CN108017619B

CN108017619B - Topiroxostat impurity and preparation method thereof

Info

Publication number: CN108017619B
Application number: CN201711278437.1A
Authority: CN
Inventors: 随裕敏; 王继英
Original assignee: Chengdu Weibang Pharmaceutical Co ltd
Current assignee: Chengdu Weibang Pharmaceutical Co ltd
Priority date: 2017-12-06
Filing date: 2017-12-06
Publication date: 2020-08-11
Anticipated expiration: 2037-12-06
Also published as: CN108017619A

Abstract

The invention provides impurity F of topiroxostat shown in formula (I). And provides a preparation method of topiroxostat impurity F. The method for preparing the impurity F of topiroxostat has the advantages of easily obtained raw materials, simple synthesis process and purification process and good repeatability; the purity of the obtained topiroxostat impurity F meets the quality requirement of the impurity. Can be effectively applied to qualitative and quantitative analysis research on impurities F related to the topiroxostat bulk drug and the preparation thereof, promotes the bulk drug synthesis process and the preparation quality control research, and ensures the treatment effect and safety of clinical medication.

Description

Topiroxostat impurity and preparation method thereof

Technical Field

The invention relates to topiroxostat impurity and a preparation method thereof, and belongs to the technical field of medicines.

Background

Gout is a disease caused by purine metabolic disorder, is listed as one of the 21 st century 20 persistent ailments by the united nations, and is the second largest metabolic disease next to diabetes. The disease can be divided into two main categories of primary and secondary according to different causes: primary gout refers to the condition caused by congenital purine metabolic disorder and/or uric acid excretion disorder on the basis of other diseases; the secondary gout refers to the reduction of uric acid excretion caused by secondary kidney diseases or certain medicines, myeloproliferative diseases, uric acid generation increase caused by tumor chemotherapy and the like. Under the existing medical conditions, the primary gout is mainly controlled by drug therapy to be blood uric acid, the blood uric acid of general gout patients is below 360 mu mol/L, and the blood uric acid of patients with gout is below 238 mu mol/L, so that the gout symptoms can be relieved.

Topiroxostat (Topiroxostat) is an effective drug for treating gout and hyperuricemia, and is a non-purine xanthine oxidoreductase inhibitor with high selectivity. Was developed by fuji drug co, approved by japan ministry of accrual, japan in 2013, 8 months and marketed in japan for the first time.

In order to better control the quality standard of the topiroxostat bulk drug and the preparation thereof, the impurity content of the topiroxostat needs to be strictly controlled. Currently, research on topiroxostat impurities is mainly focused on intermediate residues and degraded substances of the drug substance. Topiroxostat degradation impurity A, B, C, D was reported in the literature (synthetic studies of topiroxostat and related impurities [ D ]. north heyday, 2016); CN106336399A discloses topiroxostat intermediate impurity. However, the impurities formed from the topiroxostat starting material and its isomers were not studied.

Disclosure of Invention

In order to solve the above problems, the present invention provides a novel impurity of topiroxostat and a preparation method thereof, and the novel impurity of topiroxostat is named as topiroxostat impurity F.

The invention firstly provides impurities F of topiroxostat shown in a formula (I):

the invention also provides a preparation method of the topiroxostat impurity F, which comprises the following steps:

(1) taking 2, 6-dicyanopyridine and sodium methoxide, and reacting in an organic solvent A at the temperature of 20 +/-3 ℃ for 1-3 hours to obtain a reaction solution of a compound shown in a formula (a); adding isoniazid into the reaction solution, heating to 30-60 ℃, and reacting for 1-3 h to obtain the compound shown in the formula (b)

(2) Dissolving the compound shown in the formula (B) in an organic solvent B, adding phosphoric acid, and reacting at 80-150 ℃ for 1-3 h to obtain a crude product of topiroxostat impurity;

(3) purifying the crude product with preparative chromatographic column to obtain refined product of Topiroxostat impurity.

Further, in the step (1), the molar ratio of the 2, 6-dicyanopyridine to the sodium methoxide to the isoniazid is 1: 1-1.5: 1-2; preferably 1: 1.2: 1.3 to 1.5.

