Acetylsalicylic acid derivatives having a vinyl group EP 0732322 B1

• Fig. 1 is a ¹H-NMR spectrum of 2-acetyl-5-methacrylamidosalicylic acid obtained in Example 3.
• Fig. 2 is a ¹H-NMR spectrum of 2-acetyl-4-methacrylamidosalicylic acid obtained in Example 4.

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Example 3Synthesis of 2-acetyl-5-methacrylamidosalicylic acid(1) 5-methacrylamidosalicylic acid (intermediate)
• [0069]
  5-aminosalicylic acid (50.0 millimole, 7.7 g), methacrylic anhydride (60.0 millimole, 9.3 g), and butylhydroxytoluene (20.0 mg) were suspended in dimethyl sulfoxide (50.0 ml). After sealing the suspension, its temperature was raised to 60° C by oil bath while stirring, and the suspension became homogeneous quickly. The mixture was further kept at 60° C for five hours while stirring to give a viscous liquid having dark brown color. The reaction was kept proceeding till the viscous liquid gave brown precipitate. The precipitate was filtrated, washed by dichloromethane to give brownish gray powder. The powder was recrystallized by a solution of 0.5% hydroquinone in methanol, and dried under a reduced pressure to give brownish gray crystal of 5-methacrylamidosalicylic acid: yield 9.27 g, 83.8%.
(2) 2-acetyl-5-methacrylamidosalicylic acid (the present invention)
• [0070]
  5-methacrylamidosalicylic acid (30 millimole, 6.7 g) was mixed with butylhydroxytoluene (20 mg), acetic anhydride (10.0 g), and acetic acid (15.0 g). After sealing the solution, its temperatures was raised to 60° C, and the solution was kept at 60°C for 30 min while stirring. Then, a mixture (1.0 g) of concentrated sulfuric acid (1 part) with hydrochloric acid (10 parts) was added to the solution, followed by raising its temperature to 90° C, and kept at 90° C for one hour to proceed the reaction. After the reaction was over, the solution was stood to cool to room temperature to give brown crystal. The crystal was filtrated, and recrystallized by a solution of 0.5% hydroquinone in methanol. Dried under a reduced pressure, 2-acetyl-5-methacrylamidosalicylic acid was obtained as pale reddish brown crystal having a needle shape: mp. 192.4°C, yield 2.54 g, 64.1%.
Elemental analysis (calculated as C₁₃H₁₃O₅N)
• [0071]

  	C	H	N
  calc.(%)	59.31	4.98	5.32
  exp.(%)	59.31	4.98	5.17

  
  

  • ¹H-NMR(DMSO-d₆, ppm)
  • δ: 13.11 (COOH), 9.99 (CONH), 8.27, 7.96, 7.93, 7.92, 7.16, 7.12 (C₆ H₃ ), 5.85, 5.55 (=CH₂ ), 2.23 (OCOCH₃ ), 1.96 (CH₃ ).
• [0072]
  A ¹H-NMR spectrum of the compound is shown in Fig. 1.
Example 4Synthesis of 2-acetyl-4-methacrylamidosalicylic acid(1) 4-methacrylamidosalicylic acid (intermediate)
• [0073]
  4-aminosalicylic acid was used as a starting material. The same procedures as the step (1) in Example 3 gave 4-methacrylamidosalicylic acid as yellow powder: yield 7.64 g, 68.9%.
(2) 2-acetyl-4-methacrylamidosalicylic acid (the present invention)
• [0074]
  4-methacrylamidosalicylic acid was used as a starting material. The same procedures as the step (2) in Example 3 gave 2-acetyl-4-methacrylamidosalicylic acid as pale yellow crystal having a needle shape: mp. 178.1°C; yield 3.51 g, 44.8%.
Elemental analysis (calculated as C₁₃H₁₃O₅N)
• [0075]

  	C	H	N
  calc.(%)	59.31	4.98	5.32
  exp.(%)	59.28	5.00	5.38

  
  

  • ¹H-NMR(DMSO-d₆, ppm)
  • δ: 12.86 (COOH), 10.18 (CONH), 7.93, 7.92, 7.88, 7.74, 7.65, 7.61 (C₆ H₃ ), 5.85, 5.60 (=CH₂ ), 2.25 (OCOCH₃ ), 1.95 (CH₃ ).
• [0076]
  A ¹H-NMR spectrum of the compound is shown in Fig. 2.

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