Diisopropylethylamine → (6S)-N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

HRID 589014Notes

Reaction equation

HRID 589014 reaction equation
[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH2:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@@:26]21[CH2:44][C:36]1=[N:37][CH:38]=[C:39]([C:41](O)=[O:42])[CH:40]=[C:35]1[CH2:34]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:41]([C:39]2[CH:40]=[C:35]3[CH2:34][C@@:26]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]4=[O:24])[CH2:44][C:36]3=[N:37][CH:38]=2)=[O:42])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68746980(S)-2'-oxo-1',2',5,7-tetrahydrospiro(cyclopenta(b)pyridine-6,3'-pyrrolo(2,3-b)-bipyridine)-3-carboxylic acid2×HCID 117992070(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine

Product 1

HCID 117992085(6S)-N-[(5S,6S,9R)-5-Azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine (the mixture of diastereomers described in Intermediate 11) (90 mg, 0.28 mmol), (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 4) (85 mg, 0.30 mmol) and HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (160 mg, 0.43 mmol) in DMF (3.0 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was partially purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-100:0:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium carbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (50 mL) and dichloromethane (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of four diastereomers. Separation of the diastereomers was achieved by SFC on a ChiralCel OJ-H column, eluting with CO2:MeOH-80:20, to give four diastereomers in approximately a 2:1:2:5 ratio:

Workup

  1. customThe reaction mixture was partially purified by reversed-phase HPLC on a C-18 column
  2. washeluting with a gradient of H2O
  3. customthe acetonitrile was removed by evaporation under reduced pressure
  4. extractionThe resulting mixture was extracted with ethyl acetate (50 mL) and dichloromethane (2×50 mL)
  5. dry with materialthe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-3d7ba322f86342c4acd4be8c17cc0465
Source dataset
uspto-grants-2016_01
Patent number
US09227973B2

Reaction notes

Loading…