Potassium Phosphate, Tribasic → (+/-)-(cis)-Benzyl 3-(3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylpyrrolidine-1-carboxylate

HRID 877729Notes

Reaction equation

HRID 877729 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12]3)=[C:8]([C:27](=[O:29])[NH2:28])[CH:7]=[N:6][N:5]2[CH:30]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([C:8]1[CH:7]=[N:6][N:5]2[CH:30]=[C:2]([C:36]3[CH:37]=[N:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:12]1)(=[O:29])[NH2:28]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 68350361(3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate

Product 1

HCID 68350364(+/-)-(cis)-Benzyl 3-(3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylpyrrolidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of (+/−)-(cis)-benzyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-4-methylpyrrolidine-1-carboxylate (0.40 g, 0.847 mmol), (6-methoxypyridin-3-yl)boronic acid (0.168 g, 1.10 mmol), palladium acetate (9.51 mg, 0.042 mmol) and 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.040 g, 0.085 mmol) in dioxane (3.0 mL) was degassed by purging with argon for 3 min. Aqueous potassium phosphate (2.0 M) (1.27 mL, 2.54 mmol) was added and purging with argon was continued for 2 min. The reaction vial was sealed and heated at 95° C. for 3 h then the resulting mixture was cooled and concentrated to remove dioxane and the residue was taken up in EtOAc (300 mL). The resulting solution was washed with water, brine and dried over MgSO4, filtered and concentrated to afford a yellow solid as the crude product mixture. This material was purified by preparative chromatography using CH2Cl2/MeOH mixtures as the eluant and a 40 g silica cartridge. Fractions containing the major product were combined and concentrated to afford a bright yellow solid as the title compound. HPLC (method B) retntion time=3.65 min. LCMS (m+1)=501.3.

Workup

  1. customwas degassed
  2. customby purging with argon for 3 min
  3. custompurging with argon
  4. customThe reaction
  5. customvial was sealed
  6. temperaturethe resulting mixture was cooled
  7. concentrationconcentrated
  8. customto remove dioxane
  9. washThe resulting solution was washed with water, brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customto afford a yellow solid as the crude product mixture
  14. customThis material was purified by preparative chromatography
  15. additionFractions containing the major product
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-0da3d084739b43e0afe2ff68d3884fad
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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