Trifluoroacetic acid → HCID 178522300, compound

HRID 1943449Notes

Reaction equation

HRID 1943449 reaction equation
C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24]2[CH:25]=[C:26]([N:43]([CH:53]3[CH2:55][CH2:54]3)CC3C=CC(OC)=CC=3)[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH2:19][CH2:18]1.[N:56]1([C:62](OC(C)(C)C)=[O:63])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1.C(O)(C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH:53]1([NH:43][C:26]2[C:27]3[N:28]([C:30]([C:33]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][C:37]=4[F:42])=[O:34])=[CH:31][N:32]=3)[N:29]=[C:24]([NH:23][C@H:20]3[CH2:21][CH2:22][C@H:17]([NH:16][C:62]([N:56]4[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)=[O:63])[CH2:18][CH2:19]3)[CH:25]=2)[CH2:54][CH2:55]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 90495Di-tert-butyl dicarbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 178490952HCID 178490952, compound

Product 1

HCID 178522300HCID 178522300, compoundYield 59.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To di-tert-butyl dicarbonate (10.66 μL, 0.046 mmol) in dichloromethane (1 mL) was added DMAP (2.80 mg, 0.023 mmol) followed by 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.046 mmol, 83A). The clear yellow solution was stirred at room temperature for 10 minutes then tert-butyl piperazine-1-carboxylate (8.55 mg, 0.046 mmol) was added, and stirred at room temperature for 1 hr. TFA (0.5 mL) was added, and after 10 minutes, the reaction mixture was concentrated to dryness, taken up in DMSO and methanol and purified using reverse phase HPLC to isolate 8-(cyclopropylamino)-N-(3-fluoropyridin-4-yl)-6-((trans)-4-(piperazine-1-carboxamido)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (22 mg, 0.027 mmol, 59.5% yield) 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=1.39 minutes [M+H]=537.37. 1H NMR (500 MHz, METHANOL-d3) δ ppm 8.90 (1H, t, J=6.64 Hz), 8.76 (1H, d, J=3.67 Hz), 8.50 (1H, d, J=5.96 Hz), 8.05-8.22 (1H, m), 6.11 (1H, s), 3.84-4.03 (1H, m), 3.61-3.72 (4H, m), 3.58 (1H, t, J=10.77 Hz), 3.14-3.27 (4H, m), 2.51-2.62 (1H, m, J=6.76, 6.76, 3.67, 3.44 Hz), 2.19 (2H, d, J=12.37 Hz), 1.98 (2H, d, J=13.29 Hz), 1.21-1.69 (4H, m), 0.84-1.05 (2H, m), 0.51-0.71 (2H, m)

Workup

  1. stirringstirred at room temperature for 1 hr
  2. waitafter 10 minutes
  3. concentrationthe reaction mixture was concentrated to dryness
  4. custommethanol and purified

Sources & evidence

ORD record
ord-ab4e0ef60bbf412184034fff6ec15915
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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