Slexipag impurity and preparation method thereof

Abstract

The invention relates to a medicine technology, in particular to a selepag impurity and a preparation method thereof. The synthetic route of the selepacagel impurity shown in the formula III is as follows: # imgabs0 controls the content of the impurity, so that the quality of a selepacagel product is favorably controlled, and the selepacagel process research is guided.

Description

Technical Field

[0001] The present invention relates to pharmaceutical technology, and in particular to a selexipag impurity and a preparation method thereof. Background Art

[0002] Selexipag, chemically named 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butyl}-N-(methylsulfonyl)acetamide, is the first new oral long-acting selective PGI2 receptor agonist. Ordinary PGI2 analogs have low selectivity and poor pulmonary artery relaxation effects, while Selexipag has high selectivity for PGI2 receptors, similar pulmonary artery and pulmonary arteriole relaxation effects, and is not affected by vascular endothelial cell replacement and regeneration.

[0003] The trade name of Selexipag tablets is "Uptravi", with specifications of 0.2mg, 0.4mg, 0.6mg, 0.8mg, 1.0mg, 1.2mg, 1.4mg, and 1.6mg. The drug was approved for marketing by the FDA on December 21, 2015, and by the European Medicines Agency (SLPA) on May 12, 2016, for the treatment of pulmonary arterial hypertension.

[0004] It is necessary to further study the synthesis process of Selexipag and control the quality of Selexipag products. Summary of the invention

[0005] The present invention discovers a new selexipag impurity, whose structure is shown in the following formula III, and provides a preparation method of the impurity. The impurity will affect the purity of selexipag, and controlling the content of the impurity is beneficial to controlling the quality of selexipag products and guiding selexipag process research.

[0006] A selexipag impurity, the structure of which is shown in Formula III below:

[0007]

[0008] The present invention also provides a method for preparing the selexipag impurity shown in the above formula III. The method has a simple preparation process and mild reaction conditions. The obtained selexipag impurity has a high purity and can be used for quality research.

[0009] The preparation method of the selexipag impurity shown in formula III, the synthesis route thereof is as follows:

[0010]

[0011] The method for separating the selexipag impurity represented by the above formula III comprises: providing a mixture containing the selexipag impurity represented by the above formula III and compound 6; separating by a high pressure preparative chromatography purification method; the mobile phase A is 2% glacial acetic acid-acetonitrile; the mobile phase B is 2% glacial acetic acid-water; and the following gradient elution is used:

[0012] time Mobile phase A, % Mobile phase B, % 0 22 78 20 22 78 20.1 30 70 25 30 70 25.1 22 78 40 22 78。

[0013]

[0014] Specifically, the separation method further comprises: starting to collect the eluent when the peak height of the chromatographic peak reaches 100 mAU, and stopping the collection when the peak height drops to 50 mAU.

[0015] Specifically, the separation method further includes: adding ethyl acetate to the collected eluate for extraction, collecting the ethyl acetate phase, and concentrating under reduced pressure (50° C.) to obtain a yellow oily substance, which is the selexipag impurity shown in Formula III.

[0016] Application of the selexipag impurity represented by formula III in the quality control of selexipag. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the selexipag impurity separated in the embodiment of the present invention.

[0018] Figure 2 This is the mass spectrum of the selexipag impurity prepared in Example 1 of the present invention.

[0019] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the selexipag impurity prepared in Example 1 of the present invention.

[0020] Figure 4 It is the mass spectrum of the compound shown in formula IV.

[0021] Figure 5 It is the hydrogen nuclear magnetic resonance spectrum of the compound represented by formula IV. DETAILED DESCRIPTION

[0022] According to the literature report (Yan Long. Synthesis of CDK4 / 6 inhibitor Abemaciclib and pulmonary arterial hypertension orphan drug Selexipag [D]. Wuhan University of Technology, 2018. hereinafter referred to as document 1, and the full text is introduced in this article for reference), the synthesis route of Selexipag is as follows:

[0023]

[0024] The compound numbers in the above-mentioned synthesis route of selexipag will continue to be used below.

