CN111285876A - Linagliptin intermediate isomer impurity, preparation method and application thereof - Google Patents
Linagliptin intermediate isomer impurity, preparation method and application thereof Download PDFInfo
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- CN111285876A CN111285876A CN201811486330.0A CN201811486330A CN111285876A CN 111285876 A CN111285876 A CN 111285876A CN 201811486330 A CN201811486330 A CN 201811486330A CN 111285876 A CN111285876 A CN 111285876A
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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
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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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
- G01N30/04—Preparation or injection of sample to be analysed
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
Abstract
The invention relates to a linagliptin intermediate isomer. The invention also provides a preparation and purification method for obtaining the linagliptin intermediate isomer through the reaction of the 4-methyl-2-halogenated methyl quinazoline and 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-diketone in a silicone reagent and alkali. The preparation method has the advantages of simple operation, low cost and high purity of the obtained linagliptin intermediate isomer. The effective synthesis and purification of linagliptin intermediate isomers lay a good foundation for the quality research and control of linagliptin and linagliptin intermediates.
Description
Technical Field
The invention relates to the technical field of medicaments, in particular to a medicament linagliptin isomer, a preparation method and application thereof.
Background
Linagliptin (linagliptin, formula II), 8- [ (3R) -3-amino-1-piperidinyl ] -7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione; the English chemical name is 8- [ (3R) -3-amino-1-piperidinyl ] -7- (2-butyl) -3, 7-dihydo-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, which is an oral hypoglycemic drug developed by Boehringer Invitrogen pharmaceutical Inc (Boehringer Ingelheim Pharmaceuticals Inc.) in Germany, and is approved by FDA in 5/2.2011 and sold on the market under the trade name of Tradjenta. The product is in the form of tablet, and can be used in combination with diet and exercise for improving blood sugar control ability of type 2 diabetic patients. Linagliptin has good blood glucose reducing effect, slight adverse reaction and obvious metabolic advantage, and is superior in DPP-4 inhibitor with the same action mechanism (linagliptin: superior in DPP-4 inhibitor, pharmaceutical economy report/2012/3 months/5 days/011 th edition). The chemical structural formula of linagliptin is as follows:
the currently reported preparation methods of linagliptin (linagliptin synthetic route diagram, journal of chinese medical industry, vol 25, No. 11, No. 2014, 1193-:
the key intermediate is prepared from 4-methyl-2-chloromethyl quinazoline and 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione serving as raw materials under the action of potassium carbonate through a reaction formula shown in figure 1, and researches show that a plurality of impurities are generated in the preparation process of the key intermediate, and reports related to separation confirmation and application research of the linagliptin key intermediate impurities are not found.
According to the existing research flow of the medicine, the impurities of the medicine preparation intermediate are researched and determined, and the corresponding impurities in the finished medicine are traced, so that the method is a key link and method for effectively controlling the quality of the finished bulk medicine. The person skilled in the art therefore strives to clarify the structure and preparation of impurities in the intermediate that have an effect on the final product.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a medicament, namely a linagliptin isomer, and a preparation method and application thereof.
Specifically, the linagliptin intermediate isomer impurity has a structure shown in a formula (I):
the invention also provides a preparation method of the linagliptin intermediate isomer impurity, which is characterized in that the linagliptin intermediate isomer impurity is obtained by reacting 4-methyl-2-halogenated methyl quinazoline and 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-diketone with a silicone ester reagent and alkali, wherein the reaction formula is shown in figure 2:
further, the silicone ester reagent is trifluoromethanesulfonic acid silicone ester or trifluoroacetic acid silicone grease.
Further, trimethylhalosilane or silicosulfuric acid is also used in the preparation reaction, and the trimethylhalosilane is selected from the group consisting of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane.
Further, the halogenation in the 4-methyl-2-halogenated methyl quinazoline is chloro, bromo or iodo.
Further, the alkali is metal hydride, metal alcoholate and organic amine. The alkali metal hydride may be sodium hydride or calcium hydride, and the metal alkoxide may be selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, but is not limited to the above choices. The organic amine is selected from DBU, DBN or DMAP, but is not limited to these.
Further, the preparation method further comprises a purification step selected from any one of recrystallization, preparative chromatography, or a combination thereof.
Further, the recrystallization solvent is selected from alcohols, and the alcohols are selected from any one of methanol, ethanol, isopropanol, n-propanol and tert-butanol or the combination thereof.
Further, the preparative chromatographic separation condition is any one selected from methanol-0.02M potassium dihydrogen phosphate, acetonitrile-0.02M potassium dihydrogen phosphate and methanol-acetonitrile-0.02M potassium dihydrogen phosphate, isocratic or gradient elution is carried out, product fractions are collected, organic solvents are removed by concentration, and the product is obtained by suction filtration. The 0.02M potassium dihydrogen phosphate solution can be used by adjusting the pH value to 3-7 with phosphoric acid; the flow rate of the preparative liquid chromatography purification is 25-55 mL/min; the single sample injection amount of the preparative liquid chromatography purification is 100-500 mg; the detection wavelength of the preparative liquid chromatography purification is 220 nm-300 nm.
