An intermediate of sugammadex sodium and a method for preparing the same

Abstract

The application relates to a preparation method of the muscle relaxant succinylcholine sodium, which comprises the following steps: adopting gamma-cyclodextrin, carrying out total halogenation, and then reacting with potassium thioacetate to prepare a key intermediate compound 6-full deoxy-6-full thioacetate-gamma-cyclodextrin, and then directly reacting with acrylic acid through one-pot synthesis to prepare succinylcholine sodium. The application has the advantages of mild reaction condition, simple post-treatment operation, good process reproducibility and high yield.

Description

Technical Field

[0001] This invention relates to an intermediate for preparing sugammadextrose sodium and a method for preparing the same, specifically a method for preparing sugammadextrose sodium using the intermediate. Background Technology

[0002] Sugammadex, marketed as Pretin, is originally manufactured by Organon AG (which merged into Schering-Plough in November 2007, and subsequently into Merck in November 2009). It was first approved by the EMA in July 2008, followed by approval from the Japanese PMDA in January 2010, FDA approval in December 2015, and CFDA approval in April 2017. Pretin is a neuromuscular blockade recovery agent that does not act by inhibiting acetylcholinesterase and is the world's first selective relaxant antagonist (SRBA). This drug is indicated for the recovery of neuromuscular blockade caused by the use of rocuronium and vecuronium.

[0003] Literature CN1402737A and literature CN108290964A reported the synthetic route of sugammadextrin sodium. First, the hydroxyl group of γ-cyclodextrin is halogenated to obtain the intermediate 6-per-deoxy-6-per-halogenated-γ-cyclodextrin. This intermediate is then substituted with 3-mercaptopropionic acid or 3-mercaptopropionate to prepare sugammadextrin sodium. The main difference lies in the different halogenation methods and API purification methods used. Traditional processes directly prepare sugammadextrin sodium from fully halogenated γ-cyclodextrin intermediates. Although the reaction steps are relatively short, structurally similar impurities generated during the preparation of fully halogenated γ-cyclodextrin affect the purity of the subsequent preparation of sugammadextrin sodium, increasing the difficulty of post-reaction processing. In addition, the structural characteristics and strong water solubility of sugammadextrin sodium make it easy to encapsulate inorganic salts and small organic molecules during the production process. Therefore, the purification of sugammadextrin sodium is mostly carried out by column chromatography or membrane dialysis. This results in the use of a large amount of solvent in the purification process, increasing the post-processing operations, leading to a large time and energy consumption, poor process reproducibility, and unsuitability for large-scale production. In addition, CN105348412A reports a method for purifying sugammadextrose sodium without column chromatography and membrane dialysis. This patent involves acidifying crude sugammadextrose sodium to release it, then reacting it with an organic amine to prepare sugammadextrose ammonium salt, followed by recrystallization purification. The ammonium salt is then released into acid, which is reacted with sodium hydroxide to prepare sugammadextrose sodium. This method avoids column chromatography and membrane dialysis, but requires repeated switching between free acid and salt. Due to the cumbersome steps, the operation inevitably leads to an increase in oxidative impurities and acid-base degradation products. Therefore, the yield and purity of sugammadextrose sodium prepared by this process are both low. Summary of the Invention

[0004] To address the shortcomings of existing technologies, there is a need to develop a simple, reproducible, environmentally friendly method for preparing sugammadextrin sodium with high yield and purity. This invention uses γ-cyclodextrin as the starting material, which is fully brominated and then reacted with potassium thioacetate to prepare the key intermediate 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin. This intermediate is then hydrolyzed and directly reacted with acrylic acid in a one-pot reaction to prepare sugammadextrin sodium.

[0005] This invention discloses a novel intermediate compound, 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin, as shown in structural formula (Ⅰ):

[0006]

[0007] Equation (I);

[0008] This compound is used to prepare sugammadextrose sodium.

