Purification method of triphenylphosphine

Abstract

The invention provides a method for purifying triphenylphosphine, and belongs to the field of chemistry. The method comprises the following steps: (1) dissolving a triphenylphosphine crude product in an organic solvent A, filtering, mixing filtrate with an alkaline aqueous solution, stirring, standing for liquid separation, taking an organic phase layer, and carrying out vacuum concentration to remove the organic solvent A so as to obtain a concentrated product; (2) mixing the concentrated product with a solvent B, and carrying out the following operations under the condition of nitrogen or inert gas protection or in the air atmosphere: heating to 50 DEG C to the reflux temperature of the solvent B, then cooling to 0-40 DEG C, and crystallizing; and (3) carrying out solid-liquid separation and drying to obtain a pure triphenylphosphine product. The triphenylphosphine purified by the purification method is high in yield and low in impurity content, has unexpected technical effects, and can be used for preparing sugammadex sodium.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemistry, in particular to a purification method of triphenylphosphine. BACKGROUND

[0002] Sugammadex Sodium, chemical name, 6-fully deoxy-6-fully (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, CAS number: 343306-79-6, molecular formula: C 72 H 104 Na8O 48 S8, molecular weight: 2178.01, is a chemical synthetic drug, used for rapid reversal of neuromuscular blockade caused by anesthetic rocuronium, vecuronium in adult patients during surgery.

[0003] At present, the synthesis process of Sugammadex Sodium generally uses γ-cyclodextrin as raw material, reacts with halogenating agent and triphenylphosphine, and then combines with 3-mercaptopropionic acid to form Sugammadex Sodium; such as the preparation method of Sugammadex Sodium disclosed in patent application CN109879986A. However, the inventors found that the triphenylphosphine used in the reaction contains diphenylphosphine impurities, which can produce multiple phosphorus-containing impurities in the form of prototypes or derivatives with the synthesis process of Sugammadex Sodium. The above-mentioned impurities are difficult to remove by using conventional purification methods (such as the refining method in patent application CN109879986A), which seriously affects the product quality of Sugammadex Sodium.

[0004] Therefore, it is urgent to develop an effective purification method of triphenylphosphine. SUMMARY

[0005] To solve the above technical problems, the present application provides the following technical solutions.

[0006] In a first aspect, the present application provides a purification method of triphenylphosphine.

[0007] A purification method of triphenylphosphine, comprising:

[0008] (1) dissolving triphenylphosphine crude product in organic solvent A, filtering, mixing the filtrate with an alkaline aqueous solution, stirring, standing and separating, taking the organic phase layer, removing the organic solvent A under reduced pressure to obtain a concentrated product;

[0009] (2) mixing the concentrated product with solvent B, and under the condition of nitrogen or inert gas protection or in air atmosphere, operating as follows: warming to 50℃-solvent B reflux temperature, then cooling to 0℃-40℃, and crystallizing;

[0010] (3) solid-liquid separation, drying, to obtain triphenylphosphine pure product.

[0011] In some preferred embodiments, the step (2) comprises: mixing the concentrated product with solvent B, under the condition of nitrogen or inert gas protection, warming to 50°C- solvent B reflux temperature (for example 50°C, 55°C, 60°C, 65°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C or 130°C), and then cooling to 0°C-40°C (for example 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C), to crystallize.

[0012] In some embodiments, the organic solvent A comprises at least one of dichloromethane, ethyl acetate, toluene, chloroform. In some preferred embodiments, the organic solvent A comprises at least one of dichloromethane, toluene, chloroform. In some more preferred embodiments, the organic solvent A is dichloromethane.

[0013] In some embodiments, the mass ratio of the organic solvent A to the crude triphenylphosphine is 1:1-50:1. In some embodiments, the mass ratio of the organic solvent A to the crude triphenylphosphine is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 35:1, 40:1, 45:1 or 50:1. In some embodiments, the mass ratio of the organic solvent A to the crude triphenylphosphine is 1:1-5:1. In some preferred embodiments, the mass ratio of the organic solvent A to the crude triphenylphosphine is 2:1.