[0025] The inventors found that the above synthetic route produced an unknown impurity that affected the quality of Selexipag. After a large number of experiments, the inventors separated the unknown impurity and identified its structure.

[0026] Specifically, the structure of the selexipag impurity is shown in the following formula III:

[0027]

[0028] The chemical name of the selexipag impurity is 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)-2-(4-(((5,5-diphenylpyrazol-2-yl))(isopropanol)amino)butoxy)acetic acid butyl ester, referred to as the selexipag dimer impurity in this article.

[0029] The separation, purification and identification process of the impurity is as follows: the inventors prepared compound 6 according to the selexipag synthesis route in the above-mentioned document 1. When performing HPLC detection, they found that there was always a large unknown impurity (content of about 10%) close to the peak of compound 6. This impurity affected the purity of compound 6. This unknown impurity can be partially removed when preparing compound 7, and a small amount remains in compound 7. However, it tends to increase when preparing the finished product, and ultimately requires multiple recrystallizations to remove it.

[0030] During the research process, it was found that the above unknown impurity was difficult to separate because the impurity overlapped with the spot of compound 6 during TLC monitoring and had very similar polarity. The traditional column chromatography method could not obtain the impurity with high purity. The inventors finally separated and obtained the impurity with high purity by high-pressure preparative chromatography purification.

[0031] The specific separation process is as follows:

[0032] A mixture containing the unknown impurity and compound 6 is provided (based on the synthesis route of Selexipag in the above document 1); separation is performed by a high pressure preparative chromatography purification method; mobile phase A is 2% glacial acetic acid-acetonitrile; mobile phase B is 2% glacial acetic acid-water; and the following gradient elution is used:

[0033] time Mobile phase A, % Mobile phase B, % 0 22 78 20 22 78 20.1 30 70 25 30 70 25.1 22 78 40 22 78

[0034] Specifically, the preparation column was: 100×250 mm, Daisogel C18-10 um-120A.

[0035] Specifically, temperature: 5~15°C.

[0036] Specifically, the flow rate of the mobile phase was 20 mL / min.

[0037] Specifically, the eluate collection started when the peak height of the chromatographic peak reached 100 mAU, and the collection was stopped when the peak height dropped to 50 mAU.

[0038] Specifically, ethyl acetate was added to the collected eluate for extraction, and the ethyl acetate phase was collected and concentrated under reduced pressure (50° C.) to obtain a yellow oily substance, which was the unknown impurity.

[0039] The detailed separation method can be found in Example 4 below.

[0040] After the inventors separated and obtained the impurity, they performed NMR characterization. The specific spectrum is shown in Figure 1 , and its structure was determined to be the above formula III through NMR characterization and other means.

[0041] According to the structure of the impurity, the inventors determined the production pathways, which mainly include three pathways, as follows:

[0042] The first route: When preparing compound 6, the unconverted compound 4 in the reaction system can undergo an ester exchange reaction with compound 6 to generate selexipag dimer impurities. The specific route is as follows:

[0043]

[0044] The second approach: When compound 4 remaining in compound 7 is used to prepare selexipag, the two can also generate selexipag dimer impurities under the action of a condensation agent (CDI).

[0045]

[0046] The third approach: Selexipag is an active amide structure, and the residual compound 4 in compound 7 can also react with Selexipag to form Selexipag dimer impurities.

[0047]

[0048] There are many ways for selexipag dimer impurities to be produced, which have a great impact on the quality of selexipag. Therefore, sufficient research is needed to determine its control strategy to ensure the quality of selexipag products.

[0049] After obtaining the above impurity (ie, the compound represented by formula III), the inventors also studied its synthesis process.

[0050] The first approach described above can generate the compound of formula III, but the conversion rate is low, and the yield and purity of the obtained product are both low.

[0051] The third approach mentioned above can generate the compound of formula III, but the conversion rate is also low, and the yield and purity of the obtained product are both low.

