Ethyl Acetate → tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

HRID 2095695Notes

Reaction equation

HRID 2095695 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][C@@H:47]2[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]2)(=O)=O)=CC=1.CCOC(C)=O>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH2:46][C@@H:47]4[CH2:51][O:50][C:49]([CH3:53])([CH3:52])[O:48]4)=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:5]2=[N:6][CH:7]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 2723760(S)-(+)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-ToluenesulfonateHCID 67003938tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Product 1

HCID 67003941tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-6-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

To a suspension of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (84.5 mg, 0.180 mmol) and potassium carbonate (104.5 mg, 0.7561 mmol) in DMF (3 mL), ((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (103.6 mg, 0.3618 mmol) in DMF (2 mL) was added and the reaction mixture was heated to 60° C. for a total of 23 h. EtOAc was added to dilute the reaction mixture and a standard aqueous workup was performed. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was adsorbed onto a pre-filled silica gel loading cartridge [RediSepRf 5 gram] and purified using the Teledyne/ISCO system [RediSepRf 12 g Gold Silica], eluting with a 5-20% EtOAc:heptane solvent system. Fractions containing product were combined and concentrated in vacuo. The material obtained was dissolved in MeOH, passed through a syringe filter, and purified a second time by MDP, under acidic conditions (formic acid). Fractions containing product were pooled together and concentrated in vacuo, affording the title material as a clear and colorless film. 1H NMR (400 MHz, CDCl3): δ=8.43 (d, J=2.3 Hz, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.02 (dd, J=9.1, 8.3 Hz, 1H), 6.70 (dd, J=9.1, 4.0 Hz, 1H), 4.92 (q, J=7.0 Hz, 1H), 4.31 (quint, J=5.7 Hz, 1H), 3.97 (dd, J=8.3, 6.6 Hz, 1H), 3.91 (dd, J=9.0, 5.9 Hz, 1H), 3.65 (br s, 1H), 3.46 (br s, 1H), 1.76 (d, J=7.1 Hz, 3H), 1.69 (s, 9H), 1.36 (d, J=5.3 Hz, 6H). MS (ES+): m/z 605.30/606.98/608.99 (23/61/9) [MH++Na]. HPLC: tR 4.15 min (ZQ3, nonpolar—5 min).

Workup

  1. additionwas added
  2. additionto dilute the reaction mixture
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. custompurified
  8. washeluting with a 5-20% EtOAc
  9. additionFractions containing product
  10. concentrationconcentrated in vacuo
  11. customThe material obtained
  12. custompassed through a syringe
  13. filtrationfilter
  14. custompurified a second time by MDP
  15. additionFractions containing product
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-5cedbee6805144f5af218cf156052599
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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