TWI703163B - Method for preparing sugammadex sodium and crystalline form thereof - Google Patents

Abstract

The present invention provides a method for preparing Sugammadex sodium, in which 6-per-deoxy-6-per-(2-carboxy ethyl)thio-γ-cyclodextrin, methyl ester is synthesized at lower reaction temperature and hydrolyzed to Sugammadex sodium. Additionally, the present invention further provides different crystalline forms of Sugammadex sodium.

Description

The preparation method and crystal form of Sodium Gluconate

The present invention relates to a preparation method and crystal form of Sodium Gluconate.

Shugeng Sodium Gluconate (chemical name: 6-deoxy-6-all (2-carboxyethyl) thio-γ-cyclodextrin sodium salt) is the first highly selective muscle relaxant antagonist. Neuromuscular blockers commonly used when reversing surgical anesthesia, such as rocuronium. Sodium Gluconate is a modified γ-cyclodextrin, which is substituted with -S(CH ₂ ) ₂ COONa to replace the hydroxyl group at the sixth carbon position of γ-cyclodextrin. Its structure is shown below.

The following preparation method of Sodium Gluconate is disclosed in US Patent No. 6,670,340:

Later, another patent publication WO 2012/025937 further proposed another method for preparing Sodium Gluconate as follows:

Although the above two preparation methods are different in the first reaction step, the final step is to use 3-mercaptopropionic acid and sodium hydride to react with halogenated cyclodextrin at 70°C. However, 3-mercaptopropionic acid is easily decomposed into acrylic acid and sodium hydrosulfide (NaHS) at high temperature, and NaHS will undergo side reactions with halogenated cyclodextrins, resulting in decreased reaction yield and increased by-products.

In addition, how to improve purity is another problem faced by Sodium Gluconate. The US patent US 6,670,340 mainly uses dialysis for purification, but the dialysis method uses a lot of water, and the final product obtained after dialysis is soluble in water. Because the final product has a large solubility in water, it is not conducive to purification. Therefore, it is difficult to obtain high-purity sugammadex sodium only for purification by dialysis. In addition, the Chinese Patent Publication CN 105348412 also provides another method for purifying the crude Sodium Gluconate product, which is to hydrolyze the crude Sodium Gluconate product under acidic conditions to obtain the solid Sodium Gluconate, and water Wash the sugamma gluconate solids, and then react the sugsug gluconate solids with organic amines to form the sugamma gluconate ammonium salt, and use recrystallization to purify the sugamma gluconate ammonium salt, and then the sugamma gluconate ammonium salt After reacting under acidic conditions to form Shugain gluconate solids, the Shugain gluconate solids are washed with water, and finally reacted with sodium hydroxide to obtain pure Shugain gluconate sodium. However, this purification step requires multiple conversions between acid and salt, which is quite complicated and inconvenient to operate.

One purpose of the present invention is to provide a method for preparing Sodium Gluconate to solve the problem of reduced yield and purity of the target compound caused by the conventional use of 3-mercaptopropionic acid for reaction at high temperature.

其中，該三級膦為三正丁基膦或三苯基膦，該鹵素分子為氟分子、氯分子、溴分子或碘分子，即X為F、Cl、Br或I；(b)於鹼金屬氫化物之存在下，使該式(I)化合物與3-巰基丙酸甲酯於一有機溶劑下進行反應，以製得如下所示之式(II)化合物，

其中，該式(I)化合物與該3-巰基丙酸甲酯係於低於50℃下進行反應；以及(c)使該式(II)化合物進行水解反應，以製得該舒更葡糖鈉。 To achieve the above objective, the present invention provides a method for preparing Sodium Gluconate, which includes the following steps: (a) reacting γ-cyclodextrin, tertiary phosphine and halogen molecules in an organic solvent to prepare The compound of formula (I) is obtained as shown below,

Wherein, the tertiary phosphine is tri-n-butyl phosphine or triphenyl phosphine, and the halogen molecule is a fluorine molecule, a chlorine molecule, a bromine molecule or an iodine molecule, that is, X is F, Cl, Br or I; (b) a base In the presence of a metal hydride, the compound of formula (I) is reacted with methyl 3-mercaptopropionate in an organic solvent to prepare the compound of formula (II) as shown below,

Wherein, the compound of formula (I) and the methyl 3-mercaptopropionate are reacted at a temperature lower than 50°C; and (c) the compound of formula (II) is subjected to a hydrolysis reaction to prepare the sugammadex sodium.

