N-bromobutanimide → 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester

HRID 2039112노트

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HRID 2039112 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH:27]=[CH:28][C:29](Br)=[CH:30][C:25]=3[S:24][C:23]=2[CH:32]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.C1C(=O)N(Br)C(=O)C1.[C:59]([O:63][C:64]([N:66]1[CH:71]([C:72]([OH:74])=[O:73])[CH:70]2[CH2:75][CH:67]1[CH2:68][CH2:69]2)=[O:65])([CH3:62])([CH3:61])[CH3:60]>O1CCOCC1.C(OCC)(=O)C.CN(C=O)C.CC#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:59]([O:63][C:64]([N:66]1[CH:71]([C:72]([O:74][CH2:39][C:38]([C:29]2[CH:28]=[CH:27][C:26]3[C:22]4[CH:21]=[CH:20][C:19]([C:17](=[O:18])[CH2:16][O:15][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14])=[CH:32][C:23]=4[S:24][C:25]=3[CH:30]=2)=[O:40])=[O:73])[CH:70]2[CH2:75][CH:67]1[CH2:68][CH2:69]2)=[O:65])([CH3:62])([CH3:60])[CH3:61]

참가 물질

11

반응물 4

HCID 67184N-bromobutanimideHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 150563882-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acidHCID 66620445Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester

생성물 1

HCID 679716832-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl]-2-oxo-ethyl) ester 2-tert-butyl ester

시약·촉매·용매 6

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 6228Dimethylformamide용매2회HCID 6342Acetonitrile용매HCID 8857Ethyl Acetate용매2회HCID 312751,4-Dioxane용매

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온도
80 °C

실험 절차

[1,1′-Bis(triphenylphosphine)dichloropalladium(II)(3%, 14 mg, 0.02 mmol) and tetrakis(triphenylphosphine)palladium (3%, 23 mg, 0.02 mmol) were added to the mixture of Pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-dibenzothiophen-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (345 mg, 0.665 mmol) and tributyl(1-ethoxyvinyl)tin (1.2 eq., 0.269 mL) in 5 mL dioxane. The reaction was heated to 80° C. under Are for 4 hours. The reaction was cooled to room temperature. 1.5 mL water was added and followed by NBS (1 eq., 142 mg). The reaction was stirred at room for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated down and dried on vacuum to give residue which was used in next step. The residue was dissolved in 4 mL anhydrous DMF. 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (2 eq., 321 mg, 1.33 mmol g) was added, followed by TEA (2.2 eq., 204 mg) in 4 mL MeCN and 3 mL DMF dropwise. The reaction was stirred at room temperature overnight. The reaction crude was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane) to give 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzothiophen-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester as a yellow residue (92.5 mg, yield 19%). LCMS-ESI−: calc'd for C38H44N2O10S: 720.83; Found: 743.2 (M+Na+).

후처리

  1. temperatureThe reaction was cooled to room temperature
  2. washwashed with saturated sodium bicarbonate solution
  3. dry with materialThe organic layer dried (MgSO4)
  4. concentrationconcentrated down
  5. customdried on vacuum
  6. customto give residue which
  7. stirringThe reaction was stirred at room temperature overnight
  8. customThe reaction crude
  9. washwashed with saturated sodium bicarbonate solution
  10. dry with materialThe organic layer dried (MgSO4)
  11. concentrationconcentrated
  12. custompurified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexane)

출처 및 근거

ORD 기록
ord-1c8d07c7e6cb441ea6f5c3536a295de5
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08575118B2

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