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

HRID 2098456Notes

Reaction equation

HRID 2098456 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[C@H:18]12[CH2:24][C@H:21]([NH:22][CH2:23]1)[CH2:20][N:19]2[C:25]([C@@H:27]([NH:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:22]3[CH2:23][C@@H:18]4[CH2:24][C@H:21]3[CH2:20][N:19]4[C:25]([C@@H:27]([NH:32][C:33]([C:35]3[NH:36][C:37]4[C:42]([CH:43]=3)=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:17])=[N:13][CH:14]=2)=[CH:7][CH:8]=1)#[N:2]

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 509985415-(4-Cyanophenyl)picolinic 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 67072469N-{(1S)-1-[((1S,4S)-5-{[5-(4-cyanophenyl)-2-pyridinyl]carbonyl}-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamideYield 62.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 10340Sodium CarbonateSolvent

Procedure

To a 200 ml flask was added 5-(4-cyanophenyl)-2-pyridinecarboxylic acid (0.76 g, 3.39 mmol), N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (1 g, 2.82 mmol), EDC (1.30 g, 6.77 mmol), HOBt (0.52 g, 3.39 mmol), CH2Cl2 (28 ml), DIEA (1.971 ml, 11.29 mmol). The mixture was stirred at room temperature overnight then diluted with CH2Cl2, water and sat. Na2CO3. The two layers were separated and the organic washed with 2N HCl, sat. NaHCO3 and brine. The CH2Cl2 was passed over a phase separator and concentrated to afford a brown residue. The residue was purified by reverse phase chromatography on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 2CV water, the 0-100% ACN/Water over 20 CV. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the CH2Cl2 was dried and concentrated to afford the desired product (1.0 g, 1.75 mmol) as an off white solid. LCMS (m/z): 561.3 (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), 3.37-4.03 (m, 4H), 4.55-5.26 (m, 3H), 6.87-7.24 (m, 2H), 7.26-7.68 (m, 3H), 7.78-8.41 (m, 7H), 8.48-9.18 (m, 1H), 11.52-11.87 (m, 1H).

Workup

  1. customThe two layers were separated
  2. washthe organic washed with 2N HCl, sat. NaHCO3 and brine
  3. concentrationconcentrated
  4. customto afford a brown residue
  5. customThe residue was purified by reverse phase chromatography on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 2CV water
  6. additionThe fractions containing the product
  7. additiondiluted with CH2Cl2 and sat. NaHCO3
  8. customThe layers were separated
  9. dry with materialthe CH2Cl2 was dried
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-57181f5a6749401d96d8f67f9122cdf7
Source dataset
uspto-grants-2013_05
Patent number
US08450484B2

Reaction notes

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