In step (a) of the preparation method of the present invention, the halogen molecule is preferably a bromine molecule, X is preferably Br, and the organic solvent is preferably dimethylformamide. In addition, since tri-n-butyl phosphine will form tri-n-butyl phosphine oxide during the reaction of step (a), and triphenyl phosphine will form triphenyl phosphine oxide, after the reaction is completed, it is preferable to add The crude product obtained by the reaction is stirred in an alcohol solvent to remove the tri-n-butyl phosphine oxide or triphenyl phosphine oxide formed in the reaction using the alcohol solvent. For example, a preferred embodiment of the present invention uses isopropanol to remove tri-n-butyl phosphine oxide or triphenyl phosphine oxide. In addition, after removing the tri-n-butyl phosphine oxide or the triphenyl phosphine oxide, the mixed solvent of dimethylformamide and isopropanol can be used for recrystallization to obtain a higher purity formula (I ) Compound, and then the compound of formula (I) after recrystallization and purification can be used for the reaction of step (b).

In step (b) of the preparation method of the present invention, the alkali metal hydride is preferably sodium hydride, and the organic solvent is preferably dimethylformamide. Compared with the conventional use of 3-mercaptopropionic acid for the reaction at a high temperature of 70°C, step (b) of the present invention is to use 3-mercaptopropionic acid for the reaction, which can be used at a reaction temperature below 50°C The following reaction with the compound of formula (I) can improve the problem of increased by-products and decreased yield due to the decomposition of 3-mercaptopropionic acid at high temperature in the conventional manufacturing process. Preferably, methyl 3-mercaptopropionate and the compound of formula (I) are reacted at or below 0°C. For example, the reaction temperature in this step (b) can be -80°C to 0°C, preferably -60°C to 0°C, more preferably -10°C to 0°C, most preferably -5°C to 0°C . In addition, after the completion of the reaction, the crude product obtained by the reaction can be recrystallized in a mixed solvent of acetonitrile and water to obtain a compound of formula (II) with higher purity, and then the compound of formula (II) can be purified by recrystallization. ) The compound undergoes the reaction of step (c).

In step (c) of the preparation method of the present invention, the compound of formula (II) is preferably subjected to a hydrolysis reaction with sodium hydroxide to prepare sugammadex sodium. Here, recrystallization or column chromatography can be used to obtain high-purity Sodium Gluconate. For example, in a preferred embodiment of the present invention, the crude sugammadex sodium obtained after the reaction can be recrystallized for the first time in the first mixed solvent of methanol and water to purify sugammadex Sodium; In addition, the second mixed solvent of dimethylformamide and water can be recrystallized for the second time to obtain the comfort sodium gluconate with HPLC purity up to 98.2%, and the comfort sodium gluconate is type I Crystal type; optionally, if the third recrystallization is carried out with a third mixed solvent of methanol and water, the purity of Sodium Gluconate can be further increased to 99.3%, and the crystal of Sodium Gluconate can be further improved. The type is transformed from type I crystal type to type II crystal type. Alternatively, the Sepharose Q strong anion exchange resin column can be used to purify the column with an aqueous sodium chloride solution as the eluent. Preferably, the aqueous sodium chloride solution is subjected to a gradient wash with a concentration of 0.02M to 0.6M. mention. After column purification, the aqueous solution of Sodium Gluconate can be desalinated by Sephadex G-10 column, Sephadex G-25 column, reverse osmosis filtration or tangential flow filtration. In this way, amorphous sodium sugammadex with HPLC purity up to 98.0% can be obtained.

