CN105503872B - A kind of Li Gelieting impurity and its preparation method and application - Google Patents
A kind of Li Gelieting impurity and its preparation method and application Download PDFInfo
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- CN105503872B CN105503872B CN201510854253.XA CN201510854253A CN105503872B CN 105503872 B CN105503872 B CN 105503872B CN 201510854253 A CN201510854253 A CN 201510854253A CN 105503872 B CN105503872 B CN 105503872B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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Abstract
The invention discloses the Li Gelieting impurity shown in a kind of formula (I), the compounds process for production thereof is also disclosed and its in Li Gelieting Related substances separations as the purposes of impurity reference substance.The product quality of Li Gelieting can be effectively controlled using the impurity as standard reference material, and reduce drug safety risk, so as to ensure the security and validity of Li Gelieting preparation Clinical practices.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of Li Gelieting impurity, preparation method and quality control
The purposes of Shi Zuowei impurity reference substances.
Background technology
Li Gelieting is a kind of potent, selective dipeptidyl peptidase-4 (DPP-4) suppression of Boehringer Ingelheim company research and development
Preparation, can improve the different blood glucose levels of diabetes B (T2DM) adult patients on the basis of diet control and physical training.
Relative to other row spit of fland class medicines, Li Gelieting has excellent renal safety.In May, 2011 obtains U.S. FDA approval listing.
Li Gelieting chemistry is entitled：8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls -1) -3,7- dihydro -3- methyl isophthalic acids -
[(4- methyl -2- quinazolyls) methyl] -1H purine -2,6- diketone, chemical constitution is：
The content of the active ingredient of medicine is the important symbol for reflecting pharmaceutical purity, and the direct shadow of impurity present in medicine
Ring the curative effect to medicine and the generation of toxic and side effect may be caused.Impurity of the drug be produce, store during introduction or generation
Medicine beyond other chemical substances, the presence of impurity not only influences the purity of medicine, can also bring the poison of non-treatment activity
Side effect, it is necessary to be controlled by.Safely and effectively to use medicine, the quality standard of medicine to the purity of effective ingredient and
The limit of impurity has more strict regulation, it is however generally that, the impurity of the drug more than 0.1% should be reflected by process for selective
Determine and quantify.
The domestic Study of synthesis method for Li Gelieting is more, such as document (Chinese pharmaceutical chemistry impurity, 2011 the 21st
Volume 5 phase of Supreme Being page 408) Zhong Gong Kailiao Li Gelieting synthetic route：
During synthesizing according to above-mentioned technique, sent out in the Li Gelieting raw materials detection collection of illustrative plates of a collection of enlarged experiment wherein
An existing new unknown impuritie, the impurity is not the intermediate of above-mentioned reaction, therefore, it is necessary to enter to the new impurity of Li Gelieting
Row research.
The content of the invention
The present invention provides the Li Gelieting impurity compounds shown in a kind of formula (I), preparation method and its as standard control
Application of the product in Li Gelieting raw materials and preparation.
The present invention gropes preparative separation process route, optimization by the numerous studies to Li Gelieting medicine physico-chemical properties
Preparation parameter obtains the impurity compound, and its experimental data is analyzed so as to confirm the structure of the compound, its chemistry
Shown in structural formula such as following formula (I)：
According to the reaction mechanism in document (Chinese pharmaceutical chemistry impurity, 5 phase of Supreme Being page 408 of volume 21 in 2011), it is difficult to solve
The generation path of the impurity is released, therefore, the present invention provides the Li Gelieting impurity shown in formula (I) on the basis of lot of experiments
Preparation method, comprise the following steps：
The first step, in the presence of potassium carbonate or sodium carbonate, with 1-METHYLPYRROLIDONE or DMF as molten
Agent, the bromo- 3- methyl xanthines of 8- and the bromo- 2- butine reactions of 1-, so as to obtain 3- methyl -7- (2- butine -1- bases) bromo- Huangs of -8-
Purine；
Second step, the methylquinazolin of 2- chloromethyls -4 is added into first step reaction solution, heats 115~120 DEG C of reactions,
Post processing obtains 1- [(4- methylquinazolin -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- bromine xanthine；
3rd step, with 1-METHYLPYRROLIDONE or DMF as solvent, after adding second step product, is added dropwise
DIPEA or triethylamine react, column chromatography for separation obtain target product.
Reaction described in the first step is carried out in 1-METHYLPYRROLIDONE or DMF, particularly preferably
Selected from 1-METHYLPYRROLIDONE；Described reaction is carried out under conditions of potassium carbonate or sodium carbonate are present, particularly preferably
Selected from sodium carbonate.
Li Gelieting impurity 1- [(4- methylquinazolin -2- bases) methyl] -3- methyl shown in offer formula (I) of the present invention -
The purposes of 7- (2- butine -1- bases) xanthine is Li Gelieting about material inspection when as impurity reference substance.It can use
It is the quality control and stability analysis of finished product, as normative reference in analysis Li Gelieting.
