Methanol → 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-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

HRID 1499544Notes

Reaction equation

HRID 1499544 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][CH:42]=[C:41]([O:46][CH3:47])[C:40]=4[F:48])[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.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[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:44]([F:45])=[CH:43][CH:42]=[C:41]([O:46][CH3:47])[C:40]=4[F:48])[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 4

HCID 887MethanolHCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 867267744-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate

Product 1

HCID 86726775N-[4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-({[6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (8.0 mg, 0.012 mmol), MeOH (140 μL), THF (71 μL) and 1.0 M aq. NaOH (78 μL, 0.078 mmol) was stirred at room temperature for 20 min. The organic solvents were removed under vacuum and dried to give the crude intermediate, which was dissolved in DCM (0.1 mL), followed by the addition of TFA (0.12 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 20 min. The solution was then concentrated under reduced pressure and 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 both 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 were removed under vacuum
  2. customdried
  3. customto give the crude intermediate, which
  4. stirringThe reaction mixture was stirred at room temperature for 20 min
  5. concentrationThe solution was then concentrated under reduced pressure
  6. additionthe residue was diluted with MeOH
  7. filtrationfiltered
  8. custompurified 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-60af44b6f52341aea7caa1ef564e5a83
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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