Trifluoroacetic acid → HCID 90311664, compound

HRID 716201Notes

Reaction equation

HRID 716201 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]3)=[N:16][N:17]=2)[N:14]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[NH2:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:18][C:15]2[N:13]3[N:14]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=[CH:11][C:12]3=[N:17][N:16]=2)[CH2:26]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 131734131HCID 131734131, compound

Product 1

HCID 90311664HCID 90311664, compoundYield 33.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine 2,2,2-trifluoroacetate (Example 67) and (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine 2,2,2-trifluoroacetate (Example 68). A glass microwave reaction vessel was charged with (S)-tert-butyl (1-(3-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (175 mg, 0.39 mmol) and 2,6-difluorophenylzinc bromide (0.5 M in THF, 2.36 mL, 1.18 mmol, Rieke Metals, Inc.) followed by A-Phos (14 mg, 0.020 mmol, Sigma-Aldrich). The reaction mixture was stirred and heated at 90° C. for 2 h. The mixture was cooled to RT and quenched with EDTA solution (pH 7.4) and extracted with CHCl3/i-PrOH (4/1). The combined organic layers were dried over MgSO4, filtered and concentrated to give (S)-tert-butyl (1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (206 mg), which was used in the next reaction without further purification. A mixture of (S)-tert-butyl (1-(3-((6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)pyridin-4-yl)piperidin-3-yl)carbamate (206 mg, 0.39 mmol) and TFA (0.2 mL, 2.69 mmol) in DCM (1 mL) was stirred for 15 min at RT. The mixture was concentrated and the residue was purified with prep HPLC (5-30% MeCN in water with 0.1% TFA for 30 min) using Phenomenex Gemini C18 column (100×50 mm, 10 μm) at 90 mL/min. with UV detection at 254 nm to give (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine 2,2,2-trifluoroacetate (70 mg, 0.13 mmol, 33% yield, Example 67) as a yellow solid. MS (ESI, pos. ion) m/z: 422.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1 H, br. s.), 8.84 (1 H, s), 8.45 (1 H, d, J=9.6 Hz), 8.39 (1 H, d, J=6.5 Hz), 8.02 (3 H, br. s.), 7.67-7.77 (1 H, m), 7.53 (1 H, d, J=9.8 Hz), 7.33-7.44 (3 H, m), 3.82 (1 H, d, J=12.5 Hz), 3.30-3.38 (3 H, m), 3.21 (1 H, dd, J=11.8, 6.9 Hz), 1.93 (1 H, dd, J=8.2, 4.1 Hz), 1.73-1.85 (1 H, m), 1.61-1.71 (1 H, m), 1.41-1.53 (1 H, m). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.04, −113.49; and (S)-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-amine 2,2,2-trifluoroacetate (27 mg, 0.09 mmol, Example 68) as a light yellow solid. MS (ESI, pos. ion) m/z: 311.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (1 H, s), 8.36 (1 H, d, J=6.5 Hz), 8.09 (3 H, br. s.), 7.43 (1 H, d, J=6.5 Hz), 7.24 (1 H, d, J=11.7 Hz), 5.92-6.13 (1 H, m), 3.76 (1 H, d, J=12.5 Hz), 3.43-3.59 (1 H, m), 2.99-3.30 (3 H, m), 1.88-2.04 (2 H, m), 1.54-1.78 (2 H, m).

Workup

  1. customwas used in the next reaction without further purification
  2. concentrationThe mixture was concentrated
  3. customthe residue was purified with prep HPLC (5-30% MeCN in water with 0.1% TFA for 30 min)

Sources & evidence

ORD record
ord-ff2dd7b70b0b4c8dbc305b404d1b3ea6
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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