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 1751586Notes

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

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 (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 (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 the product 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-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (878 mg). LCMS-ESI+: calc'd for C47H51F2N7O5: 831.9 (M+); Found: 832.7 (M+H+).

Workup

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

Sources & evidence

ORD record: ord-6109dc289dec4394bdb24e41f17aed5c
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09156823B2

Reaction notes

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