CN111471121A - A kind of synthetic method of sugammadex sodium dimer impurity - Google Patents

Abstract

A method for synthesizing a sodium sugammadex dimer impurity, the present invention relates to the technical field of chemical substance synthesis and preparation, and discloses a method for preparing a sodium sugammadex dimer impurity. Using octa-(6-bromo-6-deoxy)-γ-cyclodextrin as a raw material, a sulfide is added to react to obtain an intermediate product intermolecular thioether. The obtained intermediate product reacts with 3-mercaptopropionic acid in a sodium hydroxide aqueous solution to obtain a final product sodium sugammadex dimer impurity. The beneficial effect of the present invention is that the present invention improves the quality of sodium sugammadex raw materials, improves the accuracy of qualitative and quantitative analysis, reduces the risk of clinical medication, and is more conducive to studying and monitoring impurities in sodium sugammadex raw materials and preparations.

Description

A kind of synthetic method of sugammadex sodium dimer impurity

technical field

The invention belongs to the technical field of synthetic preparation of chemical substances, and in particular relates to a method for synthesizing a dimer impurity of sodium sugammadex.

Background technique

Sugammadex sodium, chemical name: eight-6-all-deoxy-6-all (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, chemical structure is as follows:

Sugammadex Sodium was approved by the European Union in 2008, and its trade name is Bridion. It was subsequently launched in Japan and the United States in 2010 and 2015, and has been marketed in many countries around the world. Sodium sugammadex is produced by the Dutch company Organon and was owned by Merck through an acquisition transaction in 2009. Britin is the first selective relaxation antagonist for the reversal of neuromuscular blocking agents, the first and only selective relaxation antagonist.

WO2017144734A2 provides a method for synthesizing sodium sugammadex, the Vilsmeier Haack reagent prepared by the reaction of DMF, triphenylphosphine and Br ₂ reacts with γ-cyclodextrin to obtain eight-(6-bromo-6-de oxy)-γ-cyclodextrin intermediate. Eight-(6-bromo-6-deoxy)-γ-cyclodextrin reacts with sodium hydroxide aqueous solution of 3-mercaptopropionic acid to obtain the finished product of sodium sugammadex.

The dimer impurity formula 1 is a reaction by-product, and there is no reference substance available at home and abroad, and there is no report on the synthesis method of this impurity in domestic and foreign literature and patents. To improve the quality of sodium gluconate raw materials and preparations and reduce the risk of clinical medication, it is necessary to conduct more detailed research and monitoring of impurities in the raw materials and preparations of gluconate sodium. The synthetic method of the reference substance becomes a top priority.

SUMMARY OF THE INVENTION

The purpose of this invention is to provide a kind of preparation method of sugammadex sodium dimer impurity, and to provide qualified reference substance for the quality control of sugammadex sodium. The preparation method has the advantages of convenient operation, mild and controllable reaction conditions and high reaction stability. The technical scheme adopted in the present invention is as follows: a method for synthesizing sodium glucosamine dimer impurity, its chemical structural formula is such as formula 1:

Its synthetic route is as follows:

Synthetic steps of the present invention:

A, take compound 2, namely eight-(6-bromo-6-deoxy)-γ-cyclodextrin as raw material, and obtain intermediate product 3 after adding sulfide;

B. 3-mercaptopropionic acid is added to the aqueous sodium hydroxide solution, and then compound 3 is added to react to obtain the final product formula 1, and the obtained compound 1 is the impurity of sodium glucosamine dimer.

Preferably, in the step A, the molar ratio of compound 2 and sulfide is 1:(0.1-5); the sulfide is selected from one or more of sodium sulfide and its hydrate, potassium sulfide and its hydrate.

Preferably, the step A is carried out in a polar solvent; the polar solvent includes one or more of DMSO, DMF, DMAC, and NMP, preferably DMF; the amount of the solvent is 1 to 5 times the volume of compound 2 .

In step A, the reaction temperature is -5 to 45°C.

In step B, the molar ratio of compound 3 to 3-mercaptopropionic acid is 1:(15-45).

In step B, compound 3 is added after being dissolved in a polar solvent, and the polar solvent includes one or more of DMSO, DMF, DMAC, and NMP.

In step B, the reaction temperature is 25-80°C.

The beneficial effect is that the present invention improves the quality of the raw material of sodium gluconate, improves the accuracy of qualitative and quantitative, reduces the risk of clinical medication, and is more conducive to the research and monitoring of the impurities in the raw material and preparation of sodium gluconate. .

Description of drawings

Figure 1 ¹ H NMR spectrum of compound 1;

Figure 2 Low-resolution mass spectrum of compound 1;

Figure 3 High-resolution mass spectrum of compound 1;

Detailed ways

Below in conjunction with accompanying drawing, the present invention is described in detail, as shown in Figure 1, a kind of succinct sodium gluconate dimer impurity synthesis method, its chemical structural formula is such as formula 1:

Its synthetic route is as follows:

Synthetic steps of the present invention:

A, take compound 2, namely eight-(6-bromo-6-deoxy)-γ-cyclodextrin as raw material, and obtain intermediate product 3 after adding sulfide;

B. 3-mercaptopropionic acid is added to the aqueous sodium hydroxide solution, and then compound 3 is added to react to obtain the final product formula 1, and the obtained compound 1 is the impurity of sodium glucosamine dimer.

Preferably, in the step A, the molar ratio of compound 2 to the sulfide is 1: (0.1-5); the sulfide is selected from one or more of sodium sulfide and its hydrate, potassium sulfide and its hydrate; More preferably, it is sodium sulfide nonahydrate.

