CN110818817A - Sugammadex sodium diphenyl phosphine oxide derivative impurity and preparation method thereof - Google Patents

Abstract

The present invention relates to the technical field of pharmaceutical synthesis, in particular to a kind of sugammadex sodium diphenyl oxonate derivative impurity and a preparation method thereof. The chemical structural formula of the impurity is as formula I:

, the preparation method includes the following steps: (1) dissolving 3-mercaptopropionic acid and diphenylphosphine oxide methanol in an organic solvent, adding sodium hydride under the protection of inert gas, stirring and reacting at a certain temperature for a period of time, then adding formula II Compound 6-per-deoxy-6-per-iodo-γ-cyclodextrin is reacted at a certain temperature for a period of time, and after post-processing, the crude compound of formula I is obtained; (2) the obtained crude compound of formula I is separated and purified, Obtaining a single compound of formula I, the impurities provided in the present invention provide a standard reference substance for the quality control of sugammadex sodium, and it is particularly important to study the impurities of sugammadex sodium and control the impurity content; the technology adopted in the present invention The beneficial effects of the scheme are convenient operation, mild and controllable reaction conditions, high reaction stability, and high yield and high purity of the reaction product.

Description

A kind of sugammadex sodium diphenyl oxonate derivative impurity and preparation method thereof

technical field

The invention relates to the technical field of drug synthesis, in particular to an impurity of a sodium diphenyl oxonate derivative of sugammadex and a preparation method thereof.

Background technique

Sugammadex sodium, chemical name is octa-6-all-deoxy-6-all (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, trade name is Bridion, CAS: 343306- 71-8, the structural formula is as follows:

Sugammadex sodium is a selective relaxation binder for reversing the effects of the muscle relaxants rocuronium or vecuronium, first discovered by Organon Biosciences in the Netherlands. On July 25, 2008, the European Medicines Agency has approved the listing of Sugammadex Sodium in Europe. On October 20, 2010, Sugammadex Sodium was approved for listing in Japan. In November 2015, the FDA approved the drug for listing in the United States. . At present, on April 26, 2017, the CFDA has approved the listing of Sugammadex Glucose Sodium in China, and the drug has a good market prospect.

It is known in the art that national and international regulations are required to establish extremely low limits for the identification of toxicologically non-characteristic impurities prior to commercialization of an effective pharmaceutical ingredient (API) product for safety in human administration.

It is also known in the art that impurities in any active ingredient (API) of sodium sugammadex may arise from the degradation of the API itself and the manufacturing process, including chemical synthesis. Process impurities include unreacted raw materials, impurities contained in raw materials and their chemical derivatives, synthesis by-products, and degradation products.

In the preparation process of sugammadex sodium, triphenylphosphine is used, so it will react with triphenylphosphine to obtain related analog impurities, that is, the compound of formula I. Research on the impurity and impurity content of sugammadex sodium Control is also particularly important.

SUMMARY OF THE INVENTION

The purpose of the present invention is to: overcome the deficiencies in the prior art, provide a kind of sugammadex sodium diphenyl oxonate derivative impurities, and provide a qualified reference substance for the quality control of sugammadex sodium; another aspect of the present invention The purpose is to provide a preparation method of sugammadex sodium impurity, which is convenient to operate, mild and controllable reaction conditions, high reaction stability, and high yield and high purity of the reaction product.

In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is as follows:

A kind of sugammadex sodium diphenyl oxide derivative impurity, the chemical structural formula of described impurity is such as formula I:

A preparation method of sugammadex sodium diphenyl oxide derivative impurities, comprising the following steps:

(1) Dissolve 3-mercaptopropionic acid and diphenylphosphine oxymethanol in an organic solvent, add sodium hydride under the protection of inert gas, stir and react for a period of time at a certain temperature, and then add compound 6-deoxy-6 of formula II - all-iodine-γ-cyclodextrin, react for a period of time at a certain temperature, and obtain a crude product of the compound of formula I after post-processing;

(2) The obtained crude compound of formula I is separated and purified to obtain a single compound of formula I.

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

Further, the inert gas in described step (1) selects nitrogen, helium or argon for use;

Further, in the step (1), 3-mercaptopropionic acid and diphenylphosphine oxide methanol are dissolved in an organic solvent, and the temperature is controlled to be less than or equal to 5° C. After stirring for 1-1.2 h, sodium hydride is added.