Need testing solution：Take this product appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70: 30) ultrasonic dissolution and quantitatively dilute
Release and be made the solution containing 0.5mg in every 1ml, as need testing solution.
Impurity reference substance solution：Take Li Gelieting impurity appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70: 30) dissolving
And quantify dilution and be made in every 1ml the solution containing 0.5 μ g, as impurity reference substance solution.
Chromatographic condition：It is filler with octadecylsilane chemically bonded silica；With phosphate buffer as mobile phase A, with first
Alcohol-acetonitrile (55: 45) is Mobile phase B, and A-B (65: 35) is mobile phase；Column temperature is 55 DEG C；Detection wavelength is 225nm.Precision amount
Need testing solution and each 10 μ l of contrast solution are taken, liquid chromatograph, 8 times of record chromatogram to retention time is injected separately into.For
If any impurity peaks in the chromatogram of test sample solution, by external standard method with calculated by peak area, impurity containing Li Gelieting must not cross 0.1%.
The technical effects of the invention are that：The invention discloses a kind of important impurity produced in Li Gelieting production processes
Compound 1- [(4- methylquinazolin -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) xanthine, this impurity compound
How much content directly affects the drug quality of Li Gelieting, and the present invention is directed to Li Gelieting medicines physico-chemical property and its interaction
Mechanism carries out substantial amounts of research, gropes preparative separation process route, optimization preparation parameter and obtains the compound.1- [(4- methyl
Quinazoline -2- bases) methyl] the impurity of -3- methyl -7- (2- butine -1- bases) when being detected as the relevant materials of Li Gelieting compares
Product, can effectively, easily monitor the relevant material in Li Gelieting, and the present invention is effectively controlled the quality of Li Gelieting, from
And ensure the security and validity of Li Gelieting preparation Clinical practices.
Brief description of the drawings
Fig. 1 be formula (I) compound nuclear magnetic resonance-1H collection of illustrative plates.
Fig. 2 is HPLC chromatogram, is the detection level of above-claimed cpd in pharmaceutical composition.
Specific embodiment
The present invention is further illustrated below by embodiment, it should be noted that the following example is not to the present invention
The limitation of protection domain, those skilled in the art under the teachings of the present invention, using the modification of equivalent means, still fall within this
In the range of invention is claimed.
According to embodiments of the present invention, there is provided a kind of preparation method of Li Gelieting impurity.
Embodiment 1：
Step one：
Will 1-METHYLPYRROLIDONE (1000ml) add reactor in, sequentially added under stirring L409-1101 (166g,
0.18mol) with sodium carbonate (180g, 1.7mol), 45~50 DEG C of N- first for starting that L409-1102 (99.5g, 0.75mol) is added dropwise
Base pyrrolidones (375ml), and in completion of dropping in 1 hour, TLC monitorings after reaction completely, obtain L409-11.
Step 2：
Step one reaction solution is heated to 100 DEG C, by L409-2203 (144g, 0.75mol) addition reactors, is used in combination
1-METHYLPYRROLIDONE (208ml) washing kettle wall；115~120 DEG C of reaction 3~6h, HPLC monitorings, after reaction completely, post processing,
Dry brown solid (L409-22) 222g, yield 72%.
Step 3：
Step 2 is obtained into product (222g, 0.48mol) to add into reactor, 1-METHYLPYRROLIDONE is added
(666ml), is slowly stirred, and is warming up to 115~120 DEG C, and in be added dropwise at this temperature DIPEA (253g,
1.97mol), 1h is dripped off；HPLC is monitored, and after reaction completely, closes heating, is cooled to room temperature, and column chromatography for separation obtains above-mentionedization
Compound.Nuclear magnetic resonance-1H spectrums are shown in Figure of description 1.
Embodiment 2
Formula (I) impurity determines the relevant material of Li Gelieting as the reference substance about material.
Chromatographic condition：It is filler with octadecylsilane chemically bonded silica；With phosphate buffer as mobile phase A, with first
Alcohol-acetonitrile (55: 45) is Mobile phase B, and A-B (65: 35) is mobile phase；Column temperature is 55 DEG C；Detection wavelength is 225nm.
Need testing solution：Take this product appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70: 30) ultrasonic dissolution and quantitatively dilute
Release and be made the solution containing 0.5mg in every 1ml, as need testing solution.
Impurity reference substance solution：Take Li Gelieting impurity shown in formula (I) appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70
: 30) dissolve and quantify dilution and be made in every 1ml the solution containing 0.5 μ g, as impurity reference substance solution.
Determination method：Precision measures need testing solution and each 10 μ l of contrast solution, is injected separately into liquid chromatograph, records chromatogram
Figure is to 8 times of retention time.If any impurity peaks in the chromatogram of need testing solution, by external standard method with calculated by peak area, containing sharp lattice
Row spit of fland impurity must not cross 0.1%.