Through the above-mentioned purification method, the present invention not only obtains high-purity Sodium Gluconate, but also obtains Sodium Gluconate with different polymorphs (ie crystal form I and crystal form II) through a recrystallization method. The X-ray powder diffraction spectrum of crystal form I (represented by the diffraction angle 2θ) at 6.7°±0.2°, 7.2°±0.2°, 17.6°±0.2°, 20.8°±0.2° and 21.4°±0.2° There is a diffraction peak at the position, and it can also have a diffraction peak at at least one of the following positions: 7.5°±0.2°, 10.7°±0.2°, 20.2°±0.2°, 22.2°±0.2° and 22.3°±0.2° , And the X-ray powder diffraction spectrum of Form II (indicated by the diffraction angle 2θ) has diffraction at 5.9°±0.2°, 7.3°±0.2°, 17.6°±0.2° and 22.6°±0.2° Peaks, and may have diffraction peaks at least at one of the following positions: 9.2°±0.2°, 17.0°±0.2°, 17.4°±0.2°, and 18.6°±0.2°. In addition, the crystal form II of Sodium Gluconate can be converted into crystal form III after drying and heating. For example, the crystal form II of Sodium Gluconate can be converted into crystal form III by drying and heating at 80°C to 90°C. Form III, where the X-ray powder diffraction spectrum of Form III (indicated by the diffraction angle 2θ) is at 6.1°±0.2°, 6.4°±0.2°, 8.5°±0.2°, 18.0°±0.2°, 19.0 °±0.2°, 20.5°±0.2°, and 21.6°±0.2° positions have diffraction peaks, and can also have diffraction peaks at at least one of the following positions: 7.6°±0.2°, 16.5°±0.2° and 17.4°±0.2°.

Since different polymorphs have different characteristics (such as solubility, hygroscopicity, melting point, stability, etc.), they may affect the bioavailability, efficacy, toxic and side effects, preparation process and stability of the drug. Therefore, the development of new crystalline or polymorphic drugs will facilitate the development of drugs with better quality and efficacy. Accordingly, the present invention has developed different polymorphs of Sodium Gluconate, which will help to improve or modify at least one of the following properties: chemical purity, fluidity, solubility, morphology or crystal properties, stability (such as storage stability) Properties, dehydration stability, polymorphic transformation stability, low hygroscopicity, low residual solvent content.

Figure 1 is an X-ray powder diffraction diagram of Sodium Gluconate Form I in a preferred embodiment of the present invention.

Figure 2 is an X-ray powder diffraction diagram of Sodium Gluconate Form II in a preferred embodiment of the present invention.

Fig. 3 is an X-ray powder diffraction diagram of Sodium Gluconate Form III in a preferred embodiment of the present invention.

Example 1: Preparation of 6-per-deoxy-6-per-bromo-γ-cyclodextrin (6-per-deoxy-6 -per-bromo-γ-cyclodextrin)-compound I

Add dimethylformamide (DMF, 1.7kg) and tri-n-butylphosphine (P(n-Bu) ₃ (540g, 2.67mol) into the reaction flask and stir for about 5 minutes. Then, put it in the reaction flask again Add bromine (420g, 2.63mol) and maintain the temperature at about 20°C to 30°C and stir for about 20 minutes. Suspend γ-cyclodextrin (180g, 0.139mol) in DMF (850g) and add it to the reaction flask Afterwards, the reaction mixture was heated to about 70°C and stirred for 4-6 hours. Finally, 25% sodium methoxide solution (580g) and methanol (480g) were added to quench the reaction, and concentrated to remove the methanol, and then water (4.5 kg) to form a precipitate, and then wash the obtained crude product with water (200 g).

