Potassium Carbonate → 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

HRID 1256571

Reaction equation

HRID 1256571 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:36])=[O:37])=[CH:39][CH:40]=3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 10423982(4-((4-Methylpiperazin-1-yl)sulfonyl)phenyl)boronic acidHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole

Product 1

HCID 469176512-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazoleYield 31%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (200 mg, 0.504 mmol), 4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655 mmol), PdCl2(dppf) (29 mg, 0.0355 mmol), and aq. K2CO3 (2M, 3 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase extracted with CH2Cl2 (9×). The combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25), followed by chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (93 mg, 31%).

Workup

  1. temperaturewas refluxed under nitrogen for 1 hr
  2. extractionthe aqueous phase extracted with CH2Cl2 (9×)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. customthe solvent was removed under vacuum
  5. washChromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25)
  6. washeluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes

Sources & evidence

ORD record
ord-f28b1cf8f2014da382f1e33ece08ab77
Source dataset
uspto-grants-2013_06
Patent number
US08461158B2

Linked notes

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