Purification method and application of beraprost sodium

Abstract

The invention relates to a method for adjusting the ratio of two configurations 16-R and S in beraprost sodium shown in a formula (I) through recrystallization. The method comprises the following steps: adding a mixed solvent into a beraprost sodium crude product, and stirring to obtain a system, so as to obtain the beraprost sodium crystal. According to the method disclosed by the invention, the 16-R / S ratio of the beraprost sodium crude product can be adjusted to 0.9-1.1 / 1 from about 1.2-1.4 / 1, so that the beraprost sodium API pharmacopoeia standard is met. The invention also provides a crystal of beraprost sodium. The method disclosed by the invention is simple to operate and easy to produce, and can be industrially amplified. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry. Specifically, the present invention relates to a method for purifying beta prostaglandin sodium, wherein the 16-R / S ratio of beta prostaglandin sodium is adjusted within the range of 0.9 to 1.1 / 1 by recrystallization. The present invention also relates to a new crystal form of beta prostaglandin sodium. Background Art

[0002] Beprostaglandin sodium (Formula I) is a prostaglandin agonist and platelet aggregation antagonist developed by Toray Industries, Ltd. of Japan. It is a derivative of prostaglandin I2 and is clinically used to treat peripheral vascular disease and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion. The marketed beprostaglandin sodium is composed of two racemic compounds, 16-S configuration shown in formula (II) and 16-R configuration shown in formula (III), and the ratio of the two components should be between 0.9-1.1 / 1.

[0003]

[0004] The synthesis method of beraprost sodium shown in formula (I) can refer to the original European patent EP84856, as well as the Chinese patent applications CN1680351, CN103509044 and CN118572962 for the research and optimization of beraprost sodium process in recent years. These process improvement patents are mainly aimed at optimizing the process, but in the final preparation of beraprost sodium finished product, the ratio of 16-S configuration shown in formula (II) and 16-R configuration shown in formula (III) is not studied, and how to purify it to the API quality standard range is not explained at all.

[0005] Based on the consideration of drug production safety, there is an urgent need in the art to develop a low-cost, simple, easy and industrially scalable purification method for beraprost sodium suitable for pharmaceutical use. Summary of the invention

[0006] The object of the present invention is to provide a method for purifying sodium beta prostaglandin, wherein the method can adjust the 16-R / S ratio of sodium beta prostaglandin within the range of 0.9 to 1.1 / 1.

[0007] The present invention also aims to provide a new crystal form of beta prostaglandin sodium.

[0008] In a first aspect, the present invention provides a method for purifying beraprost sodium represented by formula (I), the method comprising the following steps:

[0009] 1) adding a mixed solvent to the crude product of beta prostaglandin sodium shown in formula (I),

[0010] 2) stirring the system obtained in step 1) to obtain beta prostaglandin sodium crystals;

[0011] In the beprostaglandin sodium crystal, the ratio of the 16-S configuration compound represented by formula (II) to the 16-R configuration compound represented by formula (III) is 0.9-1.1 / 1;

[0012]

[0013] In a preferred embodiment, the "system obtained in the stirring step 1)" is obtained by slurrying the amorphous foamy solid of beraprost sodium represented by formula (I) in a mixed solvent.

[0014] In a specific embodiment, the mixed solvent used is selected from a combination of a protic good solvent and an aprotic poor solvent.

[0015] In a specific embodiment, the protic good solvent is methanol, and the aprotic poor solvent is acetonitrile.

[0016] In a specific embodiment, the volume ratio of methanol to acetonitrile is 15-25%.

[0017] In a specific embodiment, the stirring temperature in step 2) is 15 to -10°C; preferably, 0 to -10°C.

[0018] In a specific embodiment, the solvent multiple of the mixed solvent is 8 to 36 times; preferably 12 to 24 times.

