CN109912512B - New telmisartan impurity compound and preparation method and application thereof - Google Patents
New telmisartan impurity compound and preparation method and application thereof Download PDFInfo
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- CN109912512B CN109912512B CN201711326291.3A CN201711326291A CN109912512B CN 109912512 B CN109912512 B CN 109912512B CN 201711326291 A CN201711326291 A CN 201711326291A CN 109912512 B CN109912512 B CN 109912512B
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Abstract
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a novel telmisartan impurity compound, a preparation method and application thereof.
Background
Telmisartan was developed by the company bringen, 1999 approved as a commercial product, under the trade name mecamylin, for the treatment of essential hypertension, having the structural formula:
impurity research is an important content of medicine research and development, and throughout the medicine research and development, the existence of impurities directly influences the safety, effectiveness and quality controllability of medicines.
Disclosure of Invention
The inventor can generate a new impurity in the process of generating telmisartan by the sulfuric acid hydrolysis of the nitrile telmisartan compound shown in the research formula II, the impurity compound has a growing trend along with the extension of the reaction time, the impurity generation amount is related to the concentration and the temperature of the sulfuric acid aqueous solution, and the higher the sulfuric acid concentration or the temperature is, the larger the impurity generation amount is. Thus, there is an urgent need to determine the specific structure of the impurity and develop a method for preparing the impurity compound rapidly and economically. The method has great practical significance for process development, stability research and analysis method development of telmisartan. The structure of the compound shown in the formula II is as follows:
the structural formula of the novel telmisartan impurity is shown as the following formula (I):
the compound shown in the formula I passes nuclear magnetic resonance 1 H NMR 13 C NMR), infrared (IR) and mass spectrometry (ESI-MS) for structural characterization, and detection results are dividedAs shown in fig. 1, 2, 3 and 4, respectively. The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum are analyzed, and the following attributes are included:
1 H NMR(600MHz,d 6 -DMSO)δ0.96(t,J=10.8Hz,3H,CH 3 ),1.78(m,2H,CH 2 ),2.63(s,3H,CH 3 ),2.89(t,J=10.8Hz,2H,CH 2 ),3.84(s,3H,CH 3 ),5.64(s,2H,CH 2 ),7.18-7.26(m,2H,Ar),7.32-7.36(m,3H,Ar),7.49(s,1H,Ar),7.55-7.63(m,4H,Ar),7.74(t,J=11.4Hz,2H,Ar),7.80(s,1H,Ar);
13 C NMR(100MHz,d 6 -DMSO)δ13.8,16.5,20.7,28.7,31.7,45.8,109.1,110.4,118.7,121.2,121.5,121.8,121.9,122.0,123.4,123.5,124.0,128.3,128.7,129.5,133.3,133.7,134.7,135.5,136.6,138.9,142.5,142.6,143.1,143.5,154.0,156.1,192.8;
the characteristic parameters of this impurity compound are described below:
mass Spectrometry (ESI-MS) gives [ M+H ]] + The molecular ion peak of = 497.30, which is 17 different from telmisartan (molecular weight: 514.62), is almost completely consistent with the theoretical molecular weight of impurity structure 496.23.
Impurity I Compound 1 HNMR and telmisartan 1 HNMR has 1 hydrogen less aromatic region.
Impurity I Compound 13 CNMR and telmisartan 13 CNMR has one less characteristic carboxyl carbon (about 165-175 ppm) and one more characteristic carbonyl carbon (192.8 ppm).
The IR spectrum of the impurity I compound is dulled 1693cm less than that of telmisartan -1 And absorption peaks of 2000-3100cm -1 Is more than one sharp 1717cm -1 Is a strong absorption peak (carbonyl characteristic peak).
Based on the above data, the inventors determined that the compound has the structure shown in formula I:
through structural analysis, the inventor considers that the impurity is formed by telmisartan self-friedel-crafts acylation, and the specific impurity generation mechanism is as follows:
in a second aspect, the present invention also relates to a process for the preparation of a compound of formula I, comprising the steps of:
reacting 4'- ((1, 4' -dimethyl-2 '-n-propyl- (2, 6' -bi-1H-benzimidazole) -1 '-group) methyl) - (1, 1' -biphenyl) -2-cyano group with sulfuric acid water solution at 120-150 ℃ to obtain the compound shown in the formula I by separation.
The concentration of the aqueous sulfuric acid solution in the step is 50% to 70%, preferably 60% to 70%, and more preferably 70%.
The heating temperature in the step is preferably 140 to 150℃and more preferably 145 to 150 ℃.
The reaction time in the step is 12 to 72 hours, preferably 18 to 48 hours, and more preferably 24 to 36 hours.
The purity of the impurity I compound obtained by the production method according to the present invention is 90% or more, preferably 95% or more, and more preferably 99% or more.
The impurity I compound is used as an impurity reference substance in the quality detection of telmisartan finished products.
The invention also provides a method for controlling the quality of a telmisartan finished product, which is characterized in that: and using the impurity I compound as an impurity reference substance. A preferred quality control method comprises the steps of: weighing a proper amount of impurity I compound, and dissolving the impurity I compound in a diluent to prepare an impurity reference substance solution with proper concentration; then, the impurity I compound contained in the telmisartan sample is subjected to qualitative or quantitative research by using a reverse phase liquid chromatography method.
