Triethylamine → HCID 136121337, compound

HRID 2062291Notes

Reaction equation

HRID 2062291 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(OC(=O)[NH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(C)(C)C.C(O)(=O)C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[NH2:27][CH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[OH:20])[N:3]=2)[CH2:30]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 86761304HCID 86761304, compoundHCID 1361213752-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol

Product 1

HCID 136121337HCID 136121337, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.0 g, 3.46 mmol) was dissolved in 15 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled using an ice bath and (S)-piperidin-3-ylmethyl-carbamic acid tert-butyl ester/oxalic acid (1.16 g, 3.81 mmol) was added in portions, followed by triethylamine (1.05 g, 1.45 mL, 10.4 mmol). The reaction was allowed to warm to room temperature and was complete after 1.5 hour. The mixture was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to a yellow solid. This solid was suspended in 40 mL CH2Cl2 and 20 mL of TFA were added. The reaction was complete after 1 hour. The solvent and the excess TFA were removed in vacuo, the residue was re-dissolved in CH2Cl2, and the pH was adjusted to 7 using an aqueous 1 M solution of NaOH. The reaction was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71% overall yield) as a yellow solid. LC/MS: m/z 367.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Workup

  1. temperaturecooled
  2. customThe mixture was partitioned between CH2Cl2 and H2O
  3. customseparated
  4. extractionthe aqueous layer was extracted once more with CH2Cl2
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to a yellow solid
  8. addition20 mL of TFA were added
  9. waitThe reaction was complete after 1 hour
  10. customThe solvent and the excess TFA were removed in vacuo
  11. dissolutionthe residue was re-dissolved in CH2Cl2
  12. customThe reaction was partitioned between CH2Cl2 and H2O
  13. customseparated
  14. extractionthe aqueous layer was extracted once more with CH2Cl2
  15. dry with materialdried over Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated to yield of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71% overall yield) as a yellow solid
  18. waitLC/MS: m/z 367.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA))

Sources & evidence

ORD record
ord-569588d3632046218a4efa76b543ab17
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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