[0009] The intermediate formula (Ⅰ) of the present invention is prepared by reacting 6-per-deoxy-6-per-halogenated-γ-cyclodextrin, i.e. formula (Ⅱ), with potassium thioacetate;

[0010]

[0011] Formula (II)

[0012] Where X is Cl, Br, or I, preferably Cl or Br, and even more preferably Br;

[0013] The molar ratio of 6-per-deoxy-6-per-halogenated-γ-cyclodextrin to potassium thioacetate is 1:12-1:32, and in some embodiments it may be 1:16-1:18.

[0014] The 6-per-deoxy-6-per-halogenated-γ-cyclodextrin of this invention is prepared by reacting γ-cyclodextrin (i.e., formula III) with a halide.

[0015]

[0016] Formula (Ⅲ);

[0017] The halides mentioned are N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and N-iodosuccinimide (NIS).

[0018] The intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention is used to prepare sugammadextrin sodium, and the specific preparation method is as follows:

[0019] (1) Using γ-cyclodextrin as the starting material, 6-peroxy-6-perhalogenated-γ-cyclodextrin was obtained by halogenation in an organic solvent, wherein the organic solvent was N,N-dimethylformamide (DMF).

[0020] (2) 6-Hyperdeoxy-6-Hyperhalogenated-γ-cyclodextrin is reacted with potassium thioacetate in an organic solvent at 20-80℃ for 6-15h to obtain the intermediate 6-Hyperdeoxy-6-Hyperthioethyl ester-γ-cyclodextrin.

[0021] (3) The intermediate 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin is hydrolyzed for 2-6 hours under alkaline conditions to obtain intermediate compound 5. No separation is required. Intermediate compound 5 is directly reacted with acrylic acid at 20-80℃ for 5-10 hours to obtain sodium sugammadextrin.

[0022] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention, the organic solvent in step (2) is N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, and in some embodiments, N-methylpyrrolidone.

[0023] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl γ-cyclodextrin described in this invention, the reaction temperature of 6-per-deoxy-6-per-halo-γ-cyclodextrin with potassium thioacetate in step (2) can be further preferably 40-50℃.

[0024] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl γ-cyclodextrin described in this invention, the reaction time of 6-per-deoxy-6-per-halo-γ-cyclodextrin with potassium thioacetate in step (2) can be further preferably 8-10 h.

[0025] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention, the alkaline solvent in step (3) is sodium hydroxide or potassium hydroxide.

[0026] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention, the concentration of the alkaline solvent in step (3) is 0.5-2 mol / L, and in some embodiments it is 1.5 mol / L.

[0027] In the method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention, the hydrolysis reaction time in step (3) is 2-3 h.

[0028] In the method for preparing sugammadextrin sodium from the intermediate compound 6-perdeoxy-6-perthioethyl ester-γ-cyclodextrin described in this invention, the molar ratio of acrylic acid added in step (3) to the amount of compound 6-perdeoxy-6-perthioethyl ester-γ-cyclodextrin is 16:1-32:1. In some embodiments, the molar ratio is 20:1-24:1. In further embodiments, the molar ratio is 20:1, 21:1, 22:1, 23:1, or 24:1.

[0029] In the method for preparing sodium sugammadextrin from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention, the reaction temperature with acrylic acid in step (3) is 40-50℃ and the reaction time is 6-7h.

[0030] The method for preparing sugammadextrin sodium from the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin described in this invention may include a purification method for sugammadextrin sodium, using an alcohol-water mixed solvent as the purification solvent, and employing a recrystallization process to purify sugammadextrin sodium, wherein the alcohol solvent may be methanol or ethanol.

[0031] The synthetic route of this invention is as follows:

[0032]

[0033] As is known to those skilled in the art, according to relevant national guidelines for drug application, the single and total impurities in the active pharmaceutical ingredient (API) must be controlled within certain ranges during drug application. Generally, the total impurities should not exceed 0.5%, and the single impurities should not exceed 0.1%. The preparation of intermediates directly affects the purity of the final product. If difficult-to-separate impurities or too many types of impurities are generated during the preparation process, the purity of the final product will decrease, the purification difficulty will increase, and there is a high possibility of generating impurities that are difficult to remove, resulting in a final product that does not meet the standards. Therefore, obtaining high-purity APIs is the ultimate goal of those skilled in the art during the preparation of APIs. The present invention describes... Compared with existing technologies, the method for preparing sugammadextrin sodium from the intermediate 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin adds the preparation of the intermediate compound 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin. Although this adds one reaction step, it effectively improves the purity of sugammadextrin sodium, ensuring that the purity of the final product sugammadextrin sodium is higher than 99%. Furthermore, the use of recrystallization purification avoids the need for column chromatography, greatly simplifying the purification process and effectively improving the yield. In summary, the method described in this invention can obtain high-purity sugammadextrin sodium product, and the process is more operable, more suitable for industrial production, and has strong reproducibility. Attached Figure Description

