Potassium Carbonate → (S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester

HRID 1185876Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1185876
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[CH:63]=[C:62]([C:67]1[NH:71][C:70]([C@@H:72]3[CH2:78][C:75]4([CH2:77][CH2:76]4)[CH2:74][N:73]3[C:79](=[O:89])[C@@H:80]([NH:84][C:85](=[O:88])[O:86][CH3:87])[CH:81]([CH3:83])[CH3:82])=[N:69][CH:68]=1)[CH:61]=[CH:60]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CS(C)=O.O1CCOCC1>[CH3:87][O:86][C:85](=[O:88])[NH:84][C@@H:80]([CH:81]([CH3:82])[CH3:83])[C:79]([N:73]1[C@H:72]([C:70]2[NH:71][C:67]([C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:2]5[CH:7]=[CH:6][C:5]([C:8]6[NH:12][C:11]([C@@H:13]7[CH2:21][C:16]8([O:17][CH2:18][CH2:19][O:20]8)[CH2:15][N:14]7[C:22](=[O:32])[C@@H:23]([NH:27][C:28]([O:29][CH3:30])=[O:31])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=6)=[CH:4][CH:3]=5)[CH:58]=4)[CH:63]=3)=[CH:68][N:69]=2)[CH2:78][C:75]2([CH2:76][CH2:77]2)[CH2:74]1)=[O:89]

Komponenten

10

Edukt 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 59610362((S)-1-{(S)-8-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 59610490methyl(S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Produkt 1

HCID 59610451(S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 679Dimethyl SulfoxideLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

Methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (200 mg, 0.39 mmol), bis(pinacolato)diboron (130 mg, 0.51 mmol), potassium acetate (116 mg, 1.18 mmol), and Pd(dppf)Cl2 (29 mg, 0.039 mmol) were all weighed out in a glass pressure vessel and anhydrous 1,4-Dioxane (2 mL) was added. The mixture was bubbled with nitrogen gas for about 5 min. The vessel was then capped and sealed and heated in an oil bath at 90° C. overnight with continuous stirring. The reaction vessel was cooled down to room temperature and methyl (S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate (215 mg, 0.41 mmol), 2M K2CO3, and Pd(PPh3)4 (46 mg, 0.04 mmol) were all added along with 2 mL of DMSO and the mixture was bubbled with nitrogen gas for 5 minutes. The vessel, again, was capped, sealed and placed in an oil bath at 100° C. for 4 hours. The resulting crude mixture was diluted with ethyl acetate and washed, respectively, with brine, 10% Na2CO3, 10% citric acid, saturated solution of NH4Cl, and brine. The organic layer was then dried over Na2SO4 and the volatiles were removed on rotovap. The residue was first purified on normal phase chromatography and then on prep HPLC. Yield=205 mg (60%). 1H-NMR: 400 MHz, (CDCl3). δ 8.18-7.97 (m, 1H), 7.83-7.6 (m, 8H), 7.82-7.22 (m, 3H), 5.47-5.34 (m, 4H), 4.33-4.26 (m, 1H), 4.08-4.03 (m, 4H), 3.94-3.89 (m, 1H), 3.78-3.69 (m, 8H), 3.22 (brs, 1H), 2.96-2.94 (m, 1H), 2.49-2.46 (m, 1H), 2.22-2.17 (m, 1H), 1.99 (brs, 1H), 1.08-1.04 (m, 2H), 0.94-0.79 (m, 12H), 0.71 (m, 4H). MS (ESI) m/z 873.79 [M+H]+.

Aufarbeitung

  1. customall weighed out in a glass pressure vessel
  2. customThe mixture was bubbled with nitrogen gas for about 5 min
  3. customThe vessel was then capped
  4. customsealed
  5. temperatureThe reaction vessel was cooled down to room temperature
  6. customthe mixture was bubbled with nitrogen gas for 5 minutes
  7. customThe vessel, again, was capped
  8. customsealed
  9. additionThe resulting crude mixture was diluted with ethyl acetate
  10. washwashed
  11. dry with materialThe organic layer was then dried over Na2SO4
  12. customthe volatiles were removed on rotovap
  13. customThe residue was first purified on normal phase chromatography

Quellen und Nachweise

ORD-Eintrag
ord-f55d4e2303854f24863c071ee66e50b8
Quelldatensatz
uspto-grants-2014_03
Patentnummer
US08669234B2

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