Cesium carbonate → HCID 178510026, compound

HRID 1943431Notes

Reaction equation

HRID 1943431 reaction equation
Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C@H:79]1([NH2:86])[CH2:84][CH2:83][C@H:82]([NH2:85])[CH2:81][CH2:80]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:85][C@H:82]1[CH2:83][CH2:84][C@H:79]([NH:86][C:6]2[CH:7]=[C:2]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=3)[C:3]3[N:4]([C:9]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[F:21])=[O:13])=[CH:10][N:11]=3)[N:5]=2)[CH2:80][CH2:81]1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 8182602-Amino-5-cyanopyridineHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 178511674HCID 178511674, compound

Product 1

HCID 178510026HCID 178510026, compoundYield 4%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 1-dram vial equipped with a stir bar and septum cap was charged with dioxane (0.767 mL) and the solvent was degassed by bubbling argon through it with vigorous stirring for 10 min. 5A (0.050 g, 0.153 mmol), 6-aminonicotinonitrile (0.022 g, 0.184 mmol), cesium carbonate (0.100 g, 0.307 mmol), Xantphos (4.44 mg, 7.67 μmol), and Pd2(dba)3 (7.02 mg, 7.67 μmol) were added to the degassed solvent in one portion, and the resulting dark brown suspension was pump/purged with argon three times. The mixture was then heated to 100° C. for 24 h. The suspension was cooled to room temperature and then triturated with water. The resulting olive green suspension, was carefully filtered through a medium-porosity frit. The solid was collected, suspended in THF, and azeotroped with PhMe to remove residual water and MeOH. The crude solid was suspended in NMP (0.767 mL) and (trans)-cyclohexane-1,4-diamine (0.210 g, 1.840 mmol) was added. The resulting brown suspension was irradiated in a CEM Discover 300 W microwave at 110° C. for 20 min. Upon cooling, the mixture was diluted with DMF and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=48.454 min. The appropriate fractions were concentrated and lyophilized overnight, and 6-((trans)-4-aminocyclohexylamino)-8-(5-cyanopyridin-2-ylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.006 g, 6.11 μmol, 3.99% yield) was obtained as a light tan lyophile. HPLC: Rt=3.445 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. MS: [M+H]=487.1. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.16 (1H, s), 10.48 (1H, s), 8.75 (1H, d, J=2.01 Hz), 8.65 (1H, d, J=2.52 Hz), 8.44-8.50 (1H, m), 8.40-8.44 (1H, m), 8.17 (1H, d, J=2.27 Hz), 8.13-8.16 (1H, m), 7.97 (1H, s), 7.81 (2H, s), 7.65 (1H, d, J=8.81 Hz), 7.45 (1H, s), 3.83 (1H, s), 3.07 (1H, s), 2.12 (2H, s), 1.95 (2H, d, J=1.01 Hz), 1.26-1.47 (4H, m).

Workup

  1. customA 1-dram vial equipped with a stir bar
  2. customseptum cap
  3. customthe solvent was degassed
  4. customby bubbling argon through it
  5. customthe resulting dark brown suspension was pump/purged with argon three times
  6. temperatureThe suspension was cooled to room temperature
  7. customtriturated with water
  8. filtrationThe resulting olive green suspension, was carefully filtered through a medium-porosity frit
  9. customThe solid was collected
  10. customazeotroped with PhMe
  11. customto remove residual water and MeOH
  12. customThe resulting brown suspension was irradiated in a CEM Discover 300 W microwave at 110° C. for 20 min
  13. temperatureUpon cooling
  14. custompurified via preparatory HPLC
  15. customB=100, gradient time 60 min, flow rate 25 mL/min
  16. concentrationThe appropriate fractions were concentrated
  17. waitlyophilized overnight

Sources & evidence

ORD record
ord-ee0b0b4bfd0a4bbb8b8405694f39616b
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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