reaction notes

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