[0019] In a preferred embodiment, the ratio of the 16-S configuration compound represented by formula (II) to the 16-R configuration compound represented by formula (III) in the crude product of sodium beta prostaglandin represented by formula (I) is 1.2 to 1.4 / 1.

[0020] In a preferred embodiment, the ratio of the 16-S configuration compound represented by formula (II) to the 16-R configuration compound represented by formula (III) is the ratio of the peak areas in HPLC detection.

[0021] In a preferred embodiment, in step 2), filtration is performed under nitrogen protection.

[0022] In a preferred embodiment, in step 2), the obtained beta prostaglandin sodium crystals are vacuum dried.

[0023] In a preferred embodiment, the crystal of beraprost sodium represented by formula (I) has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction pattern: 3.80°; 5.34°; 6.52° and 22.13°.

[0024] In a preferred embodiment, the crystals of beraprost sodium represented by formula (I) have characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction pattern: 5.97°; 8.51°; 12.59°; 19.66°; 19.94° and 25.76°.

[0025] In a preferred embodiment, the X-ray diffraction pattern of the crystal of beraprost sodium shown in formula (I) is as follows Figure 6 shown.

[0026] In a preferred embodiment, the differential scanning calorimetry (DSC) thermogram of the crystals of beraprost sodium represented by formula (I) contains two endothermic peaks, wherein the peak onset temperature is 194.52±2°C and the peak maximum values ​​are 198.73±1°C and 213.49±1°C.

[0027] In a preferred embodiment, the differential scanning calorimetry (DSC) thermal analysis diagram of the crystal of beraprost sodium shown in formula (I) is as follows: Figure 7 shown.

[0028] In a preferred embodiment, the total purity of beta-prostaglandin sodium crystals is above 99.8%.

[0029] In a second aspect, the present invention provides a crystal of beraprost sodium represented by formula (I), wherein the crystal has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 3.80°; 5.34°; 6.52° and 22.13°.

[0030] In a specific embodiment, the crystal also has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction pattern: 5.97°; 8.51°; 12.59°; 19.66°; 19.94° and 25.76°.

[0031] In a specific embodiment, the X-ray diffraction pattern of the crystal is as follows Figure 6 shown.

[0032] In a specific embodiment, the crystal has a differential scanning calorimetry (DSC) thermogram comprising two endothermic peaks, wherein the peak onset temperature is 194.52±2°C and the peak maximum values ​​are 198.73±1°C and 213.49±1°C.

[0033] In a preferred embodiment, the differential scanning calorimetry (DSC) thermal analysis diagram of the crystal of beraprost sodium shown in formula (I) is as follows: Figure 7 shown.

[0034] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the crystals of beraprost sodium obtained by the method of the first aspect or the crystals of the second aspect, and a pharmaceutically acceptable excipient.

[0035] In a fourth aspect, the present invention provides the use of the beraprost sodium crystals obtained by the method of the first aspect or the crystals of the second aspect in the preparation of a drug for treating peripheral vascular disease and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion.

[0036] In a fifth aspect, the present invention provides a method for treating peripheral vascular disease and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion, the method comprising administering a therapeutically effective amount of the polymorph of beraprost sodium prepared by the method described in the first aspect or the polymorph of beraprost sodium or the pharmaceutical composition described in the second aspect to a subject in need thereof.

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The HPLC chart of the pure amorphous powder of beraprost sodium prepared in the reference example of the present invention is shown;

[0039] Figure 2 The X-ray powder diffraction (XRPD) pattern of the pure amorphous powder of beraprost sodium prepared in the reference example of the present invention is shown;

[0040] Figure 3 The differential scanning calorimetry (DSC) thermogram of the pure amorphous powder of beraprost sodium prepared in the reference example of the present invention is shown;

[0041] Figure 4 The HPLC chart of the crude beraprost sodium prepared in Example 1 of the present invention is shown;

[0042] Figure 5 The HPLC chart of pure beraprost sodium crystals prepared in Example 1 of the present invention is shown;

