Sodium Carbonate → tert-Butyl {1-[4-(2-isoquinolin-6-yl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate

HRID 1047062Notes

Reaction equation

HRID 1047062 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH:38]1[C:47]2[C:42](=[CH:43][C:44](B(O)O)=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:38]1[C:47]2[C:42](=[CH:43][C:44]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:45][CH:46]=2)[CH:41]=[CH:40][N:39]=1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 44119669(Isoquinolin-6-yl)boronic acidHCID 136331865tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate

Product 1

HCID 68067390tert-Butyl {1-[4-(2-isoquinolin-6-yl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamateYield 74%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), isoquinolin-6-ylboronic acid (31 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:4) to afford the desired product (40 mg, 74%) as a white solid. 1HNMR (CDCl3) 400 MHz δ: 9.17 (s, 1H), 8.45 (d, J=6.3 Hz, 1H), 8.22 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.13-8.11 (m, 1H), 8.04 (dd, J=4.0 Hz and 1.1 Hz, 1H), 7.82-7.73 (m, 2H), 7.54 (d, J=5.7 Hz, 1H), 7.41 (dd, J=8.6 Hz and 1.7 Hz, 2H), 7.33 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.21-7.17 (m, 2H), 6.97 (d, J=6.9 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.62 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.27 (s, 1H), 5.16 (br s, 1H), 2.60-2.52 (m, 2H), 2.52-2.30 (m, 2H), 2.23-2.13 (m, 1H), 1.96-1.88 (m, 1H), 1.39 (br s, 9H). LCMS: 607 [M+H].

Workup

  1. additionwas treated with microwave (160° C. for 1 hour)
  2. washwashed with water(×3), brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltrated through Celite pad
  5. concentrationThe filtrate was concentrated
  6. customthe residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:4)

Sources & evidence

ORD record
ord-1da49d03f5e34d05ac1130cc1b887a86
Source dataset
uspto-grants-2013_10
Patent number
US08569331B2

Reaction notes

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