[0014] In some embodiments, the solvent B comprises a mixture of an alcoholic solvent and water or an alcoholic solvent. In some embodiments, the solvent B is a mixture of an alcoholic solvent and water. In some embodiments, the solvent B is an alcoholic solvent.

[0015] In some embodiments, the alcoholic solvent comprises at least one of ethylene glycol, methanol, ethanol, isopropanol. In some embodiments, the alcoholic solvent is ethanol. In some embodiments, the alcoholic solvent is ethylene glycol.

[0016] In some embodiments, the volume ratio of the alcoholic solvent to water in the solvent B is > 1 :5. In some embodiments, the volume ratio of the alcoholic solvent to water in the solvent B is 1 :5, 1 :4, 1 :3, 1 :2, 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 25: 1, 30: 1, 35: 1, 40: 1, 45: 1, 50: 1, 55: 1, 60: 1, 65: 1, 70: 1, 75: 1, 80: 1, 85: 1, 90: 1, 95: 1, 99: 1, or 100:0.

[0017] In some embodiments, the mass ratio of the solvent B to the crude triphenylphosphine is 7: 1-18: 1. In some embodiments, the mass ratio of the solvent B to the crude triphenylphosphine is 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, or 18: 1.

[0018] In some embodiments, the crystallization time of the step (2) is 0.5 h-5.0 h. In some embodiments, the crystallization time of the step (2) is 0.5 h, 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, or 5.0 h.

[0019] In some embodiments, the basic aqueous solution is an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous solution of sodium hydroxide and potassium hydroxide.

[0020] In some embodiments, the concentration of the base in the basic aqueous solution is 0.5 mol / L-5.0 mol / L. In some embodiments, the concentration of the base in the basic aqueous solution is 0.5 mol / L, 1.0 mol / L, 1.5 mol / L, 2.0 mol / L, 2.5 mol / L, 3.0 mol / L, 3.5 mol / L, 4.0 mol / L, 4.5 mol / L, or 5.0 mol / L.

[0021] In some embodiments, the stirring time in the step (1) is 0.5 h-5.0 h. In some embodiments, the stirring time of the stirring in the step (1) is 0.5 h, 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, or 5.0 h.

[0022] In some embodiments, the temperature of the reduced pressure concentration in step (1) is 30-60°C. In some embodiments, the temperature of the reduced pressure concentration in step (1) is 30°C, 35°C, 40°C, 45°C, 50°C, 55°C or 60°C.

[0023] In some embodiments, the drying in step (2) is vacuum drying.

[0024] In some embodiments, the inert gas comprises at least one of helium, neon, argon, krypton, xenon.

[0025] In some embodiments, the triphenylphosphine crude contains triphenylphosphine oxide impurity and / or diphenylphosphoric acid impurity, and the purification method is used to remove the triphenylphosphine oxide impurity and / or diphenylphosphoric acid impurity in the triphenylphosphine crude;

[0026] The structure of the triphenylphosphine oxide impurity is:

[0027] The structure of the diphenylphosphoric acid impurity is:

[0028] In a second aspect, the present application provides a triphenylphosphine purified by the purification method according to the first aspect.

[0029] A triphenylphosphine purified by the purification method according to the first aspect.

[0030] In a third aspect, the present application provides use of the triphenylphosphine purified by the purification method according to the first aspect or the triphenylphosphine according to the second aspect in the preparation of sodium glycofurol.

[0031] Use of the triphenylphosphine purified by the purification method according to the first aspect or the triphenylphosphine according to the second aspect in the preparation of sodium glycofurol.

[0032] Advantages

[0033] Compared with the prior art, the present application has at least one of the following advantages:

[0034] (1) The use of alkali washing in step (1) of the present application is conducive to the removal of triphenylphosphine oxide impurity and diphenylphosphoric acid impurity.

[0035] (2) In step (1) of the present application, compared with other aqueous alkali solutions, the use of aqueous sodium hydroxide solution or aqueous potassium hydroxide solution is more conducive to the removal of triphenylphosphine oxide impurity.

