CN110590783A - Preparation method of unknown impurity of sitagliptin phosphate tablet - Google Patents
Preparation method of unknown impurity of sitagliptin phosphate tablet Download PDFInfo
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- CN110590783A CN110590783A CN201910816429.0A CN201910816429A CN110590783A CN 110590783 A CN110590783 A CN 110590783A CN 201910816429 A CN201910816429 A CN 201910816429A CN 110590783 A CN110590783 A CN 110590783A
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- sitagliptin
- impurity
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- sitagliptin phosphate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
- G01N24/087—Structure determination of a chemical compound, e.g. of a biomolecule such as a protein
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
Abstract
The invention discloses a preparation method of an unknown impurity of a sitagliptin phosphate tablet, which relates to the technical field of organic synthesis, wherein sitagliptin and maleic anhydride are used as raw materials, and the sitagliptin impurity is obtained through an addition reaction under the action of a catalyst; the sitagliptin impurity (I) can be efficiently synthesized by the preparation method, and the structure of the impurity is determined by nuclear magnetism and mass spectrum characterization; and the impurity is used as a reference substance to qualitatively and quantitatively analyze whether the sitagliptin phosphate preparation generates the impurity or not in the processing or placing process and the content of the impurity in the sitagliptin phosphate preparation, so that the quality of the sitagliptin phosphate preparation is favorably controlled, and the sitagliptin phosphate preparation is ensured to exert expected drug effect.
Description
The technical field is as follows:
the invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of an unknown impurity of sitagliptin phosphate tablets.
Background art:
according to the data and the reckoning of diabetes and Impaired Glucose Tolerance (IGT) published by the International Diabetes Federation (IDF), the number of diabetic patients is 1.94 hundred million in 2003, and reaches 3.33 hundred million in 2025; the number of IGTs was 3.14 billion in 2003 and as high as 4.72 billion in 2025. In recent years, with the continuous improvement of the living standard of people and the change of the dietary structure, the number of diabetes patients in China also increases on a large scale.
The antidiabetic drugs currently used clinically are mainly insulin-like drugs, sulfonylureas, metformin, and recently marketed α -glucosidase inhibitors and insulin sensitizer thiazolidinedione-like drugs. The medicines have good curative effect, but still have the defect that the long-term curative effect cannot be maintained due to long-term use of the medicines, and are easy to cause a plurality of adverse reactions such as hypoglycemia, weight gain, hepatotoxicity and the like.
Dipeptidyl peptidase IV (DPP-IV) can rapidly and effectively degrade glucagon-like peptide 1 (GLP-1), GLP-1 is one of the most effective stimulators for insulin generation and secretion, so that the effect of endogenous GLP-1 can be enhanced by inhibiting DPP-IV, the content of insulin in blood is increased, and the blood sugar level of a diabetic patient is reduced and maintained. At present, the DPP-IV inhibitor is proved to be a novel antidiabetic therapeutic drug by medicine, and clinical results show that the drug has good hypoglycemic effect. Since GLP-1 plays a role in promoting insulin production and secretion and is glucose-dependent, adverse reactions such as hypoglycemia and weight gain caused by antidiabetic drugs do not occur.
Sitagliptin phosphate, developed and marketed by merck corporation, is the first dipeptidyl peptidase-4 (DPP-4) inhibitor, is used alone or is combined with other oral hypoglycemic agents to form a compound drug for treating type 2 diabetes, and has the advantages of good safety and low incidence of adverse reactions such as hypoglycemia and weight gain. The drug was marketed in the united states at 16/10/2006 and 30/3/2007, and was approved by the U.S. FDA for the treatment of type 2 diabetes in combination with metformin, and has been marketed in several countries in europe. In 8 months 2009, the drug was approved by the european union as a first line drug for the treatment of type 2 diabetes. Sitagliptin was introduced in japan by Ono corporation at 12 months 2009 for the treatment of type 2 diabetes mellitus, 5 months 2011, which approved combination with alpha glucosidase inhibitor, and 9 months 2011, which approved combination with insulin.
