Water → HCID 67959729, compound

HRID 1529352Notes

Reaction equation

HRID 1529352 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[Br-].[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[Zn+].C1COCC1.O.C(CN(CCO)CCN(CC([O-])=O)CC([O-])=O)([O-])=O.[Na+].[Na+].[Na+].O>C(Cl)Cl.[Pd](Cl)Cl.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:42]=1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1

Participants

8

Reactant 5

HCID 962WaterHCID 8028TetrahydrofuranHCID 16211347Glycine, N-[2-[bis(carboxymethyl)amino]ethyl]-N-(2-hydroxyethyl)-, trisodium salt hydrateHCID 67959732HCID 67959732, compoundHCID 178505730HCID 178505730, compound

Product 1

HCID 67959729HCID 67959729, compound

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

A 75 mL threaded pressure vessel was flushed with argon and was charged with a stir bar, bis(4-(di-tert-butylphosphino)-N,N-dimethyl-benzenamine) palladium dichloride (0.061 g, 0.086 mmol) and (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.00 g, 1.711 mmol). (2,6-Difluorophenyl)zinc(II) bromide 0.5 M in THF (Rieke metals) (5.13 mL, 2.57 mmol) was added, the reaction was sealed, and the slurry was heated to 70° C. After ˜10 min, a clear solution resulted. After 3 h the reaction was cooled and judged complete by LCMS. The reaction was treated with sodium 2,2′-(2-((carboxylatomethyl)(2-hydroxyethyl)amino)ethylazanediyl)diacetate hydrate 10 wt % in water (10.23 mL, 2.82 mmol) (10% aqueous EDTA-H) and DCM. An additional 2-3 mL of 10% EDTA-H solution was added to break up emulsion. The layers were separated, and the aqueous layer was extracted 3×DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) eluting with 0-40% EtOAc/hexane. The product-containing fractions were concentrated to afford (4R)-tert-butyl 4-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (1.10 g, 1.781 mmol, quant.) as a light-yellow foam: MS (ESI, pos. ion) m/z: 618 (M+1)

Workup

  1. customwas flushed with argon
  2. additionwas charged with a stir bar
  3. customthe reaction was sealed
  4. customa clear solution resulted
  5. temperatureAfter 3 h the reaction was cooled
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted 3×DCM
  8. dry with materialThe combined organics were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. additionThe material was treated with DCM
  12. custompurified by silica gel chromatography (80 g column)
  13. washeluting with 0-40% EtOAc/hexane
  14. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-fdc4f858a6164768a1049e08e72d5e6a
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

Loading…