CN109912512A - A kind of new Telmisartan impurity compound and its preparation method and application - Google Patents
A kind of new Telmisartan impurity compound and its preparation method and application Download PDFInfo
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- CN109912512A CN109912512A CN201711326291.3A CN201711326291A CN109912512A CN 109912512 A CN109912512 A CN 109912512A CN 201711326291 A CN201711326291 A CN 201711326291A CN 109912512 A CN109912512 A CN 109912512A
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- telmisartan
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Abstract
The invention discloses compounds shown in a kind of Formulas I, also disclose the compounds process for production thereof and its purposes in Telmisartan quality inspection of finished products as impurity reference substance, implementation of the invention is effectively controlled the quality of Telmisartan, to guarantee the safety and validity of Telmisartan clinical use.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to new Telmisartan impurity compound of one kind and preparation method thereof and use
On the way.
Background technique
Telmisartan is developed by Boehringer Ingelheim company, goes through to list within 1999, trade name Micardis, is used
In treatment essential hypertension, structural formula is as follows:
Impurity research is the important content of drug research and development, and always through drug research and development, the presence of impurity directly affects
Safety, validity and the quality controllability of drug.
Summary of the invention
The technique mistake of inventor's itrile group telmisartan compound sulphuric acid hydrolysis shown in Research-type II generation Telmisartan
Cheng Zhonghui generates a kind of new impurity, which with the extension of reaction time, shows a increasing trend, and impurity yield
It is temperature dependent with the concentration of aqueous sulfuric acid, sulfuric acid concentration or temperature are higher, and impurity yield is bigger.Therefore, there is an urgent need to
It determines the specific structure of the impurity and develops a kind of method that fast, economical prepares the impurity compound.This work to Telmisartan
Skill exploitation, stability study and analysis method exploitation have very big practical significance.Compound structure shown in Formula II is as follows:
Above-mentioned new Telmisartan impurity, shown in structural formula such as following formula (I):
Compound shown in Formulas I by nuclear magnetic resonance (1H NMR and13C NMR), infrared spectroscopy (IR) and mass spectrum (ESI-MS)
Structural characterization is carried out, testing result is respectively as shown in Fig. 1, Fig. 2, Fig. 3 and Fig. 4.Nuclear magnetic resonance spectroscopy and carbon spectrum are parsed,
Belong to as follows:
1H NMR(600MHz,d6- DMSO) δ 0.96 (t, J=10.8Hz, 3H, CH3),1.78(m,2H,CH2),2.63(s,
3H,CH3), 2.89 (t, J=10.8Hz, 2H, CH2),3.84(s,3H,CH3),5.64(s,2H,CH2),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)；
13C NMR(100MHz,d6-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 parameter of this impurity compound is described below:
Mass spectrum (ESI-MS) provides [M+H]+=497.30 molecular ion peak, with Telmisartan (molecular weight: 514.62)
Difference 17, it is almost consistent with impurity structural theory molecular weight 496.23.
Impurity Compound I1HNMR and Telmisartan1HNMR is compared, and fragrant area lacks 1 hydrogen.
Impurity Compound I13CNMR and Telmisartan13CNMR is compared, carboxyl carbon (the about 165- of a few feature
175ppm), the carbonyl carbon (192.8ppm) of more features.
The IR spectrogram of impurity Compound I has lacked blunt 1693cm compared with the IR spectrogram of Telmisartan-1Absorption peak and
2000-3100cm-1Wide absorption peak (characteristic peak of carboxyl), more sharp 1717cm-1Strong absworption peak (carbonyl
Characteristic peak).
According to above data, inventor determines that the compound structure is shown in formula I:
By structural analysis, inventor thinks that this impurity is that Telmisartan itself friedel-crafts acylation forms, and specific impurity is raw
It is as follows at mechanism:
The second aspect of the invention further relates to the preparation method of compound shown in Formulas I, comprising the following steps:
By 4'- ((1,4'- dimethyl -2'- n-propyl-(2,6'- connection -1H- benzimidazole) -1'- base) methyl)-(1,1'-
Biphenyl) -2- cyano reacts at 120-150 DEG C with aqueous sulfuric acid, isolated Formulas I compound represented.
