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

HRID 877779Notes

Reaction equation

HRID 877779 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.[O:64]=[C:65]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67](=[O:74])[N:66]1[CH2:75][C:76]1[N:81]=[CH:80][C:79](B(O)O)=[CH:78][CH:77]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)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:79]3[CH:80]=[N:81][C:76]([CH2:75][N:66]4[C:65](=[O:64])[C:73]5[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=5)[C:67]4=[O:74])=[CH:77][CH:78]=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:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12]1)(=[O:30])[NH2:29]

Participants

8

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 682911926-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamideHCID 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-carboxylateHCID 68350505(6-((1,3-Dioxoisoindolin-2-yl)methyl)pyridin-3-yl)boronic acid

Product 1

HCID 68350391(3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylateYield 44.7%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
90 °C

Procedure

A mixture of 100 mg (0.206 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-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)boronic acid (174 mg, 0.617 mmol), potassium phosphate, tribasic, 2M (0.514 mL, 1.028 mmol) and PdCl2(dppf) (30.1 mg, 0.041 mmol) in DMA (2 mL) was stirred at 90° C. for 1 hr. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was washed with 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a brown oil that was chromatographed on a 40 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-benzyl 3-((3-carbamoyl-6-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (59 mg, 0.092 mmol, 44.6% yield) as a tan solid. The material was used as is in the next step. MS (ES+) m/z: 644.3 (M+H); LC retention time: 2.916 min (analytical HPLC Method O).

Workup

  1. customprepared
  2. temperatureAfter cooling to rt
  3. filtrationthe reaction mixture was filtered through celite
  4. customthe filtrate was partitioned between EtOAc (30 ml) and water (30 ml)
  5. washThe organic layer was washed with 10% LiCl solution (2×30 ml) and brine (30 ml)
  6. customAfter drying
  7. filtration(MgSO4) and filtration
  8. concentrationthe organic layer was concentrated to a brown oil that
  9. customwas chromatographed on a 40 gm ISCO silica gel cartridge
  10. washeluting with a 0-100% EtOAc/Hex gradient
  11. concentrationThe pure fractions were concentrated

Sources & evidence

ORD record
ord-814f456ad2034dbab253f301e2efa168
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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