Trifluoroacetic acid → N-[4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-6-(2,6-difluoro-4-methylsulfinylphenyl)-5-fluoropyridine-2-carboxamide

HRID 1499560Notes

Reaction equation

HRID 1499560 reaction equation
C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([S:46]([CH3:48])=[O:47])=[CH:41][C:40]=4[F:49])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO.C1COCC1.C(Cl)Cl>[NH2:21][C@H:16]1[CH2:17][C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:40]([F:49])=[CH:41][C:42]([S:46]([CH3:48])=[O:47])=[CH:43][C:44]=4[F:45])[N:33]=3)=[O:31])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1

Participants

7

Reactant 3

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 867267844-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate

Product 1

HCID 86726785N-[4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-6-(2,6-difluoro-4-methylsulfinylphenyl)-5-fluoropyridine-2-carboxamide

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (3.0 mg, 0.0043 mmol) was dissolved in MeOH (0.02 mL) and THF (0.08 mL), followed by the addition of 1.0 M aq. NaOH (0.017 mL, 0.017 mmol). The reaction mixture was stirred at room temperature for 20 min. The organic solvents and trace of water were removed under vacuum to give the crude intermediate, which was dissolved in DCM (0.044 mL), followed by the addition of TFA (0.044 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 20 min. After concentration, the residue was diluted with MeOH, filtered and 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 two mixtures of diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had the following properties:

Workup

  1. customThe organic solvents and trace of water were removed under vacuum
  2. customto give the crude intermediate, which
  3. stirringThe reaction mixture was stirred at room temperature for 20 min
  4. concentrationAfter concentration
  5. additionthe residue was diluted with MeOH
  6. filtrationfiltered
  7. custompurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.
  8. washeluting with a gradient of MeCN and water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-c402919ba634490ebc6f206b9f55d064
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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