Reaktion #306371

Reaktionsgleichung

N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine

tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate

cesium carbonate

→

1,5-naphthyridin-4-amine

Lösungsmittel

dioxane

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigewas sparged with argon for 10 min
2. 2
   SonstigeReaction
3. 3
   Sonstigethen partitioned between 9:1 CHCl3/IPA (50 mL) and 1M NaOH (25 mL)
4. 4
   ExtraktionAqueous further extracted with 9:1 CHCl3/IPA (20 mL)
5. 5
   TrocknenCombined organics then dried over MgSO4
6. 6
   Einengenconcentrated
7. 7
   Sonstigepurified on 40 g silica eluting with 7>8% of 2M NH3 in MeOH/DCM
8. 8
   SonstigeProduct then further purified on prep HPLC
9. 9
   Wascheneluting with water/ACN (0.1% TFA)
10. 10
    workup.STIRRINGBOC intermediate then stirred as a solution in DCM (1 mL)
11. 11
    SonstigeSolvents removed under reduced pressure and residue
12. 12
    workup.DISSOLUTIONdissolved in MeOH (8 mL)
13. 13
    workup.STIRRINGSolution then stirred with Si-Carbonate from Silicycle (1 g/with a labeled loading of 0.77 mmol/g) for 1 h at 23° C
14. 14
    FiltrationSuspension filtered

Vorschrift

A suspension of N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (300 mg, 878 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (419 mg, 1097 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (193 mg, 263 μmol), cesium carbonate (1144 mg, 3511 μmol) in dioxane (6 mL) and water (1 mL) was sparged with argon for 10 min then heated to 100° C. for 20 h with stirring. Reaction then partitioned between 9:1 CHCl3/IPA (50 mL) and 1M NaOH (25 mL). Aqueous further extracted with 9:1 CHCl3/IPA (20 mL). Combined organics then dried over MgSO4, concentrated, and purified on 40 g silica eluting with 7>8% of 2M NH3 in MeOH/DCM. Product then further purified on prep HPLC eluting with water/ACN (0.1% TFA). BOC intermediate then stirred as a solution in DCM (1 mL) and TFA (3 mL) for 30 min. Solvents removed under reduced pressure and residue dissolved in MeOH (8 mL) and DCM (8 mL). Solution then stirred with Si-Carbonate from Silicycle (1 g/with a labeled loading of 0.77 mmol/g) for 1 h at 23° C. Suspension filtered and filtrate reduced to a film under reduced pressure. Product was lyophilized from 1:1 ACN/water (1.5 mL) to provide N-((6-(4-(1-aminoethyl)-3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy)-1,5-naphthyridin-4-amine as an off white fluffy solid. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C23H21ClN8O: 460.

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