[0052] Based on extensive research, the inventors finally determined the preparation method of the selexipag impurity shown in Formula III, and the synthesis route thereof is as follows:

[0053]

[0054] The compound of formula I is 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid, abbreviated as selexipaglic acid.

[0055] The compound of formula II is 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-1-ol, abbreviated as selexipagol.

[0056] Formula I and Formula II are known compounds and can be purchased commercially or synthesized by yourself.

[0057] Specifically, the molar ratio of the compound of formula I to the compound of formula II is 1.0:(1.0-1.2), for example 1.0:1.0, 1.0:1.1, 1.0:1.2. Studies have found that when the amount of the compound of formula II is too much, an impurity 4-((5,6-diphenylpyrazine-2-yl)(isopropyl)amino)1H-imidazole-1-carboxylic acid butyl ester will be generated, the specific structure of which is shown in formula IV below, and its mass spectrum and nuclear magnetic resonance hydrogen spectrum can be found in Figure 4 and Figure 5 .

[0058]

[0059] The generation of the impurity represented by formula IV affects the yield and purity of the selexipag dimer impurity. When the amount of the compound of formula II is too small, the conversion of the compound of formula I is incomplete, which also affects the yield and purity of the selexipag dimer impurity.

[0060] After extensive research, it was found that controlling the molar ratio of the compound of formula I to the compound of formula II within this range is beneficial to improving the yield and purity of selexipag dimer impurities.

[0061] Specifically, the reaction temperature of the compound of formula I and the compound of formula II is 0-10° C., for example, 0° C., 5° C., 10° C. Studies have shown that when the reaction temperature is too low, the conversion rate is slow; when the reaction temperature is too high, the amount of impurity 4-((5,6-diphenylpyrazine-2-yl)(isopropyl)amino)1H-imidazole-1-carboxylic acid butyl ester (shown in formula IV) generated will increase, so the reaction temperature should be controlled within this range.

[0062] Specifically, the reaction time of the compound of formula I and the compound of formula II is 1-2 hours.

[0063] Specifically, the compound of formula I and the compound of formula II are reacted in the presence of solvent N,N-dimethylformamide (DMF). The reaction solvent should be a solvent that can dissolve the compound of formula I and the compound of formula II. Although alcohol solvents can dissolve, alcohol solvents should not be selected. Because alcohol solvents can condense the compound of formula I to form corresponding esters, it is not conducive to the generation of the target product. The inventor screened solvents such as acetonitrile, tetrahydrofuran, DMF, and finally found that DMF is the best reaction solvent, and other solvents are not conducive to the conversion of the compound of formula II, and the yield is low.

[0064] Specifically, the reaction process of the compound of formula I and the compound of formula II further includes adding 4-dimethylaminopyridine (DMAP) and / or N,N'-carbonyldiimidazole (CDI).

[0065] The role of 4-dimethylaminopyridine is to catalyze the esterification reaction and increase the reaction rate.

[0066] N,N'-Carbonyldiimidazole acts as a condensation agent.

[0067] Specifically, the molar ratio of the compound of formula I to DMAP is 1:(0.01-0.05), for example 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05.

[0068] Specifically, the molar ratio of the compound of formula I to CDI is 1:(1.1-1.3), for example 1:1.1, 1:1.2, 1:1.3.

[0069] Specifically, the preparation method further comprises the steps of separating and purifying the reaction product of the compound of formula I and the compound of formula II. Specifically, the reaction product can be extracted with ethyl acetate; passed through a silica gel column, first eluted with n-hexane, then eluted with ethyl acetate:n-hexane=1:5 (v / v), the eluate is collected, and the eluate is concentrated under reduced pressure to obtain a yellow oily substance, which is the selexipag dimer impurity (i.e., the compound shown in formula III).

