阅读说明：本技术 一种舒更葡糖钠中间体二苯基磷酸衍生物杂质及其制备方法 (Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof ) 是由 魏文国 张波 童勇 叶学进 于 2021-08-24 设计创作，主要内容包括：本发明涉及药物杂质合成技术领域,具体公开了一种舒更葡糖钠制备中间体γ-ICD中的二苯基磷酸衍生物杂质及其制备方法,该杂质的制备方法包括以下步骤：(1)将二苯基磷酸溶于有机溶剂中,惰性气体保护下加入一定量的碱,一定温度下搅拌反应一段时间后,再加入6-全脱氧-6-全碘代-γ-环糊精,在一定温度下反应一段时间,后处理后得到式I化合物粗品；(2)将粗品分离纯化,得到单一式Ⅰ化合物。本发明为舒更葡糖钠中间体γ-ICD的质量控制提供了标准对照品,对舒更葡糖钠中间体γ-ICD的杂质研究及质量控制尤为重要；本发明采用的制备方法的有益效果是操作便捷,反应条件温和可控,反应的稳定性高,并且反应产物收率高,纯度高。(The invention relates to the technical field of drug impurity synthesis, and particularly discloses a diphenylphosphoric acid derivative impurity in an intermediate gamma-ICD prepared from sugammadex sodium and a preparation method thereof, wherein the preparation method of the impurity comprises the following steps: (1) dissolving diphenyl phosphoric acid in an organic solvent, adding a certain amount of alkali under the protection of inert gas, stirring and reacting for a period of time at a certain temperature, then adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin, reacting for a period of time at a certain temperature, and performing post-treatment to obtain a crude product of the compound shown in the formula I; (2) the crude product was isolated and purified to give the single compound of formula I. The invention provides a standard reference substance for the quality control of the sugammadex sodium intermediate gamma-ICD, and is particularly important for the impurity research and the quality control of the sugammadex sodium intermediate gamma-ICD; the preparation method has the advantages of convenient operation, mild and controllable reaction conditions, high reaction stability, high yield of reaction products and high purity.)

1. A diphenyl phosphate derivative impurity of a sugammadex sodium preparation intermediate is shown in a formula I:

2. a process for the preparation of diphenyl phosphate ester impurity of sugammadex sodium preparation intermediate of claim 1, comprising the steps of:

(1) dissolving diphenyl phosphoric acid in an organic solvent, adding a certain amount of alkali under the protection of inert gas, stirring and reacting for a period of time at a certain temperature, then adding 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin, reacting for a period of time at a certain temperature, and carrying out post-treatment to obtain a crude product of the compound shown in the formula I;

dissolving and dispersing the 6-full-deoxy-6-full-iodo-gamma-cyclodextrin by using an organic solvent before adding the 6-full-deoxy-6-full-iodo-gamma-cyclodextrin;

(2) the resulting crude compound of formula I is purified.

3. The method of claim 2, wherein: the organic solvent in the step (1) is selected from N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide.

4. A method according to claim 2 or 3, characterized in that: the inert gas in the step (1) is nitrogen, helium or argon.

5. A method according to claim 2 or 3, characterized in that: the alkali in the step (1) is cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide.

6. The method of claim 5, wherein: in the step (1), after the diphenyl phosphoric acid is dissolved in the organic solvent, the alkali is added under the condition that the temperature in the reaction liquid is controlled to be less than or equal to 10 ℃.

7. The method of claim 5, wherein: and (2) adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin in the step (1), controlling the reaction temperature to be 30-90 ℃, and reacting for 8-18 h.

8. The method of claim 5, wherein: the post-treatment step in the step (1) is as follows: cooling to 20-30 deg.C, adding water, stirring, vacuum filtering, and drying at 60-65 deg.C for 10-13h to obtain crude product.

9. The method of claim 5, wherein: in the step (1), the molar ratio of the 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to the alkali to the diphenylphosphoric acid is 5-12: 5: 5-12.

10. The method of claim 7, wherein: adding 6-per-deoxy-6-per-iodo-gamma-cyclodextrin in the step (1), and reacting at 60-65 ℃ for 18 hours.

Technical Field

The invention relates to the field of synthesis of medicine impurities, in particular to a sugammadex sodium intermediate diphenyl phosphate derivative impurity and a preparation method thereof.

