Potassium Phosphate, Tribasic → Tert-butyl (S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

HRID 1777822Notes

Reaction equation

HRID 1777822 reaction equation
Cl[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([CH:18]([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH2:35])=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(O)(C)(C)C>[CH2:21]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:2]2[CH:3]=[C:4]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:8]([CH:18]([CH3:20])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:34])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 824947162-(4-(Ethylsulfonyl)phenyl)acetamideHCID 118274870tert-butyl (S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

Product 1

HCID 118274878Tert-butyl (S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylateYield 57.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 44233348Di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-(1,1'-biphenyl)-2-yl)phosphineCatalystHCID 6386tert-ButanolSolvent

Conditions

Temperature
110 °C

Procedure

To a flame-dried vial equipped with a stir bar was added tert-butyl(S)-3-chloro-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (74.7 mg, 252 μmol), 2-(4-(ethylsulfonyl)phenyl)acetamide (68.6 mg, 302 μmol), and potassium phosphate (64.1 mg, 302 μmol). Tert-butanol (1.5 mL) was added, then the mixture was degassed with N2 for 15 min. Tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 252 nmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (4.9 mg, 10.1 μmol) were added to the mixture, then the vial was sealed and heated at 110° C. for 15 h. The mixture was cooled to rt, then partitioned between EtOAc (15 mL) and brine (15 mL). The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%) to afford 70.2 mg of Tert-butyl(S)-3-(2-(4-(ethylsulfonyl)phenyl)acetamido)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (57%). LC-MS tR=0.90 min in 1 min chromatography, MS (ESI) m/z 488.5 [M+H]+. 1H NMR (CD3OD, 400 MHz, mixture of rotamers): δ 8.58 (s, 0.5H), 8.54 (s, 0.5H), 8.10 (s, 1H), 7.89 (dd, J=8.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 4.77 (d, J=15.6 Hz, 1H), 4.51 (m, 2H), 3.87 (s, 2H), 3.21 (q, J=7.2 Hz, 2H), 2.46-2.37 (m, 1H), 1.52 (s, 9H), 1.22 (t, J=7.6 Hz, 3H), 1.02 (d, J=6.8 Hz, 1.5H), 0.99 (d, J=6.4 Hz, 1.5H), 0.77 (d, J=7.2 Hz, 1.5H), 0.73 (d, J=6.8 Hz, 1.5H).

Workup

  1. customTo a flame-dried vial equipped with a stir bar
  2. customthe mixture was degassed with N2 for 15 min
  3. customthe vial was sealed
  4. temperatureThe mixture was cooled to rt
  5. custompartitioned between EtOAc (15 mL) and brine (15 mL)
  6. customThe organic phase was separated
  7. dry with materialdried over anhydrous MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%)

Sources & evidence

ORD record
ord-bb3487f65ec348f2949e09bacdc2ee7b
Source dataset
uspto-grants-2016_02
Patent number
US09266886B2

Reaction notes

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