Cyanoacetic acid → HCID 178511194, compound

HRID 1943450Notes

Reaction equation

HRID 1943450 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:55][CH:56]3[CH2:58][CH2:57]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[C:50]([Cl:54])[CH: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:68]([CH2:70][C:71](O)=[O:72])#[N:69]>C(Cl)Cl>[Cl:54][C:50]1[CH:49]=[C:48]([NH:47][C:45]([C:42]2[N:40]3[N:41]=[C:36]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([NH:28][C:71](=[O:72])[CH2:70][C:68]#[N:69])[CH2:34][CH2:33]4)[CH:37]=[C:38]([NH:55][CH:56]4[CH2:57][CH2:58]4)[C:39]3=[N:44][CH:43]=2)=[O:46])[CH:53]=[CH:52][N:51]=1

Participants

6

Reactant 4

HCID 9740Cyanoacetic acidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 178511615HCID 178511615, compound

Product 1

HCID 178511194HCID 178511194, compoundYield 48.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

BOP (60.2 mg, 0.136 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20.00 mg, 0.045 mmol), DIEA (0.032 mL, 0.181 mmol) and 2-cyanoacetic acid (7.72 mg, 0.091 mmol) in DCM (1 mL). The clear reaction mixture was stirred at room temperature for 30 min, concentrated and diluted with MeOH and purified by 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 isolate N-(2-chloropyridin-4-yl)-6-((trans)-4-(2-cyanoacetamido)cyclohexylamino)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (11 mg, 0.022 mmol, 47.7% yield) as 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=1.772 minutes. [M+H]=508.11. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.39 (1H, m), 7.95-8.03 (1H, m), 7.87-7.97 (1H, m), 7.51-7.67 (1H, m), 5.98-6.11 (1H, m), 3.60-3.83 (2H, m), 2.47-2.66 (1H, m), 2.19-2.37 (2H, m), 1.96-2.19 (2H, m), 1.28-1.55 (4H, m), 0.77-0.96 (2H, m), 0.52-0.75 (2H, m).

Workup

  1. concentrationconcentrated
  2. additiondiluted with MeOH
  3. custompurified by 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-2aca4b45007348299413c3e3dfa45308
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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