Tetrahydrofuran → HCID 178426341, compound

HRID 1943452Notes

Reaction equation

HRID 1943452 reaction equation
Br[C:2]1[C:3]2[N:4]([C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:12]=2)[N:5]=[C:6](Cl)[C:7]=1[CH3:8].ClC1C(C)=[C:25](Cl)[C:26]2[N:27](C(C(NC3C=CN=CC=3)=O)=CN=2)N=1.[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([NH2:50])=[N:48][CH:49]=1.C[Si]([NH-])(C)C.C[Si]([NH-:60])(C)C.[Li+].[Li+].[CH2:63]1[CH2:67]O[CH2:65][CH2:64]1>ClCCl.O>[NH2:60][C@H:63]1[CH2:67][CH2:25][C@H:26]([NH:27][C:6]2[C:7]([CH3:8])=[C:2]([NH:50][C:47]3[CH:46]=[CH:45][C:44]([CH3:43])=[CH:49][N:48]=3)[C:3]3[N:4]([C:10]([C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[O:14])=[CH:11][N:12]=3)[N:5]=2)[CH2:65][CH2:64]1

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 153482-Amino-5-methylpyridineHCID 59624525HCID 59624525, compoundHCID 59624841HCID 59624841, compoundHCID 86588160Lithim bis(trimethylsilylamide)

Product 1

HCID 178426341HCID 178426341, compoundYield 2.32%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

A vial charged with a mixture of 8-bromo-6-chloro-7-methyl-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 6,8-dichloro-7-methyl-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 35E (0.108 g, 0.295 mmol) and 5-methylpyridin-2-amine (0.032 g, 0.295 mmol) was purged with nitrogen. THF (1 mL) and lithium bis(trimethylsilylamide) (0.88 mL, 0.88 mmol, 1M in THF) were added and the mixture was stirred at room temperature and monitored by LC/MS. After 5 h the mixture was concentrated to dryness under a stream of N2. Trans-cyclohexyldiamine (0.168 g, 1.47 mmol) was added to the resulting residue and the mixture was heated at 160° C. After 30 min, 1.5 mL water and 1.5 mL dichloromethane are added to the vial and the vial was shaken until all solids dissolve. The dichloromethane layer was drawn off with a pipette and concentrated to dryness. The resulting residue was dissolved in 2 mL methanol and 2 mL Solvent B (90% MeOH, 10% water, 0.1% TFA). 1 drop of TFA was added to the solution, the sample was split into 3 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 10-60% solvent B gradient, 20 mL/min, 220 nM UV detection to provide 6-((trans)-4-aminocyclohexylamino)-7-methyl-8-(5-methylpyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0063 g, 6.83 μmol, 2.320% yield). 1H NMR (500 MHz, MeOH-D4) δ ppm 8.65 (2H, d, J=7.15 Hz), 8.21 (2H, d, J=7.15 Hz), 8.08 (1H, s), 7.89-7.91 (1H, m), 7.72 (1H, s), 7.13 (1H, d, J=8.80 Hz), 3.95-4.01 (1H, m), 3.08 (1H, m), 2.27 (2H, m), 2.22 (3H, s), 2.19 (3H, s), 2.69 (2H, m), 1.47-1.54 (4H, m). LC/MS: HPLC Retention time: 1.17 min, MS: 472 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)

Workup

  1. customwas purged with nitrogen
  2. concentrationAfter 5 h the mixture was concentrated to dryness under a stream of N2
  3. temperaturethe mixture was heated at 160° C
  4. stirringwas shaken until all solids
  5. dissolutiondissolve
  6. concentrationconcentrated to dryness
  7. dissolutionThe resulting residue was dissolved in 2 mL methanol
  8. addition1 drop of TFA was added to the solution
  9. customthe sample was split into 3 equal volumes
  10. custompurified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 10-60% solvent B gradient, 20 mL/min, 220 nM UV detection

Sources & evidence

ORD record
ord-b318fdc463b040f68e8e918a8e92347f
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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