1-Bromo-2-fluorobenzene → HCID 66996644, compound

HRID 2363636Notes

Reaction equation

HRID 2363636 reaction equation
[CH3:1][N:2]([C@@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:11]([NH:13][C@@H:14]1[C@@H:21]2[C@@H:17]([CH2:18][NH:19][CH2:20]2)[CH2:16][CH2:15]1)=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(O)(CC)(C)C.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]>[F:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:19]1[CH2:20][C@@H:21]2[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:15][CH2:16][C@@H:17]2[CH2:18]1

Participants

7

Reactant 4

HCID 612591-Bromo-2-fluorobenzeneHCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 66997073HCID 66997073, compound

Product 1

HCID 66996644HCID 66996644, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 64052-Methyl-2-butanolSolvent

Conditions

Temperature
80 °C

Procedure

To a microwave vial under nitrogen was added tert-butyl methyl((S)-4-methyl-1-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylamino)-1-oxopentan-2-yl)carbamate from Step 1 (118 mg, 0.334 mmol), 1-bromo-2-fluorobenzene (0.038 mL, 0.350 mmol), potassium phosphate, tribasic (116 mg, 0.668 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.11 mg, 6.68 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 12.73 mg, 0.027 mmol) in t-amyl alcohol (1.0 mL). The reaction was heated at 80° C. for 18 hours. The solvent was removed and the solids were washed with 2×2 mL of ethyl acetate. The solvent was removed under a stream of nitrogen. The crude material was applied to a 12 g silica gel cartridge with ether and purified using 1-50% ethyl acetate/hexanes to give tert-butyl(S)-1-((3aR,4S,6aS)-2-(2-fluorophenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.47-8.39 (m, 1H), 7.12 (ddd, J=13.9, 8.0, 1.4, 1H), 7.06 (td, J=7.8, 1.4, 1H), 6.86-6.77 (m, 2H), 5.17 (ddd, J=10.0, 7.5, 1.0, 1H), 4.46-4.35 (m, 1H), 3.65 (d, J=9.4, 1H), 3.30-3.21 (m, 1H), 3.17 (d, J=9.1, 1H), 3.13-3.03 (m, 4H), 2.69-2.57 (m, 2H), 2.11-1.98 (m, 1H), 1.94-1.82 (m, 3H), 1.66-1.55 (m, 2H), 1.48 (s, 9H), 1.39 (dddd, J=21.2, 19.9, 9.7, 4.0, 1H), 0.91 (d, J=6.5, 3H), 0.87 (d, J=6.6, 3H); MS (ESI+) m/z 448 (M+H)+.

Workup

  1. customThe solvent was removed
  2. washthe solids were washed with 2×2 mL of ethyl acetate
  3. customThe solvent was removed under a stream of nitrogen
  4. custompurified

Sources & evidence

ORD record
ord-0e443a6f34a14498aedaaba41a724116
Source dataset
uspto-grants-2014_04
Patent number
US08691865B2

Reaction notes

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