Nitrogen → HCID 86696416, compound

HRID 870714Notes

Reaction equation

HRID 870714 reaction equation
[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21](Br)=[CH:22][N:23]=2)[N:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])[NH2:27].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>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:32]3[CH:33]=[CH:34][C:29]([C:26](=[O:28])[NH2:27])=[CH:30][CH:31]=3)=[CH:22][N:23]=2)[N:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2]

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 27378114-Aminocarbonylphenylboronic acidHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 86696415HCID 86696415, compound

Product 1

HCID 86696416HCID 86696416, compound

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 [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-phenyl-carbamic acid ethyl ester (354.7 mg, 0.9 mmol), (4-carbamoylphenyl)boronic acid [123088-59-5] (174.2 mg, 1.1 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (368.8 mg, 1.6 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (74.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (13 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 and ethyl acetate. The phase separated extract was dried (MgSO4), evaporated, flash chromatographed (silica gel eluted with 10% (v/v) methanol/ethyl acetate) and further purified by preparative RP-HPLC to provide {2-[3-(4-carbamoyl-phenyl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-phenyl-carbamic acid ethyl ester as a white powder, mp. 227-228° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 2H) 2.51 (dt, J=3.73, 1.80 Hz, 2H) 3.31 (s, 1H) 3.48 (q, J=6.23 Hz, 2H) 3.91-4.04 (m, 3H) 6.69 (d, J=9.85 Hz, 1H) 7.18-7.35 (m, 5H) 7.76 (d, J=9.85 Hz, 1H) 7.91-8.01 (m, 3H) 8.21 (d, J=8.59 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.25, 48.18, 60.95, 112.37, 124.91, 125.75, 126.00, 126.35, 127.18, 127.79, 128.77, 130.81, 131.93, 132.15, 137.57, 141.78, 153.40, 154.85, 167.49. LRMS (ESI) m/z 445.1 [(M+H)]+, calc'd for C24H24N6O3: 444.50.

Workup

  1. customcontained in a 25 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 and ethyl acetate
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (MgSO4)
  12. customevaporated
  13. customflash chromatographed
  14. wash(silica gel eluted with 10% (v/v) methanol/ethyl acetate)
  15. customfurther purified by preparative RP-HPLC

Sources & evidence

ORD record
ord-12ee8bba6ce74d44902b4c49ffb40ef4
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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