Bulletin of the Korean Chemical Society

  • 제35권9호
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  • Pages.2859-2862
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  • 2014
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  • 0253-2964(pISSN)
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  • 1229-5949(eISSN)
대한화학회 (Korean Chemical Society)
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A Synthesis of Novel Pyrazolylthienopyrimidine Derivatives as IL-6/STAT3 Inhibitors

  • 투고 : 2014.04.22
  • 심사 : 2014.05.26
  • 발행 : 2014.09.20
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초록

키워드

Experimental

Chemistry. Melting points were determined in capillary tubes on Büchi apparatus and are uncorrected. Each compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F254 and purified by column chromatography Merck silica gel (70-230 mesh). The 1H NMR spectra were recorded on Unity Inova 400NB FT NMR spectrometer (400 MHz) with Me4Si as internal standard and chemical shifts are given in ppm (δ). Mass spectra were recorded on a HP 59580 B spectrometer. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.

General Procedure for the Preparation of 3A and 3B. 4-Hydrazinothienopyrimidine 1A or 1B (10 mmol) and the appropriate (E)-3-(dimethylamino)-1-phenylprop-2-en-1- one 2 (10 mmol) were mixed in ethanol (50 mL) containing HCl (1 eq), and the mixture was heated to 70 ℃ for 6 h. After evaporation of the solvent, the residue was purified by column chromatography using as eluent CH2Cl2-EtOAc (8:2) to give 3A and 3B, respectively.

4-(5-Phenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Aa). Yield 65%; mp 54-55 ℃; 1H NMR (DMSO-d6) δ 8.89 (s, 1H, pyrimidine), 8.62 (d, 1H, J = 5.9 Hz, thiophene), 8.36 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.97 (d, 2H, phenyl), 7.60 (d, 1H, J = 5.9 Hz, thiophene), 7.48 (m, 3H, phenyl), 6.90 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 278.93 (M+). Anal. Calcd. For C15H10N4S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.54; H, 3.50; N, 20.27.

4-(5-(4-Ethylphenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ab). Yield 76%; mp 135-136 ℃; 1H NMR (DMSO-d6) δ 8.45 (s, 1H, pyrimidine), 7.92 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.70 (d, 2H, phenyl), 7.62 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (d, 1H, J = 5.9 Hz, thiophene), 7.30 (d, 2H, phenyl), 6.79 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.63 (q, 2H, CH2), 1.17 (t, 3H, Me); MS (ESI): (m/z) 306.95 (M+). Anal. Calcd. For C17H14N4S: C, 66.64; H, 4.61; N, 18.29. Found: C, 66.48; H, 4.50; N, 18.44.

4-(5-m-Tolyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ac). Yield 70%; mp 162-163 ℃; 1H NMR (DMSO-d6) δ 8.50 (s, 1H, pyrimidine), 8.05 (d, 1H, J = 6.0 Hz, thiophene), 7.96 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.72 (s, 1H, phenyl, H2'), 7.67 (d, 1H, phenyl, H6'), 7.54 (d, 1H, J = 5.9 Hz, thiophene), 7.32 (t, 1H, phenyl, H5'), 7.10 (d, 1H, phenyl, H4'), 6.89 (d,1H, J = 1.6 Hz, H-4, pyrazole), 2.26 (s, 3H, Me); MS (ESI): (m/z) 292.79. (M+). Anal. Calcd. For C16H12N4S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.70; H, 4.05; N, 19.02.

4-(5-p-Tolyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ad). Yield 78%; mp 164-165 ℃; 1H NMR (DMSO-d6) δ 8.47 (s, 1H, pyrimidine), 8.17 (d, 1H, J = 6.0 Hz, thiophene), 7.88 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J = 5.9 Hz, thiophene), 7.74 (d, 2H, phenyl), 7.24 (d, 2H), 6.77 (d, 1H,J= 1.6 Hz, H-4, pyrazole), 2.20 (s, 3H, Me); MS (ESI): (m/z) 292.66. (M+). Anal. Calcd. For C16H12N4S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.57; H, 4.11; N, 19.27.

4-(5-3-Bromophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ae). Yield 60%; mp 142-143 ℃; 1H NMR (DMSO-d6) δ 8.48 (s, 1H, pyrimidine), 7.98 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.90 (d, 1H, J = 5.9 Hz, thiophene), 7.74 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (s, 1H, phenyl, H2'), 7.42-7.35 (m, 3H), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 358.97. (M+). Anal. Calcd. For C15H9BrN4S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.20; H, 2.42; N, 15.88.