Preferably, the step A is carried out in a polar solvent; the polar solvent includes one or more of DMSO, DMF, DMAC, and NMP, preferably DMF; the amount of the solvent is 1 to 5 times the volume of compound 2 , preferably 3 times the volume.

In step A, the reaction temperature is -5 to 45°C, preferably 20 to 30°C.

In step B, the molar ratio of compound 3 to 3-mercaptopropionic acid is 1:(15-45), preferably 1:30.

In step B, compound 3 is added after being dissolved in a polar solvent, and the polar solvent includes one or more of DMSO, DMF, DMAC, and NMP, preferably DMSO.

In step B, the reaction temperature is 25-80°C, preferably 45-50°C.

Example 1

The examples are used to illustrate the present invention, but should not be construed to limit the present invention.

Preparation of Intermediate 3:

Eight-(6-bromo-6-deoxy)-γ-cyclodextrin (40 g, 22.2 mmol) and 140 mL of DMF were added to a 250 mL reaction flask, and the solution was stirred to dissolve. After adding sodium sulfide nonahydrate (2.67 g, 11.1 mmol), the mixture was reacted at 20° C. for 24 hours. Filter to remove undissolved sodium sulfide nonahydrate. The filtrate was diluted with 140 mL of DMF, 450 mL of methyl isobutyl ketone was added dropwise, and the mixture was stirred for half an hour and filtered to obtain a crude product. The crude product was purified by DMF/methyl isobutyl ketone for 3 to 5 times to remove the raw material octa-(6-bromo-6-deoxy)-γ-cyclodextrin. The crude product was further purified by DMF/MeOH/water 5 times to remove the intramolecular sulfide by-product. Vacuum-dry at 45°C to finally obtain 2.2 g of intermediate 3 as a light gray solid.

Example 2

The examples are used to illustrate the present invention, but should not be construed to limit the present invention.

Preparation of compound 1:

100mL three-necked flask, add sodium hydroxide (1.47g, 36.6mmol), 6.4mL of purified water, stir to dissolve and then fully replace the protection with nitrogen, cool to 0 ~ 10 ℃ and dropwise add 3-mercaptopropionic acid (1.95g, 18.3mmol) ). After dropping, the temperature was raised to 40° C., 2.12 g (0.63 mmol) of intermediate 3 in 16 mL DMSO solution was slowly added, and the reaction was performed at 45-50° C. for four hours after the addition. 11.2 mL of water was added, and the reaction solution became clear. After maintaining the temperature for half an hour, 4.2 mL of DMSO was added, and the temperature was lowered to 0 to 5 °C for crystallization and filtration. The crude product was recrystallized from water/methanol and dried under vacuum at 40°C to obtain 1.1 g of compound 1 as a white solid.

¹ H NMR (500MHz, D ₂ O) δ2.41～2.50(28H,m), δ2.81～2.84(28H,m), δ2.89～3.00(16H,m), δ3.07～3.17(14H) , m), δ3.35 (2H, d), δ3.51 (2H, t), δ3.60～3.65 (28H, m), δ3.75 (2H, t), δ3.85～3.95 (16H, m), δ4.00～4.03 (16H, m), δ5.13～5.19 (16H, m).

The mass spectrum shows that 14 sodium ions in the molecule are replaced by protons one by one to form 14 groups of equidistant ion peak clusters (m/z difference of 11), m/z=1934～2080. Among them, the single sodium form molecule C ₁₃₈ H ₂₁₃ NaO ₉₂ S ₁₅ has the most content, and the quasi-molecular ion peak formed with two sodium ions has the highest abundance isotope peak of [M+2Na+3] ²⁺ , m/z= 1946.9.

HRMS: (ESI+) calcld. for C ₁₃₈ H ₂₁₄ Na ₂ O ₉₂ S ₁₅ [M+2Na] ²⁺ = 1934.3831, found 1934.3785.

The above technical solutions only represent the preferred technical solutions of the technical solutions of the present invention, and some changes that those skilled in the art may make to some parts of them all reflect the principles of the present invention and fall within the protection scope of the present invention.

Claims (7)

1. A method for synthesizing impurities of sugammadex sodium dimer, wherein the chemical structural formula of the impurities is as shown in formula 1:

the method is characterized in that: the synthetic route is as follows:

the specific synthesis steps comprise:

A. taking a compound 2, namely octa- (6-bromo-6-deoxy) -gamma-cyclodextrin as a raw material, and adding a sulfide to obtain an intermediate product 3;

B. adding 3-mercaptopropionic acid into a sodium hydroxide aqueous solution, and then adding an intermediate product 3 to obtain a final product 1, wherein the final compound 1 is the sugammadex dimer impurity.

2. The method of preparing sugammadex sodium dimer impurity of claim 1, wherein: the molar ratio of the compound 2 to the sulfide in the step A is 1: (0.1-5); the sulfide is selected from one or more of sodium sulfide and hydrate thereof, potassium sulfide and hydrate thereof.

3. The method of preparing sugammadex sodium dimer impurity of claim 1, wherein: said step a is carried out in a polar solvent; the polar solvent comprises one or more of DMSO, DMF, DMAC and NMP, and is preferably DMF; the amount of solvent used is 1 to 5 times by volume of compound 2.

4. The method according to any one of claims 1 to 4, wherein: in the step A, the reaction temperature is-5-45 ℃.

5. The method of claim 1, wherein: the molar ratio of the compound 3 to the 3-mercaptopropionic acid in step B was 1: (15-45).

6. The method of claim 1, wherein: and B, dissolving the compound 3 in the step B by using a polar solvent, and adding the dissolved compound into the solvent, wherein the polar solvent comprises one or more of DMSO, DMF, DMAC and NMP.

7. The method according to any one of claims 5 to 6, wherein: and the reaction temperature in the step B is 25-80 ℃.

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