Add isopropanol (IPA, 2.83 kg) and the crude product into the reaction flask, and heat to 35°C to 50°C and stir for about 1 hour to remove tri-n-butylphosphine oxide (TBPO). Subsequently, using DMF (380g)/IPA (2.83kg) solvent, recrystallization, followed by filtration and washing with IPA (500g), the target product (Compound I , 170g) can be obtained: ¹ H-NMR (400MHz, DMSO ): δ 5.95-5.99(m,16H),5.01(d,8H),3.97(d,8H),3.81(t,8H),3.58-3.70(m,16H),3.36-3.42(m,16H) ; ¹³ C-NMR (100MHz, DMSO): δ 101.95, 83.98, 72.21, 72.12, 70.95, 61.95, 34.28, 25.41; HRMS (ESI-TOF) C ₄₈ H ₇₂ Br ₈ O ₃₂ ([M+Na] ⁺ ) Calculated value: 1822.729, experimental value: 1822.731.

Example 2: Preparation of 6-per-deoxy-6-per-bromo-γ-cyclodextrin (6-per-deoxy-6-per-bromo-γ-cyclodextrin)-Compound I

DMF (2.8 kg) and triphenylphosphine (PPh ₃ 969 g, 3.69 mol) were added to the reaction flask and stirred for about 15 minutes. Then, add bromine (588g, 3.69mol) to the reaction flask, and keep the temperature at about 0°C to 10°C, and stir for about 30 minutes. Suspend γ-cyclodextrin (300g, 0.231mol) in DMF (2.8kg) and add it to the reaction flask, then heat the reaction mixture to about 70°C, stir for 12 hours and concentrate to remove DMF (2.7kg) ). Subsequently, 18% sodium methoxide solution (1140 g) was added to quench the reaction, and isopropanol (IPA, 18 kg) was added to form a precipitate, and the obtained crude product was washed with IPA (300 g). Finally, IPA was used to remove triphenyl phosphine oxide (TPPO) and purified to obtain compound I.

Example 3: Preparation of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-methyl ester of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin -cyclodextrin,methyl ester)-Compound II

Under nitrogen, DMF (400 g) and 60% NaH (50 g) were added to the reaction flask, and then the reaction mixture was degassed and purged with nitrogen three times. Methyl 3-mercaptopropionate (210g, 1.75mol) and DMF (400g) were added to the reaction flask, and the temperature was reduced to -10°C to 0°C during the addition. After the addition, the temperature was increased to -5°C to 0°C, and then the DMF (810g) solution containing compound I (170g, 0.97mol) was added to the reaction mixture and stirred for 1 to 1.5 hours, and HPLC was used to determine whether the reaction was carry out. After the reaction was completed, water (2.88 kg) and ammonium chloride (320 g) aqueous solution were added to quench the reaction and gradually form a precipitate. The mixture was filtered and washed with water (400 g) to obtain a crude product of compound II . Finally, use an acetonitrile (1.57kg)/water (1kg) solution to recrystallize to obtain the target product (compound II , 200g) in white powder form: ¹ H-NMR (400MHz, DMSO): δ 5.93 (s, 16H) ), 4.92 (d, 8H), 3.71-3.78 (m, 8H), 3.54-3.57 (m, 32H), 3.25-3.40 (m, 16H), 3.06-3.09 (m, 8H), 2.70-2.83 (m , 24H), 2.56-2.60 (m, 16H); ¹³ C-NMR (100MHz, DMSO): δ 171.78,102.01,84.31,72.46,72.37,71.63,51.32,34.19,33.06,27.63; HRMS (ESI-TOF) C ₈₀ H ₁₂₈ O ₄₈ S ₈ ([M+Na] ⁺ ) calculated value: 2135.524, experimental value: 2135.533.

