Benzyl Bromide → HCID 69207830, compound

HRID 1394896Notes

Reaction equation

HRID 1394896 reaction equation
[C:1]([O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([C:13]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 7498Benzyl BromideHCID 10796Cesium carbonateHCID 69207214HCID 69207214, compound

Product 1

HCID 69207830HCID 69207830, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl/amino]-cyclopentanecarboxylic acid. 1-(Tert-butoxycarbonyl)cyclopentanecarboxylic acid (3.37 g, 14.7 mmol) was dissolved in DMF (40 mL) and treated with Cs2CO3 (5.28 g, 16.2 mmol) and benzyl bromide (1.1 mL, 16.2 mmol), the mixture was stirred at rt overnight and then at 70° C. for 3 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (250 mL). The organic phase was washed with water (100 mL) and brine (100 mL); dried over Na2SO4, filtered and concentrated to afford benzyl 1-(t-butoxycarbonyl)cyclopentanecarboxylate as a white solid. A portion of the solid (1.4 g) was dissolved in CH2Cl2 (40 mL) and treated with TFA (5 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo to afford the TFA salt of benzyl 1-aminocyclopentanecarboxylate as an off-white solid. LCMS: m/e 220 (M+H)+, ret time 1.30 min, column 3, 2 minute gradient. This solid was then dissolved in THF (20 mL) and dimethyl-4-morpholinyl]carbonyl]-N-[(methylamino)sulfonyl]-,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-, (1.4 g, 4.2 mmol) was added followed by DMAP (1.54 g, 1.27 mmol) and HATU (2.4 g, 6.3 mmol). The mixture was stirred at rt for 48 h. Solvent was removed in vacuo. Water (100 mL) and AcOEt (100 mL) were added. The organic phase was separated, dried over Na2SO4 and purified using silica gel (AcOEt/Hex 10%-70%) to afford the benzyl protected cyclopentanecarboxylic acid, 1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl]amino]-, as a bright yellow solid (1.4 g). LCMS: m/e 700 (M+H)+, ret time 2.46 min, column 3, 2 minute gradient. The benzyl protected compound (578 mg, 0.8 mmol) was dissolved in a 1:1 mixture of THF/MeOH (10 mL) and treated with 1N NaOH (2 mL). The mixture was stirred at rt for 18 h. Same procedure was repeated with 822 mg of the benzyl protected compound and the reactions were reunited. HCl (1N) was added to pH=5 and the precipitated formed was collected by filtration to afford the title compound as a pale yellow solid (650 mg). A small portion was purified using reverse phase HPLC. 1HNMR (500 MHz, DMSO) δ 8.33 (br s, 1H), 8.30 (br s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 5H), 6.92 (br s, 1H), 5.15 (br s, 1H), 4.37 (br s, 1H), 4.22-3.05 (m, 6H), 2.75 (m, 1H), 2.50-1.10 (m, 24H). LCMS: m/e 610 (M+H)+, ret time 2.35 min, column 3, 2 minute gradient.

Workup

  1. waitat 70° C. for 3 h
  2. extractionextracted with EtOAc (250 mL)
  3. washThe organic phase was washed with water (100 mL) and brine (100 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-38ae7c55b4f44aa88baf68b215d770ed
Source dataset
uspto-grants-2008_03
Patent number
US07348425B2

Reaction notes

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