[0036] (3) Compared with using other recrystallization solvents (solvent B), the use of the mixed solvent of alcohol and water as the recrystallization solvent (solvent B) in the present application is beneficial to the removal of triphenyl phosphine oxide impurity, diphenyl phosphate impurity and other impurities, wherein the use of the aqueous solution of ethanol, the aqueous solution of methanol or the aqueous solution of ethylene glycol is preferred, and the use of the aqueous solution of ethylene glycol is more preferred, which is more beneficial to the removal of triphenyl phosphine oxide impurity.

[0037] (4) The use of the aqueous solution of ethylene glycol, the aqueous solution of DMF (N,N-dimethylformamide) or the aqueous solution of glycerol as the recrystallization solvent (solvent B) in the present application is more beneficial to the removal of triphenyl phosphine oxide impurity, but the use of the aqueous solution of DMF or the aqueous solution of glycerol as the recrystallization solvent (solvent B) results in a lower product yield, therefore, the use of the aqueous solution of ethylene glycol as the recrystallization solution is preferred, which is more beneficial to the increase of the product yield and the decrease of the impurity content.

[0038] (5) The use of the aqueous solution of ethanol, the aqueous solution of isopropyl alcohol, the aqueous solution of ethylene glycol, and more preferably the aqueous solution of ethylene glycol as the recrystallization solvent (solvent B) in the present application is more beneficial to the increase of the yield of the pure triphenyl phosphine product.

[0039] (6) Compared with the recrystallization using water without alcohol solvent, the use of the mixed solvent of alcohol solvent: water≥1:5 (V / V) as the recrystallization solvent (i.e. solvent B) is more beneficial to the removal of triphenyl phosphine oxide impurity.

[0040] (7) The use of the purified triphenyl phosphine obtained by the purification method provided in the present application for the preparation of sodium glycopyrronium has the unexpected technical effect of reducing the content of diphenyl phosphine oxide impurity 1, diphenyl phosphine oxide impurity 2, triphenyl phosphine and other impurities in the obtained sodium glycopyrronium.

[0041] Term explanation

[0042] The term "room temperature" means ambient temperature, which refers to a temperature of about 10°C to about 35°C, or about 20°C to 30°C, or about 25°C.

[0043] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, the skilled person in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples without contradiction.

[0044] In the following disclosure, all numbers disclosed herein are approximations that can vary depending on the desired properties sought to be obtained by those of ordinary skill in the art. The modifiers "about" and "approximately" used in connection with a recited numerical value can mean ± 1%, ± 2%, ± 5%, ± 7%, ± 8%, ± 10%, ± 15% or ± 20% of the recited value, as would be understood by those of ordinary skill in the art. Any numerical value, however, can explicitly, be included in the disclosure even though it can not be mentioned in the specification. For example, when a numerical value is disclosed as having a value of N, any numerical value having N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% of the value of N is explicitly disclosed, where "+" and "-" mean plus or minus. DETAILED DESCRIPTION

[0045] Those skilled in the art can make appropriate modifications to the chromatographic condition parameters based on the content herein. In particular, it should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present application. The method of the present application has been described by way of preferred embodiments, and those skilled in the art can obviously make modifications or appropriate changes and combinations to the method described herein without departing from the content, spirit and scope of the present application, to realize and apply the present application.

[0046] I. Chromatographic conditions for detecting phosphorus-containing impurities

[0047] Chromatographic column: Waters xbridge BEH C18 (2.5 μm, 75 mm*4.6 mm);

[0048] Mobile phase and elution mode: phosphate buffer (pH 4.0) (weigh 2.72 g of potassium dihydrogen phosphate into 1.0 L of ultrapure water, dissolve, adjust the pH value to 4.0 with dilute phosphoric acid, and filter with a 0.22 μm filter membrane) - acetonitrile (950:50) as mobile phase A; acetonitrile as mobile phase B; gradient elution according to the table below,

[0049] Time (min) Mobile phase A (%) Mobile phase B (%) 0 85 15 5 85 15 5.1 25 75 20 25 75 20.1 85 15 25 85 15

[0050] Detection wavelength: 225 nm;

[0051] Column temperature: 25°C;

[0052] Flow rate: 1 ml / min.