Background

Sugammadex Sodium (Sugammadex Sodium), chemical name 6-per-deoxy-6-per (2-carboxyethyl) thio-gamma-cyclodextrin Sodium salt, trade name Bridion, CAS: 343306-71-8. The structural formula is as follows:

sugammadex sodium is a selective relaxant binder used to reverse the effects of the muscle relaxant rocuronium bromide or vecuronium bromide, first discovered by the company oganong (organic Biosciences) in the netherlands. The european medicines regulatory agency has approved sugammadex sodium to be marketed in europe at 7/25/2008, sugammadex sodium is approved to be marketed in japan at 10/2010 and 20/2015, and FDA approved the drug to be marketed in the united states at 11/2015. At present, CFDA has approved Shugeng sodium gluconate to be listed in China in 2017, 4 and 26 months, and the medicine has good market prospect.

The sugammadex sodium diphenylphosphate impurity is an API impurity reported in the prior art (such as CN 110818817A), but the source of the impurity has not been reported and researched.

WO0140316 discloses the structure and preparation of sugammadex sodium, which is also the most popular synthesis method for sugammadex sodium currently on the market. The method comprises two steps, wherein in the first step, gamma-cyclodextrin is used as a raw material, and Vilsmeier-Hack reaction is firstly carried out on the raw material, triphenylphosphine and iodine in N, N-dimethylformamide to obtain 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (also named gamma-ICD); the second step is that 6-full deoxidation-6-full iodo-gamma-cyclodextrin reacts with 3-mercaptopropionic acid in the presence of sodium hydride to obtain 6-full deoxidation-6-full (2-carboxyethyl) -gamma-cyclodextrin sodium salt.

According to ICH guidance (International society for human drug registration technology) Q116-total deoxy-total iodo-gamma-cyclodextrin (gamma-ICD) as a key intermediate necessary in the last step of the process for producing sugammadex sodium, impurity research of 6-total deoxy-6-total iodo-gamma-cyclodextrin is particularly important. According to the guidelines, it is desirable to be able to ascertain as far as possible the production, elimination and setting of reasonable limits for each impurity greater than 0.1%.

In the repeated process of WO0140316, the inventor of the present application found that the last step has 0.3% -0.5% of impurities which are difficult to remove by crystallization purification means, and the repeated process is not feasible. In addition, it was difficult to reduce the impurity content by changing the reaction conditions of the process, and it was finally confirmed that the process was difficult to remove impurities. Molecular weight was 2268.07 by LCMS. But the content was too low to prepare by enrichment for confirmation of its impurity structure by HNMR. By comparison to the reported molecular weights of the impurities in the literature. The preliminary determination is:

at present, the Tianjin Kolon pharmaceutical application CN110627926A provides 21 sugammadex API related substances, and a preparation method and application thereof, but no report is made on sugammadex diphenylphosphate impurities, so that the impurities are not well directionally synthesized, and cannot be obtained by enrichment due to too low content.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a diphenyl phosphate derivative impurity of a sugammadex sodium preparation intermediate, and provides a qualified reference substance for quality control of sugammadex sodium.

The sugammadex sodium intermediate diphenyl phosphate derivative impurity reported by the invention is a process impurity found in the process of developing the sugammadex sodium process, and has a structure shown in a figure 1 as a formula I. The structure is determined by examination means such as LCMS and HNMR.

Another object of the invention is: the preparation method for preparing the intermediate impurity by using sugammadex sodium is convenient to operate, mild and controllable in reaction conditions, high in reaction stability, high in reactant yield and high in purity.

For the third purpose: the invention discloses a diphenyl phosphate derivative impurity in an intermediate gamma-ICD prepared from sugammadex sodium and a preparation method thereof, so that the diphenyl phosphate derivative impurity (with a structure shown in a formula 1) can be obtained in a large amount and efficiently. Then, the impurity sugammadex sodium diphenyl phosphate which is difficult to obtain is synthesized by the following method.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

an impurity of diphenyl phosphate derivatives of a sugammadex sodium preparation intermediate, the impurity having the structure of formula I:

a preparation method of diphenyl phosphate impurity as an intermediate in preparation of sugammadex sodium comprises the following steps:

(1) dissolving diphenyl phosphate in an organic solvent, adding a certain amount of alkali under the protection of inert gas, stirring and reacting for a period of time at a certain temperature, adding 6-fully-deoxy-6-fully iodo-gamma-cyclodextrin (gamma-ICD) of a compound in a formula II, reacting for a period of time at a certain temperature, and performing post-treatment to obtain a crude product of the compound in the formula I;

the compound 6-full-deoxy-6-full-iodo-gamma-cyclodextrin (gamma-ICD) of the formula II is dissolved and dispersed by an organic solvent before being added, so that the compound is convenient to drop.

(2) The resulting crude compound of formula I is purified to yield a single compound of formula I.

Further, the organic solvent in the step (1) is selected from N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide.