[0043] Figure 6 The X-ray powder diffraction (XRPD) pattern of the pure beraprost sodium crystals prepared in Example 1 of the present invention is shown;

[0044] Figure 7 The differential scanning calorimetry (DSC) thermogram of the pure beraprost sodium crystals prepared in Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0045] The inventors have found through research that the ratio of the two 16-R / S configurations of beraprost sodium obtained by the method of the prior art is 1.2 to 1.4 / 1, which does not meet the quality standard range of the ratio of the two 16-R / S configurations in the API in the range of 0.9 to 1.1 / 1. Therefore, the production method of the prior art has obvious production defects and cannot prepare qualified beraprost sodium API. It is necessary to further purify beraprost sodium, reasonably adjust the 16-R / S ratio in the range of 0.9 to 1.1 / 1, improve the purity, and produce qualified beraprost sodium API for pharmaceutical use.

[0046] After extensive and in-depth research, the inventors found that by adjusting the peak area ratio of the two 16-S configuration compounds shown in formula (II) and the 16-R configuration compounds shown in formula (III) in the beraprost sodium compound shown in formula (I) by recrystallization, the 16-R / S ratio can be adjusted from the initial 1.2 to 1.4 / 1 to the range of 0.9 to 1.1 / 1, and the total purity is above 99.8%, which meets the Pharmacopoeia API standard. On this basis, the present invention was completed.

[0047] Beprostaglandin sodium and 16-R / S ratio

[0048] The "prostaglandin sodium" described herein is a compound shown in formula I,

[0049]

[0050] The marketed beprostaglandin sodium is composed of two racemic compounds, 16-S configuration shown in formula (II) and 16-R configuration shown in formula (III).

[0051]

[0052] Accordingly, the "16-R / S ratio" described herein refers to the ratio of the two racemic compounds of the 116-S configuration shown in formula (II) and the 16-R configuration shown in formula (III). According to the requirements of beprostaglandin sodium API, the 16-R / S ratio should be between 0.9-1.1 / 1.

[0053] The method for purifying sodium beta prostaglandin of the present invention

[0054] The present inventors have found that the peak area ratio of the two 16-S configuration compounds represented by formula (II) and the 16-R configuration compounds represented by formula (III) in the beraprost sodium compound represented by formula (I) can be adjusted by recrystallization, so that the 16-R / S ratio falls within the range of 0.9 to 1.1 / 1.

[0055] To achieve the above object, the present invention adopts a method different from conventional crystallization and recrystallization, that is, a method for beraprost sodium amorphous powder to be pulped in a mixed solvent. In a specific embodiment, purification method of the present invention comprises: adding a mixed solvent to the beraprost sodium crude product shown in formula (I), and stirring the obtained system to obtain beraprost sodium crystals. In a preferred embodiment, filtering can be performed under nitrogen protection. In another preferred embodiment, vacuum drying can be performed to the beraprost sodium crystals obtained.

[0056] In the purification method of the present invention, the mixed solvent used, the ratio of the mixed solvent and the stirring temperature have a significant effect on the 16-R / S ratio of the purified beraprost sodium. In the purification method of the present invention, the mixed solvent used is selected from a combination of a protic good solvent and an aprotic poor solvent. In a specific embodiment, the protic good solvent is methanol and the aprotic poor solvent is acetonitrile.

[0057] In the method of the present invention, the volume ratio of methanol to acetonitrile is 15-25%.

[0058] In the method of the present invention, the stirring temperature is 15 to -10°C; preferably 0 to -10°C.

[0059] The inventors also found that in the purification method of the present invention, the volume of the mixed solvent also has an effect on the purification yield. Therefore, in this article, the "solvent multiple" is used to describe the effect of the volume of the mixed solvent on the purification yield. The "solvent multiple" used in this article refers to the ratio of the solvent volume (ml) to the mass (g) of beraprost sodium. In a specific embodiment, the solvent multiple of the mixed solvent is 8 to 36 times; preferably 12 to 24 times.

