Toluene → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride

HRID 657188

Reaction equation

HRID 657188 reaction equation
[C:1]([Cl:4])(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([C:1]([Cl:4])=[O:2])[CH2:28][CH2:27]1

Participants

7

Reactant 5

HCID 1140TolueneHCID 6224Trisodium citrateHCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 595517346,7-Dimethoxy-4-(piperidin-4-yl)quinazoline

Product 1

HCID 587707144-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chlorideYield 51%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a −78° C. solution of 1.85 M phosgene in toluene (15.8 mL, 29.3 mmol) and DCM (32 mL) was added 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (4.00 g, 14.6 mmol), prepared as described in Example 1d, in one portion with stirring, followed immediately by the rapid addition of DIEA (2.66 mL, 16.1 mmol) along the walls of the flask over ˜5 sec. The flask was sealed and stirred at −78° C. for another 5 min before placing the flask in an ice bath with stirring at 0° C. for 30 min. The opaque easily stirred slurry was then poured into a mixture of DCM (70 mL), 0.5 M trisodium citrate (60 mL), and ice (60 mL), and partitioned. The aqueous layer was extracted with DCM (1×50 mL) and the organic layers combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as an orange solid. Purification by flash chromatography (7:1→4:1 DCM/acetone) afforded the title compound as a beige solid (2.50 g, 51%). 1H-NMR (300 MHz, CDCl3) 9.07 (s, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 4.58-4.47 (m, 2H), 4.072 (s, 3H), 4.068 (s, 3H), 3.65 (tt, J=10.9 Hz, 4.0 Hz, 1H), 3.46-3.33 (m, 1H), 3.28-3.14 (m, 1H), 2.30-2.06 (m, 2H), 2.06-1.95 (m, 2H). LC/MS (ESI): calcd mass 335.1, found 336.1 (MH)+.

Workup

  1. customprepared
  2. customThe flask was sealed
  3. stirringstirred at −78° C. for another 5 min
  4. stirringwith stirring at 0° C. for 30 min
  5. custompartitioned
  6. extractionThe aqueous layer was extracted with DCM (1×50 mL)
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated under reduced pressure
  9. customto give the crude title compound as an orange solid
  10. customPurification by flash chromatography (7:1→4:1 DCM/acetone)

Sources & evidence

ORD record
ord-f75f36d1dfc74616a47209bd80938edf
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Linked notes

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