The impurity I compound discovered according to the invention has important application significance in process development, stability research and analysis method development of telmisartan. In addition, the impurity I compound discovered by the invention can more easily and intuitively control the quality of telmisartan finished products. In addition, the preparation method of the impurity I compound has low process cost, easy control and easily available raw materials; and the obtained product has stable quality and high yield.
The invention has the beneficial effects that: the invention discovers a novel impurity compound I, provides a preparation method of the impurity compound I and the application of the impurity compound I as a reference substance when detecting the quality of a telmisartan finished product, and can effectively control the quality of telmisartan so as to ensure the safety and effectiveness of clinical use of telmisartan.
Drawings
Fig. 1: of compounds of formula I 1 HNMR spectra.
Fig. 2: of compounds of formula I 13 CNMR spectra.
Fig. 3: IR spectra of compounds of formula I.
Fig. 4: ESI-MS spectra of the compound of formula I.
Detailed Description
Example 1
Preparation of the compound of formula I:
adding 10g of nitrile telmisartan shown in a formula II into 30mL of 70% sulfuric acid aqueous solution, stirring at 145 ℃ for 36 hours, monitoring the reaction progress through HPLC analysis, and cooling to room temperature after the reaction is completed; the reaction solution was extracted three times with 80mL of methylene chloride, the methylene chloride phase was washed three times with 30% aqueous sodium hydroxide solution (30 mL), and the organic phase was concentrated and evaporated to dryness to give 7.2g of a yellowish green powder as a pure product (purity 97.0%) of the target impurity compound I in a yield of 72%.
Example 2
Preparation of the compound of formula I:
adding 10g of nitrile telmisartan shown in a formula II into 50mL of 70% sulfuric acid aqueous solution, stirring at 150 ℃ for 28 hours, monitoring the reaction progress through HPLC analysis, and cooling to room temperature after the reaction is completed; 100mL of methylene chloride is added to the reaction solution for extraction three times, the methylene chloride phase is washed three times by 30% sodium hydroxide aqueous solution (50 mL), the organic phase is concentrated and evaporated to dryness, 6.2g of yellow green powder is obtained, and the yield is 62% as a pure product (purity of 95.3%) of the target impurity compound.
Example 3
Preparation of the compound of formula I:
adding 10g of nitrile telmisartan shown in a formula II into 40mL of 70% sulfuric acid aqueous solution, stirring at 150 ℃ for 24 hours, monitoring the reaction progress through HPLC analysis, and cooling to room temperature after the reaction is completed; 100mL of methylene chloride is added to the reaction solution for extraction three times, the methylene chloride phase is washed three times by 30 percent of sodium hydroxide aqueous solution (30 mL), the organic phase is concentrated and evaporated to dryness, 6.5g of yellow green powder is obtained, and the yield is 65 percent.
Example 4
This example illustrates the use of a compound of formula I as an impurity control in the quality detection of telmisartan finished products.
Chromatographic conditions:
instrument: high performance liquid chromatograph equipped with ultraviolet detector
Chromatographic column: kromasil C18 x 4.0mm 5 μm
Mobile phase a:2.0g of potassium dihydrogen phosphate and 3.8g of sodium pentanesulfonate are dissolved in 1000mL of water, and the pH is adjusted to 3.0 by phosphoric acid
Mobile phase B: methanol: acetonitrile = 200:800 (V/V)
Column temperature: detection wavelength at 40 ℃): 230nm
Flow rate: sample injection amount of 1.0 mL/min: 2 mu L
Mobile phase gradient:
time (min) | Mobile phase a (%) | Mobile phase B (%) |
0 | 70 | 30 |
2 | 70 | 30 |
27 | 20 | 80 |
32 | 20 | 80 |
32.1 | 70 | 30 |
37 | 70 | 30 |
Preparation of telmisartan stock solution: accurately weighing 50mg of telmisartan standard, adding into a 10mL volumetric flask, adding 100 μl of 1M sodium hydroxide solution, dissolving with methanol, diluting to scale, and mixing. (5 mg/mL)
Preparing an impurity reference substance stock solution: accurately weighing 50mg of the compound shown in the formula I, adding into a 10mL volumetric flask, dissolving with methanol, diluting to a scale, uniformly mixing, then transferring into a 5.0mL to 100mL volumetric flask, diluting to the scale with methanol, and uniformly mixing.
Preparing a reference substance solution: accurately transferring the telmisartan impurity reference substance stock solution from 1.0mL to 10mL of volumetric flask, diluting to scale with methanol, mixing well, transferring the solution from 1.0mL to 5.0mL of telmisartan impurity reference substance stock solution from 10mL of volumetric flask, diluting to scale with methanol, and mixing well.
Preparing a test solution: accurately weighing 50mg to 10mL volumetric flask of telmisartan sample, adding 100 mu L of 1mol/L sodium hydroxide solution, dissolving with methanol and diluting to scale, mixing well, transferring to 5.0mL to 10mL volumetric flask, diluting with methanol to scale, and mixing well. (0.5 mg/mL)
The quality inspection result of the telmisartan finished product measured by using the impurity I compound as an impurity reference substance is as follows:
Claims (1)
1. a process for the preparation of a compound of formula I comprising the steps of:
reacting 4'- ((1, 4' -dimethyl-2 '-n-propyl- (2, 6' -bi-1H-benzimidazole) -1 '-group) methyl) - (1, 1' -biphenyl) -2-cyano group with 70% sulfuric acid water solution at 145-150 ℃ for 24-36 hours, separating to obtain the compound shown in the formula I
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