The chemical name of sitagliptin phosphate is 7- [ (3R) -3-amino-1-oxo-4- (2,4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3-trifluoromethyl-1, 2, 4-triazolo [4,3-a ] pyrazine, and the structure is as follows:
the preparation method comprises the following steps that when sitagliptin phosphate is prepared into sitagliptin phosphate tablets and sitagliptin metformin tablets, sitagliptin reacts with one auxiliary material sodium stearyl fumarate in the preparation process, and the reaction occurs in the preparation and placement processes, and the generated impurity structural formula is as shown in formula I:
the method has the advantages that the standard of European pharmacopoeia and American pharmacopoeia sitagliptin tablets does not contain impurity I, unknown impurities are generated in the detection process of related substances of the sitagliptin phosphate tablets, the impurities are increased through an accelerated stability test of a sample, the impurity is judged to be possibly I, no reference substance for the impurities is supplied on the market, no report of a synthetic method for the impurities is provided in domestic and foreign documents and patents, and the accuracy of qualitative and quantitative determination is poor due to the adoption of a self-comparison method at present.
In order to improve the quality of the sitagliptin phosphate tablets and sitagliptin metformin phosphate tablets and reduce the risk of clinical medication, research and monitoring on related substances in the sitagliptin phosphate tablets and sitagliptin metformin phosphate tablets are needed. Since the content of impurities in the sitagliptin phosphate tablets and sitagliptin metformin tablets is strictly controlled, it is urgent to provide a synthetic method capable of simply and efficiently obtaining an impurity I reference substance.
The invention content is as follows:
the invention aims to solve the technical problem of providing a preparation method of unknown impurities in sitagliptin phosphate tablets, which has the advantages of short reaction route, low energy consumption, low production cost, simple operation and suitability for industrial production; and the yield is high, and the prepared sitagliptin has high impurity purity.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
the preparation method of the unknown impurity of the sitagliptin phosphate tablet takes sitagliptin and maleic anhydride as raw materials, and the sitagliptin impurity is obtained through addition reaction under the action of a catalyst, wherein the structural formula of the sitagliptin impurity is shown as a formula I:
the catalyst is pyridine, piperidine, triethylamine, diazabicyclo, CuCl and AlCl3、ZnCl2At least one of (1) and (b).
The temperature of the reaction is 20-50 ℃.
The reaction time is 2-10 h.
The solvent for the reaction is one or more of tetrahydrofuran, N-dimethylformamide, ethanol and methanol.
The molar ratio of sitagliptin to maleic anhydride is 1: 1-1.2.
The weight ratio of the catalyst to sitagliptin is 0.5-1: 1.
The specific synthetic route is as follows:
the invention also aims to provide an application of the sitagliptin impurity synthesized according to the preparation method in preparing a sitagliptin impurity reference substance so as to provide the impurity reference substance for the quality control of sitagliptin.
The invention has the beneficial effects that: the sitagliptin impurity (I) can be efficiently synthesized by the preparation method, and the structure of the impurity is determined by nuclear magnetism and mass spectrum characterization; and the impurity is used as a reference substance to qualitatively and quantitatively analyze whether the sitagliptin phosphate preparation generates the impurity or not in the processing or placing process and the content of the impurity in the sitagliptin phosphate preparation, so that the quality of the sitagliptin phosphate preparation is favorably controlled, and the sitagliptin phosphate preparation is ensured to exert expected drug effect.
Description of the drawings:
FIG. 1 shows sitagliptin impurity (I)1H NMR chart;
FIG. 2 shows sitagliptin impurity (I)13C NMR chart;
figure 3 is the MS diagram of sitagliptin impurity (I).