[0053] II. Impurity structures and their positioning in the chromatogram under the chromatographic conditions

[0054] The structure of the triphenyl phosphine oxide impurity is: RRT (relative retention time) is about 0.39;

[0055] The structure of the diphenyl phosphoric acid impurity is: RRT (relative retention time) is about 0.25;

[0056] The structure of the triphenylphosphine is: RRT (relative retention time) is about 1.00;

[0057] The structure of the diphenylphosphine oxide impurity 1 is: RRT (relative retention time) is about 2.64;

[0058] The structure of the diphenylphosphine oxide impurity 2 is: RRT (relative retention time) is about 2.49.

[0059] Example 1: Detection of phosphorus-containing impurities in commercially available triphenylphosphine

[0060] Different commercially available triphenylphosphine was taken to detect the content of phosphorus-containing impurities therein, and the results are shown in Table 1.

[0061] Table 1: Content of phosphorus-containing impurities in triphenylphosphine from different commercially available manufacturers

[0062] Manufacturer Triphenylphosphine oxide impurity content Diphenylphosphoric acid impurity content Total amount of other impurities Manufacturer 1 1.41％ 0.36％ 0.13％ Manufacturer 2 1.23％ 0.32％ 0.13％ Manufacturer 3 1.51％ 0.38％ 0.12％

[0063] Example 2: Preparation of sodium sulodexide using commercially available triphenylphosphine

[0064] Preparation was carried out according to the method of Example 1 of the reference patent application CN109879986A, as follows:

[0065] Step 1: Preparation of 6-perdeoxy-6-perbromo-γ-cyclodextrin

[0066] Under nitrogen protection, 400 g of N,N-dimethylformamide, 150 g of γ-cyclodextrin (105°C dried) and 500 g of triphenylphosphine (manufacturer 1) were sequentially added to the solution. The reaction system was cooled to 5°C, and 350 g of a solution of dibromohydantoin in DMF was added dropwise. The temperature was controlled to be <60°C during the dropwise addition. After the dropwise addition was completed, the reaction system was warmed to 90°C, and the stirring reaction was carried out for 4 h. After the reaction was completed, the temperature was lowered to room temperature, 200 g of methanol was added, 30 wt% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 8, then 3 kg of water was added, and then the system was stirred at room temperature for 4 h. Filtration was carried out to obtain a first filter cake. The first filter cake was washed with 500 g of methanol by slurry washing, and then filtration was carried out to obtain a second filter cake. The second filter cake was dried at 70°C under vacuum to obtain 6-perdeoxy-6-perbromo-γ-cyclodextrin.

[0067] Step 2: Preparation of crude sodium sulodexide (i.e. the sodium sulodexide refined in Example 1 of CN109879986A, which is defined as crude sodium sulodexide in the present application)

[0068] Under nitrogen protection, 1.36 kg of dimethylformamide, 120 g of 6- perdeoxy-6-perbrominated-γ-cyclodextrin obtained in step 1 and 92 g of 3- mercaptopropionic acid were added successively. The reaction system was cooled to 5°C, and a previously prepared methanol solution containing 70 g of sodium hydroxide was added dropwise slowly, with the temperature controlled to be <25°C during the dropwise addition. After the dropwise addition was completed, the temperature was controlled to be 80°C for 4 h.

[0069] After the reaction was completed, the reaction system was cooled to 50°C, and 960 g of water was added dropwise. After the dropwise addition was completed, the temperature was controlled to be 50°C for 1 h of stirring reaction. Then, the reaction system was cooled to 25°C, and the temperature was maintained for 5 h of crystallization. Filtration was performed to obtain a third filter cake. The third filter cake was slurried in 180 g of methanol for 2 h, and filtration was performed to obtain a fourth filter cake.

[0070] Subsequently, 360 g of water and the fourth filter cake were added successively, and the reaction system was heated to 50°C under nitrogen protection. Then, 1.72 kg of dimethyl sulfoxide was added dropwise. After the dropwise addition was completed, the temperature was controlled to be room temperature, and the system was stirred for 5 h of crystallization. Filtration was performed to obtain a fifth filter cake. The fifth filter cake was slurried in ethanol, and filtration was performed to obtain a sixth filter cake. The sixth filter cake was collected, and vacuum drying was performed at 75°C for 20 h to obtain a crude sodium sulodexide. The content of phosphorus impurities and other impurities in the obtained crude sodium sulodexide was detected, and the results were as follows:

[0071] The content of diphenyl phosphine oxide impurity 1 was 0.22%;

[0072] The content of diphenyl phosphine oxide impurity 2 was 0.21%;

[0073] The content of triphenyl phosphine oxide was 0.31%;

[0074] The total content of other impurities was 0.14%.