4-(5-4-Bromophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Af). Yield 66%; mp 85-86 ℃; 1H NMR (DMSO-d6) δ 8.76 (s, 1H, pyrimidine), 8.10 (d, 1H, J = 5.9 Hz, thiophene), 7.95 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J= 5.9 Hz, thiophene), 7.54 (d, 2H, phenyl), 7.28 (d, 2H, phenyl), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 358.81. (M+). Anal. Calcd. For C15H9BrN4S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.31; H, 2.42; N, 15.61.

4-(5-3-Chlorophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ag). Yield 63%; mp 168-169 ℃; 1H NMR (DMSO-d6) δ 8.48 (s, 1H, pyrimidine), 7.98 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.74 (d, 1H, J = 5.9 Hz, thiophene), 7.57 (d, 1H, J = 5.9 Hz, thiophene), 7.47 (s, 1H, phenyl, H2'), 7.45-7.39 (m, 3H), 6.76 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 312.95 (M+). Anal. Calcd. For C15H9ClN4S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.69; H, 2.79; N, 17.77.

4-(5-4-Chlorophenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (3Ah). Yield 65%; mp 172-173 ℃; 1H NMR (DMSO-d6) δ 8.76 (s, 1H, pyrimidine), 8.09 (d, 1H, J = 5.9 Hz, thiophene), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.89 (d, 1H, J= 5.9 Hz, thiophene), 7.49 (d, 2H, phenyl), 7.35 (d, 2H, phenyl), 6.87 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 312.87 (M+). Anal. Calcd. For C15H9ClN4S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.44; H, 2.82; N, 18.14.

4-(5-Phenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Ba). Yield 62%; mp 91-93 ℃; 1H NMR (DMSO-d6) δ 8.56 (s, 1H, pyrimidine), 8.33 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 8.31 (d, 1H, J = 5.9 Hz, thiophene), 7.80 (d, 2H, phenyl), 7.46 (m, 3H, phenyl), 7.38 (d, 1H, J = 5.9 Hz, thiophene), 6.84 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 278.95 (M+). Anal. Calcd. For C15H10N4S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.81; H, 3.52; N, 20.02.

4-(5-(4-Ethylphenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bb). Yield 72%; mp 177-178 ℃; 1H NMR (DMSO-d6) δ 8.69 (s, 1H, pyrimidine), 8.06 (d, 1H, J = 5.9 Hz, thiophene), 7.85 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.63 (d, 2H, phenyl), 7.61 (d, 1H, J = 5.9 Hz, thiophene), 7.31 (d, 2H, phenyl), 6.50 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.70 (q, 2H, CH2), 1.26 (t, 3H, Me); MS (ESI): (m/z) 306.90 (M+). Anal. Calcd. For C17H14N4S: C, 66.64; H, 4.61; N, 18.29. Found: C, 66.52; H, 4.68; N, 18.18.

4-(5-m-Tolyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bc). Yield 76%; mp 111-112 ℃; 1H NMR (DMSO-d6) δ 8.67 (s, 1H, pyrimidine), 8.01 (d, 1H, J = 6.0 Hz, thiophene), 7.95 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.73 (s, 1H, phenyl, H2'), 7.60 (d, 1H, phenyl, H6'), 7.50 (d, 1H, J = 5.9 Hz, thiophene), 7.28 (t, 1H, phenyl, H5'), 7.18 (d, 1H, phenyl, H4'), 6.85 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.32 (s, 3H, Me); MS (ESI): (m/z) 292.92. (M+). Anal. Calcd. For C16H12N4S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.61; H, 4.00; N, 19.11.

4-(5-p-Tolyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bd). Yield 70%; mp 131-132 ℃; 1H NMR (DMSO-d6) δ 8.47 (s, 1H, pyrimidine), 7.83 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.74 (d, 2H, phenyl), 7.70 (d, 1H, J = 6.0 Hz, thiophene), 7.40 (d, 1H, J = 5.9 Hz, thiophene), 7.28 (d, 2H), 6.75 (d, 1H, J = 1.6 Hz, H-4, pyrazole), 2.20 (s, 3H, Me); MS (ESI): (m/z) 292.67. (M+). Anal. Calcd. For C16H12N4S: C, 65.73; H, 4.14; N, 19.16. Found: C, 65.68; H, 4.22; N, 19.02.

