CN111961145A - Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof - Google Patents
Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof Download PDFInfo
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- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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Abstract
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.
Description
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 CN110818817A), but the source of the impurity has not been reported and researched.
WO0140316 first discloses the structure and preparation method of sugammadex sodium, which is prepared by subjecting gamma-cyclodextrin as a raw material to Vilsmeier-Hack reaction with triphenylphosphine and iodine in N, N-dimethylformamide to obtain 6-fully deoxy-6-fully iodo-gamma-cyclodextrin (also known as gamma-ICD). Reacting 6-per-deoxy-6-per-iodo-gamma-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydride to obtain 6-per-deoxy-6-per (2-carboxyethyl) -gamma-cyclodextrin sodium salt.
In the existing process for producing sugammadex sodium, most of 6-fully-deoxy-fully-iodo-gamma-cyclodextrin is used as a preparation intermediate, and the structure of 6-fully-deoxy-6-fully-iodo-gamma-cyclodextrin (gamma-ICD) is as follows:
at present, Tianjin Kolon pharmaceutical application CN110627926A provides 21 sugammadex API related substances, and a preparation method and application thereof, but no report is provided on sugammadex diphenylphosphate impurities, and no mention is made on the research on the diphenylphosphate derivative impurities of a sugammadex intermediate.
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.
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, N-dimethylformamide (10.5ml) and diphenyl phosphoric acid (2.87g, 13.16mmol) were added into a 100ml three-necked flask, cesium carbonate (4.29g, 13.16mmol) was added while controlling the internal temperature to be 10 ℃ or less, the reaction was stirred for 0.5 hour, and N, N-dimethyl formamide was added into a 100ml beaker while stirring the reactionAmide (18ml), adding 6-full-deoxy-6-full-iodo-gamma-cyclodextrin (3.58g, 1.65mmol), stirring until the solid is completely dissolved for later use, after stirring and reacting for 0.5 hour, dropwise adding the solution of the 6-full-deoxy-6-full-iodo-gamma-cyclodextrin into a 100ml three-neck flask, after dropwise adding, heating to 60-65 ℃ for reacting for 18 hours, then cooling to 20-30 ℃, adding 100ml of purified water into the reaction system, stirring for 1 hour at room temperature, filtering, drying a filter cake in a blast drying oven at 60 ℃, collecting after 12 hours, obtaining 3.8g of crude product with the purity of 34.9% (see figure 2, peak with number of 22), then preparing, purifying and separating the crude product to obtain 110mg of product with the purity of 99.07%, and determining the purity as shown in a chromatogram of figure 4. And (3) product qualitative detection result: MS (ESI) M/z2266.59(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:
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%.
Claims (10)
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.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010986211.2A CN111961145A (en) | 2020-09-18 | 2020-09-18 | Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof |
| CN202110976982.8A CN113603813A (en) | 2020-09-18 | 2021-08-24 | Impurity of diphenyl phosphate derivative as sugammadex sodium intermediate and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110818817A (en) * | 2019-08-29 | 2020-02-21 | 常州亚邦制药有限公司 | Sugammadex sodium diphenyl phosphine oxide derivative impurity and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3421504B1 (en) * | 2017-06-30 | 2019-09-18 | Synthon B.V. | Process for making sugammadex |
| CN110818817A (en) * | 2019-08-29 | 2020-02-21 | 常州亚邦制药有限公司 | Sugammadex sodium diphenyl phosphine oxide derivative impurity and preparation method thereof |
| CN114349882A (en) * | 2020-09-30 | 2022-04-15 | 四川科伦药物研究院有限公司 | Sugammadex sodium potential genotoxicity impurity and its preparation method and use |
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- 2020-09-18 CN CN202010986211.2A patent/CN111961145A/en not_active Withdrawn
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110818817A (en) * | 2019-08-29 | 2020-02-21 | 常州亚邦制药有限公司 | Sugammadex sodium diphenyl phosphine oxide derivative impurity and preparation method thereof |
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Application publication date: 20201120 |