[0075] Conclusion: The triphenyl phosphine oxide impurity and the diphenyl phosphine oxide impurity in the triphenyl phosphine cannot be removed by the method in the prior art.

[0076] Example 3: Ethanol aqueous solution was used as a recrystallization solvent (solvent B)

[0077] (1) 1 kg of crude triphenyl phosphine (commercial product, manufacturer 1) was dissolved in 2 kg of dichloromethane, and filtration was performed. The filtrate was mixed with 1 mol / L of an aqueous sodium hydroxide solution (2 L), and stirring was performed for 30 min. The system was allowed to stand to separate into layers, and the organic phase layer was taken. Concentration was performed under reduced pressure at 40°C to remove the dichloromethane, and a concentrated product was obtained.

[0078] (2) The concentrated product was mixed with 12 kg of an ethanol aqueous solution (ethanol: water = 5: 1 (V / V)). Under nitrogen protection, the following operations were performed: the temperature was increased to 80°C, and then the temperature was decreased to 30°C. Crystallization was performed for 1 h.

[0079] (3) Solid-liquid separation was performed, and vacuum drying was performed to obtain a pure triphenyl phosphine product.

[0080] The triphenyl phosphine oxide impurity content, the diphenyl phosphoric acid impurity content and the total amount of other impurities of the triphenyl phosphine crude product and the triphenyl phosphine pure product were detected respectively, and the results are shown in Table 2.

[0081] Table 2: Impurity content before and after purification

[0082]

[0083]

[0084] Summary: The method provided in this example can effectively remove the triphenyl phosphine oxide impurity and the diphenyl phosphoric acid impurity in the triphenyl phosphine crude product.

[0085] Example 4: Using methanol aqueous solution as recrystallization solvent (solvent B)

[0086] (1) 1 kg of triphenyl phosphine crude product (commercial product, manufacturer 2) was dissolved in 2 kg of dichloromethane, filtered, the filtrate was mixed with 1 mol / L sodium hydroxide aqueous solution (2 L), stirred for 30 min, and then allowed to stand to separate the liquid, and the organic phase layer was taken, and dichloromethane was removed by concentration under reduced pressure at 40°C to obtain a concentrated product;

[0087] (2) The concentrated product was mixed with 10 kg of methanol aqueous solution (methanol: water = 5: 1 (V / V)), and the following operations were carried out under nitrogen protection: warmed to 80°C, then cooled to 30°C, and crystallized for 1 h;

[0088] (3) Solid-liquid separation and vacuum drying were carried out to obtain a triphenyl phosphine pure product.

[0089] The triphenyl phosphine oxide impurity content, the diphenyl phosphoric acid impurity content and the total amount of other impurities of the triphenyl phosphine crude product and the triphenyl phosphine pure product were detected respectively, and the results are shown in Table 3.

[0090] Table 3: Impurity content before and after purification

[0091]

[0092] Summary: The method provided in this example can effectively remove the triphenyl phosphine oxide impurity and the diphenyl phosphoric acid impurity in the triphenyl phosphine crude product.

[0093] Example 5: Using toluene as an organic solvent A to dissolve the triphenyl phosphine crude product

[0094] (1) 1 kg of triphenyl phosphine crude product (commercial product, manufacturer 1) was dissolved in 2 kg of toluene, filtered, the filtrate was mixed with 1 mol / L sodium hydroxide aqueous solution (2 L), stirred for 30 min, and then allowed to stand to separate the liquid, and the organic phase layer was taken, and toluene was removed by concentration under reduced pressure at 40°C to obtain a concentrated product;

[0095] (2) The concentrated product was mixed with 12 kg of an ethanol aqueous solution (ethanol: water = 5: 1 (V / V)), and the following operations were performed under nitrogen protection: warming to 80°C, and then cooling to 30°C, and crystallization for 1 h;

[0096] (3) Solid-liquid separation, vacuum drying, to obtain pure triphenylphosphine (yield 98%).

