Trifluoroacetic acid → HCID 178501622, compound

HRID 1943443Notes

Reaction equation

HRID 1943443 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:35][CH:36]3[CH2:38][CH2:37]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[C:25]([O:27]CC5C=CC=CC=5)[N:24]=[CH:23][N:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:49][C:50]([O:52][CH3:53])=[O:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([NH:35][C:11]2[C:12]3[N:13]([C:15]([C:18](=[O:19])[NH:20][C:21]4[CH:26]=[C:25]([OH:27])[N:24]=[CH:23][N:22]=4)=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:38][CH2:37]1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 60984Methyl bromoacetateHCID 81531DiisopropylethylamineHCID 178511617HCID 178511617, compound

Product 1

HCID 178501622HCID 178501622, compoundYield 38%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
45 °C

Procedure

To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (30.0 mg, 0.058 mmol) in DCM (2 mL) was added DIEA (0.041 mL, 0.234 mmol) and methyl 2-bromoacetate (13.40 mg, 0.088 mmol). The reaction solution was stirred at 45° C. for 14 hrs. The reaction mixture was concentrated and treated with TFA (0.270 mL, 3.50 mmol) at 65° C. for 1 hr. The reaction mixture was concentrated and diluted with MeOH, and purified by 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 obtain methyl 2-((trans)-4-(8-(cyclopropylamino)-3-(6-hydroxypyrimidin-4-ylcarbamoyl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylamino)acetate (11 mg, 0.022 mmol, 38.0% 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=1.295 minutes. [M+H]=496.19. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43-12.79 (1H, m), 11.67 (1H, s), 9.11 (2H, d, J=4.77 Hz), 8.31 (1H, s), 7.96 (1H, s), 7.63 (1H, s), 6.90-7.18 (2H, m), 5.95 (1H, s), 4.14 (2H, t, J=5.65 Hz), 3.80 (3H, s), 3.53-3.79 (1H, m), 2.91-3.21 (1H, m), 2.21 (2H, d, J=10.79 Hz), 2.10 (2H, d, J=11.54 Hz), 1.61 (2H, br. s.), 1.24 (2H, d, J=12.30 Hz), 0.76 (2H, d, J=5.02 Hz), 0.62 (2H, d, J=2.51 Hz).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. concentrationThe reaction mixture was concentrated
  3. additiondiluted with MeOH
  4. custompurified by 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-10ef6abd5d9f4c1f99356305abc2a4f8
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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