Potassium Phosphate, Tribasic → (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

HRID 877787Notes

Reaction equation

HRID 877787 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.N[C@H]1[C@@H](CC)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:64][O:65][CH2:66][C:67]([NH:69][CH2:70][C:71]1[N:76]=[CH:75][C:74](B(O)O)=[CH:73][CH:72]=1)=[O:68].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O.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:28]([C:8]1[CH:7]=[N:6][N:5]2[CH:31]=[C:2]([C:74]3[CH:75]=[N:76][C:71]([CH2:70][NH:69][C:67](=[O:68])[CH2:66][O:65][CH3:64])=[CH:72][CH:73]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12]1)(=[O:30])[NH2:29]

Participants

9

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 682911926-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamideHCID 68291194(6-((2-Methoxyacetamido)methyl)pyridin-3-yl)boronic acidHCID 68350332(3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylateHCID 68350390(3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate

Product 1

HCID 68350395(3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 94%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 180 mg (0.370 mmol) of (3S,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (prepared by coupling Intermediate 2 and Intermediate 9 using the method described in Step 1 of Example 52), (6-((2-methoxyacetamido)methyl)pyridin-3-yl)boronic acid (332 mg, 1.480 mmol), potassium phosphate, tribasic, 2M (0.925 mL, 1.850 mmol) and PdCl2(dppf) (54.2 mg, 0.074 mmol) in DMA (2.5 mL) was stirred at 90° C. for 45 minutes. After cooling to rt, the reaction mixture was diluted with ˜40 ml of EtOAc. The resulting dark mixture was filtered through celite and the filtrate was washed with water (40 ml), 10% LiCl solution (2×40 ml) and brine (40 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a brown oil that was chromatographed on a 4 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient, followed by a 0-10% MeOH/CH2Cl2 gradient. The pure fractions were concentrated to afford a brown oil that was triturated with ethyl ether. Filtration and drying afforded (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (203 mg, 0.347 mmol, 94% yield) as a tan solid. The material will be used as is in the next step. MS (ES+) m/z: 586.3 (M+H); LC retention time: 2.388 min (analytical HPLC Method O).

Workup

  1. customprepared
  2. temperatureAfter cooling to rt
  3. filtrationThe resulting dark mixture was filtered through celite
  4. washthe filtrate was washed with water (40 ml), 10% LiCl solution (2×40 ml) and brine (40 ml)
  5. customAfter drying
  6. filtration(MgSO4) and filtration
  7. concentrationthe organic layer was concentrated to a brown oil that
  8. customwas chromatographed on a 4 gm ISCO silica gel cartridge
  9. washeluting with a 0-100% EtOAc/Hex gradient
  10. concentrationThe pure fractions were concentrated
  11. customto afford a brown oil that
  12. customwas triturated with ethyl ether
  13. filtrationFiltration
  14. customdrying

Sources & evidence

ORD record
ord-820d7632fa15439f89d3bef8d3f3dbad
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

Loading…