[0070] Specifically, the preparation method of the selexipag impurity shown in formula III has a synthetic route as follows:

[0071]

[0072] Specifically, the preparation method of the selexipag impurity shown in Formula III comprises:

[0073] Add N,N-dimethylformamide to the reaction container, add selexipaglic acid under stirring, add DMAP to the system after the feed liquid is dissolved, cool to 0°C, add CDI to the system in batches (for example, 3 batches) to control the temperature to 0-10°C (add in about 30 minutes), stir until the feed liquid is dissolved, then add selexipag alcohol, control the temperature to 0-10°C and stir to react for 1-2 hours; then add purified water and ethyl acetate to the reaction liquid, let the feed liquid stand (for example, 10 minutes), separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50°C to obtain a yellow oil;

[0074] The yellow oil was dissolved in ethyl acetate and added with silica gel (200-300 mesh), and concentrated under reduced pressure at 50°C; silica gel (200-300 mesh) was added to the column chromatography column, and eluted with n-hexane first, and then with ethyl acetate: n-hexane = 1:5 (v / v), the eluate was collected, and the eluate was concentrated under reduced pressure (50°C) to obtain a yellow oil, which is the selexipag impurity (i.e., the compound shown in Formula III).

[0075] After obtaining the selexipag impurity shown in formula III, it can be used for quality control in the selexipag synthesis process.

[0076] Specifically, after obtaining the dimerization impurity of Selexipag, the inventors optimized the synthesis process of Selexipag based on the Selexipag synthesis route in the above-mentioned document 1, combined with the source and removal pathway of the impurity, and the results are as follows:

[0077] 1) First, by adjusting the reaction temperature, amount of base, reaction time, and reaction solvent for the preparation of compound 6, the optimal preparation parameters were determined, and the selexipag dimer impurity was controlled within 2%;

[0078] 2) Then, the optimal preparation parameters were determined by adjusting the reaction temperature, base dosage, reaction time, and reaction solvent for the preparation of compound 7 (selexipag acid), and the selexipag dimerization impurity and compound 4 (selexipag alcohol) were controlled within 0.1% and 0.1% respectively;

[0079] 3) Compound 7 (selexipag acid) is controlled as a key intermediate to control the selexipag dimer impurity and compound 4 (selexipag alcohol) within 0.2%. The selexipag dimer impurity in the prepared selexipag crude product can be controlled within 0.2%, and then the selexipag dimer impurity can be removed to less than 0.1% by refining.

[0080] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0081] In the following examples, the preparation route of the selexipag impurity shown in Formula III is as follows:

[0082]

[0083] The following are the detection methods of selexipag impurities, selexipag intermediates and selexipag (HPLC detection conditions):

[0084] Take an appropriate amount of this product, dissolve it in acetonitrile and quantitatively dilute it to make a solution containing 1 mg per 1 ml, shake well, and use it as the test solution. Use octadecyl bonded silica gel as the filler; use sodium heptane sulfonate solution (dissolve 3.5g of sodium heptane sulfonate in an appropriate amount of water, add 1ml of phosphoric acid, dilute to 1000ml with water, shake well) as mobile phase A, and acetonitrile as mobile phase B; perform gradient elution according to the table below; flow rate is 1.0ml / min; detection wavelength is 302nm; injection volume is 20μl.

[0085] Time T(min) A(％) B(％) 0 35 65 5 35 65 20 5 95 25 5 95 26 35 65 35 35 65

[0086] Example 1

[0087] This embodiment provides a method for preparing selexipag impurities, which is as follows:

[0088] Add 42 ml of DMF to the reaction bottle, add 4.20 g of selexipag acid under stirring, after the liquid is dissolved, add 0.037 g of DMAP to the system, cool to 5°C, add 1.95 g of CDI to the system in three batches, control the temperature at 5°C, after the addition is complete, stir until the liquid is dissolved, then add 3.98 g of selexipag alcohol, after the addition is complete, control the temperature at 5°C and stir to react for 1.5 hours, then add 420 ml of purified water and 420 ml of ethyl acetate to the reaction liquid, stir the liquid for 10 min, let it stand, separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50°C to obtain a yellow oil.

