Trifluoroacetic acid → HCID 178462171, compound

HRID 1943420Notes

Reaction equation

HRID 1943420 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:62][CH:63]3[CH2:65][CH2:64]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[C:52]([O:54]CC5C=CC=CC=5)[N:51]=[CH:50][N:49]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:82][C@H:83]([CH3:87])[C:84](O)=[O:85])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:82][C@@H:83]([C:84]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:62][CH:63]3[CH2:64][CH2:65]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[N:49]=[CH:50][NH:51][C:52](=[O:54])[CH:53]=4)=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1)=[O:85])[CH3:87]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 637606BOC-D-alanineHCID 178511617HCID 178511617, compound

Product 1

HCID 178462171HCID 178462171, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

BOP (129 mg, 0.292 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (50.0 mg, 0.097 mmol), DIEA (0.068 mL, 0.39 mmol) and (R)-2-(tert-butoxycarbonylamino)propanoic acid (36.8 mg, 0.195 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min and concentrated. TFA (0.450 mL, 5.84 mmol) was added, and the reaction mixture was heated at 70° C. for 1 hr. The reaction mixture was diluted in methanol and purified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% 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, 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(6-oxo-1,6-dihydro-4-pyrimidinyl)imidazo[1,2-b]pyridazine-3-carboxamide, as a white solid (26 mg, 0.053 mmol, 54.0% yield). 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=1.393 (M+H=495.16).). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.56 (1H, br. s.), 11.73 (1H, s), 8.29 (1H, d, J=7.78 Hz), 8.18 (1H, s), 8.06 (3H, d, J=4.27 Hz), 7.90-8.00 (1H, m), 7.61 (1H, s), 7.05 (1H, s), 7.00 (1H, d, J=7.78 Hz), 5.96 (1H, s), 3.68-3.92 (2H, m), 3.46-3.69 (1H, m), 2.10 (2H, d, J=10.54 Hz), 1.82 (2H, d, J=2.51 Hz), 1.43-1.69 (2H, m), 1.16-1.43 (5H, m), 0.69-0.86 (2H, m), 0.51-0.70 (2H, m).

Workup

  1. concentrationconcentrated
  2. temperaturethe reaction mixture was heated at 70° C. for 1 hr
  3. custompurified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% 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-13f89e441ea840c1a3329f2fee87c9fc
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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