Ethanol → tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate

HRID 1046971Notes

Reaction equation

HRID 1046971 reaction equation
Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].C(O)C.C(=O)(O)[O-].[Na+].[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH2:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:39]=[CH:38][C:37]=1[C:51]1([NH:55][C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:59])[CH3:60])[CH2:54][CH2:53][CH2:52]1

Participants

6

Reactant 4

HCID 702EthanolHCID 516892Sodium BicarbonateHCID 675042963-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepineHCID 69087614Tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate

Product 1

HCID 69087650tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamateYield 152.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of 3-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.06 g, 1 eq.) in a mixture of toluene (0.5 mL), ethanol (0.5 mL), and saturated sodium bicarbonate (0.1 mL) was added tert-butyl (1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (0.088 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.017 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (30 mL). The aqueous phase was extracted with dichloromethane (2×30 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (5% ethyl acetate in dichloromethane) gave tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.133 g, 40%). M.p.: 138-140° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.63 (s, 1H), 8.13 (d, J=4.4 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.37-7.26 (m, 2H), 7.25-7.13 (m, 5H), 7.08 (t, J=7.4 Hz, 1H), 6.95 (bs. S, 1H), 6.74 (br. S, 1H), 6.69-6.63 (m, 2H), 2.42-2.28 (m, 4H), 2.08 (s, 3H), 2.04-1.94 (m, 1H), 1.76-1.64 (m, 1H), 1.34-1.10 (m, 9H, rotamers from BOC group); LCMS: 588 [M+H].

Workup

  1. customThe reaction was degassed (nitrogen) for 5 minutes
  2. additiontetrakis(triphenylphosphine)palladium(0) added (0.017 g)
  3. customThe reaction was again degassed for 5 minutes
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additionpoured onto water (30 mL)
  6. extractionThe aqueous phase was extracted with dichloromethane (2×30 mL)
  7. washwashed with water (1×50 mL), brine (1×50 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customPurification by column chromatography (5% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-577b1d366cd64290b309a4348992d9fa
Source dataset
uspto-grants-2013_10
Patent number
US08569331B2

Reaction notes

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