Purity detection and preparation method of methyl 2-cyano-4-pyridinecarboxylate_Industrial additives

Background and overview of purity detection and preparation methods of 2-cyano-4-pyridinecarboxylic acid methyl ester

Tobinostat is used to treat chronic hyperuricemia in gout. Compared with the traditional drug allopurinol (purine analogue), Tobinostat does not affect the metabolism of purine and pyridine and the activity of its enzymes. It has the effect of reducing uric acid. It is stronger, does not require repeated administration of large doses, and is safer. Methyl 2-cyano-4-pyridinecarboxylate is an important raw material for the synthesis of tobinostat.

Purity detection and preparation method of methyl 2-cyano-4-pyridinecarboxylatePurity detection

The impurities produced during the synthesis of methyl 2-cyano-4-pyridinecarboxylate mainly include methyl isonicotinate and methylisonicotinic acid N-oxide.

The polarities of 2-cyano-4-pyridinecarboxylic acid basic copper carbonate methyl ester and the main impurity methyl isonicotinate are similar. CN201610560075.4 provides a method to achieve 2-cyano-4- by isocratic elution. Methyl pyridinecarboxylate can be completely separated from adjacent impurity peaks, and the peak shape is good, achieving accurate analysis of the content of methyl 2-cyano-4-pyridinecarboxylate. The invention relates to a high-performance liquid chromatography purity detection method that completely separates 2-cyano-4-pyridinecarboxylic acid methyl ester from its main impurities, including the following steps:

a. Prepare the test solution: Take 2-cyano-4-pyridinecarboxylic acid methyl ester and dissolve it with mobile phase or methanol to prepare a solution with a concentrated tetrahydrofurancarboxylic acidity of 0.5 mg/ml to 1.2 mg/ml. , as the test solution.

b. Prepare the impurity reference solution: take methylisonicotinate and methylisonicotinate N-oxide and dissolve them with mobile phase or methanol to make a solution with a concentration of 0.5mg/ml~1.2mg/ml. , as impurity reference solution.

c. Use high performance liquid chromatography to detect the test solution and the impurity reference solution respectively. The detection conditions are: the chromatographic column is a C18 column; the mobile phase is methanol-buffer salt, and the volume ratio of methanol to buffer is 10%: 90%～90%: 10%; injection volume: 20ul, flow rate: 0.5ml/min～1.5ml/min; column temperature: 10℃～40℃; detection wavelength: 200nm～300mn.

d. Calculate the peak areas of methylisonicotinate and methylisonicotinate N-oxide according to the peak area normalization method.

Purity detection and preparation method of methyl 2-cyano-4-pyridinecarboxylate

Add methylisonicotinic acid-N-oxide (15.31g, 0.1mol) and 200ml acetonitrile into a 250ml three-necked flask, stir and dissolve completely, then add triethylamine (15g, 0.15mol) and trimethylsilyl cyanide. (29.76g, 0.3mmol) and then refluxed under nitrogen protection for 20 hours, and TLC detected the end of the reaction. The solvent was distilled to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with dichloromethane-methanol (50:1) to obtain white crystals in a yield of 13.48g, 83.14%. ¹HNMR (600MHz, DMSO-d6, δppm): 4.03 (s, 3H,), 8.11 (d, 1H,), 7.76 (s, 1H), 8.26 (s, 1H), 8.89 (d,1H).

References

[1][Chinese invention] CN201610560075.4 A high-performance liquid chromatography purity detection method for complete separation of 2-cyano-4-pyridinecarboxylic acid methyl ester and its main impurities

[2] [Invented in China] CN201610150069.1 A synthesis method of topinostat impurities