Nitrogen → 4-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 870736Notes

Reaction equation

HRID 870736 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1B(O)O.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.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].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:32]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[O:26][CH3:25])=[CH:21][N:22]=3)[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 467390183-Methoxypyridine-4-boronic acid hydrateHCID 686481214-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 866964454-[3-(3-Methoxy-pyridin-4-yl)-imidazo[1,2-b]pyridazin-6-yl]-piperazine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a mixture of 4-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (524.4 mg, 1.4 mmol), 3-methoxypyridine-4-boronic acid hydrate [1072952-50-1] (253.1 mg, 1.7 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (632.2 mg, 2.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (117.6 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (25 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (CaSO4) and evaporated to afford a brown oil which was purified by preparative RP-HPLC to obtain a white powder, mp. 205-206° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 3.46-3.55 (m, 8H) 4.02 (s, 3H) 7.30 (d, J=10.10 Hz, 1H) 8.00 (d, J=9.85 Hz, 1H) 8.13 (s, 1H) 8.35 (d, J=5.05 Hz, 1H) 8.41 (d, J=5.05 Hz, 1H) 8.51 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 28.04, 45.53, 56.33, 79.10, 111.13, 120.39, 120.75, 124.25, 126.24, 134.48, 135.69, 137.20, 142.26, 151.08, 153.85, 154.60. LRMS (ESI) m/z 411.3 [(M+H)]+, calc'd for C21H26N6O3: 410.48.

Workup

  1. customcontained in a 50 mL round bottomed flask
  2. customThe reaction
  3. custompot was fitted to a reflux condenser
  4. customlowered into an ambient temperature
  5. stirringThe rapidly stirred
  6. customreaction
  7. temperaturethen cooled
  8. custompartitioned between brine (
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (CaSO4)
  12. customevaporated
  13. customto afford a brown oil which
  14. customwas purified by preparative RP-HPLC
  15. customto obtain a white powder, mp. 205-206° C. (dec.)

Sources & evidence

ORD record
ord-e91d595658284061a3aec645aa12802a
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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