Further, in the step (1), the organic solvent A is selected from methanol, ethanol, propanol and isopropanol; methanol is preferred.

Further, in the step (1), the weight-volume ratio of the 2, 6-dicyanopyridine to the organic solvent A is 1: 10-20 g/ml; preferably 1: 14-16 g/ml.

Further, in the step (1), the reaction time was 2 hours.

Further, in the step (2), the molar ratio of the compound of the formula (b) to phosphoric acid is 1: 1-3; preferably 1: 1.7 to 2.5.

Further, in the step (2), the organic solvent B is selected from dimethylformamide, dichloromethane, toluene and tetrahydrofuran; dimethylformamide is preferred.

Further, in the step (2), the weight volume ratio of the compound of the formula (B) to the organic solvent B is 1: 10-50 g/ml, preferably 1: 25-45 g/ml.

Further, in the step (2), the reaction temperature is 110-120 ℃, and the reaction time is 2 hours.

Further, in the step (3), the purification conditions are as follows:

the preparation method of the liquid chromatograph comprises the following steps: agilent preparative chromatograph with model number CHEETAH-MP 200;

a chromatographic column: octadecylsilane chemically bonded silica gel column;

the gradient elution conditions were:

detection wavelength: 214 nm;

flow rate: 20-40 ml/min, preferably 30 ml/min;

and collecting impurities of topiroxostat within 30-40 min to obtain a refined product.

The method for preparing the impurity F of topiroxostat has the advantages of easily obtained raw materials, simple synthesis process and purification process and good repeatability; the purity of the obtained topiroxostat impurity F meets the quality requirement of the impurity. Can be effectively applied to qualitative and quantitative analysis research on impurities F related to the topiroxostat bulk drug and the preparation thereof, promotes the bulk drug synthesis process and the preparation quality control research, and ensures the treatment effect and safety of clinical medication.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is an HPLC purity check spectrum of impurity F of topiroxostat in example 1 of the present invention.

FIG. 2 is a nuclear magnetic hydrogen spectrum of topiroxostat impurity F of the present invention.

FIG. 3 is a mass spectrum of impurity F of topiroxostat according to the present invention.

FIG. 4 is an HPLC purity check spectrum of impurity F of topiroxostat in example 2 of the present invention.

FIG. 5 is a chromatogram of a topiroxostat impurity F control of the present invention.

FIG. 6 is a chromatogram of topiroxostat drug substance of the present invention.

Detailed Description

Example 1 preparation of impurity F of topiroxostat according to the invention

(1) Synthesis of Compound of formula (a)

In a 250ml flask, 1.6g of sodium methoxide was added to 50ml of anhydrous methanol, and dissolved by stirring to be uniform. 3.3g of 2, 6-dicyanopyridine is weighed and added, stirred and reacted for 2 hours at room temperature, and then the reaction liquid of the 2-methyl imido ethyl ester-6-cyano-pyridine shown in the formula (a) is obtained.

(2) Synthesis of Compound of formula (b)

And (2) weighing 5.2g of isoniazid, adding the isoniazid into the reaction liquid obtained in the step (1), stirring, heating, and reacting for 2 hours at 40-50 ℃. After the reaction, methanol was removed by distillation under reduced pressure to obtain 3.8g of N, - (6-cyanopyridine-2-methylimino) -methyl-isoniazid represented by the solid formula (b).

(3) Synthesis of Topiroxostat impurity F

In a 250ml flask, 3.8g of the compound of formula (b) was dissolved in 160ml of Dimethylformamide (DMF), 2.2g of phosphoric acid was added, stirred well, heated to 110 ℃ and reacted for 2 hours. And cooling to room temperature after the reaction is finished, adding purified water, crystallizing, filtering, and drying to obtain 1.6g of white solid, namely the crude product of impurity F of topiroxostat.