Further, in the step (1), sodium hydride is added and stirred at room temperature for 1-1.2 h.

Further, in the step (2), after adding the compound of formula II, the reaction temperature is controlled to be 30-90° C., and the reaction time is 10-25 h.

Further, after adding the compound of formula II in the step (2), the reaction temperature is controlled to be 50-70° C., and the reaction time is 16-20 h.

Further, the post-processing steps in the step (1) are: cooling to 18-20 ° C, slowly adding water, then adding methanol, stirring at room temperature for 1 h, suction filtration, washing the filter cake with methanol once, 55- Dry at 60°C for 10-12h to obtain crude product.

Further, in the step (1), the molar ratio of 6-per-deoxy-6-per-iodo-γ-cyclodextrin, 3-mercaptopropionic acid and diphenylphosphine methanol is 1:6～10:1 ~3.

The beneficial effects of adopting the technical scheme of the present invention are:

The impurity provided in the present invention provides a standard reference substance for the quality control of sugammadex sodium, and is particularly important for the impurity research and impurity content control of sugammadex sodium.

The beneficial effects of the technical solution adopted in the present invention are convenient operation, mild and controllable reaction conditions, high reaction stability, and high yield and high purity of the reaction product. In addition, the compound of formula I can provide the required impurity reference substance for the quality control of sugammadex sodium.

Description of drawings

Figure 1 is the H NMR spectrum of the compound of formula I in the present invention.

Accompanying drawing 2 MS spectrum of impurity I.

Detailed ways

The present invention will now be further described with reference to specific embodiments.

About the used sugammadex sodium, it is mainly synthesized with reference to the technology of the patent (WO-0140316) of Akzo Nobel company, and its synthetic route is as follows:

In this route, γ-cyclodextrin is used as raw material, and in N,N-dimethylformamide, the Vilsmeier-Hack reaction with triphenylphosphine, iodine and N,N-dimethylformamide is carried out to obtain 6- All-deoxy-6-all-iodo-γ-cyclodextrin, and then undergo a substitution reaction with 3-mercaptopropionic acid to generate sodium sugammadex.

Example 1

Reaction formula:

3-Mercaptopropionic acid (1.2 g, 11.3 mmol) and diphenylphosphine methanol (0.64 g, 2.76 mmol) were added to DMF (45 ml), and under nitrogen protection, the internal temperature was controlled to be less than or equal to 5 °C and stirred for 1 h. Sodium hydrogen (1.7 g, 70.8 mmol). After the addition, the mixture was stirred at room temperature for 1 h, 6-perodeoxy-6-periodo-γ-cyclodextrin (3.0 g, 1.38 mmol) was added, and the reaction was stirred at 55-60° C. for 16 h. Cool to 20°C, slowly add 5ml of water, then add 60ml of methanol, stir at room temperature for 1h, suction filter, wash the filter cake with methanol (20ml*1) once, and dry at 60°C for 10h to obtain 2.5g of crude product. Then the crude product was purified and isolated to obtain 30 mg of compound I with a purity of 94.7%.

Compound I:

MS (m/z): 1062 [M-7Na+5H] ⁻ /2.

¹ H-NMR (400MHz, D ₂ O): δ2.48-2.85 (m, 36H), 3.04 (m, 8H), 3.44-3.84 (m, 34H), 5.03 (m, 8H), 7.54-7.75 ( m, 10H).

Example 2

Reaction formula:

3-Mercaptopropionic acid (2.4 g, 22.6 mmol) and diphenylphosphine methanol (1.28 g, 5.52 mmol) were added to DMSO (60 ml), and under nitrogen protection, the internal temperature was controlled to be less than or equal to 5 °C and stirred for 1 h. Sodium hydrogen (2.5 g, 104 mmol). After the addition, the mixture was stirred at room temperature for 1 h, 6-per-deoxy-6-per-iodo-γ-cyclodextrin (6.0 g, 2.72 mmol) was added, and the reaction was stirred at 55-60° C. for 16 h. Cool to 20°C, slowly add 12ml of water, then add 120ml of methanol, stir at room temperature for 1h, suction filter, wash the filter cake with methanol (30ml*1) once, and dry at 60°C for 10h to obtain 4.8g of crude product. Then, the crude product was purified and isolated to obtain 50 mg of compound I with a purity of 92.3%.