The concentration of aqueous sulfuric acid is 50%-70%, preferably 60%-70%, further preferably 70% in step.
Heating temperature is preferably 140-150 DEG C in step, and further preferably 145-150 DEG C.
The reaction time is 12-72 hours, preferably 18-48 hours, further preferably 24-36 hours in step.
The impurity Compound I purity that preparation method according to the present invention obtains is 90% or more, preferably 95% or more, into
One step is preferably 99% or more.
Purposes of the impurity Compound I according to the present invention when Telmisartan final product quality is detected as impurity reference substance.
The present invention also provides a kind of methods that the quality for Telmisartan finished product is controlled, it is characterised in that: benefit
Use impurity Compound I as impurity reference substance.Preferred method of quality control, comprising the following steps: weigh suitable impurity Iization
Object is closed, the impurity reference substance solution that dilution is prepared into suitable concentration is dissolved in；Then with reversed-phase liquid chromatography method to for meter Sha
Impurity Compound I contained in smooth sample is qualitatively or quantitatively studied.
Process exploitation, stability study and analysis method of the impurity Compound I found according to the present invention in Telmisartan
Exploitation has important application value.In addition, present invention discover that impurity Compound I make it possible to more easily, more intuitively
Quality control is carried out to Telmisartan finished product.In addition, the preparation method process costs of impurity Compound I according to the present invention are low,
It is easy to control, raw material is easy to get；And obtained stable product quality, high income.
The beneficial effects of the present invention are: present invention finds new impurity compound I, and provide the impurity compound
Preparation method and purposes as reference substance when as detection Telmisartan final product quality, Telmisartan can be effectively controlled
Quality, to guarantee the safety and validity of Telmisartan clinical use.
Detailed description of the invention
Fig. 1: compound shown in Formulas I1HNMR spectrogram.
Fig. 2: compound shown in Formulas I13CNMR spectrogram.
Fig. 3: the IR spectrogram of compound shown in Formulas I.
Fig. 4: the ESI-MS spectrogram of compound shown in Formulas I.
Specific embodiment
Embodiment 1
The preparation of compound shown in Formulas I:
Itrile group Telmisartan 10g shown in Formula II is added in 70% aqueous sulfuric acid of 30mL, 145 DEG C of stirrings 36 are small
When, monitoring reaction process is analyzed by HPLC, end of reaction is cooled to room temperature；80mL methylene chloride extraction three is added in reaction solution
Secondary, methylene chloride is mutually washed three times with 30% sodium hydrate aqueous solution (30mL), and organic phase concentration is evaporated, and obtains the yellowish green toner of 7.2g
End is target impurity compound I sterling (purity 97.0%), yield 72%.
Embodiment 2
The preparation of compound shown in Formulas I:
Itrile group Telmisartan 10g shown in Formula II is added in 70% aqueous sulfuric acid of 50mL, 150 DEG C of stirrings 28 are small
When, monitoring reaction process is analyzed by HPLC, end of reaction is cooled to room temperature；100mL methylene chloride extraction three is added in reaction solution
Secondary, methylene chloride is mutually washed three times with 30% sodium hydrate aqueous solution (50mL), and organic phase concentration is evaporated, and obtains the yellowish green toner of 6.2g
End is target impurity pure compounds (purity 95.3%), yield 62%.
Embodiment 3
The preparation of compound shown in Formulas I:
Itrile group Telmisartan 10g shown in Formula II is added in 70% aqueous sulfuric acid of 40mL, 150 DEG C of stirrings 24 are small
When, monitoring reaction process is analyzed by HPLC, end of reaction is cooled to room temperature；100mL methylene chloride extraction three is added in reaction solution
Secondary, methylene chloride is mutually washed three times with 30% sodium hydrate aqueous solution (30mL), and organic phase concentration is evaporated, and obtains the yellowish green toner of 6.5g
End is target impurity pure compounds (purity 96.2%), yield 65%.
Embodiment 4
The present embodiment illustration is to compound shown in Formulas I when Telmisartan final product quality is detected as impurity reference substance
Purposes.
