Hydrogen Bromide → (1-[6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester

HRID 1751585Notes

Reaction equation

HRID 1751585 reaction equation
C([O:8][C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=5)[C:26]([F:38])([F:37])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.Br.CCN([CH:46]([CH3:48])[CH3:47])C(C)C.[CH3:49][N:50](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[CH2:74][O:75][C:76](C)=[O:77]>C(Cl)Cl.CC(O)=O.CN(C=O)C>[CH3:74][O:75][C:76](=[O:77])[NH:50][CH:49]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=5)[C:26]([F:38])([F:37])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:8])[CH:46]([CH3:47])[CH3:48]

Participants

9

Reactant 5

HCID 260Hydrogen BromideHCID 8857Ethyl AcetateHCID 81531Diisopropylethylamine2×HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66620314(6S)-6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-azaspiro[2.4]heptane-5-carboxylic acid phenylmethyl ester

Product 1

HCID 66621335(1-[6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 mL) and HBr in AcOH (37%, 2 mL) was added and stirring at room temperature was continued. After 180 minutes, the suspension was diluted with hexanes and the solid was collected via filtration and was washed with hexanes and subjected to vacuum. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of 2-(L)-Methoxycarbonylamino-3-methyl-butyric acid (242 mg, 1.38 mmol), HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 50 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by silica gel chromatography (eluent: EtOAc/hexanes) to yield the slightly impure product (1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (878 mg). LCMS-ESI+: calc'd for C29H29BrF2N4O3: 599.5 (M+); Found: 598.5/600.5 (M+H+).

Workup

  1. filtrationthe solid was collected via filtration
  2. washwas washed with hexanes
  3. customThe crude material was used in the next step without further purification
  4. dissolutionThe crude material was dissolved in DMF (4.0 mL)
  5. stirringThe reaction was stirred at room temperature
  6. waitAfter 50 minutes
  7. washwas washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
  8. dry with materialwas dried over sodium sulfate
  9. filtrationFiltration and removal of solvents in vacuo
  10. customgave the crude material, which
  11. customwas purified by silica gel chromatography (eluent: EtOAc/hexanes)

Sources & evidence

ORD record
ord-d3ffc8afb3e8487b98a0cc606007907f
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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