CN108017619A - A kind of Topiroxostat impurity and preparation method thereof - Google Patents
A kind of Topiroxostat impurity and preparation method thereof Download PDFInfo
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- CN108017619A CN108017619A CN201711278437.1A CN201711278437A CN108017619A CN 108017619 A CN108017619 A CN 108017619A CN 201711278437 A CN201711278437 A CN 201711278437A CN 108017619 A CN108017619 A CN 108017619A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
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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
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Abstract
The present invention provides the Topiroxostat impurity F as shown in formula (I).And provide the preparation method of Topiroxostat impurity F.The method that the present invention prepares Topiroxostat impurity F, raw material are easy to get, and synthesis technique and purifying process are simple, reproducible；The purity of gained Topiroxostat impurity F meets the quality requirement of impurity.Topiroxostat bulk pharmaceutical chemicals and its qualitative and quantitative analysis research of preparation relative substance F can be efficiently applied to, promotes bulk pharmaceutical chemicals synthesis technique and quality of the pharmaceutical preparations control research, it is ensured that the therapeutic effect and security of clinical application.
Description
Technical field
The present invention relates to a kind of Topiroxostat impurity and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Gout is the disease caused by a kind of purine metabolic disturbance, is classified as one of 20 big chronic disease of 21 century by the United Nations, is
It is only second to the second largest metabolism class disease of diabetes.It can be divided into two major class of primary and Secondary cases according to cause of disease difference：Primary pain
Wind refers on the basis of other diseases are excluded, caused by congenital purine metabolic disturbance and (or) uric acid excretion disorder；After
Hair property gout refers to secondary to underexcretion caused by kidney trouble or some drugs, myeloproliferative disease and chemotherapy of tumors institute
Uric acid generation is caused to increase.Under existing medical condition, primary gout mainly controls blood uric acid by drug therapy, generally
Gout patient blood uric acid 360 μm of below ol/L, with tophus patient in 238 μm of below ol/L, gout symptom can be slowed down.
Topiroxostat (Topiroxostat) is a kind of active drug for treating gout and high lithemia, is the non-of high selectivity
Purines xanthine oxidoreductase inhibitors.Developed by Japanese fuji medicine Co., Ltd., obtain Japan in August, 2013 and improve people's living condition
Save approval and listed first in Japan.
To better control over the quality standard of Topiroxostat bulk pharmaceutical chemicals and its preparation, need strictly to control the miscellaneous of Topiroxostat
Matter content.At present, it is concentrated mainly on the miscellaneous Quality Research of Topiroxostat on the degradation material of intermediate residual and bulk pharmaceutical chemicals.
As document (study on the synthesis of Zhang Mengtian Topiroxostats and related impurities [D] Hebei Normal University, 2016) reports support department
His degradation impurity A, B, C, D；CN106336399A discloses a kind of Topiroxostat intermediate impurities.But originated by Topiroxostat
The impurity that raw material and its isomers are formed but has no research.
The content of the invention
To solve the above-mentioned problems, the present invention provides a kind of new Topiroxostat impurity and preparation method thereof, and will be new
Topiroxostat impurity be named as Topiroxostat impurity F.
Present invention firstly provides Topiroxostat impurity F of the one kind as shown in formula (I)：
Present invention also offers the preparation method of above-mentioned Topiroxostat impurity F, comprise the following steps：
(1) 2,6- dicyanopyridines and sodium methoxide are taken, at 20 ± 3 DEG C, 1~3h is reacted in organic solvent A, up to formula
(a) reaction solution of compound shown in；Isoniazid is added into reaction solution, is warming up to 30~60 DEG C, 1~3h is reacted, up to formula (b)
Shown compound
(2) above-mentioned formula (b) compound is dissolved in organic solvent B, adds phosphoric acid, react 1~3h in 80~150 DEG C, to obtain the final product
Topiroxostat impurity crude product；
(3) by above-mentioned crude product with chromatography is prepared, up to the highly finished product of Topiroxostat impurity.
Further, in step (1), 2,6- dicyanopyridines, sodium methoxide, the molar ratio of isoniazid are 1：1~1.5：1~
2；It is preferred that 1:1.2：1.3~1.5.
Further, in step (1), organic solvent A is selected from methanol, ethanol, propyl alcohol, isopropanol；It is preferred that methanol.