Chromatographic condition:
Instrument: high performance liquid chromatograph is equipped with UV detector
Chromatographic column: 5 μm of Kromasil C18 125*4.0mm
Mobile phase A: 2.0g potassium dihydrogen phosphate and 3.8g sodium pentanesulfonate are dissolved in 1000mL water, with phosphoric acid tune pH3.0
Mobile phase B: methanol: acetonitrile=200:800 (V/V)
Column temperature: 40 DEG C of Detection wavelengths: 230nm
Flow velocity: 1.0mL/min sample volume: 2 μ L
Eluent 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 |
The preparation of Telmisartan stock solution: accurately weighing Telmisartan standard items 50mg, is added in 10mL volumetric flask, adds
The sodium hydroxide solution of the 1M concentration of 100 μ L is diluted to scale after being dissolved with methanol, mix.(5mg/mL)
The preparation of impurity reference substance stock solution: accurately weighing compound 50mg shown in Formulas I, is added in 10ml volumetric flask,
It is diluted to scale after being dissolved with methanol, is pipetted in 5.0mL to 100mL volumetric flask again after mixing, with methanol dilution to scale, mixes
It is even.
The preparation of reference substance solution: Telmisartan impurity reference substance stock solution 1.0mL to 10mL volumetric flask is accurately pipetted
Middle methanol dilution to scale mixes, then pipettes solution 1.0mL and Telmisartan stock solution 5.0mL to 10mL volumetric flask
In, with methanol dilution to scale, mix.
The preparation of test solution: it accurately weighs in Telmisartan sample 50mg to 10mL volumetric flask, adds 100 μ L's
The sodium hydroxide solution of 1mol/L dissolves with methanol and is diluted to scale, is pipetted in 5.0mL to 10mL volumetric flask again after mixing,
With methanol dilution to scale, mix.(0.5mg/mL)
Impurity Compound I is as follows as the quality examination result of impurity reference substance measurement Telmisartan finished product:
Claims (9)
1. compound shown in Formulas I:
2. compound according to claim 1, purity is 90% or more, preferably 95% or more, further preferably
99% or more.
3. use of the compound according to claim 1 or 2 when Telmisartan final product quality is detected as impurity reference substance
On the way.
4. a kind of preparation method of compound shown in Formulas I, comprising the following steps:
By 4'- ((1,4'- dimethyl -2'- n-propyl-(2,6'- connection -1H- benzimidazole) -1'- base) methyl)-(1,1'- connection
Benzene) -2- cyano reacts at 120-150 DEG C with aqueous sulfuric acid, isolated Formulas I compound represented.
5. according to the method described in claim 4, it is characterized by: the concentration of aqueous sulfuric acid is 50%-70%, preferably
60%-70%, further preferably 70%.
6. according to the described in any item methods of claim 4 or 5, it is characterised in that: heating temperature is preferably 140-150 DEG C, into
One step is preferably 145-150 DEG C.
7. according to the described in any item methods of claim 4 to 6, it is characterised in that: the reaction time is 12-72 hours, preferably
18-48 hours, further preferably 24-36 hours.
8. a kind of method that the quality for Telmisartan finished product is controlled, it is characterised in that: utilize compound shown in Formulas I
As impurity reference substance.
9. according to the method described in claim 8, the following steps are included:
The shown compound for weighing suitable Formulas I is dissolved in the impurity reference substance solution that dilution is prepared into suitable concentration；Then it uses
Reversed-phase liquid chromatography method qualitatively or quantitatively studies the shown compound impurities of Formulas I contained in Telmisartan sample.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110836943A (en) * | 2019-11-29 | 2020-02-25 | 江西杏林白马药业有限公司 | Analysis method for impurity detection of telmisartan tablets and telmisartan capsules |
| CN111454148A (en) * | 2020-04-23 | 2020-07-28 | 东南大学 | Telmisartan impurity compound and preparation method thereof |
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| CN111454148A (en) * | 2020-04-23 | 2020-07-28 | 东南大学 | Telmisartan impurity compound and preparation method thereof |
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| CN109912512B (en) | 2023-05-30 |
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