Sodium Carbonate → N-(6-(6-Chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide

HRID 1162470Notes

Reaction equation

HRID 1162470 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=1)(=[O:10])=[O:11]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 57416507N-[2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-(difluoromethoxy)benzene-1-sulfonamideHCID 59519510N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide

Product 1

HCID 44125259N-(6-(6-Chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamideYield 30%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
100 °C

Procedure

A glass microwave reaction vessel was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (1.1 g, 2.4 mmol), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.25 g, 1.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (87 mg, 0.012 mmol, Strem Chemical, Inc., Newburyport, Mass.), sodium carbonate (0.25 g, 2.4 mmol), and dioxane-H2O (5 mL, 4:1). Ar was bubbled in the solution for 1 minute. The reaction mixture was sealed and heated at 100° C. for 2 h and then was concentrated in vacuo. Purification by silica gel chromatography (5-20% MeOH/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 30 to 80% CH3CN/H2O, 0.1% TFA, over 12 min) (Phenomenex, Torrance, Calif.) provided the title compound (0.18 g, 30% yield) as a tan solid. MS (ESI positive ion) m/z: 524 (M+1). 1H NMR (400 MHz, MeOH-d): δ ppm 2.22 (s, 3H), 6.88 (t, J=73.07 Hz, 1H), 7.43 (dd, J=8.12, 1.86 Hz, 1H), 7.54-7.62 (m, 2H), 7.63-7.68 (m, 1H), 7.74 (d, J=9.59 Hz, 1H), 7.98 (d, J=9.59 Hz, 1H), 8.44 (s, 1H), 8.57 (d, J=2.15 Hz, 1H), 8.82 (d, J=2.35 Hz, 1H).

Workup

  1. customA glass microwave reaction vessel
  2. customAr was bubbled in the solution for 1 minute
  3. customThe reaction mixture was sealed
  4. concentrationwas concentrated in vacuo
  5. customPurification by silica gel chromatography (5-20% MeOH/CH2Cl2)
  6. customfollowed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 30 to 80% CH3CN/H2O, 0.1% TFA, over 12 min) (Phenomenex, Torrance, Calif.)

Sources & evidence

ORD record
ord-d4d34f8e60964deb9384e81192d0893d
Source dataset
uspto-grants-2010_10
Patent number
US07820665B2

Reaction notes

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