Trifluoroacetic acid → N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide

HRID 1943507Notes

Reaction equation

HRID 1943507 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([N:20]([CH:30]4[CH2:32][CH2:31]4)CC4C=CC(OC)=CC=4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:18]=[C:19]([NH:20][CH:30]4[CH2:32][CH2:31]4)[C:14]3=[N:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 2

HCID 6422Trifluoroacetic acidHCID 59624640N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide

Product 1

HCID 59624377N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamideYield 44.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 0.013 mmol) in DCM (1 mL) was treated with TFA (0.5 mL, 6.49 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=35.169 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.5 mg, 35.9%). 1H NMR 400 MHz, DMSO-D6) δ ppm 11.40 (1H, s), 8.38 (1H, d, J=5.54 Hz), 7.97 (1H, s), 7.75 (1H, s), 7.70 (1H, d, J=5.79 Hz), 7.65 (1H, s), 7.10 (1H, d, J=6.55 Hz), 6.00 (1H, s), 3.85-4.06 (3H, m), 1.93-2.08 (2H, m), 1.43-1.61 (2H, m), 0.71-0.81 (2H, m, J=5.54 Hz), 0.57-0.68 (2H, m). HPLC Rt=4.160 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=428.0.

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. customThe crude reaction product
  3. custompurified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm)
  4. customThe product (retention time=35.169 minutes) was isolated

Sources & evidence

ORD record
ord-c178f481ac00404d963c72a4f1dba6e3
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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