Hydrochloric Acid → N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

HRID 1499623Notes

Reaction equation

HRID 1499623 reaction equation
C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:47]([F:48])=[CH:46][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:44][C:43]=4[F:53])[N:36]=3)=[O:34])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.O1CCOCC1>CO.C1COCC1>[NH2:24][C@H:16]1[CH2:17][C@@H:18]([C:20]([F:21])([F:22])[F:23])[CH2:19][N:14]([C:13]2[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:43]([F:53])=[CH:44][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:46][C:47]=4[F:48])[N:36]=3)=[O:34])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 312751,4-DioxaneHCID 867268394-[(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate

Product 1

HCID 86726840N-{4-[(3S,5R)-3-Amino-5-(trifluoromethyl)piperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl}-6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.015 g, 0.020 mmol) in MeOH (0.8 mL), THF (0.8 mL) and 1.0 M aq. NaOH (0.8 mL, 0.8 mmol) was stirred at room temperature for 0.5 h. The solution was then concentrated under reduced pressure and the remaining aqueous phase was extracted with EtOAc. The organic extract was concentrated to dryness under reduced pressure. The residue was treated with 4.0 M HCl in dioxane (0.20 mL, 0.80 mmol) for 20 min. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in 4.5 mL of MeOH, neutralized with NH4OH solution, and purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two separated diastereoisomers of the title compound as white powders.

Workup

  1. concentrationThe solution was then concentrated under reduced pressure
  2. extractionthe remaining aqueous phase was extracted with EtOAc
  3. extractionThe organic extract
  4. concentrationwas concentrated to dryness under reduced pressure
  5. concentrationThe reaction mixture was then concentrated under reduced pressure
  6. dissolutionThe residue was dissolved in 4.5 mL of MeOH
  7. custompurified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size
  8. washeluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.)

Sources & evidence

ORD record
ord-69e8aa3f6a9d497da50368bd71bb0e5f
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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