[0060] Beraprost sodium crystal and pharmaceutical composition of the present invention

[0061] Through the purification method of the present invention, a beraprost sodium crystal is obtained, and the 16-R / S ratio of the crystal falls within the range of 0.9 to 1.1 / 1.

[0062] Therefore, the present invention also provides a crystal of beraprost sodium shown in formula (I), wherein the crystal has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 3.80°; 5.34°; 6.52° and 22.13°. In a preferred embodiment, the crystal also has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 5.97°; 8.51°; 12.59°; 19.66°; 19.94° and 25.76°. In a more preferred embodiment, the X-ray diffraction spectrum of the crystal is as follows Figure 6 shown.

[0063] The crystals of the present invention can also be characterized by a differential scanning calorimetry (DSC) thermogram, which contains two endothermic peaks, wherein the peak onset temperature is 194.52±2°C and the peak maximum values ​​are 198.73±1°C and 213.49±1°C. In a preferred embodiment, the differential scanning calorimetry (DSC) thermogram of the crystals of beraprost sodium of the present invention is as follows Figure 7 shown.

[0064] Based on the crystals of beraprost sodium provided by the present invention, those skilled in the art will understand that the crystals of the present invention can be prepared into drugs for treating peripheral vascular diseases and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion. Therefore, the present invention also provides a pharmaceutical composition comprising the crystals of the present invention and optional pharmaceutically acceptable excipients.

[0065] The specific excipients in the pharmaceutical composition and the specific dosage form of the pharmaceutical composition can be manufactured by those skilled in the art according to specific needs in a known manner. For example, the polymorph of the present invention can be made into an oral preparation, such as a tablet, by conventional mixing, granulation, tableting, dissolution or freeze-drying processes. Suitable excipients may include fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium hydroxymethylcellulose, or polyvinyl pyrrolidone. If necessary, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. Auxiliary agents are particularly flow regulators and lubricants, for example, silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycol. If desired, the tablet core can be provided with a suitable coating that can resist gastric juice. For this reason, a concentrated carbohydrate solution can be used. This solution can contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. In order to prepare a coating resistant to gastric juice, an appropriate cellulose solution can be used, for example cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments can be added to the coating of the tablet or tablet core. For example, for identification or in order to characterize the combination of active ingredient dosages.

[0066] Based on the crystal and pharmaceutical composition, the present invention also provides a method for treating peripheral vascular disease and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion, which comprises administering a therapeutically effective amount of the crystal or pharmaceutical composition of the present invention to a subject in need thereof.

[0067] The main advantages of the present invention are:

[0068] 1. The present invention provides for the first time a method for adjusting the peak area ratio of two compounds of beraprost sodium, 16-S configuration shown in formula (II) and 16-R configuration shown in formula (III), in HPLC detection by recrystallization;

[0069] 2. The peak area ratio of the two compounds of 16-S configuration represented by formula (II) and 16-R configuration represented by formula (III) in the pure beraprost sodium purified by the method of the present invention is in the range of 0.9 to 1.1 / 1 in HPLC detection, which meets the API quality standard range;

[0070] 3. The purification method of the present invention is simple, easy to operate, low in cost, and can be industrially scaled up.

[0071] The technical scheme of the present invention is further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation of the present invention, and all various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0072] Example

[0073] Materials and Methods

[0074] HPLC detection method

[0075] Shimadzu LC2030C 3D HPLC, PDA detector, Labsolution workstation Column: H087-InertSustain C18 4.6*250mm 5um

[0076] Flow rate: 1.0ml / min;

[0077] Column temperature: 25°C;

[0078] Sample temperature: 5°C;

[0079] Detection wavelength: 285nm;

[0080] Injection volume: 5ul;

[0081] Mobile phase: A: water: acetonitrile: methanol: acetic acid = 640:330:30:1; B: acetonitrile: water: acetic acid = 900:100:1

[0082] Reference Example. Preparation of pure amorphous powder of beraprost sodium

[0083] 2.7g crude beraprost sodium was prepared by referring to the method of CN102952107A, and 1.4g pure beraprost sodium amorphous powder was obtained by preparative chromatography. HPLC detection showed that 16-R, S was 49.350%, 50.299%, 16-R / S ratio was 0.98 / 1, and the total purity was 99.65%. Figure 1 , XRPD and DSC results are as follows Figure 2 and Figure 3 .

