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

HRID 1499525Notes

Reaction equation

HRID 1499525 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.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[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[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([NH:18][C:17]1[C:12]([N:8]2[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]([CH3:31])([CH3:33])[CH3:32])[CH2:7]2)=[C:13]2[CH2:21][CH2:20][CH:19]([OH:22])[C:14]2=[N:15][CH:16]=1)=[O:56])=[O:40])([CH3:37])([CH3:35])[CH3:36]

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 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-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 86726756tert-Butyl {(3R,4R,5S)-1-[3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-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 (11.0 mg, 0.024 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (12 mg, 0.032 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 1 M NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h, and was then concentrated under reduced pressure. The resulting 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 C34H43F2N6O7S (M+H)+: m/z=717.3. Found: 717.3.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for 1 h
  2. concentrationwas then concentrated under reduced pressure
  3. extractionThe resulting 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)

Sources & evidence

ORD record
ord-d086a732c48c47a284bc2c54efbc3afc
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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