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
2.00g of sitagliptin and 0.98g of maleic anhydride are added into a reaction bottle, 20mL of tetrahydrofuran is added, the mixture is stirred at room temperature until the mixture is completely dissolved, 1.60g of diazabicyclo is added, the color of the reaction mixture gradually becomes orange red, and the stirring is continued for 3 hours at room temperature. After sitagliptin completely reacts, 0.70g of anhydrous potassium carbonate is added into a reaction bottle, 20mL of water is added at the same time, and stirring is carried out for 1h at room temperature. Then, the mixture was extracted twice with 50mL of dichloromethane, and the organic layer was separated. Dilute hydrochloric acid was slowly dropped into the water layer to adjust the pH to 7, and the mixture was extracted twice with 100mL dichloromethane, the organic layer was separated, and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate and n-hexane to obtain 1.99g of a white powdery solid with a yield of 80%. The structure characterization maps of the products are shown in figure 1, figure 2 and figure 3.
1H NMR(400MHz,DMSO-d6)δ14.39(s,1H),8.92(d,J＝8.3Hz,1H),7.53–7.35(m,2H),6.33–6.13(m,2H),4.98(s,1H),4.94–4.81(m,1H),4.49–4.36(m,1H),4.32–4.19(m,1H),4.14–4.04(m,1H),4.00–3.91(m,2H),3.03–2.87(m,1H),2.84-2.70(m,3H).
13C NMR(100MHz,DMSO-d6)δ169.46,166.02,165.40,157.60,155.28,151.43,151.25,147.39,145.09,143.23,142.84,133.15,132.08,122.62,120.30,119.83,117.61,106.10,47.36.32.52.
MS-{M+H+}＝506.2，MS-{M+Na+}＝528.1
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. A preparation method of unknown impurities in sitagliptin phosphate tablets is characterized by comprising the following steps: the method comprises the following steps of taking sitagliptin and maleic anhydride as raw materials, and carrying out addition reaction under the action of a catalyst to obtain sitagliptin impurities, wherein the structural formula of the sitagliptin impurities is shown as a formula I:
2. the method of claim 1, wherein: the catalyst is pyridine, piperidine, triethylamine, diazabicyclo, CuCl and AlCl3、ZnCl2At least one of (1) and (b).
3. The method of claim 1, wherein: the temperature of the reaction is 20-50 ℃.
4. The method of claim 1, wherein: the reaction time is 2-10 h.
5. The method of claim 1, wherein: the solvent for the reaction is one or more of tetrahydrofuran, N-dimethylformamide, ethanol and methanol.
6. The method of claim 1, wherein: the molar ratio of sitagliptin to maleic anhydride is 1: 1-1.2.
7. The method of claim 1, wherein: the weight ratio of the catalyst to sitagliptin is 0.5-1: 1.
8. The use of sitagliptin impurity synthesized by the preparation method of claim 1 in the preparation of sitagliptin impurity reference substance.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234080A (en) * | 2021-05-26 | 2021-08-10 | 乳源东阳光药业有限公司 | Sitagliptin phosphate intermediate impurity and preparation method thereof |
| CN113979896A (en) * | 2021-11-18 | 2022-01-28 | 浙江永太手心医药科技有限公司 | Sitagliptin impurity I and preparation method thereof |
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| CN106349245A (en) * | 2016-08-09 | 2017-01-25 | 重庆植恩药业有限公司 | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities |
| CN107188893A (en) * | 2017-06-23 | 2017-09-22 | 合肥华方医药科技有限公司 | A kind of preparation method of Xi Gelieting impurity |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014000629A1 (en) * | 2012-06-25 | 2014-01-03 | 广东东阳光药业有限公司 | Hexahydropentaleno derivatives, preparation method and use in medicine thereof |
| CN106349245A (en) * | 2016-08-09 | 2017-01-25 | 重庆植恩药业有限公司 | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234080A (en) * | 2021-05-26 | 2021-08-10 | 乳源东阳光药业有限公司 | Sitagliptin phosphate intermediate impurity and preparation method thereof |
| CN113979896A (en) * | 2021-11-18 | 2022-01-28 | 浙江永太手心医药科技有限公司 | Sitagliptin impurity I and preparation method thereof |
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