[0034] Figure 1High-resolution mass spectrum of 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin;

[0035] Figure 2 6-Hyperdeoxy-6-perthioethyl ester-γ-cyclodextrin 1 H-NMR spectrum;

[0036] Figure 3 High-resolution mass spectrum of 6-per-deoxy-6-per-thiol-γ-cyclodextrin;

[0037] Figure 4 Sugan Glucosamine Sodium 1 H-NMR spectrum;

[0038] Figure 5 Example 3, Scheme 1: HPLC chromatogram of sugammadextrose sodium;

[0039] Figure 6 Comparative example: HPLC chromatogram of sodium sugammadextrose;

[0040] Figure 7 HPLC chromatogram of original sugammadextrose sodium injection (batch number: R005535). Detailed Implementation

[0041] Test materials

[0042] serial number Reagent (solvent) name factory 1 γ-Cyclodextrin Shandong Binzhou Zhiyuan Biotechnology Co., Ltd. 2 N-bromosuccinimide Jiangxi Dassault Chemical Co., Ltd. 3 Triphenylphosphine Shanghai Gaolang Chemical Technology Co., Ltd. 4 Potassium thioacetate Beijing Huawi Ruike Technology Co., Ltd. 5 acrylic acid Beijing Ouhe Technology Co., Ltd.

[0043] serial number Instrument Name factory 1 HPLC Waters 2695 2 Electronic balance Sartorius 3 Vacuum drying oven Memert

[0044] Example 1 Synthesis of 6-per-deoxy-6-per-bromo-γ-cyclodextrin

[0045] Under ice bath conditions, dried γ-cyclodextrin (100 g, 77 mmol) and triphenylphosphine (242 g, 925 mmol) were added to DMF (1200 ml). After stirring and dissolving, NBS (164 g, 925 mmol, DMF 350 ml) solution was added dropwise. The temperature was controlled below 10 °C and the addition was completed in 30 min. The reaction solution was dark red and viscous. The temperature was raised to 90 °C with stirring and the reaction was continued for 6 h. The reaction was then stopped, and the reaction solution was cooled to room temperature and added to ice water (6 L). With stirring, 4 mol / L sodium hydroxide solution was added until the pH of the system reached 8-9. A large amount of solid precipitated out. The solid was filtered, and the filter cake was slurried with methanol (500 ml * 2). After filtration, a pale yellow solid was obtained and dried at 50 °C with forced air for 6 h to obtain 125 g of 6-per-deoxy-6-per-brominated γ-cyclodextrin, with a yield of 90%.

[0046] Purity HPLC: 98.5%; MS (TOF, ESI) + ): 1800.7391[M+H] + .

[0047] Example 2 Synthesis of 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin

[0048] Option 1:

[0049] At room temperature, 40 g (22.2 mmol) of the prepared 6-per-deoxy-6-per-bromo-γ-cyclodextrin was added to 400 ml of N-methylpyrrolidone. Potassium thioacetate (41 g (360 mmol)) was added in portions to the system while stirring. After the addition was complete, the system was purged with nitrogen. The reaction system was heated to 50 °C and reacted for 8 h. Heating was stopped, and 400 ml of ethanol was added to the system, resulting in the precipitation of a large amount of solid. The solid was filtered under reduced pressure, and the filter cake was washed once with ethanol / water at a ratio of 1:1 (100 ml). The solid was dried under reduced pressure to obtain 33.5 g of an off-white solid, yield: 86%.