[0084] Example 1.

[0085] The inventors have systematically studied the factors affecting the relationship between the change of the ratio of beraprost sodium 16-R / S by recrystallization purification, which mainly include factor 1: the type of mixed solvent; factor 2: the volume ratio of the two solvents in the mixed solvent; and factor 3: the stirring temperature.

[0086] Since the structure of beraprost sodium contains 6 related chiral centers, 2 hydroxyl groups (one of which is an allyl hydroxyl group), 1 carboxyl group and 1 acetylenic bond, the stereo configuration is complex and high temperature easily leads to the generation of unknown impurities, so the stirring temperature is selected at 25°C or below. The non-protonic poor solvent in the mixed solvent is acetonitrile as the basis. In order to facilitate the stirring and dispersion operation, the volume v1 / ml of acetonitrile is 20 times the mass / g of beraprost sodium, and the stirring time is 2h. Methanol, ethanol, isopropanol and pure water are selected as the research templates for the protonic good solvent in the mixed solvent, and their volumes are v2 / ml. The results are shown in Table 1 below.

[0087] Table 1

[0088]

[0089]

[0090] As shown in Table 1, factor 1, i.e. the type of mixed solvent, has a significant effect on 16-R / S, among which the methanol and acetonitrile system has the greatest effect on the change of the ratio of beraprost sodium 16-R / S. Specifically, at 0°C, 20% methanol / acetonitrile can adjust the ratio of beraprost sodium 16-R / S from the initial ratio of 1.27 / 1 to 0.99 / 1, which meets the API standard; 20% ethanol / acetonitrile can only adjust the ratio from 1.37 / 1 to 1.29 / 1, which cannot meet the API standard; similarly, 30% isopropanol / acetonitrile makes the ratio almost unchanged from 1.38 / 1 to 1.37 / 1, which also cannot meet the API standard. The pure water / acetonitrile system makes the solid of beraprost sodium agglomerate and cannot be dispersed evenly, resulting in the inability to continue the study.

[0091] Factor 2, i.e., the volume ratio of the two solvents in the mixed solvent, and factor 3, i.e., the stirring temperature, are not isolated factors that affect the 16-R / S ratio. The two factors work together to achieve the adjustment of the 16-R / S ratio within the API range standard. Specifically, at 25°C, 20% methanol, the 16-R / S ratio is 1.19 / 1, and when cooled to 0°C, it becomes 0.99 / 1, which meets the API range standard. In the ethanol / acetonitrile and isopropanol / acetonitrile solvent systems, whether at 25°C or cooled to 0°C, the ratio changes very little and cannot meet the API range standard. At the same time, the solid yield is lower than the purification yield of the 20% methanol / acetonitrile mixed solvent system. The further increase of good solvent will lead to an increase in the solubility of beraprost sodium and a further decrease in the purification yield. Continuing to study the adjustment of the 16-R / S ratio by increasing the volume ratio of ethanol or isopropanol has no practical production value, so the research on these two solvent systems has been stopped.

[0092] From the above screening results, it can be seen that the optimal condition is to use a combination of mixed solvents methanol and acetonitrile in a certain volume ratio in an appropriate range, and to adjust the beraprost sodium 16-R / S ratio to meet the API range standard by lowering the temperature.

[0093] The inventors further studied in detail the influence of the combined effect of factor 2, i.e., the volume ratio of methanol to acetonitrile and factor 3, i.e., temperature, on the change of the ratio of beraprost sodium 16-R / S and the yield. The results are shown in Table 2. For ease of comparison, only the percentages of the two peaks of 16-R / S in HPLC were taken.

