Dimethylformamide → 3-chloro-5-[(5-chloro-1H-indazol-4-yl)oxy]benzonitrile

HRID 505507Notes

Reaction equation

HRID 505507 reaction equation
BrBr.Br[C:4]1[CH:5]=[C:6]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42](C=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:19]1[CH:20]=[C:4]([CH:5]=[C:6]([O:7][C:8]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[CH:18]=1)[C:41]#[N:42]

Participants

8

Reactant 4

HCID 6228Dimethylformamide2×HCID 11776TriphenylphosphineHCID 24408BromineHCID 568336424-(3-bromo-5-chlorophenoxy)-5-chloro-1H-indazole

Product 1

HCID 568336433-chloro-5-[(5-chloro-1H-indazol-4-yl)oxy]benzonitrile

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
85 °C

Procedure

Bromine (154 g; 0.964 mole; 0.10 eq.) was added to a slurry of zinc (particle size <10 microns; 192 g; 2.940 moles; 0.30 eq.) in DMF (10 L) at room temperature. The resulting mixture was then stirred fast for 30 minutes while 4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-indazole (3.508 kg; 9.798 moles; 1.00 eq., zinc cyanide (690 g; 5.879 moles; 0.60 eq.), triphenylphosphine (308 g; 1.176 moles; 0.12 eq.), palladium acetate (66 g; 0.294 mole; 0.03 eq.) and DMF (11 L) were added at room temperature. The reaction mixture was then degassed for 15 minutes using a subsurface stream of nitrogen, heated to 85° C., and then aged for 4.5 hours. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was then diluted with THF (18 L) and heated to 50° C., after which aqueous EDTA.3Na (0.5M, 20 L) was added and the mixture aged at 50° C.-60° C. for 1 hour. The mixture was then filtered through solka floc and washed with THF (20 L), and the filtrate transferred to an extractor (100 L) filled with brine (15 L) and separated. The aqueous layer was extracted with EtOAc (15 L), and the combined organic layers were washed with a second portion of EDTA.3Na (0.5M, 20 L), then water (20 L), and then brine (15 L). The solution was treated with activated carbon (Darko KB), filtered through solka floc, concentrated to a slurry of less than 10 L, switched to toluene (6 L), concentrated to half volume, heated to 40° C., added heptane (6 L), and cooled below 25° C. The resulting slurry was filtered, washed with extra toleuene:heptane (1:3; 4 L), heptane (4 L), and dried to provide the title product as a solid.

Workup

  1. customThe reaction mixture was then degassed for 15 minutes
  2. temperatureThe reaction mixture was then cooled to room temperature
  3. additionThe reaction mixture was then diluted with THF (18 L)
  4. temperatureheated to 50° C.
  5. addition3Na (0.5M, 20 L) was added
  6. waitthe mixture aged at 50° C.-60° C. for 1 hour
  7. filtrationThe mixture was then filtered through solka floc
  8. washwashed with THF (20 L)
  9. additionfilled with brine (15 L)
  10. customseparated
  11. extractionThe aqueous layer was extracted with EtOAc (15 L)
  12. washthe combined organic layers were washed with a second portion of EDTA
  13. additionThe solution was treated with activated carbon (Darko KB)
  14. filtrationfiltered through solka floc
  15. concentrationconcentrated to a slurry of less than 10 L
  16. concentrationconcentrated to half volume
  17. temperatureheated to 40° C.
  18. additionadded heptane (6 L)
  19. temperaturecooled below 25° C
  20. filtrationThe resulting slurry was filtered
  21. washwashed with extra toleuene
  22. dry with materialheptane (1:3; 4 L), heptane (4 L), and dried

Sources & evidence

ORD record
ord-866442d85f1248379405b4c43c923b34
Source dataset
uspto-grants-2010_08
Patent number
US07781454B2

Reaction notes

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