Potassium Carbonate → 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 1053497Notes

Reaction equation

HRID 1053497 reaction equation
[CH3:1][O:2][C:3](=[O:39])[NH:4][CH:5]([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)=[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:10])[CH:6]([CH3:8])[CH3:7].[C:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59](B4OC(C)(C)C(C)(C)O4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59]([C:29]4[CH:30]=[CH:31][C:32]5[C:33]6[C:25](=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:15][CH2:14]9)[CH2:12][N:11]8[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=7)=[CH:35][CH:34]=6)[C:26]([F:38])([F:37])[C:27]=5[CH:28]=4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:41])[CH3:42]

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 66620440(1R,3S,4S)-3-[6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid 1,1-dimethylethyl esterHCID 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

Product 1

HCID 666212893-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 75.4%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
87.5 °C

Procedure

(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 612 (840 mg, 1.4 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 613 (615 mg, 1.4 mmol), Pd(PPh3)4 (161 mg, 0.14 mmol), K2CO3 (579 mg, 4.2 mmol), were dissolved in DME (15 mL)/water (3 mL) under an argon atmosphere. The mixture was heated for 120 minutes at 85-90° C. (oil bath). After 120 minutes additional boronate ester (61 mg, 0.14 mmol) was added and heating was continued. After 3 hours, the reaction was cooled to room temperature. Most of the DME was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with brine and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield compound 614 (878 mg). LCMS-ESI+: calc'd for C47H51F2N7O5: 831.9 (M+). Found: 832.7 (M+H+).

Workup

  1. temperatureheating
  2. temperaturethe reaction was cooled to room temperature
  3. customMost of the DME was removed in vacuo
  4. customthe crude reaction mixture
  5. washThe mixture was washed with brine
  6. dry with materialwas dried over sodium sulfate
  7. filtrationFiltration and evaporation of solvents
  8. customgave the crude
  9. customreaction product, which
  10. customwas purified via silica gel chromatography (eluent: EtOAc/hexanes)

Sources & evidence

ORD record
ord-5d3abfdf28b54348b62d6846c4537639
Source dataset
uspto-grants-2016_07
Patent number
US09393256B2

Reaction notes

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