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 71893ノート

反応式

HRID 71893 の反応式
[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]

参加物

8

反応物 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

生成物 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 ester収率 75.4%

試薬・触媒・溶媒 4

HCID 178418397HCID 178418397、化合物触媒HCID 962Water溶媒HCID 80711,2-Dimethoxyethane溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
87.5 °C

実験手順

(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-aza-bicyclo[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+).

後処理

  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)

出典と根拠

ORDレコード
ord-402f3980a3964981b09e81918bb44c19
出典データセット
uspto-grants-2014_09
特許番号
US08822430B2

反応ノート

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