Triethylamine → (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamide Hydrochloride

HRID 506265Notes

Reaction equation

HRID 506265 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[ClH:20].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[ClH:20].[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])=[N:12][C:11]=13)=[O:19])[CH2:46]2

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 12494973(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochlorideHCID 135957253Caboxamycin

Product 1

HCID 136344231(S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(2-hydroxyphenyl)benzoxazole-4-carboxamide HydrochlorideYield 68%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid (50 mg, 0.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg, 0.4 mmol), 1-hydroxybenzotriazole (57 mg, 0.4 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (39 mg, 0.2 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.08 mL, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL), and then treated with a saturated solution of sodium bicarbonate. The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (2×25 mL), brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by semi-preparative HPLC to afford the desired product (49 mg, 68%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.10 (dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=8.1, 0.9 Hz, 1H), 7.55-7.50 (m, 2H), 7.16 (dd, J=8.6, 0.6 Hz, 1H), 7.08 (t, J=7.0 Hz, 1H), 4.40-4.30 (m, 1H), 3.63-3.55 (m, 1H), 3.22-3.20 (m, 1H), 3.07-2.90 (m, 3H), 2.87-2.80 (m, 1H), 2.22-2.17 (m, 1H), 2.02-1.92 (m, 1H), 1.85-1.78 (m, 2H), 1.73-1.65 (m, 1H); MS (ESI+) m/z 364 (M+H).

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at room temperature for 12 h
  3. customThe organic layer was isolated
  4. extractionthe aqueous layer was further extracted with ethyl acetate (2×50 mL)
  5. washThe combined organics were washed with water (2×25 mL), brine (2×25 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude material was purified by semi-preparative HPLC

Sources & evidence

ORD record
ord-5c85cf400b4744b3a7d89ff98ed0acfd
Source dataset
uspto-grants-2010_08
Patent number
US07781430B2

Reaction notes

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