Example 3

Reaction formula:

3-Mercaptopropionic acid (2.9 g, 27.2 mmol) and diphenylphosphine methanol (1.92 g, 8.16 mmol) were added to DMSO (65 ml), and under argon protection, the internal temperature was controlled to be less than or equal to 5 °C and stirred for 1 h, Sodium hydrogen (3.2 g, 136 mmol) was added. After the addition, the mixture was stirred at room temperature for 1 h, 6-per-deoxy-6-per-iodo-γ-cyclodextrin (6.0 g, 2.72 mmol) was added, and the reaction was stirred at 55-60° C. for 16 h. Cool to 20°C, slowly add 13ml of water, then add 130ml of methanol, stir at room temperature for 1h, suction filter, wash the filter cake with methanol (30ml*1) once, and dry at 60°C for 10h to obtain 6.2g of crude product. Then the crude product was purified and isolated to obtain compound I 60 mg with a purity of 94.3%.

Example 4

Reaction formula:

3-Mercaptopropionic acid (0.9 g, 8.3 mmol) and diphenylphosphine methanol (0.32 g, 1.38 mmol) were added to DMF (40 ml), and under the protection of helium, the internal temperature was controlled to be less than or equal to 5 °C and stirred for 1 h, Sodium hydrogen (1.7 g, 70.8 mmol) was added. After the addition, the mixture was stirred at room temperature for 1 h, 6-perodeoxy-6-periodo-γ-cyclodextrin (3.0 g, 1.38 mmol) was added, and the reaction was stirred at 55-60° C. for 16 h. Cool to 20°C, slowly add 5ml of water, then add 50ml of methanol, stir at room temperature for 1h, suction filter, wash the filter cake with methanol (20ml*1) once, and dry at 60°C for 10h to obtain 2.4g of crude product. Then, the crude product was purified and isolated to obtain 31 mg of compound I with a purity of 92.1%.

Taking the above ideal embodiments according to the present invention as inspiration, and through the above description, relevant personnel can make various changes and modifications without departing from the technical idea of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention. The technical scope of the present invention is not limited to the contents in the specification, and the technical scope must be determined according to the scope of the claims.

Claims (10)

1. An impurity of a sugammadex sodium diphenyl phosphine oxide derivative, which is characterized in that: the chemical structural formula of the impurities is as shown in formula I:

formula I.

2. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities as claimed in claim 1, wherein: the method comprises the following steps:

(1) dissolving 3-mercaptopropionic acid and diphenyl phosphine oxide methanol in an organic solvent, adding sodium hydride 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 of a compound of a formula II, reacting for a period of time at a certain temperature, and performing aftertreatment to obtain a crude product of the compound of the formula I;

formula II formula I

(2) And separating and purifying the obtained crude product of the compound of the formula I to obtain a single compound of the formula I.

3. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: the organic solvent in the step (1) is one selected from N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide.

4. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: and (2) selecting nitrogen, helium or argon as the inert gas in the step (1).

5. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: in the step (1), 3-mercaptopropionic acid and diphenyl phosphine oxide methanol are dissolved in an organic solvent, stirred for 1-1.2h at the temperature of less than or equal to 5 ℃, and then sodium hydride is added.

6. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: in the step (1), sodium hydride is added and stirred for 1-1.2h at room temperature.

7. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: and (3) after the compound of the formula II is added in the step (2), controlling the reaction temperature to be 30-90 ℃ and the reaction time to be 10-25 h.

8. The method of claim 7, wherein the impurities of the sugammadex sodium diphenyl phosphine oxide derivative are: and (3) after the compound of the formula II is added in the step (2), controlling the reaction temperature to be 50-70 ℃ and the reaction time to be 16-20 h.

9. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: the post-treatment step in the step (1) is as follows: cooling to 18-20 deg.C, slowly adding water, adding methanol, stirring at room temperature for 1 hr, vacuum filtering, washing the filter cake with methanol once, and drying at 55-60 deg.C for 10-12 hr to obtain crude product.

10. The method for preparing sugammadex sodium diphenyl phosphine oxide derivative impurities according to claim 2, wherein: in the step (1), the molar ratio of the 6-per-deoxy-6-per-iodo-gamma-cyclodextrin to the 3-mercaptopropionic acid to the diphenyl oxyphosphoryl methanol is 1: 6-10: 1-3.

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