Phosphoric Acid → HCID 68292193, compound

HRID 1507986Notes

Reaction equation

HRID 1507986 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])[CH3:12])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]2[CH:21]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=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]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:16]([C:13]([CH3:15])([CH3:14])[C@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:21]=[C:2]([C:27]3[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:18]([NH2:20])=[O:19])[CH3:12])#[N:17]

Participants

9

Reactant 5

HCID 1004Phosphoric AcidHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 5462222PotassiumHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 68291011HCID 68291011, compound

Product 1

HCID 68292193HCID 68292193, compoundYield 68.5%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
135 °C

Procedure

To a mixture of (R)-6-bromo-4-((3-cyano-3-methylbutan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (160 mg, 0.457 mmol), (6-methoxypyridin-3-yl) boronic acid (105 mg, 0.685 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (21.78 mg, 0.046 mmol), palladium(II) acetate (5.13 mg, 0.023 mmol) and phosphoric acid, potassium salt (291 mg, 1.371 mmol) taken in 1,4-dioxane (2 mL) and water (0.2 mL) in a pressure tube (15 mL). The reaction mixture was degassed using nitrogen and then heated to 135° C. for 45 min. Reaction was monitored by LCMS. Reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layer was dried and concentrated under reduced pressure to get crude as brown colored oil. The crude was purified by combiflash using 24 g silicycle column eluted with 70% ethyl acetate in hexane. The fractions were concentrated under reduced pressure to get (R)-4-((3-cyano-3-methylbutan-2-yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (120 mg, 0.313 mmol, 68.4% yield) as off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.15-11.13 (d, J=9.6 Hz, 1H), 8.71-8.70 (d, J=2.4, 1H), 8.277-8.25 (t, J=8.8 and 1.2, 2H), 8.196-8.168 (dd, J=2.4 and 2.8 Hz, 1H), 7.41-7.40 (bs, 2H), 6.89-6.87 (d, J=8.4 Hz, 1H), 4.63-4.56 (m, 1H), 3.89 (s, 3H), 1.46-1.41 (m, 9H). HPLC purity: Column: Xbridge phenyl (4.6×150 mm, 3.5 μm), Buffer: 0.05% TFA in H2O (pH 2.5, adjusted with dilute ammonia), Solvent A: Buffer: CH3CN (95:5). Solvent B: Buffer: CH3CN (5:95). Time: 0-10, 25-100, 30-100 min, Flow: 1.0 mL/min Retention Time: 11.88: Purity: 98.6%. CHIRAL HPLC purity: Column: CHIRALPAK IC (250×4 6 mm) 5 micron, Mobile Phase: 0.2% DEA in Hexane:Ethanol (70:30). Flow: 1.0 mL/min: Retention Time: 10.138. Purity: 95%. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90). Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.605 min. Purity: 99.14% (m/z=379.2 M+1).

Workup

  1. customThe reaction mixture was degassed
  2. customReaction
  3. customReaction mixture
  4. customwas quenched with water (40 mL)
  5. extractionextracted with ethyl acetate (3×30 mL)
  6. customThe combined organic layer was dried
  7. concentrationconcentrated under reduced pressure
  8. customto get crude as brown colored oil
  9. customThe crude was purified by combiflash
  10. washeluted with 70% ethyl acetate in hexane
  11. concentrationThe fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-bbe9e46a6382477794f84acafb3b7f54
Source dataset
uspto-grants-2015_12
Patent number
US09221826B2

Reaction notes

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