1,2-Dichloroethane → N-[(1S)-1-({(1S,4S)-5-[(5-cyano-2,3'-bipyridin-6'-yl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1H-indole-2-carboxamide

HRID 2098455Notes

Reaction equation

HRID 2098455 reaction equation
[C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[N:51][C:52]([C:55](O)=[O:56])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>[C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[N:51][C:52]([C:55]([N:5]3[CH2:6][C@@H:1]4[CH2:7][C@H:4]3[CH2:3][N:2]4[C:8]([C@@H:10]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:56])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)#[N:42]

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 582865945-Cyano-2,3'-bipyridine-6'-carboxylic acidHCID 67072627N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide

Product 1

HCID 44624328N-[(1S)-1-({(1S,4S)-5-[(5-cyano-2,3'-bipyridin-6'-yl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)-2,2-dimethylpropyl]-1H-indole-2-carboxamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 10340Sodium CarbonateSolvent

Procedure

To a 10 ml vial was added N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (100 mg, 0.268 mmol), EDC (128 mg, 0.670 mmol), HOBt (41.0 mg, 0.268 mmol), 5-cyano-2,3′-bipyridine-6′-carboxylic acid (74.7 mg, 0.322 mmol) mmol), CH2Cl2 (2.8 ml), DMF (5.0 ml) and DIEA (0.187 ml, 1.072 mmol). The mixture was stirred at room temperature for 1 h, then at 60° C. for 3 h. After cooling to room temperature, the mixture was diluted with CH2Cl2 and sat. Na2CO3. The organic layer was passed over a phase separator, concentrated and purified by reverse phase HPLC: 30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The organic layer was separated, passed over a phase separator and concentrated to afford the desired product as an off white solid (75 mg, 0.132 mmol) as an off white solid. LCMS (m/z): 562.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.02-1.07 (m, 4H), 1.10 (s, 4H), 1.74-2.12 (m, 2H), 3.37-4.10 (m, 4H), 4.25-5.26 (m, 3H), 6.82-7.68 (m, 5H), 7.87-7.79 (m, 5H), 8.85-9.52 (m, 2H), 11.44-11.92 (m, 1H).

Workup

  1. waitat 60° C. for 3 h
  2. temperatureAfter cooling to room temperature
  3. concentrationconcentrated
  4. custompurified by reverse phase HPLC
  5. wait30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min
  6. additionThe fractions containing the product
  7. additiondiluted with CH2Cl2 and sat. NaHCO3
  8. customThe organic layer was separated
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-24b8782cbd604366be99c33261aa664c
Source dataset
uspto-grants-2013_05
Patent number
US08450484B2

Reaction notes

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