Trifluoroacetic acid → HCID 178522211, compound

HRID 1943417Notes

Reaction equation

HRID 1943417 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N:20]([CH:30]2[CH2:32][CH2:31]2)CC2C=CC(OC)=CC=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.[N:41]([C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)=[C:42]=[O:43].C(O)(C(F)(F)F)=O>O.C(Cl)Cl>[CH:30]1([NH:20][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][N:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:33][C@H:34]3[CH2:39][CH2:38][C@H:37]([NH:40][C:42]([NH:41][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:43])[CH2:36][CH2:35]3)[CH:3]=2)[CH2:31][CH2:32]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 27604933-IsocyanatopyridineHCID 59624448HCID 59624448, compoundHCID 178511674HCID 178511674, compound

Product 1

HCID 178522211HCID 178522211, compoundYield 46%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

6-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.156 mmol) and trans-1,4-diaminocyclohexane (533 mg, 4.67 mmol) were heated together at 160° C. for 1.5 hrs. The reaction mixture was suspended in water, filtered through a Buchner funnel, dried under high vacuum and taken to the next step without further purification. The crude product from the above reaction (40.0 mg, 0.076 mmol) was dissolved in DCM (1 mL) and treated with 3-isocyanatopyridine (9.11 mg, 0.076 mmol). The reaction mixture was stirred at room temperature for 30 minutes, concentrated, and treated with TFA (1.168 mL, 15.16 mmol). The reaction mixture was heated at 70° C. for 1 hr, concentrated and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-6-((trans)-4-(3-pyridin-3-ylureido)cyclohexylamino)-N-(pyrimidin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (18.4 mg, 46%), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.59 (M+H=528.28). 1H NMR (400 MHz, MeOD) δ ppm 9.27 (1H, d, J=2.27 Hz), 9.03 (1H, s), 8.71 (1H, d, J=6.04 Hz), 8.36-8.49 (2H, m), 8.32 (1H, ddd, J=8.69, 2.52, 1.13 Hz), 8.12 (1H, s), 7.95 (1H, dd, J=8.81, 5.54 Hz), 6.11 (1H, s), 3.98 (1H, s), 3.66 (1H, s), 2.60 (1H, ddd, J=6.86, 3.34, 3.15 Hz), 2.22-2.38 (2H, m), 2.08 (2H, d, J=10.58 Hz), 1.73 (2H, dd, J=12.46, 2.64 Hz), 1.31-1.57 (2H, m), 0.80-0.99 (2H, m), 0.55-0.78 (2H, m).

Workup

  1. filtrationfiltered through a Buchner funnel
  2. customdried under high vacuum
  3. customtaken to the next step without further purification
  4. customThe crude product from the above reaction (40.0 mg, 0.076 mmol)
  5. concentrationconcentrated
  6. temperatureThe reaction mixture was heated at 70° C. for 1 hr
  7. concentrationconcentrated
  8. custompurified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA))

Sources & evidence

ORD record
ord-ed23abb6c5da4d77a7a4e928c91f8d3d
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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