(4) Refining

Dissolving 1.6g of the Topiroxostat impurity F crude product with methanol, injecting the dissolved Topiroxostat impurity F crude product into an Agilent preparative chromatograph (CHEETAH-MP200), eluting the Topirostat impurity F crude product with an octadecylsilane chemically bonded silica column as a chromatographic column and dichloromethane-methanol as a mobile phase, wherein the elution procedure is shown in Table 1, the elution flow rate is 30ml/min, the detection wavelength is 214nm, collecting the Topirostat impurity F within a period of 30-40 min, evaporating the solvent under reduced pressure, and drying to obtain 0.72g of the Topirostat impurity F refined product, wherein the purity is 96.20 percent and is more than 95 percent, and the quality is qualified. The purity check HPLC profile is shown in fig. 1, the hydrogen profile of topiroxostat impurity F is shown in fig. 2, and the mass spectrum is shown in fig. 3.

TABLE 1 elution time and flow phase ratio example

Elution time (min)	Methylene chloride (%)	Methanol (%)
			0	95	5
10	90	10
			30	70	30
40	40	60

Example 2 preparation of impurity F of topiroxostat according to the invention

(1) Synthesis of Compound of formula (a)

In a 250ml flask, 3.5g of sodium methoxide was added to 100ml of anhydrous methanol, and dissolved by stirring to be uniform. Weighing 7g of 2, 6-dicyanopyridine, adding the 2, 6-dicyanopyridine, stirring, and reacting at room temperature for 1 hour to obtain a reaction solution of ethyl 2-methyliminoate-6-cyano-pyridine shown in the formula (a).

(2) Synthesis of Compound of formula (b)

And (3) weighing 10g of isoniazide into the reaction liquid obtained in the step (1), stirring, heating, and reacting for 1 hour at the temperature of 30-40 ℃. After the reaction, methanol was removed by distillation under reduced pressure to obtain 3.8g of N, - (6-cyanopyridine-2-methylimino) -methyl-isoniazid represented by the solid formula (b).

(3) Synthesis of Topiroxostat impurity F

In a 250ml flask, 6.3g of the compound of formula (b) was weighed out and dissolved in 160ml of Dimethylformamide (DMF), 5g of phosphoric acid was added, stirred well, heated to 100 ℃ and reacted for 2 hours. And cooling to room temperature after the reaction is finished, adding purified water, crystallizing, filtering, and drying to obtain 1.6g of white solid, namely the crude product of impurity F of topiroxostat.

(4) Refining

Dissolving 2.6g of the Topiroxostat impurity F crude product with methanol, injecting the dissolved Topiroxostat impurity F crude product into an Agilent preparative chromatograph (CHEETAH-MP200), eluting the Topirostat impurity F crude product with an octadecylsilane chemically bonded silica column as a chromatographic column and dichloromethane-methanol as a mobile phase, wherein the elution procedure is shown in Table 1, the elution flow rate is 30ml/min, the detection wavelength is 214nm, collecting the Topirostat impurity F within a period of 30-40 min, evaporating the solvent under reduced pressure, and drying to obtain 1.1g of the Topirostat impurity F refined product with the purity of 96.24% higher than 95%, wherein the quality is qualified. The purity check HPLC profile is shown in FIG. 4.

The advantageous effects of the present invention are described below by way of test examples.

Test example 1 detection of impurity F in Topiroxostat drug substance

1) Experimental materials

Topiroxostat: the achievement is provided by new medicine science and technology limited, lot number 20160603;

topiroxostat impurity F prepared in example 2 of the invention.

2) Detection method and results

Precisely weighing topiroxostat bulk drug, dissolving with 0.5M dilute hydrochloric acid, and diluting with mobile phase to obtain 0.5mg/ml solution as a test solution; and dissolving impurity F of Topiroxostat in 0.5M dilute hydrochloric acid, and diluting with mobile phase to obtain 1 μ g/ml solution as reference solution of impurity F of Topiroxostat. And precisely measuring 10 mu l of the two solutions, detecting the solutions by using a high performance liquid chromatograph under the following detection conditions, recording a chromatogram, and calculating the content of the impurity F in the topiroxostat bulk drug by using an external standard method. The chromatogram is shown in FIG. 5 and FIG. 6.

