1,2-Dichloroethane → N-[(1S)-2,2-dimethyl-1-({(1S,4S)-5-[(5-phenyl-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]-1H-indole-2-carboxamide

HRID 2098451Notes

Reaction equation

HRID 2098451 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]1([C:47]2[CH:48]=[CH:49][C:50]([C:53](O)=[O:54])=[N:51][CH:52]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[CH3:12][C:11]([CH3:14])([CH3:13])[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:8]([N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:53]([C:50]1[CH:49]=[CH:48][C:47]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:52][N:51]=1)=[O:54])=[O:9]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27628705-phenylpyridine-2-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 44624193N-[(1S)-2,2-dimethyl-1-({(1S,4S)-5-[(5-phenyl-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]-1H-indole-2-carboxamideYield 84.7%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 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-phenyl-2-pyridinecarboxylic acid (64.1 mg, 0.322 mmol), CH2Cl2 (2.8 ml) and DIEA (0.187 ml, 1.072 mmol). The mixture was stirred at room temperature for 4 h, then diluted with sat. Na2CO3. The organic layer was passed over a phase separator and 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 layers were separated and the resulting aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were combined, dried and concentrated to afford the desired product (123 mg, 0.227 mmol) as an off white solid. LCMS (m/z): 536.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.05 (s, 2H), 1.07 (s, 2H), 1.10 (s, 4H), 1.73-2.09 (m, 2H), 3.37-4.07 (m, 4H), 4.45-5.27 (m, 3H), 6.90-7.25 (m, 2H), 7.26-7.96 (m, 9H), 8.03-8.38 (m, 2H), 8.42-9.10 (m, 1H), 11.55-11.83 (m, 1H)

Workup

  1. concentrationconcentrated
  2. custompurified by reverse phase HPLC
  3. wait30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min
  4. additionThe fractions containing the product
  5. additiondiluted with CH2Cl2 and sat. NaHCO3
  6. customThe layers were separated
  7. extractionthe resulting aqueous layer was extracted three times with CH2Cl2
  8. customdried
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-2ca9696280884fb097b4021623028bc8
Source dataset
uspto-grants-2013_05
Patent number
US08450484B2

Reaction notes

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