Cesium carbonate → HCID 178510321, compound

HRID 2239871Notes

Reaction equation

HRID 2239871 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[OH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([O:29][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:31][CH2:32]1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 593140166-Chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carbonitrileHCID 178418329HCID 178418329, compound

Product 1

HCID 178510321HCID 178510321, compoundYield 12.6%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (20 mg, 0.05 mmol) from 1b, tert-butyl(trans)-4-hydroxycyclohexylcarbamate (22 mg, 0.1 mmol), palladium(II) acetate (1.1 mg, 0.005 mmol), 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (7.5, 0.01 mmol) and cesium carbonate (100 mg) was suspended in anhydrous dioxane (1 mL) in a Teflon lined septum capped vial. The vessel was purged with argon and heated at 105° C. for 48 h. LCMS shows that product (m/z, M+1, 569.4) is present (˜25% conversion) along with starting materials. The reaction is cooled and filtered thru a plug of celite and the celite pad rinsed with ˜5 ml of ethyl acetate. The solvents are removed in vacuo and the resulting oil suspended in 1 mL of TFA and heated at 50° C. of 2 h. The reaction showed complete removal of the p-methoxybenzyl protecting group. TFA is removed under a stream of air and the resulting mixture taken up in MeOH (2 mL) and purified by preparative HPLC to yield 2.2 mg of the titled compound as a TFA salt. MS m/e 349 (M+1); 1H NMR (MeOH, δ) 8.1 (1H, s), 7.48 (2H, t, J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 6.21 (1H, s), 5.00 1H, m), 3.21 (1H, m), 2.38 (2H, m), 2.15, 2H, m), 1.62 (4H, m).

Workup

  1. customcapped vial
  2. customThe vessel was purged with argon
  3. temperatureThe reaction is cooled
  4. filtrationfiltered
  5. washthe celite pad rinsed with ˜5 ml of ethyl acetate
  6. customThe solvents are removed in vacuo
  7. temperatureheated at 50° C. of 2 h
  8. customremoval of the p-methoxybenzyl protecting group
  9. customTFA is removed under a stream of air
  10. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-69204d4982394f39aefe9ab4e88cb448
Source dataset
uspto-grants-2010_05
Patent number
US07723336B2

Reaction notes

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