Diisopropylethylamine → 5-((5-((6-Bromobenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methyl)-5-methylimidazolidine-2,4-dione

HRID 2281175Notes

Reaction equation

HRID 2281175 reaction equation
[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]([NH:12][NH2:13])=[O:11])[S:8][C:4]=2[CH:3]=1.[CH3:16][C:17]1([CH2:24][C:25](O)=O)[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH2:9][C:10]3[O:11][C:25]([CH2:24][C:17]4([CH3:16])[NH:18][C:19](=[O:23])[NH:20][C:21]4=[O:22])=[N:13][N:12]=3)[S:8][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 111923Propylphosphonic anhydride2×HCID 2903362-(4-Methyl-2,5-dioxoimidazolidin-4-yl)acetic acidHCID 899219952-(6-Bromobenzo[d]thiazol-2-yl)acetohydrazide

Product 1

HCID 899223305-((5-((6-Bromobenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methyl)-5-methylimidazolidine-2,4-dioneYield 55%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 2-(6-bromobenzo[d]thiazol-2-yl)acetohydrazide (1.0 g, 3.5 mmol) (prepared as described in WO 2011/074560) in dioxane (10 mL) was added 2-(4-methyl-2,5-dioxoimidazolidin-4-yl)acetic acid (0.80 g, 4.2 mmol), T3P (50% in EtOAc, 5.20 mL, 8.74 mmol) and DIPEA (3.1 mL, 17.5 mmol). The reaction mixture was stirred at 90° C. for 6 h. Additional DIPEA (3.1 mL, 18 mmol) and T3P (50% in EtOAc, 3.1 mL, 1.8 mmol) were added. The reaction mixture was heated at 95° C. for 12 h. The reaction mixture was diluted with DCM, and the organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO silica gel chromatography eluting with 0-15% MeOH/DCM over 30 min gradient to give racemic material (811 mg, 1.92 mmol, 55.0% yield) as a yellow solid. The enantiomers were separated by preparative chiral SFC (Kromasil 5-Cellucoat 21×250 mm ID, 5 μm, 65 mL/min, 150 bar, 35° C., 25% MeOH/77% CO2) to afford isomer A as Example 23A (Rt=7.8 min, 37% yield), LCMS (method B) Rt=1.6 min, m/z=423.9 (M+H)+; and isomer B as Example 23B (Rt=11.2 min, 35% yield), LCMS (method B) retention time=1.6 min, m/z=423.9 (M+H)+. For Example 23B: 1H NMR (400 MHz, CDCl3) δ 8.26 (br. s., 1H), 8.01 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 6.54 (s, 1H), 4.71 (d, J=2.0 Hz, 2H), 3.40-3.21 (m, 2H), 1.59 (s, 3H).

Workup

  1. temperatureThe reaction mixture was heated at 95° C. for 12 h
  2. washthe organic portion washed with 1.5 M K3PO4, 1.0 M HCl solution and brine
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by ISCO silica gel chromatography
  7. washeluting with 0-15% MeOH/DCM over 30 min gradient

Sources & evidence

ORD record
ord-01fe492b3d4f47cdabbd20ec63c7b30b
Source dataset
uspto-grants-2015_09
Patent number
US09139578B2

Reaction notes

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