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

HRID 1499531Notes

Reaction equation

HRID 1499531 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[C:21]([N:30]4[CH2:35][C@H:34]([CH3:36])[C@@H:33]([OH:37])[C@H:32]([NH:38]C(=O)OC(C)(C)C)[CH2:31]4)=[C:22]4[CH2:28][CH2:27][CH:26]([OH:29])[C:23]4=[N:24][CH:25]=3)=[O:18])[CH:14]=[CH:13][C:12]=2[F:46])=[C:6]([F:47])[CH:5]=1)[CH3:2].C(O)(C(F)(F)F)=O.O.CC#N>C(Cl)Cl>[NH2:38][C@H:32]1[C@H:33]([OH:37])[C@@H:34]([CH3:36])[CH2:35][N:30]([C:21]2[C:20]([NH:19][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:46])=[C:11]([C:7]4[C:8]([F:10])=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[F:47])[N:16]=3)=[O:18])=[CH:25][N:24]=[C:23]3[CH:26]([OH:29])[CH2:27][CH2:28][C:22]=23)[CH2:31]1

Participants

6

Reactant 4

HCID 962WaterHCID 6342AcetonitrileHCID 6422Trifluoroacetic acid2×HCID 86726761tert-Butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate

Product 1

HCID 86726762N-[4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridine-2-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of tert-butyl {(3R,4R,5S)-1-[3-({[6-(4-ethoxy-2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-4-hydroxy-5-methylpiperidin-3-yl}carbamate (6 mg, 0.01 mmol) and 4.0 M TFA in DCM (2.0 mL) was stirred at room temperature for 1 h. After removal of the solvent 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 both diastereoisomers 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. customAfter removal of the solvent under reduced pressure
  2. additionthe residue was diluted with MeOH
  3. filtrationfiltered
  4. custompurified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min.
  5. washeluting with a gradient of MeCN and water with 0.1% NH4OH)
  6. customto give both diastereoisomers as white powders

Sources & evidence

ORD record
ord-292f4be21c6442f0a57809d7c69b5018
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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