Methanesulfonic Acid → 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride

HRID 220125Notes

Reaction equation

HRID 220125 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.C(OC([N:40]1[CH2:45][CH2:44][O:43][C@H:42]([CH2:46][O:47][NH2:48])[CH2:41]1)=O)(C)(C)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[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:48][O:47][CH2:46][C@H:42]4[O:43][CH2:44][CH2:45][NH:40][CH2:41]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

7

Reactant 4

HCID 6395Methanesulfonic Acid2×HCID 516892Sodium BicarbonateHCID 467016214-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazolineHCID 67438159(S)-2-aminooxymethyl-morpholine-4-carboxylic acid tert-butyl ester

Product 1

HCID 866309244-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochlorideYield 225.6%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 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 (VII-4, 786 mg) and 614 mg of (S)-2-aminooxymethyl-morpholine-4-carboxylic acid tert-butyl ester in 31 ml of 1,4-dioxane was added 2.21 ml of 2 mol/L methanesulfonic acid aqueous solution, followed by stirring at 80° C. for 22 hours. And, 1.32 ml of 2 mol/L methanesulfonic acid aqueous solution was additionally added, followed by further stirring for 5.5 hours. After completion of the reaction, the reaction mixture was poured into aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. After an aqueous layer was re-extracted with ethyl acetate, all organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with chloroform:methanol=9:1) to obtain a yellow oil. This oil was dissolved in 50 ml of ethyl acetate, and filtered, and 0.95 ml of 4 mol/L hydrochloric acid-ethyl acetate solution was added with stirring, followed by stirring at room temperature for 1 hour. A precipitate was filtered, and washed with ethyl acetate and hexane in this order. A substance collected by filtration was recrystallized with methanol-ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride (VIII-32, 839 mg) as a yellow crystal.

Workup

  1. stirringby further stirring for 5.5 hours
  2. customAfter completion of the reaction
  3. extractionfollowed by extraction with ethyl acetate
  4. extractionAfter an aqueous layer was re-extracted with ethyl acetate
  5. washwashed with water
  6. dry with materialdried over anhydrous magnesium sulfate
  7. concentrationAfter the filtrate was concentrated
  8. customthe residue was purified by silica gel column chromatography (eluting with chloroform:methanol=9:1)
  9. customto obtain a yellow oil
  10. filtrationfiltered
  11. addition0.95 ml of 4 mol/L hydrochloric acid-ethyl acetate solution was added
  12. stirringwith stirring
  13. stirringby stirring at room temperature for 1 hour
  14. filtrationA precipitate was filtered
  15. washwashed with ethyl acetate and hexane in this order
  16. filtrationA substance collected by filtration
  17. customwas recrystallized with methanol-ethyl acetate

Sources & evidence

ORD record
ord-965e7a6fd32045328f6b86657c82f72d
Source dataset
uspto-grants-2012_06
Patent number
US08202879B2

Reaction notes

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