Further, in step (1), the w/v of 2,6- dicyanopyridines and organic solvent A is 1:10~20g/
ml；Preferably 1:14~16g/ml.
Further, in step (1), the reaction time is 2h.
Further, in step (2), the molar ratio of formula (b) compound and phosphoric acid is 1：1~3；It is preferred that 1：1.7~2.5.
Further, in step (2), organic solvent B is selected from dimethylformamide, dichloromethane, toluene, tetrahydrofuran；
It is preferred that dimethylformamide.
Further, in step (2), the w/v of formula (b) compound and organic solvent B is 1:10~50g/ml,
Preferably 1:25~45g/ml.
Further, in step (2), reaction temperature is 110~120 DEG C, reaction time 2h.
Further, in step (3), purification condition is：
Preparative liquid chromatograph is：Agilent preparative chromatograph, model CHEETAH-MP200；
Chromatographic column：Octadecylsilane chemically bonded silica column；
Condition of gradient elution is：
Detection wavelength：214nm；
Flow velocity：20~40ml/min, preferably 30ml/min；
The Topiroxostat impurity of 30~40min periods is collected, up to highly finished product.
The method that the present invention prepares Topiroxostat impurity F, raw material are easy to get, and synthesis technique and purifying process are simple, repeatability
It is good；The purity of gained Topiroxostat impurity F meets the quality requirement of impurity.It can be efficiently applied to Topiroxostat bulk pharmaceutical chemicals and its system
The qualitative and quantitative analysis research of agent relative substance F, promotes bulk pharmaceutical chemicals synthesis technique and quality of the pharmaceutical preparations control research, it is ensured that
The therapeutic effect and security of clinical application.
Obviously, the above according to the present invention, according to the ordinary technical knowledge and customary means of this area, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, remakes further specifically the above of the present invention
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description of the drawings
Fig. 1 is the HPLC purity check collection of illustrative plates of Topiroxostat impurity F in the embodiment of the present invention 1.
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of Topiroxostat impurity F of the present invention.
Fig. 3 is the mass spectrogram of Topiroxostat impurity F of the present invention.
Fig. 4 is the HPLC purity check collection of illustrative plates of Topiroxostat impurity F in the embodiment of the present invention 2.
Fig. 5 is the chromatogram of Topiroxostat impurity F reference substance of the present invention.
Fig. 6 is the chromatogram of Topiroxostat bulk pharmaceutical chemicals of the present invention.
Embodiment
The preparation method of embodiment 1, Topiroxostat impurity F of the present invention
(1) synthesis of formula (a) compound
In 250ml flasks, 1.6g sodium methoxides are added in 50ml absolute methanols, stirring and dissolving, is allowed to uniform.Weigh 2,
6- dicyanopyridines 3.3g add, stirring, room temperature reaction 2 it is small when, up to the acetoacetic ester -6- of 2- methylene imines shown in formula (a) cyano group -
The reaction solution of pyridine.
(2) synthesis of formula (b) compound
Weigh 5.2g isoniazid to add in reaction solution obtained by step (1), stir, heating, when 40~50 DEG C of reactions 2 are small.Instead
After answering, vacuum distillation removes methanol, up to N shown in solid type (b),-(6- cyanopyridine -2- auxotox radicals)-methyl-different
Cigarette hydrazine 3.8g.
(3) synthesis of Topiroxostat impurity F
In 250ml flasks, weigh 3.8g formulas (b) compound and be dissolved in 160ml dimethylformamides (DMF), add
2.2g phosphoric acid, stirs evenly, and is heated to 110 DEG C, when reaction 2 is small.It is cooled to room temperature after reaction, addition purified water, crystallization,
Filter, drying, obtains white solid 1.6g, i.e. Topiroxostat impurity F crude product.
(4) refine
The Topiroxostat impurity F crude product of 1.6g is dissolved with methanol, injection Agilent preparative chromatograph (CHEETAH-
MP200), using octadecylsilane chemically bonded silica column as chromatographic column, methylene chloride-methanol elutes for mobile phase, and elution program is shown in
Table 1, elution flow rate 30ml/min, Detection wavelength 214nm, the Topiroxostat impurity F of collection 30~40min periods, decompression boil off
Solvent, it is dry, Topiroxostat impurity F highly finished product 0.72g is obtained, purity 96.20% is up-to-standard more than 95%.Purity check
HPLC collection of illustrative plates is shown in Fig. 1, and the hydrogen spectrum of Topiroxostat impurity F is shown in Fig. 2, and mass spectrum is shown in Fig. 3.