[0097] The triphenylphosphine oxide impurity content, the diphenylphosphoric acid impurity content, and the total amount of other impurities of the crude triphenylphosphine and the pure triphenylphosphine were detected respectively, and the results are shown in Table 4.

[0098] Table 4: Impurity content before and after purification

[0099]

[0100] Summary: The method provided in this example can effectively remove the triphenylphosphine oxide impurity and the diphenylphosphoric acid impurity in the crude triphenylphosphine.

[0101] Example 6: Using chloroform as the organic solvent A to dissolve the crude triphenylphosphine

[0102] (1) 1 kg of crude triphenylphosphine (commercial product, manufacturer 2) was dissolved in 2 kg of chloroform, filtered, the filtrate was mixed with 1 mol / L sodium hydroxide aqueous solution (2 L), stirred for 30 min, and then allowed to stand to separate into two layers, and the organic phase layer was taken, and chloroform was removed by concentration under reduced pressure at 40°C, to obtain a concentrated product;

[0103] (2) The concentrated product was mixed with 12 kg of an ethanol aqueous solution (ethanol: water = 5: 1 (V / V)), and the following operations were performed under nitrogen protection: warming to 80°C, and then cooling to 30°C, and crystallization for 1 h;

[0104] (3) Solid-liquid separation, vacuum drying, to obtain pure triphenylphosphine (yield 95%).

[0105] The triphenylphosphine oxide impurity content, the diphenylphosphoric acid impurity content, and the total amount of other impurities of the crude triphenylphosphine and the pure triphenylphosphine were detected respectively, and the results are shown in Table 5.

[0106] Table 5: Impurity content before and after purification

[0107]

[0108] Summary: The method provided in this example can effectively remove the triphenylphosphine oxide impurity and the diphenylphosphoric acid impurity in the crude triphenylphosphine.

[0109] The method of Example 3 was used to investigate the base, and "1 mol / L sodium hydroxide aqueous solution (2 L)" in the method of Example 3 was replaced by Table 6, respectively, and the rest of the operation was the same as Example 3. The product yield, the content of triphenyl phosphine oxide impurities, the content of diphenyl phosphoric acid impurities and the total amount of other impurities of the crude triphenyl phosphine and the pure triphenyl phosphine were detected, respectively. The results of the crude triphenyl phosphine are shown in Example 3, and the rest of the results are shown in Table 6.

[0110] Table 6: Investigation results of base

[0111]

[0112] Conclusion:

[0113] (1) The step (1) of the present application is beneficial to remove the triphenyl phosphine oxide impurities and the diphenyl phosphoric acid impurities.

[0114] (2) In the step (1) of the present application, compared with other basic aqueous solutions, the use of sodium hydroxide aqueous solution or potassium hydroxide aqueous solution is more beneficial to remove the triphenyl phosphine oxide impurities.

[0115] Example 8: Investigation without nitrogen protection

[0116] Based on the method of Example 3, the investigation without nitrogen protection was carried out, and "the following operations were carried out under nitrogen protection" in step (2) of the method of Example 3 was replaced by "the following operations were carried out under air conditions", and the rest of the operation was the same as Example 3. The product yield, the content of triphenyl phosphine oxide impurities, the content of diphenyl phosphoric acid impurities and the total amount of other impurities of the crude triphenyl phosphine and the pure triphenyl phosphine were detected, and the results of the crude triphenyl phosphine are shown in Example 3, and the rest of the results are shown in Table 7.

[0117] Table 7: Investigation results without nitrogen protection

[0118]

[0119] Example 9-Example 10, Comparative Example 5-Comparative Example 7: Investigation of recrystallization solvent (solvent B)

[0120] Based on the method of Example 3, the investigation of the recrystallization solvent (solvent B) was carried out, and "12 kg of ethanol aqueous solution (ethanol: water = 5:1 (V / V))" in the method of Example 3 was replaced by the recrystallization solvent shown in Table 8, respectively, and the rest of the operation was the same as Example 3. The product yield, the content of triphenyl phosphine oxide impurities, the content of diphenyl phosphoric acid impurities and the total amount of other impurities of the crude triphenyl phosphine and the pure triphenyl phosphine were detected, respectively. The results of the crude triphenyl phosphine are shown in Example 3, and the rest of the results are shown in Table 8.

