Potassium Phosphate, Tribasic → HCID 68358692, compound

HRID 1408981Notes

Reaction equation

HRID 1408981 reaction equation
[C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:18]([NH:19][C@@H:20]3[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:25])[C:21]3([CH3:36])[CH3:35])=[C:17]([C:37](=[O:39])[NH2:38])[CH:16]=[N:15][N:14]2[CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.CO.C(Cl)Cl.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(Cl)Cl>[C:37]([C:17]1[CH:16]=[N:15][N:14]2[CH:40]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:13]2[C:18]=1[NH:19][C@H:20]1[CH2:24][CH2:23][C@@:22]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:25])[C:21]1([CH3:36])[CH3:35])(=[O:39])[NH2:38]

Participants

8

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 68358691HCID 68358691, compound

Product 1

HCID 68358692HCID 68358692, compoundYield 82%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
100 °C

Procedure

To a vial charged with a solution of phenylboronic acid (215 mg, 1.760 mmol), PdCl2(dppf)-CH2Cl2 adduct (47.9 mg, 0.059 mmol) and tert-butyl (((1S,3R)-3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (290 mg, 0.587 mmol) in 1,4-dioxane (3.91 ml) was added a 2 M aqueous solution of potassium phosphate (880 μl, 1.760 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction was diluted with methanol (10 ml), filtered, and concentrated, yielding a dark oil. The oil was taken up in ethyl acetate (50 ml). The solution was washed successively with water and brine. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a dark oil. The oil was dissolved in 10% methanol-DCM (5 ml). The crude product mixture was loaded directly on a prepacked silica gel column. The crude product was purified via medium pressure chromatography (0-10% methanol-DCM solvent system over 25 minutes). The desired tert-butyl (((1S,3S)-3-((3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethyl-cyclopentyl)methyl)carbamate (236 mg, 0.480 mmol, 82% yield) was obtained as a white solid. ESI-MS m/z 492.4 ([M+H]+).

Workup

  1. customThe suspension was purged with nitrogen for 5 minutes
  2. customThe vial was sealed
  3. additionThe reaction was diluted with methanol (10 ml)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customyielding a dark oil
  7. washThe solution was washed successively with water and brine
  8. extractionThe ethyl acetate extract
  9. dry with materialwas dried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customyielding a dark oil
  13. customThe crude product was purified via medium pressure chromatography (0-10% methanol-DCM solvent system over 25 minutes)

Sources & evidence

ORD record
ord-0647df9e0cd5461ab2d15c84845c61a6
Source dataset
uspto-grants-2014_12
Patent number
US08921368B2

Reaction notes

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