Further, the inert gas in the step (1) is nitrogen, helium or argon.

Further, the alkali in the step (1) is cesium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide.

Further, after the diphenyl phosphoric acid is dissolved in the organic solvent in the step (1), alkali is added under the condition that the temperature in the reaction liquid is controlled to be less than or equal to 10 ℃.

Further, after the compound of the formula II is added in the step (1), the reaction temperature is controlled to be 30-90 ℃, and the reaction time is controlled to be 8-18 h; preferably at 60-65 deg.C for 18 hr,

further, the post-processing step in the step (1) is as follows: cooling to 20-30 deg.C, adding water, stirring, vacuum filtering, and drying at 60-65 deg.C for 10-13h to obtain crude product.

Further, in the step (1), the molar ratio of the 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to the alkali to the diphenyl phosphate is 5-12: 5: 5-12.

Compared with the prior art, the invention has the advantages and beneficial effects that:

1. the compound of the sugammadex intermediate diphenyl phosphate impurity formula I is reported for the first time, the preparation of the impurity is particularly important for the impurity research and impurity content control of the sugammadex intermediate, and a direction is provided for the oriented synthesis of the sugammadex diphenyl phosphate impurity;

2. providing diphenyl phosphate derivative impurities of a sugammadex sodium preparation intermediate, and providing a qualified reference substance for quality control of sugammadex sodium;

3. the preparation method for preparing the intermediate impurity by using sugammadex sodium is convenient to operate, mild and controllable in reaction conditions, high in reaction stability, high in reactant yield and high in purity.

Drawings

FIG. 1 is a chromatogram of an impurity of diphenyl phosphate derivative found in the process of preparing the sugammadex sodium intermediate gamma-ICD by the applicant, and a peak with the serial number of 4 is the impurity.

FIG. 2 is an HPLC chart of crude diphenylphosphoric acid derivative impurity directionally synthesized in example 1.

FIG. 3 is a HNMR map of diphenylphosphoric acid derivative impurities directionally synthesized in example 1.

FIG. 4 is an HPLC chart of purified diphenylphosphoric acid derivative impurities obtained by directed synthesis in example 1.

Detailed Description

The applicant will now describe in detail embodiments of the present invention, it should be noted that the following described embodiments are exemplary only, and are not to be construed as limiting the present invention. In addition, all reagents used in the following examples are commercially available or can be synthesized by reference to existing literature or known methods, and are conventional techniques readily available to those skilled in the art for reactions or test conditions not listed, if not specifically indicated.

Example 1 a sugammadex sodium intermediate diphenyl phosphate derivative impurity, the preparation method of which is as follows:

under the protection of nitrogen, adding N, N-dimethylformamide (10.5ml) and diphenyl phosphoric acid (2.87g, 13.16mmol) into a 100ml three-neck flask, controlling the internal temperature to be less than or equal to 10 ℃, adding cesium carbonate (4.29g, 13.16mmol), stirring for reaction for 0.5 hour, adding N, N-dimethylformamide (18ml) into a 100ml beaker while stirring for reaction, adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (3.58g, 1.65mmol), stirring until all solids are dissolved for later use, after stirring for reaction for 0.5 hour, dropwise adding the solution of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin into the 100ml three-neck flask, heating to 60-65 ℃ for reaction for 18 hours after dropwise adding, cooling to 20-30 ℃,adding 100ml of purified water into the reaction system, stirring for 1h at room temperature, filtering, drying a filter cake in a forced air drying oven at 60 ℃, collecting after 12 h to obtain 3.8g of crude product with the purity as high as 34.9% (see figure 2, peak with number 22), then carrying out preparation, purification and separation on the crude product to obtain 110mg of product with the purity of 99.07%, and determining the purity as a chromatogram in figure 4. And (3) product qualitative detection result: MS (ESI) M/z 2266.59(M + 1); combining the results of the H-spectrum detection of nuclear magnetic resonance (see the result in FIG. 3), the product is confirmed to be the compound of formula I:

wherein, the chromatographic conditions for preparing, purifying and separating the crude product are as follows:

preparing a column: a column (YMC ODS-AQ 150X 4.6mm, 3 μm);

detection wavelength: flow rate at 200nm 15ml/min column temperature: 35 deg.C

Mobile phase A: 0.1% TFA solution

Mobile phase B: acetonitrile

The gradient elution procedure was as follows:

time (min)	A(％)	B(％)
			0	50	50
3	50	50
			21	20	80
22	5	95
			27.5	5	95
28.5	50	50
			33	50	50