4-(5-3-Bromophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Be). Yield 66%; mp 111-113 ℃; 1H NMR (DMSO-d6) δ 8.55 (s, 1H, pyrimidine), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.84 (d, 1H, J = 5.9 Hz, thiophene), 7.78 (d, 1H, J = 5.9 Hz, thiophene), 7.49 (s, 1H, phenyl, H2'), 7.40-7.35 (m, 3H), 6.76 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 358.86. (M+). Anal. Calcd. For C15H9BrN4S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.57; H, 2.40; N, 15.49.

4-(5-4-Bromophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bf). Yield 65%; mp 92-95 ℃; 1H NMR (DMSO-d6) δ 8.64 (s, 1H, pyrimidine), 8.48 (d, 1H, J = 5.9 Hz, thiophene), 8.02 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.57 (d, 1H, J = 5.9 Hz, thiophene), 7.51 (d, 2H, phenyl), 7.33 (d, 2H, phenyl), 6.74 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 358.48. (M+). Anal. Calcd. For C15H9BrN4S: C, 50.43; H, 2.54; N, 15.68. Found: C, 50.30; H, 2.48; N, 15.54.

4-(5-3-Chlorophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bg). Yield 60%; mp 132-134 ℃; 1H NMR (DMSO-d6) δ 8.68 (s, 1H, pyrimidine), 7.92 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.82 (d, 1H, J = 5.9 Hz, thiophene), 7.59 (d, 1H, J = 5.9 Hz, thiophene), 7.44 (s, 1H, phenyl, H2'), 7.42-7.36 (m, 3H), 6.78 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 312.95 (M+). Anal. Calcd. For C15H9ClN4S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.46; H, 2.80; N, 17.82.

4-(5-4-Chlorophenyl-1H-pyrazol-1-yl)thieno[3,2-d]pyrimidine (3Bh). Yield 55%; mp 92-94 ℃; 1H NMR (DMSO-d6) δ 8.66 (s, 1H, pyrimidine), 8.06 (d, 1H, J = 5.9 Hz, thiophene), 7.90 (d, 1H, J = 1.6 Hz, H-3, pyrazole), 7.60 (d, 1H, J = 5.9 Hz, thiophene), 7.33 (d, 2H, phenyl), 7.21 (d, 2H, phenyl), 6.50 (d, 1H, J = 1.6 Hz, H-4, pyrazole); MS (ESI): (m/z) 312.98 (M+). Anal. Calcd. For C15H9ClN4S: C, 57.60; H, 2.90; N, 17.91. Found: C, 57.76; H, 2.80; N, 17.80.

4-(5-Phenyl-1H-pyrazol-1-yl)thieno[2,3-d]pyrimidine (4Aa). 1H NMR (DMSO-d6) δ 8.96 (s, 1H, pyrimidine), 8.60 (d, 1H, J = 5.9 Hz, thiophene), 7.97-7.94 (m, 3H, phenyl and pyrazole), 7.62 (d, 1H, J = 5.9 Hz, thiophene), 7.50-7.47 (m, 3H, phenyl), 7.10 (d, 1H, J = 2.8 Hz, H-4, pyrazole); MS (ESI): (m/z) 278.88 (M+). Anal. Calcd. For C15H10N4S: C, 64.73; H, 3.62; N, 20.13. Found: C, 64.60; H, 3.55; N, 20.03.

4-((Z)-2-((E)-1-(4-Bromophenyl)-3-(2-(thieno[3,2-d]pyramid- in-4-yl)hydrazinyl)allylidene)hydrazinyl)thieno[3,2-d]pyramid-ine (5Bf). 1H NMR (DMSO-d6) δ 10.92 (s, 1H, NH), 8.69-8.67 (m, 2H, pyrimidine), 8.47-8.44 (m, 2H, thiophene), 7.73 (d, 2H, phenyl), 7.60 (d, 2H, phenyl), 7.50- 7.47 (m, 2H, thiophene), 7.12 (m, 1H), 6.14 (m, 1H, phenyl); MS (ESI): (m/z) 524.74 (M+). Anal. Calcd. For C21H15BrN8S2: C, 48.19; H, 2.89; N, 21.41. Found: C, 48.03; H, 2.78; N, 21.23.

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피인용 문헌

  1. ChemInform Abstract: A Synthesis of Novel Pyrazolylthienopyrimidine Derivatives as IL‐6/STAT3 Inhibitors. vol.46, pp.9, 2014, https://doi.org/10.1002/chin.201509234
  2. Synthesis of new pyrazolo[3,4‐d]pyrimidine derivatives and evaluation of their anti‐inflammatory and anticancer activities vol.90, pp.1, 2014, https://doi.org/10.1111/cbdd.12929