Example 4: Preparation of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ-cyclodextrin sodium salt (6-per-deoxy-6-per-(2-carboxyethyl)thio-γ- cyclodextrin, sodium salt)-Sodium Gluconate

Under nitrogen, 1N NaOH aqueous solution (30 g NaOH, 700 g water) and Compound II were added to the reaction flask and stirred for 16 to 17 hours. Using 0.8N hydrogen chloride aqueous solution, the pH value of the clear reaction solution was adjusted to 9 to 10, and then methanol (1.5 kg) was added to form the crude product of sodium gluconate in white powder. Then, use a methanol (330g)/water (140g) solution to recrystallize to obtain water-containing comfort sodium gluconate, and then use the following recrystallization method to purify comfort sodium gluconate again; or, The crude Sodium Gluconate product obtained after the reaction can be purified by the following column chromatography. By this, you can obtain high-purity Sodium Gluconate: ¹ H-NMR (400MHz, D ₂ O): δ 5.19 (d, 8H), 4.06 (m, 8H), 3, 95 (t, 8H) ,3.63-3.68(m,16H),3.14(dd,8H),3.00(dd,8H),2.85-2.89(m,16H),2.46-2.56(m,16H); ¹³ C-NMR(100MHz,D ₂ O): δ 180.63, 100.84, 82.15, 72.65, 72.29, 71.23, 37.76, 33.42, 29.60; HRMS (ESI-TOF) C ₇₂ H ₁₀₄ Na ₈ O ₄₈ S ₈ ([M-7Na+7H] ⁺ ) calculation Value: 2023.399, experimental value: 2023.401.

[Water/DMF recrystallization]

DMF (7.5 ml) was added to the aqueous solution of Sodium Gluconate (1g Sodium Gluconate, 3ml of water) for crystallization. Stir the suspension at 25°C for about 1 hour, then filter it, and use a mixture of water and DMF to wash the mass twice to obtain Type I crystalline sugammadex sodium. Its HPLC purity is 98.2% . Please refer to Figure 1 for the X-ray powder diffraction diagram of type I crystalline Sodium Gluconate, which is at 5.5°±0.2°, 5.6°±0.2°, 6.0°±0.2°, 6.7°±0.2°, 7.2°± 0.2°, 7.5°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 8.9°±0.2°, 9.3°±0.2°, 10.0°±0.2°, 10.1°±0.2°, 10.7°±0.2° , 11.8°±0.2°, 12.8°±0.2°, 12.9°±0.2°, 13.5°±0.2°, 13.9°±0.2°, 14.2°±0.2°, 14.7°±0.2°, 15.0°±0.2°, 15.5 °±0.2°, 16.0°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.6°±0.2°, 18.3°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.3°± 0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.8°±0.2°, 21.4°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 22.3°±0.2°, 23.0°±0.2° , 23.2°±0.2°, 23.9°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 25.4°±0.2°, 26.5°±0.2° and 40.5°±0.2° positions have diffraction peaks (with The diffraction angle 2θ is expressed).

[Water/MeOH recrystallization]

MeOH (480ml) was added to the aqueous solution of sodium sugammadex (93g of crystalline sodium sugammadex, 3ml of water) for crystallization. The suspension was heated to 65°C to make the solution clear, and then slowly cooled down. When the temperature drops to 42°C to 45°C and stirring for 2 hours, crystals can be formed. The suspension was stirred at 25°C for about 2 hours, and then filtered, and the mass was washed twice with a mixture of water and MeOH to obtain type II crystalline sodium sugammadex (75g, yield 80.6%) ), its HPLC purity is 99.3%. The X-ray powder diffraction diagram of type II crystalline Sodium Gluconate is shown in Figure 2. It is at 5.9°±0.2°, 6.1°±0.2°, 7.2°±0.2°, 7.3°±0.2°, 7.6°± 0.2°, 7.9°±0.2°, 8.4°±0.2°, 8.6°±0.2°, 9.1°±0.2°, 9.2°±0.2°, 9.8°±0.2°, 10.3°±0.2°, 10.4°±0.2° , 10.9°±0.2°, 11.6°±0.2°, 11.8°±0.2°, 12.6°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 14.5°±0.2°, 14.9°±0.2°, 15.5 °±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.2°±0.2°, 16.6°±0.2°, 17.0°±0.2°, 17.4°±0.2°, 17.6°±0.2°, 18.5°± 0.2°, 18.6°±0.2°, 19.6°±0.2°, 19.8°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.6°±0.2°, 22.6°±0.2° , 22.9°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 24.0°±0.2°, 25.0°±0.2°, 25.6°±0.2°, 25.7°±0.2°, 26.1°±0.2°, 26.6 °±0.2°, 28.8°±0.2°, 29.7°±0.2°, 30.1°±0.2°, 30.7°±0.2°, 32.4°±0.2°, 33.0°±0.2°, 33.3°±0.2°, 35.4°± There are diffraction peaks at positions 0.2°, 36.2°±0.2°, 39.5°±0.2°, 40.8°±0.2° and 47.7°±0.2° (represented by the diffraction angle 2θ).

