Trifluoroacetic acid → HCID 178457956, compound

HRID 1943410Notes

Reaction equation

HRID 1943410 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4C=C[N:24]=[CH:23][C:22]=4F)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[N:41]([CH:44]([CH3:46])[CH3:45])=[C:42]=[O:43].[C:47](O)([C:49]([F:52])(F)F)=O>C(Cl)Cl>[CH:38]1([NH:28][C:11]2[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:47][C:49]=4[F:52])=[O:19])=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][C:42](=[O:43])[NH:41][CH:44]([CH3:46])[CH3:45])[CH2:3][CH2:4]3)[CH:10]=2)[CH2:39][CH2:40]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 61277Isopropyl isocyanateHCID 178490952HCID 178490952, compound

Product 1

HCID 178457956HCID 178457956, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (40.0 mg, 0.073 mmol) in CH2Cl2 (1 mL) was added 2-isocyanatopropane (0.0072 mL, 0.073 mmol). The reaction solution was stirred at room temperature for 30 min. The reaction mixture was concentrated and treated with TFA (1.132 mL, 14.69 mmol) at 70° C. for 1 hr. The reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% 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 obtain the title compound, 8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)-6-((trans-4-((isopropylcarbamoyl)amino)cyclohexyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (16.9 mg, 45.2%). 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=1.73 (M+H=510.32). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.38 (1H, s), 8.68 (1H, d, J=2.75 Hz), 8.51 (1H, t, J=6.05 Hz), 8.44 (1H, d, J=5.50 Hz), 8.01 (1H, s), 7.59 (1H, s), 6.92 (1H, br. s.), 5.99 (1H, s), 5.61 (2H, br. s.), 3.79 (2H, br. s.), 3.52-3.74 (2H, m), 2.00 (2H, d, J=9.90 Hz), 1.83 (2H, d, J=10.45 Hz), 1.12-1.41 (4H, m), 1.02 (6H, d, J=6.60 Hz), 0.71-0.83 (2H, m), 0.54-0.69 (2H, m).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customThe reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% 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-b6232ef0240247998a45371749143de6
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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