Ethanol → HCID 90311833, compound

HRID 716198Notes

Reaction equation

HRID 716198 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9]([F:14])(F)[C:10]([OH:12])=O.[NH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[NH:28][C:29]2[N:33]3[N:34]=[C:35]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=4[F:45])[CH:36]=[CH:37][C:32]3=[CH:31][N:30]=2)[CH2:17]1.F[C:47](F)(F)[C:48](O)=O.F[C:54](F)(F)[C:55](O)=O.F[C:61]1C=CC=C(F)[C:62]=1C1C=CC2N(C(NC3C=NC=CC=3[C@@H]3CCC[C@H](N4C(=O)C5C(=CC=CC=5)C4=O)C3)=NC=2)N=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC1C=CC=C(F)C=1C1C=CC2N(C(NC3C=NC=CC=3[C@H]3CCC[C@@H](N4C(=O)C5C(=CC=CC=5)C4=O)C3)=NC=2)N=1.CN.CCO>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[NH:28][C:29]2[N:33]3[N:34]=[C:35]([C:10]4[C:2]([F:7])=[CH:3][CH:48]=[CH:47][C:9]=4[F:14])[CH:36]=[CH:37][C:32]3=[CH:31][N:30]=2)[CH2:17]1.[NH2:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[NH:28][C:29]2[N:33]3[N:34]=[C:35]([C:10]4[C:2]([F:7])=[CH:3][CH:55]=[CH:54][C:9]=4[F:14])[CH:36]=[CH:37][C:32]3=[CH:31][N:30]=2)[CH2:17]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:44][C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([F:45])[C:38]=1[C:35]1[CH:36]=[CH:37][C:32]2[N:33]([C:29]([NH:28][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[C@@H:18]3[CH2:19][CH2:20][CH2:21][C@H:16]([N:15]4[C:3](=[O:5])[C:2]5[C:9](=[CH:61][CH:62]=[CH:47][CH:48]=5)[C:10]4=[O:12])[CH2:17]3)=[N:30][CH:31]=2)[N:34]=1

Participants

8

Reactant 5

HCID 702EthanolHCID 6329MethylamineHCID 90311329HCID 90311329, compoundHCID 90311733HCID 90311733, compoundHCID 90311833HCID 90311833, compound2×

Product 3

HCID 71007270HCID 71007270, compoundHCID 90311329HCID 90311329, compoundHCID 90311833HCID 90311833, compoundYield 46%

Procedure

N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine bis(2,2,2-trifluoroacetate) and N-(4-((1S,3R)-3-aminocyclohexyl)pyridin-3-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine bis(2,2,2-trifluoroacetate (1/1). A dry, 5 mL microwave pressure vessel was charged with 2-((1R,3S)-3-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)cyclohexyl)-1H-isoindole-1,3(2 H)-dione bis(2,2,2-trifluoroacetate) and 2-((1S,3R)-3-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)cyclohexyl)-1H-isoindole-1,3(2 H)-dione bis(2,2,2-trifluoroacetate) (1/1, 86 mg, 0.06 mmol), a stirbar, EtOH (3 mL) and methylamine (33% wt. solution in absolute EtOH) (0.07 mL, 0.55 mmol). The vessel was crimped with a PTFE-lined seal and placed in a 45° C. heat transfer block for 3 h. The solution was concentrated under a stream of N2 to a volume of 1 mL. The solution was treated with hydrazine, anh. (3.47 μl, 0.11 mmol), and the vessel was crimped with a PTFE line seal. The vessel was placed into a 45° C. heat transfer block for 2 h and was cooled to RT. The solution was concentrated in vacuo. The crude material was purified using prep HPLC method 1 to afford N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)-imidazo[1,5-b]pyridazin-7-amine bis(2,2,2-trifluoroacetate) and N-(4-((1S,3R)-3-aminocyclohexyl)pyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine bis(2,2,2-trifluoroacetate (1/1) (33 mg, 0.03 mmol, 46% yield). MS (ESI, pos. ion) m/z: 421.0 (M+1). 1H NMR (400 MHz, DMF-d6) δ ppm 1.51 (m, J=10.76 Hz, 2 H) 1.62 (q, J=11.70 Hz, 1 H) 1.85 (q, J=12.00 Hz, 1 H) 1.95 (m, J=6.00, 2.90 Hz, 1 H) 2.02 (d, J=9.78 Hz, 1 H) 2.20 (d, J=11.35 Hz, 1 H) 2.43 (d, J=11.93 Hz, 1 H) 3.44 (q, J=10.40 Hz, 2 H) 7.01 (br. s, 2 H) 6.85 (d, J=9.39 Hz, 1 H) 7.36 (t, J=8.31 Hz, 2 H) 7.47 (s, 1 H) 7.65 7.77 (m, 1 H) 7.72 (tt, J=8.40, 6.70 Hz, 1 H) 8.25 (d, J=9.39 Hz, 1 H) 8.42-8.65 (m, 4 H) 9.02 (br. s., 1 H) 9.07 (br. s., 1 H). 19F NMR (376 MHz, DMF-d) δ ppm −113.30 (t, J=7.15 Hz, 2 F) −74.60 (br. s., 9 F). The DMF from the NMR sample was concentrated in vacuo, and the sample was dried in a vacuum oven (60° C., <1 mm Hg) overnight. Approximately 6 mg was analyzed in D2O to check whether the TFA—aromatic fluorine ratio changed. Sample was a bis-TFA salt by 19F NMR. 1H NMR (400 MHz, D2O) δ ppm 1.38-1.59 (m, 3 H) 1.69 (q, J=11.93 Hz, 1 H) 2.00 (d, J=10.56 Hz, 2 H) 2.10 (d, J=11.15 Hz, 1 H) 2.29 (d, J=11.74 Hz, 1 H) 3.20 (t, J=11.44 Hz, 1 H) 3.35 (t, J=11.15 Hz, 1 H) 6.95 (d, J=9.59 Hz, 1 H) 7.12 (t, J=8.41 Hz, 2 H) 7.54 (tt, J=8.60, 6.50 Hz, 1 H) 7.53 (s, 1 H) 7.90 (d, J=6.06 Hz, 1 H) 8.12 (d, J=9.59 Hz, 1 H) 8.29 (s, 1 H) 8.32 (d, J=6.06 Hz, 1 H). 19F NMR (376 MHz, D2O) δ ppm −117.58 (t, J=7.15 Hz, 2 F) −78.50 (s, 6 F).

Workup

  1. customlined seal
  2. customplaced in a 45° C.
  3. temperatureheat transfer block for 3 h
  4. concentrationThe solution was concentrated under a stream of N2 to a volume of 1 mL
  5. additionThe solution was treated with hydrazine, anh. (3.47 μl, 0.11 mmol)
  6. customseal
  7. customwas placed into a 45° C.
  8. temperatureheat transfer block for 2 h
  9. concentrationThe solution was concentrated in vacuo
  10. customThe crude material was purified

Sources & evidence

ORD record
ord-9bf802bf0c76499abdf01e30941375ec
Source dataset
uspto-grants-2015_11
Patent number
US09187486B2

Reaction notes

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