In addition, type II crystalline sugammadex sodium (0.5g) can be dried under vacuum (15mmHg) and heated to 80°C or 90°C for 12 hours to obtain type III crystalline sugammadex sodium . Please refer to Figure 3 for the X-ray powder diffraction diagram of type III crystalline Sodium Gluconate, which is at 5.8°±0.2°, 6.1°±0.2°, 6.4°±0.2°, 6.9°±0.2°, 7.6°± 0.2°, 8.5°±0.2°, 10.2°±0.2°, 10.7°±0.2°, 11.6°±0.2°, 13.6°±0.2°, 13.7°±0.2°, 13.8°±0.2°, 14.9°±0.2° , 16.0°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 19.0°±0.2°, 20.5°±0.2°, 21.6°±0.2°, 24.8°±0.2° and 27.2 There is a diffraction peak at the position of °±0.2° (represented by the diffraction angle 2θ).

[Sepharose Q anion exchange resin column purification]

Dissolve the crude product of Sodium Gluconate (50g) in water (500ml) and perform column purification. The chromatography packing used is Sepharose Q strong anion exchange resin (750ml), and the extract is sodium chloride. Aqueous solution (gradient extraction: 0.02M to 0.6M) to obtain high-purity sugammadex sodium (HPLC NLT 98.0%).

Next, the purified sodium gluconate aqueous solution is desalinated, which can be desalinated using Sephadex G-10 or G-25 columns, or reverse osmosis filtration or tangential flow filtration (Tangential Flow Filtration) equipment is desalinated to obtain the desalted sodium gluconate aqueous solution, which is then concentrated in vacuo to reduce the volume of the solution (600ml).

Finally, use 0.2μm filter paper to filter the purified sodium gluconate aqueous solution and spray-dry it (feed flow rate: 20ml/min, inlet temperature: 150°C, outlet temperature: 80°C) to obtain amorphous Shu more sodium gluconate (27g).

The above-mentioned embodiments are merely examples for the convenience of description, and the scope of rights claimed in the present invention should be subject to the scope of the patent application, and not limited to the above-mentioned embodiments.

Claims (23)

A preparation method of Sodium Gluconate, which comprises the following steps: (a) reacting γ-cyclodextrin, tertiary phosphine and halogen molecules in an organic solvent to prepare the formula (I ) Compound,

Wherein, the tertiary phosphine is tri-n-butyl phosphine or triphenyl phosphine, and the halogen molecule is a fluorine molecule, a chlorine molecule, a bromine molecule or an iodine molecule, that is, X is F, Cl, Br or I; (b) a base In the presence of a metal hydride, the compound of formula (I) is reacted with methyl 3-mercaptopropionate in an organic solvent to prepare the compound of formula (II) as shown below,

