Potassium Phosphate, Tribasic → (R)-tert-butyl 4-(3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-ylamino)-3,3-dimethylpiperidine-1-carboxylate

HRID 877731Notes

Reaction equation

HRID 877731 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3([CH3:25])[CH3:24])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CN(C=O)C>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:35]3[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][C:12]1([CH3:25])[CH3:24])(=[O:28])[NH2:27]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2734368(6-Methoxypyridin-3-yl)boronic acidHCID 68291074(R)-tert-butyl 4-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-3,3-dimethylpiperidine-1-carboxylate

Product 1

HCID 68292118(R)-tert-butyl 4-(3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-ylamino)-3,3-dimethylpiperidine-1-carboxylateYield 102.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A stirred DMF (8.0 mL) solution of (R)-tert-butyl 4-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-3,3-dimethylpiperidine-1-carboxylate (1.20 g, 2.57 mmol), 6-methoxypyridin-3-ylboronic acid (0.787 g, 5.15 mmol), potassium phosphate (1.639 g, 7.72 mmol), palladium acetate (0.058 g, 0.257 mmol) and 1,1′-Bis(di-tert-butylphosphino)ferrocene (0.124 g, 0.257 mmol) was degassed by purging with argon for 5 min. The sealed tube was then heated at 90° C. for 1 h then cooled and partitioned between ethyl acetate and water. The layers were separated and the organic portion was washed with water, 10% LiCl (×2), brine and dried over anhyd. magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a tan solid (1.30 g, quantitative). HPLC (Method B) retention time=3.90 min. LCMS (m+1)=495.3. Material contained ˜10% of unreacted bromide starting material but was used without any further purification in next transformation.

Workup

  1. customby purging with argon for 5 min
  2. temperaturethen cooled
  3. custompartitioned between ethyl acetate and water
  4. customThe layers were separated
  5. washthe organic portion was washed with water, 10% LiCl (×2), brine
  6. customdried over anhyd
  7. filtrationmagnesium sulfate, filtered
  8. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-d1e41994a9334d61aabcec02ab754d7c
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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