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

HRID 2176698Notes

Reaction equation

HRID 2176698 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[N:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1.Cl.[CH3:35][O:36][C:37]1[CH:46]=[C:45]2[C:40]([C:41]([NH:47][CH2:48][C:49](O)=O)=[CH:42][CH:43]=[N:44]2)=[N:39][CH:38]=1.C(N(CC)CC)C.S(O)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CC#N.C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:49]([CH2:48][NH:47][C:41]3[C:40]4[C:45](=[CH:46][C:37]([O:36][CH3:35])=[CH:38][N:39]=4)[N:44]=[CH:43][CH:42]=3)=[N:33][N:32]=2)[N:31]=1

Participants

9

Reactant 6

HCID 6101p-Toluenesulfonic acidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 1007873-Chloro-6-hydrazinopyridazineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67502849HCID 67502849, compound

Product 1

HCID 44180710N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amineYield 69%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

In a 250 mL round bottom flask under N2 were dissolved HATU (1762 mg, 4635 μmol), 1-(6-chloropyridazin-3-yl)hydrazine (536 mg, 3708 mol), 2-(7-methoxy-1,5-naphthyridin-4-ylamino)acetic acid hydrochloride (1.00 g, 3708 μmol) in 25 mL of MeCN then stirred and cooled down at −40° C. then treated with TRIETHYLAMINE (2584 μl, 18540 μmol) and warmed to rt. After 30 min the reaction mixture based on LC-MS was evaporated under reduced pressure and dry under high vacuum. The crude solid was dissolved in 100 mL of i-PrOH then treated with Ts-OH (2821 mg, 14832 μmol) and heated at 80° C. After 3 h the reaction mixture based on LC-MS was diluted with DCM then neutralized with NaOH (1N). The aqueous phase was extracted 3× with DCM with 10% MeOH then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was triturated with hot i-PrOH then cooled down and filtered (662 mg) and the mother liquor was evaporated under reduced pressure and purified by MPLC (ISCO) (210 mg) with DCM:MeOH 100:0 to 90:10 to afforded in combined yields N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (872 mg, 69% yield) as a off-white solid. MS m/z=342.1 [M+1]+. Calc'd for C15H12ClN7O: 341.7.

Workup

  1. temperaturewarmed to rt
  2. customwas evaporated under reduced pressure
  3. customdry under high vacuum
  4. dissolutionThe crude solid was dissolved in 100 mL of i-PrOH
  5. temperatureheated at 80° C
  6. waitAfter 3 h the reaction mixture based on LC-MS
  7. extractionThe aqueous phase was extracted 3× with DCM with 10% MeOH
  8. dry with materialthe organic layer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude mixture was triturated with hot i-PrOH
  12. temperaturethen cooled down
  13. filtrationfiltered (662 mg)
  14. customthe mother liquor was evaporated under reduced pressure
  15. custompurified by MPLC (ISCO) (210 mg) with DCM:MeOH 100:0 to 90:10
  16. customto afforded

Sources & evidence

ORD record
ord-e5270270a35a48a5a4b6c32151bc846e
Source dataset
uspto-grants-2015_06
Patent number
US09066954B2

Reaction notes

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