Diisopropylethylamine → tert-Butyl {(3R,4R,5S)-1-[3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

HRID 1499523Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1499523
C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]3[CH:19]([O:22]C(=O)C)[CH2:20][CH2:21][C:13]=23)[CH2:7][C@H:6]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)C.[C:34]([O:38][C:39]([NH:41][C:42]1[C:43]([C:57](O)=[O:58])=[N:44][C:45]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[C:46]([F:48])[CH:47]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].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>CN(C=O)C.[OH-].[Na+].CO>[C:34]([O:38][C:39]([NH:41][C:42]1[C:43]([C:57]([NH:18][C:17]2[C:12]([N:8]3[CH2:9][C@H:10]([CH3:11])[C@@H:5]([OH:4])[C@H:6]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:7]3)=[C:13]3[CH2:21][CH2:20][CH:19]([OH:22])[C:14]3=[N:15][CH:16]=2)=[O:58])=[N:44][C:45]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[C:46]([F:48])[CH:47]=1)=[O:40])([CH3:37])([CH3:35])[CH3:36]

Komponenten

8

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 86726725(3R,4R,5S)-1-[7-(Acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetateHCID 867267293-[(Tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid

Produkt 1

HCID 86726754tert-Butyl {(3R,4R,5S)-1-[3-({[3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 14798Sodium HydroxideLösungsmittel

Versuchsvorschrift

A mixture of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetate (11.0 mg, 0.024 mmol), 3-[(tert-butoxycarbonyl)amino]-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (12 mg, 0.03 mmol), HATU (33 mg, 0.09 mmol) in DMF (0.09 mL) and DIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1N NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. After concentration under vacuum, the aqueous layer was extracted with DCM three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder. LCMS calc. for C36H44F3N6O7 (M+H)+: m/z=729.3. Found: 729.4.

Aufarbeitung

  1. stirringThe reaction mixture was stirred at room temperature for 1 h
  2. concentrationAfter concentration under vacuum
  3. extractionthe aqueous layer was extracted with DCM three times
  4. customThe combined organic layers were dried
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give the crude product, which
  8. customwas purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.
  9. washeluting with a gradient of MeCN and water with 0.1% NH4OH)

Quellen und Nachweise

ORD-Eintrag
ord-2323480fe47c49d79b51c826e6f5080c
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09200004B2

Notizen zur Reaktion

Wird geladen…