Diisopropylethylamine → tert-Butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-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 1499530Notes

Reaction equation

HRID 1499530 reaction equation
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.[CH2:34]([O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)[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>[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([F:54])[C:40]([C:44]2[N:49]=[C:48]([C:50]([NH:18][C:17]3[C:12]([N:8]4[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])([CH3:31])[CH3:32])[CH2:7]4)=[C:13]4[CH2:21][CH2:20][CH:19]([OH:22])[C:14]4=[N:15][CH:16]=3)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:41]([F:43])[CH:42]=1)[CH3:35]

Participants

8

Reactant 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 706552056-(4-Ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acidHCID 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 acetate

Product 1

HCID 86726761tert-Butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-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

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 14798Sodium HydroxideSolvent

Procedure

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 (12.4 mg, 0.027 mmol), 6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (8.0 mg, 0.027 mmol), HATU (37 mg, 0.098 mmol) in DMF (0.1 mL) and DIPEA (26 mg, 0.20 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1 M NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the aqueous layer was extracted with DCM three times. The combined organic layers were dried, filtered and concentrated under vacuum 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 C33H39F3N5O6 (M+H)+: m/z=658.3. Found: 658.3.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 1 h
  2. concentrationAfter concentration under reduced pressure
  3. extractionthe aqueous layer was extracted with DCM three times
  4. customThe combined organic layers were dried
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  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)

Sources & evidence

ORD record
ord-7c9476517f56401d8ec47d33b7a575a1
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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