The linagliptin intermediate isomer impurity can be used as a standard substance or a reference substance and used for researching the quality of linagliptin intermediates and finished products thereof.
The largest impurity in the linagliptin key intermediate obtained according to the preparation method shown in fig. 1 is the isomer, wherein the isomer is generally detected in a ratio of 0.2-0.6% (area normalization method). The isomers can be further reacted to form linagliptin isomers (formula IV) in the finished product:
the invention provides a preparation and purification method of a linagliptin intermediate isomer, which confirms the impurity existing in the linagliptin preparation process for the first time and has the advantages of simple operation, low cost and high purity of the obtained linagliptin intermediate isomer. The effective synthesis and purification of linagliptin intermediate isomers lay a good foundation for the quality research and control of linagliptin and linagliptin intermediates.
The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention.
Drawings
FIG. 1 reaction equation for the preparation of linagliptin intermediate in the prior art;
FIG. 2 is a reaction formula for preparing linagliptin intermediate isomer impurities;
FIG. 3 is a liquid phase diagram of the linagliptin intermediate prepared by a prior art method;
FIG. 4 is a liquid phase diagram of a linagliptin intermediate isomer prepared according to a preferred embodiment of the present invention;
FIG. 5 is a 1H NMR spectrum of linagliptin intermediate isomers prepared in a preferred embodiment of the present invention;
FIG. 6 is a 13C NMR spectrum of linagliptin intermediate isomers prepared in a preferred embodiment of the present invention;
FIG. 7 HRMS spectra of linagliptin intermediate isomers prepared in a preferred embodiment of the present invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The preferred embodiments of the present invention will be described below with reference to the accompanying drawings for clarity and understanding of technical contents. The present invention may be embodied in many different forms of embodiments and the scope of the invention is not limited to the embodiments set forth herein.
EXAMPLE 1 preparation of linagliptin intermediate isomers
The reaction scheme is shown in FIG. 2.
15g (50.7 mmol) of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione, 33.8g (0.152 mol) of trimethylsilyl trifluoromethanesulfonate, 0.55g (5.1 mmol) of trimethylchlorosilane and 150mL of toluene are added into a reaction bottle, heated and refluxed for 24 hours, and the toluene is removed under vacuum reduced pressure. DMF100mL and 10.7g (55.8 mmol) of 4-methyl-2-chloromethyl quinazoline were added to the concentrate, and the mixture was cooled to 0 ℃ and then added with 7.8g (0.162 mmol, 50%) of sodium hydride followed by reaction at 10 ℃ for 5 hours. Adding 200mL of ice water into the reaction solution, adjusting the pH value to be neutral by using acetic acid, cooling to 0-5 ℃, cooling, crystallizing for 2h, performing suction filtration, and adding 20mL of water to wash the filter cake. And drying the filter cake at 50 ℃ under normal pressure, adding 60mL of ethanol, heating to 60 ℃, stirring for 1h, cooling to room temperature, and adding 20mL of methanol for dilution to obtain 16.6g of linagliptin intermediate isomer, wherein the purity is 95.2%, and the yield is 72.5%.
Example 2 preparation of linagliptin intermediate isomers
15g (50.7 mmol) of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione, 28.3g (0.152 mol) of trimethylsilyl trifluoroacetate, 1.5g of silicosulfuric acid and 150mL of toluene were added to a reaction flask, heated under reflux for 20H, and the toluene was removed under reduced pressure. To the concentrate was added DMF100mL, 13.2g (55.8 mmol) of 4-methyl-2-bromomethyl quinazoline, the temperature was lowered to 0 ℃ and DBN12.6g (0.101 mol) was added, and the reaction was carried out at 35 ℃ for 7 hours. Adding 200mL of ice water into the reaction solution, adjusting the pH value to be neutral by using acetic acid, cooling to 0-5 ℃, cooling, crystallizing for 2h, performing suction filtration, and adding 20mL of water to wash the filter cake. And drying the filter cake at 50 ℃ under normal pressure to obtain 19.7g of crude linagliptin intermediate isomer product with the yield of 86%.
And (3) performing preparative chromatographic separation on the crude product, collecting a solution containing the isomer, concentrating to remove the organic solvent, performing suction filtration, and washing with water to obtain 14.8g of a linagliptin isomer pure product, wherein an HPLC (high performance liquid chromatography) spectrum is shown in figure 4, the purity is 98.9%, and the yield is 75.1%. As shown in fig. 7. ESI + =455.0638, isomer exact molecular weight 452.0596, theoretical molecular ion peak is M +2+ H due to bromine content, consistent with high resolution spectra. As shown in fig. 5 and 6, both 1HNMR and 13CNMR showed data consistent with the theoretical structure of the isomers.
The detection conditions of the HPLC purity are as follows:
a chromatographic column: yue Xue C184.6 x 250mm 5 μm;
flow rate: 1.0mL/min;
column temperature: 35 ℃;
wavelength: 254 nm;
mobile phase: acetonitrile: 0.02M KH2PO4=50: 50.