[0050] Purity HPLC: 97%; MS (TOF, ESI) - ): 1759.3188 [MH] - 1805.3196[M-H+ HCOOH] - .

[0051] 1 H NMR (400 MHz, DMSO-d6) δ = 5.94-5.92 (m, 16H), 5.02–4.88 (m, 8H), 3.79 (d, J=10.1, 8H), 3.71–3.55 (m, 8H), 3.43 (m, J=9.8, 8H), 3.26 (m, J=9.3,8H), 2.97 (m, J=13.4, 8H), 2.32 (s, 24H).

[0052] Option 2:

[0053] At room temperature, 40 g (22.2 mmol) of the prepared 6-per-deoxy-6-per-bromo-γ-cyclodextrin was added to 400 ml of N-methylpyrrolidone. Potassium thioacetate (46 g, 400 mmol) was added in portions while stirring. After the addition was complete, the system was purged with nitrogen. The reaction system was heated to 50 °C and reacted for 6 h. Heating was stopped, and 400 ml of ethanol was added to the system, precipitating a large amount of solid. The solid was filtered under reduced pressure, and the filter cake was washed once with ethanol / water at a ratio of 1:1 (100 ml). The cake was then dried under reduced pressure to obtain 34.1 g of an off-white solid.

[0054] Yield: 88%, Purity (HPLC): 97%

[0055] Option 3:

[0056] At room temperature, 40 g (22.2 mmol) of the prepared 6-per-deoxy-6-per-bromo-γ-cyclodextrin was added to 1500 ml of 1,4-dioxane. Potassium thioacetate (41 g (360 mmol)) was added in portions to the system while stirring. After the addition was complete, the system was purged with nitrogen, and the reaction system was heated to 80 °C and reacted for 16 h. Heating was stopped, and the system was allowed to cool to room temperature. The system was then filtered under reduced pressure. The filter cake was washed twice with ethanol and then once with ethanol / water at a ratio of 1:1 (100 ml). The mixture was dried under reduced pressure to obtain 30.6 g of an off-white solid. Yield: 79%, HPLC purity: 97%.

[0057] Example 3 Synthesis of sugammadextrose sodium

[0058] Option 1:

[0059] At room temperature and under nitrogen protection, the prepared 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin (10 g, 5.6 mmol) was added to a sodium hydroxide solution (100 ml, 1.5 mol / L). After the addition was complete, the solution was stirred until dissolved, and stirring continued for 2 h. The solution was then analyzed by LC-MS (MS (TOF, ESI-): 1423.2273 [MH]-, 1469.2310 [M-H+]. [HCOOH]-. Acrylic acid (8.1 g, 112 mmol) was added dropwise to the system over 10 min. The system temperature was raised to 50 °C and stirred for 6 h. The system was then cooled to room temperature, and ethanol (220 ml) was added. A large amount of solid precipitated. The filter cake was then slurried with a mixture of ethanol and water to remove residual salts, yielding crude sugammadextrose sodium. The crude product was dissolved in methanol / water by heating, decolorized with a small amount of activated carbon, and then recrystallized to obtain 9.1 g of refined sugammadextrose sodium as a white solid. Yield: 75%, HPLC purity: 99.5%.

[0060] 1 H NMR (400 MHz, D2O) δ = 5.12 (s, 8H), 4.04 – 3.95 (m, 8H), 3.88 (t,J=9.5, 8H), 3.62 – 3.54 (m, 16H), 3.07 (d, J=13.6, 8H), 2.93 (m, J=14.2, 6.3,8H), 2.80 (t, J=7.4, 16H), 2.43 (t, J=7.8, 16H);

[0061] Option 2:

[0062] Under nitrogen protection at room temperature, 10 g (5.6 mmol) of the prepared 6-per-deoxy-6-per-thioethyl ester-γ-cyclodextrin was added to a sodium hydroxide solution (100 ml, 1.5 mol / L). After the addition was complete, the solution was stirred until dissolved, and stirring continued for 2 h. Then, acrylic acid (9.7 g, 135 mmol) was added dropwise to the system, and the addition was completed in 10 min. The system temperature was raised to 45 °C, and stirring continued for 6 h. The system was then cooled to room temperature, and 220 ml of ethanol was added to the system, resulting in the precipitation of a large amount of solid. After filtration, the filter cake was slurried with a mixed solvent of ethanol and water to remove residual salts, yielding crude sugammadextrin. The crude product was dissolved in methanol / water by heating, decolorized with a small amount of activated carbon, and then recrystallized to obtain 9.5 g of refined sugammadextrin as a white solid. Yield: 78%, purity: 99.5% (HPLC).