1 elution time of table and mobile phase ratio
| Elution time (min) | Dichloromethane (%) | Methanol (%) |
| 0 | 95 | 5 |
| 10 | 90 | 10 |
| 30 | 70 | 30 |
| 40 | 40 | 60 |
The preparation method of embodiment 2, Topiroxostat impurity F of the present invention
(1) synthesis of formula (a) compound
In 250ml flasks, 3.5g sodium methoxides are added in 100ml absolute methanols, stirring and dissolving, is allowed to uniform.Weigh
2,6- dicyanopyridine 7g add, stirring, room temperature reaction 1 it is small when, up to the acetoacetic ester -6- of 2- methylene imines shown in formula (a) cyano group -
The reaction solution of pyridine.
(2) synthesis of formula (b) compound
Weigh in reaction solution obtained by 10g isoniazid to (1), stir, heating, when 30~40 DEG C of reactions 1 are small.Reaction finishes
Afterwards, vacuum distillation removes methanol, up to N shown in solid type (b),-(6- cyanopyridine -2- auxotox radicals)-methyl-isoniazid
3.8g。
(3) synthesis of Topiroxostat impurity F
In 250ml flasks, weigh 6.3g formulas (b) compound and be dissolved in 160ml dimethylformamides (DMF), add
5g phosphoric acid, stirs evenly, and is heated to 100 DEG C, when reaction 2 is small.It is cooled to room temperature after reaction, adds purified water, crystallization, takes out
Filter, drying, obtains white solid 1.6g, i.e. Topiroxostat impurity F crude product.
(4) refine
The Topiroxostat impurity F crude product of 2.6g is dissolved with methanol, injection Agilent preparative chromatograph (CHEETAH-
MP200), using octadecylsilane chemically bonded silica column as chromatographic column, methylene chloride-methanol elutes for mobile phase, and elution program is shown in
Table 1, elution flow rate 30ml/min, Detection wavelength 214nm, the Topiroxostat impurity F of collection 30~40min periods, decompression boil off
Solvent, it is dry, Topiroxostat impurity F highly finished product 1.1g is obtained, purity 96.24% is up-to-standard more than 95%.Purity check
HPLC collection of illustrative plates is shown in Fig. 4.
Illustrate beneficial effects of the present invention below by way of the mode of test example.
The detection of impurity F in test example 1, Topiroxostat bulk pharmaceutical chemicals
1) experimental raw
Topiroxostat：Only new medicine Science and Technology Ltd. provides in Chengdu, lot number 20160603；
Topiroxostat impurity F prepared by the embodiment of the present invention 2.
2) detection method and result
Precision weighs Topiroxostat bulk pharmaceutical chemicals, first with 0.5M diluted hydrochloric acid dissolutions, then to flow phase dilution, 0.5mg/ml is made
Solution, as test solution；It is another to take Topiroxostat impurity F, first with 0.5M diluted hydrochloric acid dissolutions, then to flow phase dilution, system
Into the solution of 1 μ g/ml, as Topiroxostat impurity F reference substance solution.Precision measures 10 μ l of above two solution and enters efficient liquid
Chromatography detects, and testing conditions are as follows, records chromatogram, and the content of impurity F in Topiroxostat bulk pharmaceutical chemicals is calculated with external standard method.
Chromatogram is shown in Fig. 5, Fig. 6.
Chromatogram monitoring condition is：
Octadecylsilane chemically bonded silica is the chromatographic column of filler；
Mobile phase：Acetonitrile：Water (percentage by volume is 0.1% trifluoroacetic acid)=20:80；
Flow velocity：1.0ml/min；Column temperature：30℃；
Detection wavelength：220nm.
From fig. 5, it can be seen that Topiroxostat impurity F is implicitly present in Topiroxostat medicine, content 0.15%.The present invention
The Topiroxostat impurity F being prepared can be efficiently applied to the qualitative, quantitative of Topiroxostat bulk pharmaceutical chemicals and its preparation relative substance F
Analysis and research.
