Triethylamine → (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide

HRID 2059703Notes

Reaction equation

HRID 2059703 reaction equation
[CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([OH:13])=O)[CH:8]=[CH:9][CH:10]=2)[N:6]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=13)=[O:13])[CH2:18]2

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 12494973(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochlorideHCID 183546282-Methyl-1,3-benzoxazole-4-carboxylic acid

Product 1

HCID 68994903(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamideYield 33%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-methylbenzoxazole-4-carboxylic acid (75 mg, 0.42 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (84 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.84 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then triethylamine (0.22 mL, 1.68 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide (39 mg, 33%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.0 Hz, 1H), 8.14 (dd, J=7.5, 1.0 Hz, 1H), 7.60 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.47 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.08-2.85 (m, 4H), 2.76 (dd, J=14.0, 4.5 Hz, 1H), 2.70 (s, 3H), 2.13-2.07 (m, 1H), 2.02-1.93 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 286 (M+H); HPLC >99% (AUC), tR=11.14 min.

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at room temperature for 12 h
  3. washwashed with a saturated solution of sodium bicarbonate (10 mL)
  4. extractionThe aqueous layer was further extracted with dichloromethane (3×15 mL)
  5. dry with materialThe combined organics were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-32bdbb21c83042f0aef48d4b41fed206
Source dataset
uspto-grants-2012_10
Patent number
US08278301B2

Reaction notes

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