Methanesulfonic Acid → 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline

HRID 1969342Notes

Reaction equation

HRID 1969342 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[O:33]([CH2:35][C@H:36]1[O:41][CH2:40][CH2:39][N:38](C([O-])=O)[CH2:37]1)[NH2:34].CS(O)(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:34][O:33][CH2:35][C@H:36]4[O:41][CH2:40][CH2:39][NH:38][CH2:37]4)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1

Participants

5

Reactant 3

HCID 6395Methanesulfonic Acid2×HCID 467016214-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazolineHCID 131730518(S)-2-aminoxymethyl-morpholine-4-carboxylate

Product 1

HCID 866309254-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (IV) (786 mg) and tert-buthyl (S)-2-aminoxymethyl-morpholine-4-carboxylate (614 mg) in 1,4-dioxane (31 mL) was added 2 mol/L methanesulfonic acid aq. solution (2.21 mL) and stirred for 22 hr at 80° C. 2 mol/L methanesulfonic acid aq. solution (1.32 mL) was added and stirred for additional 5.5 hr. After the reaction was completed, the mixture was poured into ice-sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. After the aqueous layer was extracted again with ethylacetate, all the organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1) to give yellow oil. A solution of this oil in ethyl acetate (50 mL) was filtered and 4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added under stirring and stirred for 1 hr at room temperature. The precipitate was filtered and washed with ethyl acetate and then hexane. The precipitate was recrystallized from methanol-ethyl acetate to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline.2HCl (VI-1) (839 mg) as yellow crystalline.

Workup

  1. stirringstirred for additional 5.5 hr
  2. extractionextracted with ethyl acetate
  3. extractionAfter the aqueous layer was extracted again with ethylacetate, all the organic layers
  4. washwashed with water
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationThe filtrate was concentrated
  7. customthe residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1)
  8. customto give yellow oil
  9. filtrationA solution of this oil in ethyl acetate (50 mL) was filtered
  10. addition4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added
  11. stirringunder stirring
  12. stirringstirred for 1 hr at room temperature
  13. filtrationThe precipitate was filtered
  14. washwashed with ethyl acetate
  15. customThe precipitate was recrystallized from methanol-ethyl acetate

Sources & evidence

ORD record
ord-1ae816b1838b41349ba20302847e658c
Source dataset
uspto-grants-2013_04
Patent number
US08426589B2

Reaction notes

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