[0089] The yellow oil was dissolved in 42 ml of ethyl acetate and 8 g of silica gel (200 mesh) was added, and the mixture was concentrated under reduced pressure at 50°C. 80 g of silica gel (200 mesh) was added to the column chromatography column. The mixture was first eluted with 100 ml of n-hexane, and then eluted with 600 ml of ethyl acetate: n-hexane = 1:5 (v / v), and the eluate was collected and concentrated under reduced pressure at 50°C to obtain 4.85 g of yellow oil (i.e., selexipag dimer impurity), with a yield of 63.56% and a purity of 98.5%.

[0090] The mass spectrum of the impurity of Selexipag prepared in this example is shown in Figure 2 , H NMR spectrum see Figure 3 .

[0091] Example 2

[0092] This embodiment provides a method for preparing selexipag impurities, which is as follows:

[0093] Add 42 ml of DMF to the reaction bottle, add 4.20 g of selexipag acid under stirring, after the liquid is dissolved, add 0.012 g of DMAP to the system, cool to 0°C, add 1.78 g of CDI to the system in three batches, control the temperature at 0°C, stir until the liquid is dissolved, then add 3.61 g of selexipag alcohol, after the addition is completed, control the temperature at 0°C and stir to react for 1 hour, then add 420 ml of purified water and 420 ml of ethyl acetate to the reaction liquid, stir the liquid for 10 min, let it stand, separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50°C to obtain a yellow oil.

[0094] The yellow oil was dissolved in 42 ml of ethyl acetate and 8 g of silica gel (200 mesh) was added, and the mixture was concentrated under reduced pressure at 50°C. 80 g of silica gel (200 mesh) was added to the column chromatography column. The mixture was first eluted with 100 ml of n-hexane, and then eluted with 600 ml of ethyl acetate: n-hexane = 1:5 (v / v), and the eluate was collected and concentrated under reduced pressure at 50°C to obtain 4.75 g of yellow oil (i.e., selexipag dimer impurity), with a yield of 62.25% and a purity of 98.2%.

[0095] Example 3

[0096] This embodiment provides a method for preparing selexipag impurities, which is as follows:

[0097] Add 42 ml of DMF to the reaction bottle, add 4.20 g of selexipag acid under stirring, after the liquid is dissolved, add 0.061 g of DMAP to the system, cool to 10°C, add 2.11 g of CDI to the system in three batches, control the temperature at 10°C, stir until the liquid is dissolved, then add 4.34 g of selexipag alcohol, after the addition, control the temperature at 10°C and stir to react for 2 hours, then add 420 ml of purified water and 420 ml of ethyl acetate to the reaction liquid, stir the liquid for 10 minutes, let it stand, separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50°C to obtain a yellow oil.

[0098] The yellow oil was dissolved in 42 ml of ethyl acetate and 8 g of silica gel (200 mesh) was added, and the mixture was concentrated under reduced pressure at 50°C. 80 g of silica gel (200 mesh) was added to the column chromatography column. The mixture was first eluted with 100 ml of n-hexane, and then eluted with 600 ml of ethyl acetate: n-hexane = 1:5 (v / v), and the eluate was collected and concentrated under reduced pressure at 50°C to obtain 4.77 g of yellow oil (i.e., selexipag dimer impurity), with a yield of 62.51% and a purity of 98.1%.

[0099] Example 4 Separation of Selexipag Impurities Represented by Formula III

[0100] 1. Device Name:

[0101] Equipment: LC-6000 preparative liquid chromatograph

[0102] Preparative column: 100×250mm, Daisogel C18-10um-120A

[0103] Temperature: 5~15℃

[0104] 2. Mobile phase and gradient table

[0105] time Flow rate (mL / min) A (2% glacial acetic acid-acetonitrile, %) B (2% glacial acetic acid-water, %) 0 20 22 78 20 20 22 78 20.1 20 30 70 25 20 30 70 25.1 20 22 78 40 20 22 78

[0106] 3. Operation parameters:

[0107] Flow rate: 20mL / min

[0108] Detection wavelength: 302nm.