[0063] Synthesis of comparative sugammadextrose sodium

[0064] Under ice bath conditions, 3-mercaptopropionic acid (8.8 g, 83 mmol) and DMF (50 ml) were added to a 250 ml three-necked flask. Sodium methoxide solution (9.0 g, 167 mmol in MeOH) was added dropwise with stirring. After the addition was complete, stirring continued for 30 min. Then, 6-per-deoxy-6-per-bromo-γ-cyclodextrin (10.0 g, 5.6 mmol) was added dropwise to the system. After the addition was complete, the system was heated to 70 °C and reacted overnight. The system was cooled to room temperature, filtered, and the filter cake was washed with ethanol (20 ml * 2). The resulting filter cake was then slurried with a mixture of ethanol and water to remove residual salts, yielding crude sugammadextrin. The crude product was dissolved in methanol / water by heating, decolorized with a small amount of activated carbon, and then recrystallized twice to obtain 8.5 g of purified sugammadextrin as a white solid. Yield: 71%, HPLC purity: 98.4%.

Claims

1. A method for preparing sugammadextrose sodium, Equation (I); The intermediate of formula (I) is prepared by reacting formula (II) with potassium thioacetate; Formula (II) Where X is Br; The molar ratio of compound (II) to potassium thioacetate is 1:12-1:32; compound (II) is prepared by reacting compound (III) with a halide. Formula (Ⅲ); The specific preparation method is as follows: (1) Using formula (Ⅲ) as the starting material, in an organic solvent, by halide substitution, to obtain compound formula (Ⅱ), wherein the organic solvent is N,N-dimethylformamide; (2) Compound (II) is reacted with potassium thioacetate in an organic solvent at 40-50°C for 8-10 h to obtain intermediate compound (I). (3) The intermediate compound (I) is hydrolyzed under alkaline conditions for 2-6 hours to obtain intermediate compound 5. No separation is required. Intermediate compound 5 is directly reacted with acrylic acid at 20-80℃ for 5-10 hours to obtain sodium sugammadextrose.

2. The method according to claim 1, characterized in that... The molar ratio of compound (II) to potassium thioacetate is 1:16-1:

18.

3. The method according to claim 1, characterized in that... The halide is N-bromosuccinimide.

4. The method according to claim 1, characterized in that, In the method for preparing sodium suglucose from intermediate compound of formula (I), the alkaline conditions described in step (3) are provided by sodium hydroxide solution or potassium hydroxide solution.

5. The method according to claim 4, characterized in that, In the method for preparing sugammadextrose sodium from intermediate compound of formula (I), the concentration of the sodium hydroxide solution or potassium hydroxide solution is 0.5-2 mol / L.

6. The method according to claim 1, characterized in that, In the method for preparing suglucosamine sodium from intermediate compound (Ⅰ), the hydrolysis reaction time in step (3) is 2-3 h.

7. The method according to claim 1, characterized in that, In the method for preparing suglucosamine sodium from intermediate compound (I), the molar ratio of the amount of acrylic acid added in step (3) to the amount of compound (I) is 16:1-32:

1.

8. The method according to claim 1, characterized in that, In the method for preparing sodium suglucose from intermediate compound (Ⅰ), the reaction temperature with acrylic acid in step (3) is 40-50℃ and the reaction time is 6-7h.

9. The method according to claim 1, characterized in that, The method for preparing sugammadextrose sodium from intermediate compound (I) includes a purification method for sugammadextrose sodium, using an alcohol-water mixed solvent as the purification solvent and employing a recrystallization process to purify sugammadextrose sodium, wherein the alcohol solvent is methanol or ethanol.

Images