The chromatographic monitoring conditions were:

chromatographic column with octadecylsilane chemically bonded silica as filler;

mobile phase: acetonitrile: water (0.1% by volume trifluoroacetic acid) 20: 80;

flow rate: 1.0 ml/min; column temperature: 30 ℃;

detection wavelength: 220 nm.

As can be seen from fig. 5, topiroxostat impurity F was indeed present in the topiroxostat drug at 0.15%. The impurity F of topiroxostat prepared by the invention can be effectively applied to qualitative and quantitative analysis research on the impurity F related to the topiroxostat bulk drug and the preparation thereof.

In conclusion, the method for preparing the impurity F of topiroxostat has the advantages of easily available raw materials, simple synthesis process and purification process and good repeatability; the purity of the obtained topiroxostat impurity F meets the quality requirement of the impurity. Can be effectively applied to qualitative and quantitative analysis research on impurities F related to the topiroxostat bulk drug and the preparation thereof, promotes the bulk drug synthesis process and the preparation quality control research, and ensures the treatment effect and safety of clinical medication.

Claims

1. Impurities F of topiroxostat represented by formula (i):

2. a method of preparing topiroxostat impurity F according to claim 1, characterized in that: the method comprises the following steps:

(1) taking 2, 6-dicyanopyridine and sodium methoxide, and reacting in an organic solvent A at the temperature of 20 +/-3 ℃ for 1-3 hours to obtain a reaction solution of a compound shown in a formula (a); adding isoniazid into the reaction solution, heating to 30-60 ℃, and reacting for 1-3 hours to obtain a compound shown in the formula (b); the organic solvent A is selected from methanol, ethanol, propanol and isopropanol;

(2) dissolving the compound shown in the formula (B) in an organic solvent B, adding phosphoric acid, and reacting at 80-150 ℃ for 1-3 h to obtain a crude product of impurity F of topiroxostat; the organic solvent B is selected from dimethylformamide, dichloromethane, toluene and tetrahydrofuran;

(3) purifying the crude product by using a preparative chromatographic column to obtain a refined product of the impurity F of topiroxostat.

3. The method of claim 2, wherein: in the step (1), the molar ratio of 2, 6-dicyanopyridine, sodium methoxide and isoniazid is 1: 1-1.5: 1 to 2.

4. The method of claim 3, wherein: in the step (1), the molar ratio of 2, 6-dicyanopyridine, sodium methoxide and isoniazid is 1: 1.2: 1.3 to 1.5.

5. The method of claim 2, wherein: in the step (1), the organic solvent A is selected from methanol.

6. The method of claim 2, wherein: in the step (1), the weight-volume ratio of the 2, 6-dicyanopyridine to the organic solvent A is 1: 10-20 g/ml.

7. The method of claim 6, wherein: in the step (1), the weight-volume ratio of the 2, 6-dicyanopyridine to the organic solvent A is 1: 14-16 g/ml.

8. The method of claim 2, wherein: in the step (1), the reaction time is 2 h.

9. The method of claim 2, wherein: in step (2), the molar ratio of the compound of formula (b) to phosphoric acid is 1:1 to 3.

10. The method of claim 9, wherein: in step (2), the molar ratio of the compound of formula (b) to phosphoric acid is 1: 1.7 to 2.5.

11. The method of claim 2, wherein: in the step (2), the organic solvent B is selected from dimethylformamide.

12. The method of claim 2, wherein: in the step (2), the weight-volume ratio of the compound shown in the formula (B) to the organic solvent B is 1: 10-50 g/ml; and/or in the step (2), the reaction temperature is 110-120 ℃, and the reaction time is 2 hours.

13. The method of claim 12, wherein: in the step (2), the weight-to-volume ratio of the compound of the formula (B) to the organic solvent B is 1: 25-45 g/ml.

14. The method according to any one of claims 2-13, wherein: in the step (3), the purification conditions are as follows:

a chromatographic column: octadecylsilane chemically bonded silica gel column;

the gradient elution conditions were:

detection wavelength: 214 nm;

flow rate: 20-40 ml/min;

15. The method of claim 14, wherein: the flow rate is: 30 ml/min.