[0109] 4. Specific operation process:

[0110] Based on the synthetic route of Selexipag in the above document 1, a mixture containing unknown impurities and compound 6 was obtained. Weigh 6.00g of the mixture, dissolve it in 80ml of acetonitrile and shake it well, quickly load it with a pump, and set the flow rate to 20mL / min for separation. Start collecting when the chromatographic peak height reaches 100mAU, and stop collecting when the peak height drops to 50mAU. Collect the eluent, add 500ml of ethyl acetate for extraction, collect the ethyl acetate phase, and concentrate under reduced pressure at 50°C to obtain 0.20g of yellow oil with a purity of 98.0%.

[0111] The H NMR spectrum of the selexipag impurity separated in this example is shown in Figure 1 .

[0112] Example 5: The impurity of Selexipag shown in Formula III was used as a reference substance to detect Selexipag and its intermediates

[0113] Based on the synthetic route of selexipag in the above document 1, different batches (3 batches) of compound 6, compound 7 (selexipag acid), and selexipag were prepared using the above optimized process, and tested according to the above method. The control limit of impurity of formula III in compound 6 shall not exceed 2%; the control limit of impurity of formula III in compound 7 (selexipag acid) shall not exceed 0.1%; the control limit of impurity of formula III in selexipag shall not exceed 0.1%.

[0114] The specific test results are as follows:

[0115] sample Impurity control limit of formula III (%) Batch 1 Batch 2 Batch 3 Compound 6 2％ 1.5％ 1.4％ 1.5％ Compound 7 (Selepaglic acid) 0.2％ 0.18 0.17 0.18 Sleipag 0.1％ Not detected Not detected Not detected

[0116] Comparative Example 1

[0117] The only difference from Example 1 is that the molar ratio of the compound of formula I to the compound of formula II is 1.0:1.3.

[0118] The yield of selexipag impurity (i.e., the compound represented by formula III) is 40.25%, and the purity is 96.7%.

[0119] Comparative Example 2

[0120] The only difference from Example 1 is that the reaction temperature is set at 20°C.

[0121] The yield of selexipag impurity (i.e., the compound represented by formula III) is 41.34%, and the purity is 95.8%.

[0122] Comparative Example 3

[0123] The only difference from Example 1 is that the reaction solvent is tetrahydrofuran.

[0124] The yield of selexipag impurity (i.e., the compound represented by formula III) is 43.57%, and the purity is 97.3%.

[0125] Comparative Example 4

[0126] The only difference from Example 1 is that the reaction solvent is acetonitrile.

[0127] The yield of selexipag impurity (i.e., the compound represented by formula III) is 42.08%, and the purity is 96.9%.

[0128] Comparative Example 5 Separation of Selexipag Impurities Represented by Formula III

[0129] Based on the synthetic route of Selexipag in the above-mentioned document 1, a mixture containing unknown impurities and compound 6 was obtained, and separated by conventional column chromatography. Specifically, 6 g of the mixture was weighed, dissolved with 30 ml of ethyl acetate, 6 g of silica gel (200 mesh), and concentrated under reduced pressure at 50°C. 120 g of silica gel (200 mesh) was added to the column chromatography column. First, elute with 1000 ml of n-hexane, then elute with 500 ml of ethyl acetate: n-hexane = 1:5 (v / v), collect the eluate, and concentrate the eluate under reduced pressure at 50°C to obtain 0.5 g of a yellow oil with a purity of 56.2%.

[0130] Comparative Example 6

[0131] Add 40 ml of DMF to the reaction bottle, add 4.75 g of compound 6 and 3.61 g of selexipagol under stirring, after the liquid is dissolved, add 0.1 ml of 10% sodium hydroxide aqueous solution to the system, control the temperature at 10-20 ° C and stir to react for 2 hours, then add 420 ml of purified water and 420 ml of ethyl acetate to the reaction liquid, stir the liquid for 10 minutes, let it stand, separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50 ° C to obtain a yellow oil.

