Cesium carbonate → 1,5-Naphthyridin-4-amine

HRID 40294Notes

Reaction equation

HRID 40294 reaction equation
ClC1C=CC2N(C(C[NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19](OC)=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=NN=2)N=1.ClC1C=C(B2OC(C)(C)C(C)(C)O2)C=CC=1C(NC(=O)OC(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N:16]1[C:17]2[C:22](=[N:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH2:12])=[CH:14][CH:15]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 44180710N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amineHCID 57691125Tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate

Product 1

HCID 5893541,5-Naphthyridin-4-amine

Reagents, catalysts & solvents 3

HCID 53485975CID 53485975CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

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.

Workup

  1. customwas sparged with argon for 10 min
  2. customReaction
  3. customthen partitioned between 9:1 CHCl3/IPA (50 mL) and 1M NaOH (25 mL)
  4. extractionAqueous further extracted with 9:1 CHCl3/IPA (20 mL)
  5. dry with materialCombined organics then dried over MgSO4
  6. concentrationconcentrated
  7. custompurified on 40 g silica eluting with 7>8% of 2M NH3 in MeOH/DCM
  8. customProduct then further purified on prep HPLC
  9. washeluting with water/ACN (0.1% TFA)
  10. stirringBOC intermediate then stirred as a solution in DCM (1 mL)
  11. customSolvents removed under reduced pressure and residue
  12. dissolutiondissolved in MeOH (8 mL)
  13. 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. filtrationSuspension filtered

Sources & evidence

ORD record
ord-f03b605b3b3440c3bec796771704dd59
Source dataset
uspto-grants-2013_09
Patent number
US08524900B2

Reaction notes

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