Thionyl Chloride → N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide

HRID 506237Notes

Reaction equation

HRID 506237 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.Cl.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2.C([N:37](C(C)C)CC)(C)C>C(Cl)Cl>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[CH:28]([NH:37][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:27]2

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 18755299Quinuclidine dihydrochlorideHCID 596258542-(4-Chlorophenyl)benzoxazole-4-carboxylic acid

Product 1

HCID 11523782N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamideYield 17.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A 25 mL round bottomed flask equipped with a reflux condenser was purged with nitrogen and charged with 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid (0.050 g, 0.18 mmol) followed by thionyl chloride (5 mL). The resulting suspension was heated to reflux for 1 hr, after which time a light yellow solution was obtained. The reaction was then cooled and the thionyl chloride removed under reduced pressure affording an off-white solid. This solid was dissolved in methylene chloride (10 mL) and quinuclidine dihydrochloride (0.056 g, 0.27 mmol) added followed by the drop-wise addition of diisopropylethylamine (0.371 g, 2.87 mmol) over 5 min. After stirring at room temperature for 3 hrs the reaction was quenched by the addition of water (10 mL) and the organic layer separated. Subsequent washing of the organic layer with water (10 mL) followed by brine (10 mL), drying over MgSO4, filtration and concentration afforded a tan solid. This solid was purified by preparative HPLC to afford 0.012 g (17% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide as an white solid: mp 194-196° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.13 (m, 1H), 8.23 (dd, J=6.7, 1.9 Hz, 2H), 8.03 (dd, J=8.2, 0.9 Hz, 1H), 7.97 (dd, J=7.7, 0.9 Hz, 1H), 7.78 (dd, J=6.7, 1.9 Hz, 2H), 7.58 (t, J=8.0 Hz, 1H), 4.09 (m, 1H), 3.28 (m, 1H), 2.85 (m, 2H), 2.75 (m, 2H), 2.63 (m, 1H), 2.08 (m, 1H), 1.99 (m, 1H), 1.65 (m, 2H), 1.57 (m, 1H); MS (ESI) m/z 382 [M+H]+.

Workup

  1. customA 25 mL round bottomed flask equipped with a reflux condenser
  2. customwas purged with nitrogen
  3. temperatureThe resulting suspension was heated
  4. temperatureto reflux for 1 hr
  5. customafter which time a light yellow solution was obtained
  6. temperatureThe reaction was then cooled
  7. customthe thionyl chloride removed under reduced pressure
  8. customaffording an off-white solid
  9. customwas quenched by the addition of water (10 mL)
  10. customthe organic layer separated
  11. washSubsequent washing of the organic layer with water (10 mL)
  12. dry with materialdrying over MgSO4, filtration and concentration
  13. customafforded a tan solid
  14. customThis solid was purified by preparative HPLC

Sources & evidence

ORD record
ord-d3587627ec724ed3ba8237c1bbdc1332
Source dataset
uspto-grants-2010_08
Patent number
US07781430B2

Reaction notes

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