Triethylamine → (S)-2-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]oxazole-4-carboxamide

HRID 1987964

Reaction equation

HRID 1987964 reaction equation
[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:13]([OH:15])=O)[CH:10]=[CH:11][CH:12]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:18][C@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]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:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@H:19]([NH:18][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=13)=[O:15])[CH2:20]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 689999402-Cyclopropylbenzoxazole-4-carboxylic acid

Product 1

HCID 24178536(S)-2-cyclopropyl-N-(quinuclidin-3-yl)benzo[d]oxazole-4-carboxamideYield 43.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-cyclopropylbenzoxazole-4-carboxylic acid (65 mg, 0.32 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (64 mg, 0.32 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.17 mL, 1.28 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-cyclopropylbenzoxazole-4-carboxamide (43 mg, 43%) as a colorless semisolid: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.0 Hz, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.36 (t, J=8.5 Hz, 1H), 4.28-4.22 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.75 (dd, J=14.0, 4.5 Hz, 1H), 2.28-2.20 (m, 1H), 2.12-2.06 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.69 (m, 2H), 1.60-1.50 (m, 1H), 1.35-1.22 (m, 4H); MS (ESI+) m/z 312 (M+H); HPLC>99% (AUC), tR=12.31 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-2d674c38046542f3b09ab9ea603c93f7
Source dataset
uspto-grants-2009_06
Patent number
US07553846B2

Linked notes

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