[0132] The yellow oil was dissolved in 42 ml of ethyl acetate and 8 g of silica gel (200 mesh) was added, and the mixture was concentrated under reduced pressure at 50°C. 80 g of silica gel (200 mesh) was added to the column chromatography column. The mixture was first eluted with 100 ml of n-hexane, and then eluted with 600 ml of ethyl acetate: n-hexane = 1:5. The eluate was collected and concentrated under reduced pressure at 50°C to obtain 1.2 g of yellow oil (i.e., selexipag dimer impurity), with a yield of 15.73% and a purity of 78.9%.

[0133] Comparative Example 7

[0134] Add 40 ml of DMF to the reaction bottle, add 4.96 g of selexipag and 3.61 g of selexipag alcohol under stirring, after the liquid is dissolved, control the temperature at 10°C and stir to react for 2 hours, then add 420 ml of purified water and 420 ml of ethyl acetate to the reaction liquid, stir the liquid for 10 minutes, let it stand, separate the liquids, collect the upper organic phase, and concentrate to dryness under reduced pressure at 50°C to obtain a yellow oil.

[0135] The yellow oil was dissolved in 42 ml of ethyl acetate and 8 g of silica gel (200 mesh) was added, and the mixture was concentrated under reduced pressure at 50°C. 80 g of silica gel (200 mesh) was added to the column chromatography column. The mixture was first eluted with 100 ml of n-hexane, and then eluted with 600 ml of ethyl acetate: n-hexane = 1:5. The eluate was collected and concentrated under reduced pressure at 50°C to obtain 2.2 g of yellow oil (i.e., selexipag dimer impurity), with a yield of 28.83% and a purity of 89.2%.

[0136] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. Selexipag impurity, the structure of which is shown in Formula III below:

2. A method for preparing the selexipag impurity shown in formula III, wherein the synthetic route is as follows:

3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula I to the compound of formula II is 1.0:(1.0-1.2).

4. The preparation method according to claim 2 or 3, characterized in that: The reaction temperature of the compound of formula I and the compound of formula II is 0-10°C, and can be 0°C, 5°C or 10°C.

5. The preparation method according to any one of claims 2 to 4, characterized in that: The compound of formula I reacts with the compound of formula II in the presence of N,N-dimethylformamide as a solvent.

6. The preparation method according to any one of claims 2 to 5, characterized in that: The reaction process of the compound of formula I and the compound of formula II also includes adding 4-dimethylaminopyridine and / or N,N'-carbonyldiimidazole.

7. The preparation method according to claim 6, characterized in that: The molar ratio of the compound of formula I to 4-dimethylaminopyridine is 1:(0.01-0.05), for example 1:0.01, 1:0.02, 1:0.03, 1:0.04 or 1:0.05; and / or, The molar ratio of the compound of formula I to N,N'-carbonyldiimidazole is 1:(1.1-1.3), for example 1:1.1, 1:1.2 or 1:1.

3.

8. A method for separating the selexipag impurity represented by formula III, characterized in that: include: Providing a mixture containing selexipag impurities represented by formula III and compound 6; The separation was performed by high pressure preparative chromatography purification method; mobile phase A was 2% glacial acetic acid-acetonitrile; mobile phase B was 2% glacial acetic acid-water; the following gradient elution was used:

9. The method for separating the selexipag impurity represented by formula III according to claim 8, characterized in that: The separation method further comprises: starting to collect the eluent when the peak height of the chromatographic peak reaches 100 mAU, and stopping the collection when the peak height drops to 50 mAU; and / or, The separation method further comprises: adding ethyl acetate to the collected eluate for extraction, collecting the ethyl acetate phase, and concentrating under reduced pressure to obtain a yellow oily substance, which is the selexipag impurity shown in formula III.

10. Use of the selexipag impurity represented by formula III as described in claim 1 in the quality control of selexipag.

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