Impurity compound is as follows as the Related substances separation result that the reference substance about material determines Li Gelieting：
| Lot number | L409-150727-3 | L409-150727-4 | L409-150727-5 |
| As a result | 0.03% | 0.02% | 0.01% |
Embodiment 3
Formula (I) impurity determines the relevant material in Li Gelieting pieces as the reference substance about material.
Determined according to high performance liquid chromatography (two annex VD of Chinese Pharmacopoeia version in 2010), chromatographic condition is with reference to embodiment 2.
Need testing solution：Take Li Gelieting pieces fine powder appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70: 30) ultrasound is molten
Solve and quantify dilution and be made the solution containing 0.5mg in every 1ml, as need testing solution.
Impurity reference substance solution：Take Li Gelieting impurity shown in formula (I) appropriate, it is accurately weighed, plus mobile phase A-acetonitrile (70
: 30) dissolve and quantify dilution and be made in every 1ml the solution containing 0.5 μ g, as impurity reference substance solution.
Determination method：Precision measures need testing solution and each 10 μ l of contrast solution, is injected separately into liquid chromatograph, records chromatogram
Figure is to 8 times of retention time.If any impurity peaks in the chromatogram of need testing solution, by external standard method with calculated by peak area, containing sharp lattice
Row spit of fland impurity must not cross 0.1%.Chromatogram is shown in Figure of description 2.
Claims (4)
1. a kind of Li Gelieting impurity, shown in its chemical constitution such as formula (I)：
2. the preparation method of Li Gelieting impurity according to claim 1, comprises the following steps：
The first step, in the presence of potassium carbonate or sodium carbonate, with 1-METHYLPYRROLIDONE or DMF as solvent, 8-
Bromo- 3- methyl xanthines and the bromo- 2- butine reactions of 1-, so as to obtain 3- methyl -7- (2- butine -1- bases) bromo- xanthine of -8-；
Second step, 2- chloromethyl -4- methylquinazolins are added into first step reaction solution, heat 115~120 DEG C of reactions, after
Treatment obtains 1- [(4- methylquinazolin -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- bromine xanthine；
3rd step, with 1-METHYLPYRROLIDONE or DMF as solvent, after adding second step product, is added dropwise N, N-
Diisopropylethylamine or triethylamine react, column chromatography for separation obtain target product.
3. Li Gelieting impurity according to claim 1 in Li Gelieting Related substances separations as impurity reference substance
Purposes.
4. the purposes of Li Gelieting impurity according to claim 3, it is characterised in that during Li Gelieting Related substances separations
HPLC chromatogram condition be：With octadecylsilane chemically bonded silica as filler；With phosphate buffer as mobile phase A, with first
Alcohol-acetonitrile (55:45) it is Mobile phase B, A-B (65:35) it is mobile phase；Column temperature is 55 DEG C；Detection wavelength is 225nm.
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| CN107490630B (en) * | 2016-06-10 | 2021-08-03 | 山东新时代药业有限公司 | Analytical detection method of 7-fluoro-4-hydroxyquinazoline |
| CN107764905B (en) * | 2016-08-19 | 2020-07-14 | 江苏康缘药业股份有限公司 | Detection method of quinazoline-7-ether compound and related substances thereof |
| CN107870209B (en) * | 2016-09-28 | 2020-09-11 | 广东东阳光药业有限公司 | Method for determining impurity content in linagliptin bulk drug |
| CN107870210A (en) * | 2016-09-28 | 2018-04-03 | 广东东阳光药业有限公司 | The method for determining Li Gelieting contents in Li Gelieting bulk drugs |
| CN108132313A (en) * | 2018-01-18 | 2018-06-08 | 上海药明康德新药开发有限公司 | The high-efficiency liquid chromatography method for detecting of BI 1356 |
| CN110240599A (en) * | 2018-03-07 | 2019-09-17 | 齐鲁制药有限公司 | A kind of Li Gelieting impurity and its preparation method and application |
| CN110894198B (en) * | 2018-09-13 | 2022-12-02 | 齐鲁制药有限公司 | Xanthine compound and preparation method and application thereof |
| CN112379018B (en) * | 2020-11-04 | 2022-07-19 | 济南立德医药技术有限公司 | Method for detecting 3-methylxanthine in linagliptin starting material A |
| CN112592320A (en) * | 2020-12-22 | 2021-04-02 | 江苏慧聚药业有限公司 | Related substance of linagliptin intermediate and synthesis method thereof |
| CN113004280A (en) * | 2021-03-01 | 2021-06-22 | 佛山科学技术学院 | Preparation method and application of linagliptin impurity |
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| CN104844603A (en) * | 2015-06-05 | 2015-08-19 | 武汉理工大学 | Simple preparation method of II-type antidiabetic drug linagliptin |
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