[0094] Table 2

[0095]

[0096] As can be seen from Table 2, in general, the trend of the 16-R / S ratio changes from high to low with the increase of factor 2, that is, the volume ratio of methanol / acetonitrile, and factor 3, that is, the decrease in temperature, also causes the 16-R / S ratio to change from high to low. Specifically, when the volume ratio of methanol to acetonitrile is 0-25%, the stirring temperature is 25°C, and the 16-R / S ratio decreases from 1.25 / 1 to 1.14 / 1. When the volume ratio of methanol to acetonitrile is 15%, at 25°C, the 16-R / S ratio is 1.24 / 1; when the temperature drops to 15°C, the ratio is 1.20 / 1, and at 0°C, the ratio is 1.11 / 1≈1.1 / 1, reaching the upper limit of the API range. When the volume ratio of methanol to acetonitrile is further increased by 25%, the 16-R / S ratio is 1.19 / 1 at 25°C; when the temperature is lowered to 15°C, the ratio is 1.04 / 1, and at 0°C, the ratio is 0.88 / 1≈0.9 / 1, reaching the lower limit of the API range. At the same methanol / acetonitrile volume ratio, the 16-R / S ratio tends to be stable and has no significant changes when the temperature is lowered from 0°C to -10°C. At the same methanol / acetonitrile volume ratio, the purification yield gradually increases from 15°C to 0°C, and the purification yield tends to be stable and has no significant changes from 0°C to -10°C, so there is no need for further cooling research.

[0097] From the above data, it can be seen that the volume ratio of methanol / acetonitrile is preferably 15 to 25%, and the stirring temperature range is 15 to -10°C, and more preferably 0 to -10°C.

[0098] Based on the above methanol / acetonitrile volume ratio and stirring temperature, the inventors continued to study the effect of the volume of the mixed solvent on the purification yield in the preparation method. With a volume ratio of 20% methanol / acetonitrile, a stirring temperature of 0°C, and the effect of different volume solvent multiples on the purification yield were studied, and the solvent multiple refers to the ratio of the solvent volume ml to the mass g of beraprost sodium, and the results are shown in Table 3 below.

[0099] Table 3

[0100]

[0101] As shown in Table 3, an increase in solvent volume leads to a decrease in purification yield, while too little solvent volume leads to the inability to fully adjust the 16-R / S ratio to the API range standard. Therefore, the appropriate solvent volume multiple is 8 to 36 times, and more preferably 12 to 24 times.

[0102] Example 2. Characterization of Beraprost Sodium Crystals

[0103] The inventors characterized the beraprost sodium crystals obtained in the above embodiment, whose 16-R / S ratio meets the API range standard. The crystals have characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 3.80°; 5.34°; 5.97°; 6.52°; 8.51°; 12.59°; 19.66°; 19.94°; 22.13° and 25.76°.

[0104] The specific information of Beraprost Sodium Crystals is shown in Table 4 below.

[0105] Table 4

[0106]

[0107]

[0108] The differential scanning calorimetry (DSC) thermogram of the beraprost sodium crystals prepared in the above example contains two endothermic peaks, wherein the peak onset temperature is 194.52±2°C and the peak maximum values ​​are 198.73±1°C and 213.49±1°C.

[0109] Preparation Example 1.

[0110] 1.1 Preparation of crude beraprost sodium

[0111] 0.7 g crude beraprost sodium was prepared by referring to the method of CN102952107A. HPLC detection showed 16-R, S ~ 55.910%, 43.872%, 16-R / S ratio was 1.27 / 1, and the total purity was 99.78%. Figure 4 .

