4-Methylthiazole → N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine

HRID 911147Notes

Reaction equation

HRID 911147 reaction equation
[Li]CCCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[C:36]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([NH:43][CH3:44])[N:38]=4)=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:26][CH:25]=2)=[N:15][N:14]=1>C1COCC1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])(O)=O.[Na+].[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:44][NH:43][C:39]1[N:38]=[C:37]([C:36]2[C:31]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:16]4[C:17]5[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:13]([C:9]5[S:10][CH:11]=[C:7]([CH3:6])[N:8]=5)=[N:14][N:15]=4)=[CH:29][CH:28]=3)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:42]=[CH:41][N:40]=1

Participants

8

Reactant 3

HCID 127484-MethylthiazoleHCID 426043304-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amineHCID 178418339Butyllithium

Product 1

HCID 57756238N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent3×HCID 86614166EDTA NaHCO3Solvent

Conditions

Temperature
-78 °C

Procedure

A dry 25 ml round bottom flask under nitrogen was charged with 2.5 M nBuLi in Hexanes (0.420 ml, 1.06 mmol); which was diluted with THF (1 ml). This was cooled to −78° C. and 4-methylthiazole (100 mg, 1.01 mmol) dissolved in 2 ml of THF was added slowly via syringe. This was stirred at −78° C. for 2 hours, slowly warmed up to −10° C. and stirred at this temperature for 0.5 hour. Reaction cooled back to −78° C. and 0.5M zinc(II) chloride in THF (3.03 ml, 1.51 mmol) added via syringe. Reaction stirred at −78° C. for 0.5 hour then at room temperature for 1 hour. At this time, 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (115 mg, 0.250 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) added and reaction stirred under nitrogen at 65° C. for 48 hours. Reaction stopped, cooled to room temperature, diluted with aq. EDTA/NaHCO3 solution. This was extracted with ethyl acetate. Organic portion was dried with Na2SO4, filtered, and concentrated to give light brown residue. This was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of Aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, concentrated to afford pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine as a yellow solid. MS m/z=519 [M+H]+. Calc'd for C28H22N8OS: 518.59.

Workup

  1. additionwas added slowly via syringe
  2. temperatureslowly warmed up to −10° C.
  3. stirringstirred at this temperature for 0.5 hour
  4. customReaction
  5. temperaturecooled back to −78° C.
  6. customReaction
  7. stirringstirred at −78° C. for 0.5 hour
  8. waitat room temperature for 1 hour
  9. customreaction
  10. stirringstirred under nitrogen at 65° C. for 48 hours
  11. customReaction
  12. temperaturecooled to room temperature
  13. extractionThis was extracted with ethyl acetate
  14. dry with materialOrganic portion was dried with Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customto give light brown residue
  18. customThis was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA)
  19. additionbasified by addition of Aq. NaHCO3
  20. extractionextracted with ethyl acetate
  21. dry with materialThe organic portion was dried with Na2SO4
  22. filtrationfiltered
  23. concentrationconcentrated

Sources & evidence

ORD record
ord-96906cdc94a14f51abbcbb0f15a93d2b
Source dataset
uspto-grants-2011_09
Patent number
US08022221B2

Reaction notes

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