Sodium Hydroxide → tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[2-(dimethylcarbamoyl) morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate

HRID 1852936Notes

Reaction equation

HRID 1852936 reaction equation
[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH3:61])[C:38]([CH:40]1[O:45][CH2:44][CH2:43][N:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[CH2:41]1)=[O:39].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.CCOCC.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>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([N:42]5[CH2:43][CH2:44][O:45][CH:40]([C:38](=[O:39])[N:37]([CH3:36])[CH3:61])[CH2:41]5)[CH:47]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1

Participants

8

Reactant 3

HCID 14798Sodium HydroxideHCID 71138530N,N-dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-2-carboxamideHCID 86675348tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate

Product 1

HCID 71142527tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[2-(dimethylcarbamoyl) morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamateYield 36.8%

Reagents, catalysts & solvents 4

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), N,N-dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine-2-carboxamide (73.4 mg, 0.204 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.21 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DMF (2 mL) was heated at 160° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (5×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (CHCl3/EtOAc=1:1→1:2→EtOAc) to afford crude product. The crude product was slurried in ether and collected by filtration. After the solid was washed with ether to afford desired product (25.6 mg, 36.5%) as pale yellow solid.

Workup

  1. temperatureAfter cooling to room temperature
  2. washwashed with water (5×)
  3. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  4. concentrationconcentrated
  5. customThe residue was purified by silica gel column chromatography (CHCl3/EtOAc=1:1→1:2→EtOAc)
  6. customto afford crude product
  7. filtrationcollected by filtration
  8. washAfter the solid was washed with ether

Sources & evidence

ORD record
ord-ab7a6b6fe7b64c18a3d544cce1fba815
Source dataset
uspto-grants-2015_02
Patent number
US08962619B2

Reaction notes

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