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

HRID 2281175
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HRID 2281175 반응식
[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
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참가 물질

7

반응물 4

HCID 81531Diisopropylethylamine2회HCID 111923Propylphosphonic anhydride2회HCID 2903362-(4-Methyl-2,5-dioxoimidazolidin-4-yl)acetic acidHCID 899219952-(6-Bromobenzo[d]thiazol-2-yl)acetohydrazide

생성물 1

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

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 312751,4-Dioxane용매

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온도
90 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-01fe492b3d4f47cdabbd20ec63c7b30b
출처 데이터셋
uspto-grants-2015_09
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09139578B2

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