Toluene → 4-tert-butyl-N-(2-methyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-benzamide

HRID 1969101Notes

Reaction equation

HRID 1969101 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:26]([C:30]1[CH:54]=[CH:53][C:33]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][N:17]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)[C:38]=2[CH3:52])=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]

Participants

8

Reactant 4

HCID 1140TolueneHCID 11430Potassium CarbonateHCID 57786785[6-(6-Chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanoneHCID 587289934-(tert-Butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide

Product 1

HCID 426439074-tert-butyl-N-(2-methyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-benzamideYield 10.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
170 °C

Procedure

A mixture of crude [6-(6-chloro-imidazo[1,2-b]pyridazin-8-ylamino)-pyridin-3-yl]-morpholin-4-yl-methanone (0.048 g, “0.133 mmol”), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.087 g, 0.23 mmol), potassium carbonate (0.056 g, 0.41 mmol), Pd(PPh3)4 (0.016 g, 0.014 mmol), 1 mL of toluene, 0.25 mL of ethanol and 0.25 mL of water under N2 was stirred at 170° C. in a microwave for 3 h. More Pd(PPh3)4 was added (0.025 g, 0.021 mmol) and the mixture was stirred for an additional 1 h at 170° C. in a microwave. The mixture was partitioned between 5 mL of water and 5 mL of ethyl acetate, and the aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to 0.126 g of a yellow oil. Column chromatography (1st column: 0->10% MeOH/CH2Cl2; 2nd column: 0->5% MeOH/EtOAc) afforded 0.008 g (10%) of 4-tert-butyl-N-(2-methyl-3-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-imidazo[1,2-b]pyridazin-6-yl}-phenyl)-benzamide as an off-white solid.

Workup

  1. stirringthe mixture was stirred for an additional 1 h at 170° C. in a microwave
  2. customThe mixture was partitioned between 5 mL of water and 5 mL of ethyl acetate
  3. extractionthe aqueous layer was extracted with 5 mL of ethyl acetate
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to 0.126 g of a yellow oil

Sources & evidence

ORD record
ord-654dc5ac2b4c4a0584159e0d2cfa55c0
Source dataset
uspto-grants-2013_04
Patent number
US08426441B2

Reaction notes

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