[0121] Table 8: Investigation results of recrystallization solvent (solvent B)

[0122]

[0123] Conclusion:

[0124] (1) From the results of Table 8, compared with other recrystallization solvents (solvent B), using a mixed solvent of alcohol and water as the recrystallization solvent (solvent B) is beneficial to the removal of triphenyl phosphine oxide impurity, diphenyl phosphoric acid impurity and other impurities, and preferably using an aqueous solution of ethylene glycol is more beneficial to the removal of triphenyl phosphine oxide impurity.

[0125] (2) Using an aqueous solution of ethylene glycol, an aqueous solution of DMF (N,N- dimethylformamide) or an aqueous solution of glycerol as the recrystallization solvent (solvent B) is more beneficial to the removal of triphenyl phosphine oxide impurity, but the aqueous solution of DMF or the aqueous solution of glycerol as the recrystallization solvent (solvent B) has lower product yield, therefore, preferably using the aqueous solution of ethylene glycol as the recrystallization solution is more beneficial to simultaneously improving the product yield and reducing the impurity content.

[0126] (3) Preferably using the aqueous solution of ethylene glycol as the recrystallization solvent (solvent B) is more beneficial to improving the yield of triphenyl phosphine pure product.

[0127] Examples 11-14, Comparative Examples 8-9: Investigation of volume ratio of alcohol and water in recrystallization solvent (solvent B) Based on the method of Example 3, the investigation of volume ratio of alcohol and water in recrystallization solvent (solvent B) was carried out, and “12 kg of aqueous solution of ethanol (ethanol: water = 5: 1 (V / V))” in the method of Example 3 was replaced by the recrystallization solvent shown in Table 9, respectively, and the rest of the operation was the same as Example 3. The product yield, the content of triphenyl phosphine oxide impurity, the content of diphenyl phosphoric acid impurity and the total amount of other impurities of triphenyl phosphine crude product and triphenyl phosphine pure product were detected, respectively. The results of triphenyl phosphine crude product were shown in Example 3, and the rest of the results were shown in Table 9.

[0128] Table 9: Investigation results of volume ratio of alcohol and water in recrystallization solvent (solvent B)

[0129]

[0130]

[0131] Conclusion: Compared with recrystallization using water containing no alcohol, using a mixed solvent of alcohol: water ≥ 1:5 (V / V) as the recrystallization solvent (i.e. solvent B) is more beneficial to remove triphenyl phosphine oxide impurity.

[0132] Example 15, Comparative Example 10: Preparation of sodium glycopyrronium bromide using purified triphenyl phosphine

[0133] The pure triphenyl phosphine obtained in Example 3 and the pure triphenyl phosphine obtained in Comparative Example 4 were used to prepare sodium sugammadex according to the preparation method of Example 2, and then the diphenyl phosphine oxide impurity 1, diphenyl phosphine oxide impurity 2, triphenyl phosphine oxide content and total amount of other impurities of the obtained sodium sugammadex were detected, and the results are shown in Table 10.

[0134] Table 10: Impurity situation of sodium sugammadex prepared by using purified triphenyl phosphine

[0135]

[0136] Conclusion:

[0137] The acceptable standards of impurities in sodium sugammadex are: the content of diphenyl phosphine oxide impurity 1 is ≤0.10%, the content of diphenyl phosphine oxide impurity 2 is ≤0.10%, the content of triphenyl phosphine oxide is ≤0.10%, and the total amount of other impurities is ≤0.50%.

[0138] From the results of Table 10 and Example 2, it can be seen that the content of triphenyl phosphine oxide in triphenyl phosphine has no obvious change in sodium sugammadex and its raw material triphenyl phosphine, and the total content of diphenyl phosphine oxide impurity 1 and diphenyl phosphine oxide impurity 2 in sodium sugammadex and the content of diphenyl phosphine oxide impurity in the raw material triphenyl phosphine have no significant difference or slightly increase, therefore, the content limit of triphenyl phosphine oxide impurity in triphenyl phosphine should be ≤0.50%; the content of diphenyl phosphine oxide impurity should be ≤0.20%, preferably the content of diphenyl phosphine oxide impurity is ≤0.10%; and the total amount of other impurities is ≤0.50%.