To sum up, the method that the present invention prepares Topiroxostat impurity F, raw material are easy to get, and synthesis technique and purifying process are simple, weight
Renaturation is good；The purity of gained Topiroxostat impurity F meets the quality requirement of impurity.Can be efficiently applied to Topiroxostat bulk pharmaceutical chemicals and
The qualitative and quantitative analysis research of its preparation relative substance F, promotes bulk pharmaceutical chemicals synthesis technique and quality of the pharmaceutical preparations control research, really
The therapeutic effect and security of clinical application are protected.
Claims (10)
- A kind of 1. Topiroxostat impurity F as shown in formula (I)：
- A kind of 2. preparation method of the Topiroxostat impurity F described in claim 1, it is characterised in that：Comprise the following steps：(1) 2,6- dicyanopyridines and sodium methoxide are taken, at 20 ± 3 DEG C, 1~3h is reacted in organic solvent A, up to formula (a) The reaction solution of shown compound；Isoniazid is added into reaction solution, is warming up to 30~60 DEG C, 1~3h is reacted, up to formula (b) institute Show compound；(2) above-mentioned formula (b) compound is dissolved in organic solvent B, adds phosphoric acid, 1~3h is reacted in 80~150 DEG C, up to support Take charge of his impurity F crude product；(3) by above-mentioned crude product with chromatography is prepared, up to the highly finished product of Topiroxostat impurity F.
- 3. according to the method described in claim 2, it is characterized in that：In step (1), 2,6- dicyanopyridines, sodium methoxide, different cigarette The molar ratio of hydrazine is 1：1~1.5：1~2；It is preferred that 1：1.2：1.3~1.5.
- 4. according to the method in claim 2 or 3, it is characterised in that：In step (1), organic solvent A be selected from methanol, ethanol, Propyl alcohol, isopropanol；It is preferred that methanol.
- 5. according to the method in claim 2 or 3, it is characterised in that：In step (1), 2,6- dicyanopyridines with it is organic molten The w/v of agent A is 1:10~20g/ml；Preferably 1:14~16g/ml.
- 6. according to claim 2-5 any one of them methods, it is characterised in that：In step (1), the reaction time is 2h.
- 7. according to claim 2-6 any one of them methods, it is characterised in that：In step (2), formula (b) compound and phosphoric acid Molar ratio be 1：1~3；It is preferred that 1：1.7~2.5.
- 8. according to claim 2-7 any one of them methods, it is characterised in that：In step (2), organic solvent B is selected from diformazan Base formamide, dichloromethane, toluene, tetrahydrofuran；It is preferred that dimethylformamide.
- 9. according to claim 2-7 any one of them methods, it is characterised in that：In step (2), formula (b) compound with it is organic The w/v of solvent B is 1:10~50g/ml；Preferably 1:25~45g/ml；And/or in step (2), reaction temperature is 110~120 DEG C, reaction time 2h.
- 10. according to claim 2-9 any one of them methods, it is characterised in that：In step (3), purification condition is：Chromatographic column：Octadecylsilane chemically bonded silica column；Condition of gradient elution is：Detection wavelength：214nm；Flow velocity：20~40ml/min, preferably 30ml/min；The Topiroxostat impurity of 30~40min periods is collected, up to highly finished product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112379006A (en) * | 2020-09-27 | 2021-02-19 | 江苏知原药业股份有限公司 | Method for detecting impurity C, impurity D and impurity E in topiroxostat tablets |
| CN113466378A (en) * | 2021-07-15 | 2021-10-01 | 江苏知原药业股份有限公司 | Separation and determination method for two genotoxic impurities in topiroxostat |
| CN114527213A (en) * | 2022-02-22 | 2022-05-24 | 正大制药（青岛）有限公司 | Quality detection method for topiroxostat |
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Application publication date: 20180511 Assignee: CHENGDU MIRACLE PHARMACEUTICAL Co.,Ltd. Assignor: CHENGDU WEIBANG PHARMACEUTICAL Co.,Ltd. Contract record no.: X2021510000025 Denomination of invention: The invention relates to a topiestat impurity and a preparation method thereof Granted publication date: 20200811 License type: Common License Record date: 20210722 |