[0112] 1.2 Preparation of pure beraprost sodium crystals 1

[0113] 0.7g crude beraprost sodium was added with 14ml acetonitrile and 2.8ml methanol, cooled to 0~-10℃ in an ice bath, stirred for 2h, filtered under nitrogen protection, rinsed with a small amount of acetonitrile, and dried in vacuum to obtain 0.58g white solid with a yield of 82%. HPLC detection showed that the purity was 50.360%, 49.495%, the 16-R / S ratio was 1.02 / 1, and the total purity was 99.86%. HPLC analysis showed that the purity of the solid was 50.360%, the purity of the solid was 49.495%, the 16-R / S ratio was 1.02 / 1, and the total purity was 99.86%. Figure 5 , XRPD and DSC results are as follows Figure 6 and Figure 7 .

[0114] Preparation Example 2.

[0115] 2.1 Preparation of crude beraprost sodium

[0116] 25 g of crude beraprost sodium was prepared by referring to the method of CN102952107A. HPLC detected 16-R, S ~ 55.243%, 43.608%, 16-R / S ratio was 1.26 / 1, and the total purity was 98.85%.

[0117] 2.2 Preparation of pure beraprost sodium crystals

[0118] 6g crude beraprost sodium was added with 60ml acetonitrile and 12ml methanol, cooled to 0-10℃ in an ice bath, stirred for 2h, filtered under nitrogen protection, rinsed with a small amount of acetonitrile, and dried in vacuum to obtain 5g white solid with a yield of 84%. HPLC detection showed that the content of 50.54%, 49.31%, 16-R / S ratio was 1.02 / 1, and the total purity was 99.85%.

[0119] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for purifying beraprost sodium represented by formula (I), the method comprising the following steps: 1) adding a mixed solvent to the crude product of beta prostaglandin sodium shown in formula (I), 2) stirring the system obtained in step 1) to obtain beta prostaglandin sodium crystals; In the beprostaglandin sodium crystal, the ratio of the 16-S configuration compound represented by formula (II) to the 16-R configuration compound represented by formula (III) is 0.9-1.1 / 1; 2. The purification method according to claim 1, characterized in that The mixed solvent used is selected from a combination of a protic good solvent and an aprotic poor solvent.

3. The purification method according to claim 2, characterized in that The protic good solvent is methanol, and the aprotic poor solvent is acetonitrile.

4. The purification method according to claim 3, characterized in that The volume ratio of methanol to acetonitrile is 15-25%.

5. The purification method according to claim 1, characterized in that The stirring temperature in step 2) is 15 to -10°C; preferably, 0 to -10°C.

6. The purification method according to claim 1, characterized in that The solvent multiple of the mixed solvent is 8 to 36 times, preferably 12 to 24 times.

7. A crystal of beraprost sodium represented by formula (I), wherein the crystal has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 3.80°; 5.34°; 6.52° and 22.13°.

8. The crystal according to claim 7, characterized in that The crystal also has characteristic peaks at the following 2θ angles (±0.2°) in the X-ray diffraction spectrum: 5.97°; 8.51°; 12.59°; 19.66°; 19.94° and 25.76°.

9. The crystal according to claim 7 or 8, characterized in that The X-ray diffraction pattern of the crystal is shown in FIG6 .

10. The crystal according to claim 7, characterized in that The differential scanning calorimetry (DSC) thermogram of the crystals comprises two endothermic peaks, wherein the peak onset temperature is 194.52±2°C and the peak maximum values ​​are 198.73±1°C and 213.49±1°C.

11. A pharmaceutical composition comprising a therapeutically effective amount of the crystal of beraprost sodium obtained by the method according to any one of claims 1 to 6 or the crystal according to any one of claims 7 to 10, and a pharmaceutically acceptable excipient.

12. Use of the beraprost sodium crystal obtained by the method of any one of claims 1 to 6 or the crystal of any one of claims 7 to 10 in the preparation of a medicament for treating peripheral vascular disease and pulmonary hypertension with symptoms such as ulcers, intermittent claudication, pain and cold sensation caused by arterial occlusion.

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