[0139] From the results of Table 10, it can be seen that the use of the purified triphenyl phosphine obtained by the purification method provided by the present application to prepare sodium sugammadex is beneficial to reduce the content of diphenyl phosphine oxide impurity 1, diphenyl phosphine oxide impurity 2, triphenyl phosphine oxide and other impurities in the obtained sodium sugammadex, and has unexpected technical effects.

[0140] The method of the present application has been described by preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present application to realize and apply the present application technology. Those skilled in the art can refer to the content herein to appropriately improve parameters for implementation. It is particularly pointed out that all similar substitutions and changes are obvious to those skilled in the art, and they are considered to be included in the present application.

Claims

1. A method for purifying triphenylphosphine, characterized in that, include: (1) Dissolve crude triphenylphosphine in organic solvent A, filter, mix the filtrate with alkaline aqueous solution, stir, let stand and separate the liquid, take the organic phase layer, concentrate under reduced pressure to remove organic solvent A, and obtain concentrated product. (2) Mix the concentrated product with solvent B and perform the following operation under nitrogen or inert gas protection or in air atmosphere: heat to 50℃ to the reflux temperature of solvent B, and then cool to 0℃-40℃ to crystallize. (3) Solid-liquid separation and drying were performed to obtain pure triphenylphosphine.

2. The purification method according to claim 1, wherein step (2) comprises: The concentrated product is mixed with solvent B, and the following operation is carried out under nitrogen or inert gas protection: the temperature is raised to 50°C to the reflux temperature of solvent B, and then cooled to 0°C to 40°C to induce crystallization.

3. The purification method according to claim 1, wherein the organic solvent A comprises at least one selected from dichloromethane, ethyl acetate, toluene, and chloroform; preferably at least one selected from dichloromethane, toluene, and chloroform, more preferably dichloromethane; and / or The mass ratio of the organic solvent A to the crude triphenylphosphine is 1:1-50:1, preferably 2:1; Solvent B includes a mixture of an alcohol solvent and water, or an alcohol solvent; and / or The alcohol solvent includes at least one of ethylene glycol, methanol, ethanol, and isopropanol; preferably at least one of ethanol or ethylene glycol; more preferably ethylene glycol; and / or The volume ratio of alcohol solvent to water in solvent B is ≥1:5; and / or The mass ratio of solvent B to crude triphenylphosphine is 7:1-18:1, preferably 12:1; and / or The crystallization time in step (2) is 0.5h-5.0h.

4. The purification method according to any one of claims 1-3, wherein the alkaline aqueous solution is an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of sodium hydroxide and potassium hydroxide; and / or The concentration of alkali in the alkaline aqueous solution is 0.5 mol / L to 5.0 mol / L, preferably 1.0 mol / L.

5. The purification method according to any one of claims 1-4, wherein the stirring time in step (1) is 0.5 h-5.0 h; and / or The temperature for vacuum concentration in step (1) is 30℃-60℃, preferably 40℃.

6. The purification method according to any one of claims 1-5, wherein the drying in step (2) is vacuum drying.

7. The purification method according to any one of claims 1-6, wherein the inert gas includes at least one of helium, neon, argon, krypton, and xenon.

8. The purification method according to any one of claims 1-7, wherein the crude triphenylphosphine contains triphenylphosphine oxide impurities and / or diphenylphosphine impurities, and the purification method is used to remove triphenylphosphine oxide impurities and / or diphenylphosphine impurities from the crude triphenylphosphine; The structure of the triphenyloxyphosphine impurity is as follows: The structure of the diphenylphosphine impurity is as follows:

9. A purification method according to any one of claims 1-8 for obtaining triphenylphosphine.

10. The use of triphenylphosphine obtained by the purification method according to any one of claims 1-8 or the triphenylphosphine according to claim 9 in the preparation of sugammadextrose sodium.

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