Triethylamine → N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide

HRID 506292Notes

Reaction equation

HRID 506292 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:16]1[CH:17]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:20])[CH2:25]2

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 189569979-Methyl-9-azabicyclo[3.3.1]nonan-3-amine;dihydrochlorideHCID 684583386-Chloro-2-p-tolylbenzoxazole-4-carboxylic acid

Product 1

HCID 11531928N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamideYield 26.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 6-chloro-2-p-tolylbenzoxazole-4-carboxylic acid (45 mg, 0.16 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (43 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol) and 1-hydroxybenzotriazole (43 mg, 0.31 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.07 mL, 0.63 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×22 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide (18 mg, 26%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (d, J=7.3 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.67 (d, J=1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.4 Hz, 2H), 2.70-2.57 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.90 (m, 2H), 1.65-1.52 (m, 2H), 1.51-1.48 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 424 (M+H); HPLC 95.0% (AUC), tR=13.80 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
  4. extractionThe aqueous layer was further extracted with ethyl acetate (2×22 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, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-80e2a59dc98f44cd814a7ab08c6a29c0
Source dataset
uspto-grants-2010_08
Patent number
US07781430B2

Reaction notes

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