Trifluoroacetic acid → 1-{[7-{2-[(2-fluoroethyl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-one

HRID 473882Notes

Reaction equation

HRID 473882 reaction equation
[F:1][CH2:2][CH2:3][NH:4][C:5]1[N:9](C(OCC(C)C)=O)[C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31](OC(C)(C)C)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[F:55][C:56]1[CH:57]=[C:58]([CH:62]2[CH2:67][C:66](=[O:68])[CH2:65][CH2:64][N:63]2C(Cl)=O)[CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:1][CH2:2][CH2:3][NH:4][C:5]1[NH:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:30][CH2:29][CH2:28][N:27]([C:31]([N:63]5[CH2:64][CH2:65][C:66](=[O:68])[CH2:67][CH:62]5[C:58]5[CH:59]=[CH:60][CH:61]=[C:56]([F:55])[CH:57]=5)=[O:32])[CH2:26][C:25]=4[CH:38]=3)=[CH:20][C:7]=2[N:6]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 866720291,1-dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylateHCID 866720302-(3-Fluorophenyl)-4-oxopiperidine-1-carbonyl chloride

Product 1

HCID 1785165261-{[7-{2-[(2-fluoroethyl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-oneYield 77.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1,1-Dimethylethyl 7-(2-[(2-fluoroethyl)amino]-1-{[(2-methylpropyl)oxy]carbonyl}-1H-benzimidazol-5-yl)-2,3-dihydro-1,4-benzoxazepine-4 (5H)-carboxylate (59.4 mg, 0.11 mmol) was taken into neat TFA (1 mL) and allowed to stand for 1 h at room temperature then concentrated and dried. The residue was taken into THF (5 mL) followed by addition of DIPEA (0.2 mL, 1.1 mmol) followed by addition of 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (29 mg, 0.11 mmol) in a minimum of THF and the resulting solution was stirred at room temperature for 30 minutes. The mixture was then concentrated and taken up into methanol (5 mL) followed by addition of solid potassium carbonate (80 mg, 0.56 mmol) and stirring was continued for 30 minutes. The mixture was then concentrated and partitioned with ethyl acetate and brine. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was triturated with ethyl ether and the solid collected by filtration and dried to afford 1-{[7-{2-[(2-fluoroethyl)amino]-1H-benzimidazol-5-yl}-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-2-(3-fluorophenyl)piperidin-4-one (46.4 mg, 75% yield). 1H NMR (400 MHz, d6-DMSO): 7.51 (s, 1H), 7.42 (d, 1H), 7.36 (s, 1H), 7.31 (q, 1H), 7.18 (d, 1H), 7.12-7.03 (m, 4H), 6.99 (d, 1H), 5.20 (tr, 1H), 4.66 (tr, 1H), 4.57 (dd AB, 2H), 4.54 (tr, 1H), 4.20 (br m, 2H), 3.75-3.56 (br m, 6H), 2.86 (m, 2H), 2.60 (m, 1H), 2.33 (br d, 1H). MS (EI) for C30H29F2N5O3: 547 (MH+).

Workup

  1. concentrationthen concentrated
  2. customdried
  3. concentrationThe mixture was then concentrated
  4. stirringstirring
  5. waitwas continued for 30 minutes
  6. concentrationThe mixture was then concentrated
  7. custompartitioned with ethyl acetate and brine
  8. dry with materialThe organic solution was dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe residue thus obtained
  12. customwas triturated with ethyl ether
  13. filtrationthe solid collected by filtration
  14. customdried

Sources & evidence

ORD record
ord-ff9b844c656f4009aa37c2e3313c8faa
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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