The purification conditions of the preparative chromatography are as follows:
a chromatographic column: c1850 is multiplied by 500mm and 10 mu m;
flow rate: 45mL/min;
column temperature: 25 ℃;
wavelength: 280 nm;
the gradient elution conditions are shown in the following table:
| time (min) | A | |
| 0 | 25% | 75% |
| 30 | 60% | 40% |
Wherein A is acetonitrile, and the mobile phase B is 0.02M potassium dihydrogen phosphate, and the pH value of the potassium dihydrogen phosphate is adjusted to 3.0 by phosphoric acid.
Example 3 preparation of linagliptin intermediate (formula III)
The reaction scheme is shown in FIG. 1.
11.5g (38.8 mmol) of 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione, 170mL of N-methylpyrrolidone, 8.2g (42.8 mmol) of 4-methyl-2-chloromethyl quinazoline and K2CO38.1 g (0.5827 mol) are added into a 500mL three-necked flask, heated to 80 ℃ and heated for stirring for 4H. Adding 360mL of methanol, cooling the reaction to room temperature, stirring to separate out a solid, performing suction filtration, washing the solid with water to be neutral, adding 90mL of methanol into the solid, pulping for 1h at 60 ℃, naturally returning to the room temperature, performing suction filtration, drying at 50 ℃ for 14.9g, obtaining the yield of 84.9%, and obtaining the HPLC (high performance liquid chromatography) spectrum as shown in figure 3, wherein the purity of a main peak is 99.1%, 5.627min is the linagliptin intermediate isomer, and the area normalization method accounts for 0.3272%.
Example 4 preparation of linagliptin isomer (formula IV)
9.5g (21.0 mmol) of linagliptin intermediate isomer prepared in example 1, 1900mL of methyl isobutyl ketone, K2CO313.6g (0.9667 mol), and 40.8g (0.2371 mol) of 3-aminopiperidine dihydrochloride are put into a 3000mL three-necked flask and protected by N2. After the feeding is finished, the temperature is increased and the reflux reaction is carried out for 24 hours, and nitrogen is introduced. Naturally returning to room temperature. The next day, filtration was performed, the filter cake was washed with 20mL of methyl isobutyl ketone, the filtrate was diluted with 200mL of water, adjusted to pH =4-5 with AcOH, the layers were separated, the aqueous layer was extracted 2 times with DCM (50 mL × 2), the aqueous layer was added with DCM150mL, adjusted to pH =11 with aqueous NaOH, the layers were separated, the aqueous layer was extracted 2 times with DCM (50 mL × 2), the DCM layers were combined, dried, added with 30mL of ethanol and slurried to give 8.2g of linagliptin isomer with a yield of 82.6%.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (10)
1. A linagliptin intermediate isomer impurity having a structure represented by formula (I):
2. the preparation method of linagliptin intermediate isomer impurities as claimed in claim 1, characterized in that the linagliptin intermediate isomer impurities are obtained by reacting 4-methyl-2-halomethyl quinazoline and 8-bromo-3, 7-dihydro-3-methyl-1H-purine-2, 6-dione with a silicone ester reagent and a base.
3. The method for preparing linagliptin intermediate isomer impurities according to claim 2, wherein the silicone ester reagent is trifluoromethanesulfonate silicone ester or trifluoroacetic acid silicone ester.
4. The method for preparing linagliptin intermediate isomer impurities according to claim 2, wherein trimethylhalosilane selected from trimethylchlorosilane, trimethylbromosilane or trimethyliodosilane or silicosulfuric acid is further used in the preparation reaction.
5. The method for preparing linagliptin intermediate isomer impurities according to claim 2, wherein the halogenation in the 4-methyl-2-halomethyl quinazoline is chloro, bromo or iodo.
6. The method of preparing linagliptin intermediate isomer impurities according to claim 3, wherein the base is a metal hydride, a metal alkoxide, or an organic amine.
7. The process for the preparation of linagliptin intermediate isomeric impurities according to claim 2, further comprising a purification step selected from any one of recrystallization, preparative chromatography, or a combination thereof.
8. The method for preparing linagliptin intermediate isomer impurities according to claim 7, wherein the recrystallization solvent is selected from alcohols selected from any one of methanol, ethanol, isopropanol, n-propanol, and tert-butanol, or a combination thereof.
9. The method for preparing linagliptin intermediate isomer impurities according to claim 7, wherein the preparative chromatographic separation conditions are any one selected from methanol-0.02M potassium dihydrogen phosphate, acetonitrile-0.02M potassium dihydrogen phosphate, and methanol-acetonitrile-0.02M potassium dihydrogen phosphate, isocratic or gradient elution is performed, product fractions are collected, the organic solvent is removed by concentration, and the linagliptin intermediate isomer is obtained by suction filtration.
10. Use of linagliptin intermediate isomer impurity of claim 1 as a standard or control.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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