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

HRID 1499558
Notes
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Reaction equation

HRID 1499558 reaction equation
C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][C:41]([S:45]([CH3:47])=[O:46])=[CH:40][C:39]=4[F:48])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]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>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:39]([F:48])=[CH:40][C:41]([S:45]([CH3:47])=[O:46])=[CH:42][C:43]=4[F:44])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 867267824-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-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 86726783N-[4-[(3S)-3-aminopiperidin-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)-3-[(tert-Butoxycarbonyl)amino]piperidin-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, 0.0044 mmol) was dissolved in MeOH (0.01 mL) and THF (0.05 mL), and 1.0 M aq. NaOH (0.017 mL, 0.017 mmol) was then added. The reaction mixture was stirred at room temperature for 60 min. The organic solvents and trace of water were removed under reduced pressure to give a crude intermediate. The residue was dissolved in DCM (0.04 mL), then TFA (0.044 mL, 0.58 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The solution was then concentrated again under reduced pressure. 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 reduced pressure
  2. customto give a crude intermediate
  3. stirringThe reaction mixture was stirred at room temperature for 16 h
  4. concentrationThe solution was then concentrated again under reduced pressure
  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-40e49d1298f64b1199069fe82689b6cb
Source dataset
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09200004B2

Reaction notes

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