Acetic Acid → propane-1-sulfonic acid {3-[1-(2,6-dichloro-benzoyl)-5-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide

HRID 60087Notes

Reaction equation

HRID 60087 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][N:8]([C:28](=[O:37])[C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])[C:5]2=[N:6][CH:7]=1.[NH:38]1[C:46]2[C:41](=[CH:42][C:43](B(O)O)=[CH:44][CH:45]=2)[CH:40]=[CH:39]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[C:28]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:43]3[CH:42]=[C:41]4[C:46](=[CH:45][CH:44]=3)[NH:38][CH:39]=[CH:40]4)[CH:3]=[C:4]2[C:10]([C:11]([C:13]2[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=2[F:19])=[O:12])=[CH:9]1)=[O:37]

Participants

10

Reactant 4

HCID 176Acetic AcidHCID 11430Potassium CarbonateHCID 27343615-Indolylboronic acidHCID 510010251-Propanesulfonamide, N-[3-[[5-bromo-1-(2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-

Product 1

HCID 53261972propane-1-sulfonic acid {3-[1-(2,6-dichloro-benzoyl)-5-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide

Reagents, catalysts & solvents 5

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

Propane-1-sulfonic acid {3-[5-bromo-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (11, 113 mg, 0.18 mmol) and 1H-indole-5-boronic acid (14, 44 mg, 0.27 mmol) are dissolved in 4 mL of tetrahydrofuran, then 2 mL of 1M aqueous potassium carbonate and 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (6.5 mg, 0.018 mmol, 10%) are added. The reaction mixture is heated at 70° C. overnight. The reaction is neutralized with acetic acid and diluted with ethyl acetate and water. The organic layer is washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is dissolved in 1 mL of dimethylformamide and purified by HPLC using a C8 column, eluting with water/acetonitrile and 0.1% trifluoroacetic acid, 40-85% acetonitrile at 15 mL per minute. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI)=[M+H+]+=669.5. This compound is a prodrug of P-0012, or can be further reacted to remove the dichlorobenzoyl protecting group to provide P-0012.

Workup

  1. washThe organic layer is washed with brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationthe filtrate concentrated under vacuum
  5. dissolutionThe resulting material is dissolved in 1 mL of dimethylformamide
  6. custompurified by HPLC
  7. washeluting with water/acetonitrile and 0.1% trifluoroacetic acid, 40-85% acetonitrile at 15 mL per minute
  8. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-ceb7d9eb46f84730af6776aeb314a9c6
Source dataset
uspto-grants-2016_09
Patent number
US09440969B2

Reaction notes

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