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

HRID 1987969Notes

Reaction equation

HRID 1987969 reaction equation
[CH3:1][C:2]1([C:5]2[O:6][C:7]3[C:8](=[C:10]([C:14]([OH:16])=O)[CH:11]=[CH:12][CH:13]=3)[N:9]=2)[CH2:4][CH2:3]1.Cl.Cl.[NH2:19][C@H:20]1[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]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:22]12[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23]1)[C@H:20]([NH:19][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:7]3[O:6][C:5]([C:2]4([CH3:1])[CH2:3][CH2:4]4)=[N:9][C:8]=13)=[O:16])[CH2:21]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 689963272-(1-Methylcyclopropyl)benzoxazole-4-carboxylic acid

Product 1

HCID 68995673(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamideYield 79%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-(1-methylcyclopropyl)benzoxazole-4-carboxylic acid (60 mg, 0.27 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (67 mg, 0.34 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) and 1-hydroxybenzotriazole (73 mg, 0.54 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.11 mL, 0.81 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, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(1-methylcyclopropyl)benzoxazole-4-carboxamide (69 mg, 79%) as a light brown semi-solid: 1H NMR (500 MHz, CDCl3) δ 9.61 (d, J=7.3 Hz, 1H), 8.10 (dd, J=7.8, 1.0 Hz, 1H), 7.55 (dd, J=8.0, 0.9 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 4.34-4.28 (m, 1H), 3.55 (m, 1H), 3.10-3.00 (m, 2H), 2.96-2.88 (m, 2H), 2.82-2.74 (m, 1H), 2.12-2.02 (m, 2H), 1.80-1.75 (m, 2H), 1.65 (s, 3H), 1.64-1.57 (m, 1H), 1.52-1.48 (m, 2H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 326 (M+H).

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, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide)

Sources & evidence

ORD record
ord-8ea19ec241a1442195d08d455be4803e
Source dataset
uspto-grants-2009_06
Patent number
US07553846B2

Reaction notes

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