Cesium carbonate → HCID 86682713, compound

HRID 1755328Notes

Reaction equation

HRID 1755328 reaction equation
Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH:21]12[CH2:26][CH:25]1[CH2:24][N:23]([C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=1)[CH2:22]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH:25]12[CH2:26][CH:21]1[CH2:22][N:23]([C:27]1[N:32]=[C:31]([NH:33][C:2]3[C:3]4[N:4]([CH:18]=[CH:19][N:20]=4)[N:5]=[C:6]([C:8]4[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=4)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=3)[CH:30]=[CH:29][CH:28]=1)[CH2:24]2

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86682703HCID 86682703, compoundHCID 866827126-(3-Aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-amine

Product 1

HCID 86682713HCID 86682713, compoundYield 22%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (250 mg, 0.75 mmol), 6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridin-2-amine (198 mg, 1.13 mmol), Pd2(dba)3 (43 mg, 0.075 mmol), BINAP (187 mg, 0.3 mmol), Cs2CO3 (734 mg, 2.25 mmol) and dioxane (10 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give crude product which was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 30% acetonitrile/70% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give methyl 3-(8-(6-(3-aza-bicyclo[3.1.0]hexan-3-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (70 mg, 22%) as a light yellow solid. [M+H]+, 427.1, tR=1.926 min.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe resulting mixture was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1)
  3. customto give crude product which
  4. customwas further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  5. waitgradient conditions: 30% acetonitrile/70% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min

Sources & evidence

ORD record
ord-1272519005ef4513b82450ed194ba0e4
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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