Water → 2-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrile

HRID 1966364Notes

Reaction equation

HRID 1966364 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:28].[CH3:29][N:30](C)C(=O)C.O.[OH-].[NH4+]>[Cl-].[NH4+].ClCCl.[C-]#N.[Zn+2].[C-]#N.[Zn].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].C(N(CC)CC)C.CC(C)=O>[F:28][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)=[CH:15][N:16]=3)[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:29]#[N:30]

Participants

12

Reactant 4

HCID 962Water2×HCID 14923Ammonium HydroxideHCID 31374DimethylacetamideHCID 579711886-((2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline

Product 1

HCID 445128962-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrileYield 72.6%

Reagents, catalysts & solvents 7

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 180AcetoneSolvent2×HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent2×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
110 °C

Procedure

6-((2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 200 g, 0.461 mol), zinc cyanide (ZnCN2, 32.7 g, 0.277 mol, 0.6 equiv), zinc powder (Zn, 6.0 g, 0.093 mol, 0.2 equiv) and Pd(dppf)2Cl2 (22.6 g 0.028 mol, 0.06 equiv) were suspended in premixed solution of N,N-dimethyl acetamide (DMAC, 2000 mL) and water (H2O, 40 mL). The resulting suspension was then degassed with a stream of nitrogen for 20 min before being heated to 110° C. and stirred at 110° C. for 1-2 h (homogeneous solution was observed). When LC/MS indicated the reaction was deemed complete, the reaction mixture was cooled first to room temperature and then in an ice bath to 5° C. The cooled reaction mixture was diluted with a mixture of the saturated aqueous ammonium chloride solution (aq. NH4Cl), the concentrated ammonium hydroxide aqueous solution (aq. NH4OH), and water (4:1:4 by volume, 8.1 L) and the resulting mixture was stirred at room temperature for 30 min. The resulting solids were collected by filtration and dried in a vacuum oven overnight at 45° C. to afford the crude desired product (13). This crude material was then purified by flash chromatography (SiO2, gradient elution with 1% triethylamine in dichloromethane, 2.5% acetone and 1% triethylamine in dichloromethane, 5.0% acetone and 1% triethylamine in dichloromethane, and 10.0% acetone and 1% triethylamine in dichloromethane sequentially) to afford the pure 2-fluoro-4-(7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl)benzonitrile (13, 127.4 g, 175.4 g theoretical, 72.6% yield) as yellow solids. For 13: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.81 (dd, 1H, J=4.15, 1.66 Hz), 8.26-8.12 (m, 4H), 8.02 (s, 1H), 7.95-7.93 (m, 2H), 7.76 (dd, 1H, J=8.71, 2.08 Hz), 7.47 (dd, 1H, J=8.70, 4.15 Hz), 4.62 (s, 2H); C22H13FN6 (MW 380.38), LCMS (EI) m/e 381.0 (M++H).

Workup

  1. customThe resulting suspension was then degassed with a stream of nitrogen for 20 min
  2. temperaturethe reaction mixture was cooled first to room temperature
  3. customto 5° C
  4. customThe cooled reaction mixture
  5. filtrationThe resulting solids were collected by filtration
  6. customdried in a vacuum oven overnight at 45° C.
  7. customto afford the crude desired product (13)
  8. customThis crude material was then purified by flash chromatography (
  9. washSiO2, gradient elution with 1% triethylamine in dichloromethane, 2.5% acetone and 1% triethylamine in dichloromethane

Sources & evidence

ORD record
ord-c1d0b3e2097b4c9b82898b0294d43e31
Source dataset
uspto-grants-2013_04
Patent number
US08420645B2

Reaction notes

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