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Diisopropylethylamine → (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one

HRID 2189929
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2189929
[Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11232725Propanoic acid, 2-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-, (2S)-HCID 866048312-(3-Azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole

Produkt 1

HCID 86604833
(S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one
Ausbeute 25,1 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6342AcetonitrileLösungsmittel2×

Versuchsvorschrift

To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.

Aufarbeitung

  1. stirringAfter stirring at room temperature for 16 hours
  2. concentrationthe mixture was concentrated under reduced pressure
  3. custompartitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL)
  4. extractionThe aqueous layer was extracted with ethyl acetate
  5. washthe combined organic phases were washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe brown oil was chromatographed (9:1 hexanes/ethyl acetate)

Quellen und Nachweise

ORD-Eintrag
ord-1883046dd3fd4636b2d75efbcfe18b48
Quelldatensatz
uspto-grants-2012_12
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08324257B2

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