Wherein, the compound of formula (I) and the methyl 3-mercaptopropionate are reacted at a temperature lower than 0°C; and (c) the compound of formula (II) is subjected to a hydrolysis reaction to prepare the sugammadex sodium. The preparation method described in item 1 of the scope of patent application, wherein the halogen molecule is a bromine molecule and X is Br. The preparation method described in item 1 of the scope of the patent application, wherein the organic solvent in the step (a) is dimethylformamide. The preparation method described in item 1 of the scope of the patent application, wherein the step (a) further comprises: using an alcohol solvent to remove the tri-n-butylphosphine oxide or triphenylphosphine oxide formed by the reaction. According to the preparation method described in item 4 of the scope of patent application, the alcohol solvent is isopropanol. The preparation method described in item 5 of the scope of patent application, wherein, in step (a), after removing the tri-n-butyl phosphine oxide or the triphenyl phosphine oxide, the compound of formula (I) is It is obtained by recrystallization in a mixed solvent of methyl formamide and isopropanol. The preparation method described in item 1 of the scope of patent application, wherein the alkali metal hydride is sodium hydride. The preparation method described in item 1 of the scope of patent application, wherein the organic solvent in the step (b) is dimethylformamide. According to the preparation method described in item 1 of the scope of the patent application, in the step (b), the compound of formula (II) is obtained by recrystallization in a mixed solvent of acetonitrile and water. The preparation method described in item 1 of the scope of patent application, wherein, in the step (c), the compound of formula (II) is subjected to the hydrolysis reaction by sodium hydroxide. The preparation method described in item 1 of the scope of patent application, wherein, in the step (c), the sugammadex sodium is obtained by recrystallization in a mixed solvent of methanol and water. The preparation method described in item 1 of the scope of patent application, wherein in step (c), the sugammadex sodium is recrystallized for the first time in a first mixed solvent of methanol and water, and then It is obtained by second recrystallization in a second mixed solvent of dimethylformamide and water. The preparation method described in item 1 of the scope of patent application, wherein in step (c), the sugammadex sodium is recrystallized for the first time in a first mixed solvent of methanol and water, and then It is obtained by performing a second recrystallization in a second mixed solvent of methanol and water, and then performing a third recrystallization in a third mixed solvent of methanol and water. The preparation method described in item 1 of the scope of patent application, wherein, in the step (c), the Sodium Gluconate Sulfate is obtained by column purification, and the column packing used for the column purification is Sepharose Q strong anion exchange resin, and the eluent used in the column purification is sodium chloride aqueous solution. The preparation method described in item 14 of the scope of patent application, wherein the extraction solution is gradient extraction with a concentration of 0.02M to 0.6M. The preparation method described in item 14 of the scope of patent application, wherein in step (c), the sugammadex sodium is purified by the column and then desalted. The preparation method described in item 16 of the scope of patent application, wherein the desalination is performed by Sephadex G-10 column, Sephadex G-25 column, reverse osmosis filtration or tangential flow filtration. A crystal form of Sodium Gluconate, which has X-ray powder diffraction spectra represented by a diffraction angle of 2 θ at 6.7°±0.2°, 7.2°±0.2°, 17.6°±0.2°, 20.8°±0.2° and There is a diffraction peak at the position of 21.4°±0.2°. As described in item 18 of the patent application, the crystal form of sodium gluconate, wherein the X-ray powder diffraction spectrum has diffraction peaks at least at one of the following positions: 7.5°±0.2°, 10.7°± 0.2°, 20.2°±0.2°, 22.2°±0.2° and 22.3°±0.2°. A crystalline form of Shugeng Sodium Gluconate, the X-ray powder diffraction spectrum represented by the diffraction angle 2 θ at 5.9°±0.2°, 7.3°±0.2°, 17.6°±0.2° and 22.6°±0.2° There is a diffraction peak at the place. As described in item 20 of the patent application, the crystal form of sodium gluconate, wherein the X-ray powder diffraction spectrum has a diffraction peak at least at one of the following positions: 9.2°±0.2°, 17.0°± 0.2°, 17.4°±0.2° and 18.6°±0.2°. A crystal form of Sodium Gluconate, the X-ray powder diffraction spectrum represented by the diffraction angle 2 θ at 6.1°±0.2°, 6.4°±0.2°, 8.5°±0.2°, 18.0°±0.2°, There are diffraction peaks at 19.0°±0.2°, 20.5°±0.2° and 21.6°±0.2°. As described in item 22 of the scope of patent application, the crystal form of sodium gluconate, wherein the X-ray powder diffraction spectrum has a diffraction peak at least at one of the following positions: 7.6°±0.2°, 16.5°± 0.2° and 17.4°±0.2°.

Images