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Construction of a Library of Arylpiperazinyl 1,2,3-Triazole Derivatives as Ligands for Dopamine D3/D4 Receptor

  • Kwak, Ju Myung (Department of Chemistry, Inha University) ;
  • Moon, Ji Soo (Department of Chemistry, Inha University) ;
  • Choi, Jea I (Department of Chemistry, Inha University) ;
  • Murugan, Ravichandran N. (Department of Chemistry, Korea Advanced Institute of Science and Technology) ;
  • Park, Woo Kyu (Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology) ;
  • Gong, Jae Yang (College of Pharmacy, Keimyung University) ;
  • Lee, Hee Yoon (Department of Chemistry, Korea Advanced Institute of Science and Technology) ;
  • Koh, Hun Yeong (Department of Chemistry, Inha University)
  • Received : 2013.08.05
  • Accepted : 2013.08.06
  • Published : 2013.11.20
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Abstract

Keywords

Experimental

General Procedure for the Synthesis of 3-Azido Propanol 2. A solution of alcohol (1) (where, n = 3 and 5 g, 36.0 mmol) and NaN3 (4.67 g, 71.9 mmol) in DMF (50 mL) under a nitrogen atmosphere was stirred well at 50 ℃ for 15 h. The progress of reaction was monitored by TLC. The reaction mixture was filtered after 15 h and the solvent was evaporated. The product obtained was washed with water and extracted with ethyl acetate (3 × 50 m). The collected organic layer was dried over NaSO4 and filtered. The product was isolated after evaporating the solvent using a rotary evaporator as a slightly brown colored liquid with 90％ yield.

1H NMR (200 MHz, CDCl3) δ 3.76 (t, 2H, J = 5.8 Hz), 3.45 (t, 2H, J = 6.2 Hz), 1.87-1.78 (m, 2H).

General Procedure for the Synthesis of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol (4a) and 3-(4-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol (4b). A solution of azido alcohol 2 (where, n = 3, 500 mg, 4.9 mmol) and 2-ethynyl toluene (573.8 mg, 5.0 mmol) was reacted using a microwave reactor at 150 W, 150 ℃ for 1 h. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was washed with water and the product was extracted with ethyl acetate (3 × 25 mL). The crude product thus obtained was purified by column chromatography (EA:n-Hex = 4:6) to give a liquid containing 4a and 4b in 40％ and 50％ yields, respectively.

1H NMR of compound 4a (200 MHz, CDCl3) δ 7.70 (s, 1H), 7.49-7.38(m, 4H), 4.35 (t, 2H, J = 7.0 Hz), 3.65 (t, 2H, 6.0 Hz), 2.19 (s, 3H), 2.09-1.95 (m, 3H).

1H NMR of 4b (200 MHz, CDCl3) δ 7.78-7.73 (m, 1H), 7.69 (s, 1H), 7.38-7.18 (m, 3H), 4.59 (t, 2H, J = 7.0 Hz), 3.70 (t, 2H, J = 6.0 Hz), 2.46 (s, 3H), 2.25-2.12 (m, 2H), 2.00 (br s, 1H).

Other aryl alcohol 1,2,3-triazole derivatives were synthesized similarly and characterized by 1H NMR.

General Procedure for Synthesis of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-al (5a). A solution of oxalyl chloride (0.26 mL, 2.9 mmol) in 4 mL of methylene chloride was stirred at −78 ℃ and then DMSO (0.4 mL, 5.8 mmol) in 2 mL of methylene chloride was added over 10 min. Next, a solution of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan-1-ol (4a) in 2 mL of methylene chloride was added to the reaction mixture over 30 min using a dropping funnel. Next, Et3N (1.3 mL, 9.7 mmol) was added to the reaction mixture and stirred for 5 min. The temperature of the reaction mixture was then raised to room temperature, and then stirred for 1 h. The progress of reaction was monitored by TLC (EA:n-Hex = 1:2). Water (10 mL) was added to the reaction mixture and the organic layer was separated and dried over MgSO4. The reaction mixture filtrated to remove MgSO4 and then the solvent was removed. The product was purified over column chromatography (EA:n-Hex = 1:4) to give a liquid with 53％ yield.

1H NMR of (5a) δ 9.78 (s, 1H), 7.67 (s, 1H), 7.45-7.22 (m, 4H), 4.42 (t, 2H, J = 7.0 Hz), 3.18 (t, 2H, J = 7.0 Hz), 2.19 (s, 3H).

Other aryl aldehyde 1,2,3-triazole derivatives were synthesized similarly and characterized by 1H NMR.

General Procedure for Synthesis of 1-(2-Chlorophen-yl)-4-(3-5-phenyl-1H-1,2,3-triazole-1-yl)propyl)piperazine (7a). A solution of 3-(5-o-tolyl-1H-1,2,3-triazole-1-yl)-propan- 1-al (5a) (50 mg, 0.22 mmol) and 1-(2-chlorophenyl)- piperazine (67.9 mg, 0.3 mmol) in 5 mL of methylene chloride was stirred at room temperature for 10 min. Molecular sieve (0.6 g, 4 Å) and DIPEA (0.12 mL, 0.7 mmol) were added slowly. After 30 min, NaBH(OAc)3 (146.2 mg, 0.7 mmol) was added and stirred for 12 h. The progress of reaction was monitored by TLC. After completion of the reaction, water was added and the organic layer was separated. The organic layer was dried over MgSO4 and then filtered to remove MgSO4. Finally, the product was purified by flash column chromatography (EA:n-Hex = 4:1) to give the product in 87% yield.

1H NMR (Entry 1) (400 MHz, MeOH-d4) δ 7.77 (s, 1H), 7.47-7.33 (m, 4H), 7.29-7.22 (m, 3H), 7.09-7.03 (m, 2H), 4.37 (t, 2H, J = 6.4 Hz), 3.63-3.57 (m, 4H), 3.39 (d, 2H, J = 6.4 Hz), 3.36 (br s, 2H), 3.10-3.06 (m, 2H), 2.58 (br s, 2H), 2.16 (s, 3H). ESI-MS m/z calcd for C22H26ClN5 [M + H]+ 396.1955, found 396.1618.

Other arylpiperazinyl 1,2,3-triazole derivatives were synthesized similarly and characterized 1H NMR.

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