Phosphorus oxybromide → HCID 23654543, compound

HRID 597958Notes

Reaction equation

HRID 597958 reaction equation
P(Br)(Br)([Br:3])=O.[CH3:6][CH:7]1[C:13]2[NH:14][C:15](=O)[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8]1>CN(C=O)C>[Br:3][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8][CH:7]([CH3:6])[C:13]=2[N:14]=1

Participants

4

Reactant 2

HCID 24613Phosphorus oxybromideHCID 23654542HCID 23654542, compound

Product 1

HCID 23654543HCID 23654543, compoundYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.

Workup

  1. customquenched with sat. aq. NaHCO3
  2. extractionextracted with EtOAc
  3. dry with materialThe organic layer was dried over Na2SO4
  4. concentrationconcentrated under reduced pressure
  5. custompurified by column chromatography

Sources & evidence

ORD record
ord-4cd0ca22bb8947c388a3dfa74ef02a71
Source dataset
uspto-grants-2011_03
Patent number
US07897595B2

Reaction notes

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