Methyl Isobutyl Ketone → HCID 136121425, compound

HRID 2062356Notes

Reaction equation

HRID 2062356 reaction equation
N1CC[C@@H](CN)C1.C([O-])([O-])=O.[Na+].[Na+].C(C(C)=O)C(C)C.ClC1C2C(=CC(C)=CC=2)N=C(C2C(F)=CC=CC=2O)N=1.CC(C)C/C(=[N:46]/[CH2:47][C@@H:48]1[CH2:52][CH2:51][N:50]([C:53]2[C:62]3[C:57](=[CH:58][C:59]([CH3:63])=[CH:60][CH:61]=3)[N:56]=[C:55]([C:64]3[C:69]([F:70])=[CH:68][CH:67]=[CH:66][C:65]=3[OH:71])[N:54]=2)[CH2:49]1)/C>O.C(O)(C)C>[NH2:46][CH2:47][C@@H:48]1[CH2:52][CH2:51][N:50]([C:53]2[C:62]3[C:57](=[CH:58][C:59]([CH3:63])=[CH:60][CH:61]=3)[N:56]=[C:55]([C:64]3[C:69]([F:70])=[CH:68][CH:67]=[CH:66][C:65]=3[OH:71])[N:54]=2)[CH2:49]1

Participants

7

Reactant 5

HCID 7909Methyl Isobutyl KetoneHCID 10340Sodium CarbonateHCID 1519367HCID 1519367, compoundHCID 1361213752-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenolHCID 178444801HCID 178444801, compound

Product 1

HCID 136121425HCID 136121425, compoundYield 19%

Reagents, catalysts & solvents 1

HCID 21889133Propan-2-ol--water (1/1)Solvent

Procedure

A mixture of ((S)-pyrrolidin-3-yl)methanamine (0.6 g, 6.0 mmol), Na2CO3 (2.2 g, 21 mmol) and methyl isobutyl ketone (12 mL, 6.0 mmol) under an N2 atmosphere was refluxed overnight using a Dean Stark apparatus. After allowing the reaction to cool to room temperature, 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.73 g, 5.99 mmol) was added, and the mixture was stirred overnight at room temperature under an N2 atmosphere. The reaction was then quenched with water. The aqueous layer was extracted twice with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to obtain a crude material containing 2-(4-((S)-3-((E)-(4-methylpentan-2-ylideneamino)methyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol which was then hydrolyzed by heating at 50° C. in 80 mL of a water/isopropanol mixture (1:1) for 6 hours. The reaction was cooled to room temperature, and the aqueous layer was extracted twice with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 5-20% MeOH and CH2Cl2 afforded 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (400 mg, 19% after 3 steps). LC/MS: m/z 353.1 (M+H)+ at 1.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. temperaturewas refluxed overnight
  2. customthe reaction
  3. customThe reaction was then quenched with water
  4. extractionThe aqueous layer was extracted twice with CH2Cl2
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto obtain a crude material
  9. temperatureThe reaction was cooled to room temperature
  10. extractionthe aqueous layer was extracted twice with CH2Cl2
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification via silica gel chromatography

Sources & evidence

ORD record
ord-65a5c27f370a438d9a49e46d94e8d44a
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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