Example 2 a sugammadex sodium intermediate diphenyl phosphate derivative impurity, the preparation method of which is as follows:

adding dimethyl sulfoxide (5.3ml) and diphenyl phosphoric acid (0.91g, 4.15mmol) into a 100ml three-necked flask at room temperature under the protection of nitrogen, controlling the internal temperature to be less than or equal to 10 ℃, adding sodium hydroxide (0.17g, 4.15mmol), stirring for reaction for 0.5 hour, adding dimethyl sulfoxide (9ml) into a 100ml beaker while stirring for reaction, adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (1.79g, 0.83mmol), stirring until all solids are dissolved for later use, after stirring for reaction for 0.5 hour, dropwise adding the solution of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin into the 100ml three-necked flask, heating to 60-65 ℃ for reaction for 18 hours after dropwise adding, cooling to 20-30 ℃, adding 50ml of purified water into the reaction system, stirring for 1 hour at room temperature, filtering, drying the filter cake in a forced air drying oven at 60 ℃, collecting after 12 hours to obtain 1.8g of crude product with the purity as high as 32.6%, and then carrying out preparation, purification and separation on the crude product according to the conditions in the example 1 to obtain 50mg of product with the purity of 97.4%.

Example 3 a sugammadex sodium intermediate diphenyl phosphate derivative impurity, the preparation method of which is as follows:

adding dimethyl sulfoxide (10.5ml) and diphenyl phosphoric acid (4.31g, 19.74mmol) into a 100ml three-neck flask under the protection of argon at room temperature, controlling the internal temperature to be less than or equal to 10 ℃, adding 60% sodium hydride (0.79g, 19.74mmol), stirring for reaction for 0.5 hour, adding dimethyl sulfoxide (18ml) into a 100ml beaker while stirring for reaction, adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (3.58g, 1.65mmol), stirring until all solids are dissolved for later use, after stirring for reaction for 0.5 hour, dropwise adding the solution of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin into the 100ml three-neck flask, heating to 60-65 ℃ for reaction for 18 hours after dropwise adding, cooling to 20-30 ℃, adding 100ml purified water into the reaction system, stirring for 1 hour at room temperature, filtering, drying the filter cake in a forced air drying oven at 60 ℃, collecting after 12 hours to obtain 3.9g of crude product with the purity of 33.5%, and then performing preparation, purification and separation on the crude product according to the conditions in the example 1 to obtain 105mg of product with the purity of 95.3%.

Example 4 a sugammadex sodium intermediate diphenyl phosphate derivative impurity, the preparation method of which is as follows:

adding N, N-dimethylformamide (9ml) and diphenyl phosphoric acid (2.69g, 12.34mmol) into a 100ml three-neck flask under the protection of nitrogen at room temperature, controlling the internal temperature to be less than or equal to 10 ℃, adding anhydrous potassium carbonate (1.71g, 12.34mmol), stirring for reaction for 0.5 hour, adding N, N-dimethylformamide (5.3ml) into a 100ml beaker while stirring for reaction, adding 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (1.79g, 0.83mmol), stirring until all solids are dissolved for later use, after stirring for reaction for 0.5 hour, dropwise adding the solution of the 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin into the 100ml three-neck flask, heating to 60-65 ℃ for reaction for 18 hours after dropwise adding, cooling to 20-30 ℃, adding 50ml of purified water into the reaction system, filtering, drying the filter cake in a forced air drying oven at 60 ℃, collecting after 12 hours to obtain 1.7g of crude product with the purity of 24.7%, and then performing preparation, purification and separation on the crude product according to the conditions in the example 1 to obtain 45mg of product with the purity of 94.7%.

Example 5

At room temperature under the protection of nitrogen, adding anhydrous DMF (20mL) and mercaptopropionic acid (1.2g, 11.3mmol) into a 100mL three-necked flask, controlling the internal temperature to be less than or equal to 10 ℃, then adding sodium hydride (0.3g, 12.5mmol) in batches, stirring for reaction for 0.5 hour, then adding the sugammadex intermediate diphenylphosphate impurity compound solid (1mmol) prepared according to example 1 at one time, heating to 60-65 ℃ for reaction for 3 hours, then cooling to 20-30 ℃, adding 10mL of purified water into the reaction system, stirring for 1 hour at room temperature, filtering, dissolving a filter cake with 15mL of water and DMSO (1: 1) at 60 ℃, then slowly cooling to 5 ℃ for crystallization to obtain 0.8g of crystals, drying in a dry blowing box at 60 ℃, collecting after 5 hours to obtain 0.6g of a product, wherein the purity is as high as 95.2%. Meets the requirements of the sugammadex API impurity standard. The diphenyl phosphate impurity in sugammadex API was confirmed by purchasing an impurity standard comparison.