Nitrogen → HCID 86696358, compound

HRID 870660Notes

Reaction equation

HRID 870660 reaction equation
Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.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>[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[N:7]=[C:8]([N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH3:12])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:22][CH:21]=1

Participants

9

Reactant 5

HCID 947Nitrogen2×HCID 6344DichloromethaneHCID 27343114-Aminomethylphenylboronic acid hydrochlorideHCID 22031701Potassium phosphate, tribasic, monohydrateHCID 86696357HCID 86696357, compound

Product 1

HCID 86696358HCID 86696358, 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 (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-methyl-amine (377.7 mg, 1.3 mmol), 4-aminomethylphenylboronic acid hydrochloride [75705-21-4] (302.4 mg, 1.6 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (612.7 mg, 2.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (110.4 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 (15 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), evaporated and flash chromatographed (silica gel, eluted with 1% NH4OH in 10% (v/v) methanol/ethyl acetate) to isolate a brown solid which was triturated in heptane to precipitate a brown solid. Trituration solvent was then evaporated to provide [3-(4-aminomethyl-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-butyl-methyl-amine as 41.8 mg white solid, mp. 99-101° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (t, J=7.33 Hz, 3H) 1.30-1.42 (m, 2H) 1.47-1.70 (m, 2H) 1.90 (br. s., 1H) 3.10 (s, 3H) 3.51-3.57 (m, 2H) 3.75 (s, 2H) 7.05 (d, J=9.85 Hz, 1H) 7.42 (d, J=8.34 Hz, 2H) 7.85 (d, J=10.11 Hz, 1H) 7.92 (s, 1H) 8.14 (d, J=8.34 Hz, 2H). LRMS (ESI) m/z 310.3 [(M+H)]+, calc'd for C18H23N6: 309.42.

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 (
  9. customThe phase separated
  10. extractionextract
  11. dry with materialwas dried (CaSO4)
  12. customevaporated
  13. customflash chromatographed
  14. wash(silica gel, eluted with 1% NH4OH in 10% (v/v) methanol/ethyl acetate)
  15. customto isolate a brown solid which
  16. customwas triturated in heptane
  17. customto precipitate a brown solid
  18. customTrituration solvent was then evaporated

Sources & evidence

ORD record
ord-ad3d1f5fcee84160b723193bd9189953
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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