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Intermediate of sugammadex sodium and preparation method thereof

A technology for sodium sugammadex and an intermediate, which is used in the preparation of an intermediate for sodium sugammadex and the field of preparation thereof, and can solve the problems of increased difficulty, poor process reproducibility, and increased post-processing operations.

Pending Publication Date: 2021-05-25
BEIJING TIDE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the traditional process steps, sugammadex sodium is directly prepared only through the intermediate of perhalogenated-γ-cyclodextrin. Although the reaction steps are relatively short, the structurally similar impurities produced in the preparation of perhalogenated-γ-cyclodextrin affect the subsequent The reaction purity of sugammadex sodium increases the difficulty of post-reaction treatment. In addition, the structural characteristics and strong water solubility of sugammadex sodium make it easy to wrap impurities such as inorganic salts and small molecular organic substances in the production process. Therefore, most of the purification of sugammadex sodium adopts the method of column chromatography, or purifies by membrane dialysis, which makes sugammadex sodium use a large amount of solvent in the purification process, increases post-treatment operations, and leads to process Time-consuming and energy-consuming, poor process reproducibility, not suitable for scale-up production
In addition, CN105348412A reports that sugammadex sodium is not purified by column chromatography and membrane dialysis. In this patent, the crude product of sugammadex sodium is freed by acidification, and then reacted with an organic amine to prepare sugammadex ammonium salt, and then recrystallized After purification, the ammonium salt is then freed into acid and reacted with sodium hydroxide to prepare sugammadex sodium. This method avoids column chromatography and membrane dialysis, but it needs to be repeatedly converted between free acid and salt. Due to the cumbersome steps, In the process of operation, it will inevitably lead to an increase in the degradation products of oxidized impurities and acids and bases, so the yield and purity of the pure product of sugammadex sodium prepared by this process are relatively low

Method used

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  • Intermediate of sugammadex sodium and preparation method thereof
  • Intermediate of sugammadex sodium and preparation method thereof
  • Intermediate of sugammadex sodium and preparation method thereof

Examples

Experimental program
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Embodiment 1

[0044]Example 1 Synthesis of 6-perdeoxy-6-perbromo-γ-cyclodextrin

[0045] Under ice bath, add dried γ-cyclodextrin (100g, 77mmol), triphenylphosphine (242g, 925mmol) into DMF (1200ml), stir to dissolve, add NBS (164g, 925mmol, DMF 350ml) dropwise ) solution, control the temperature below 10°C, after 30 minutes of dripping, the color of the reaction solution is dark red and viscous, heat up to 90°C under stirring and continue the reaction for 6 hours, stop the reaction, cool the reaction solution to room temperature and add to ice water (6L) , under stirring, add 4mol / L sodium hydroxide solution until the pH of the system is 8-9, a large amount of solids are precipitated, filtered, the filter cake is beaten with methanol (500ml*2), filtered to obtain a light yellow solid, and Blow drying for 6 hours to obtain 125 g of 6-perdeoxy-6-perbromoγ-cyclodextrin with a yield of 90%.

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

Embodiment 2

[0047] Example 2 Synthesis of 6-perdeoxy-6 perthioethyl ester-γ-cyclodextrin

[0048] Option One:

[0049] At room temperature, add 400ml of N-methylpyrrolidone to the prepared 6-perdeoxy-6-perbromo-γ-cyclodextrin (40g, 22.2mmol), and add potassium thioacetate (41g, 360mmol) into the system in batches, after the addition, replace the system with nitrogen, 4. Heat the reaction system to 50°C, react for 8 hours, stop heating, add 400ml of ethanol to the system, a large amount of solids are precipitated, vacuum filtration under reduced pressure, and the filter cake is reused Wash once with ethanol / water=1:1 (100ml), dry under reduced pressure to obtain 33.5g of off-white solid, yield: 86%.

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

Embodiment 3

[0057] Example 3 Synthesis of Sugammadex Sodium

[0058] Option One:

[0059] At room temperature, under nitrogen protection, the prepared 6-perdeoxy-6 perthioethyl ester-γ-cyclodextrin (10g, 5.6mmol) was added to sodium hydroxide solution (100ml, 1.5mol / L), and Complete, after stirring to dissolve completely, continue to stir for 2 hours, and send it to LC-MS (MS (TOF, ESI-): 1423.2273 [M-H]-, 1469.2310 [M-H+ HCOOH]-. Add acrylic acid (8.1g, 112mmol), after 10 minutes of dripping, raise the temperature of the system to 50°C, continue to stir for 6h, lower the system to room temperature, add ethanol (220ml) to the system, a large amount of solids are precipitated, filter the filter cake and beat it with a mixed solvent of ethanol and water , remove residual salts to obtain crude sugammadex sodium, heat and dissolve the crude product with methanol / water, add a small amount of activated carbon for decolorization, and then recrystallize to obtain 9.1 g of refined sugammadex sodi...

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Abstract

The invention relates to a preparation method of sugammadex sodium serving as a muscle relaxation antagonist. The preparation method comprises the following steps: reacting gamma-cyclodextrin with potassium thioacetate after being subjected to full halogenation to prepare a key intermediate compound 6-full deoxy-6 full thioethyl ester-gamma-cyclodextrin, then hydrolyzing, and directly reacting with acrylic acid in one pot to prepare the sugammadex sodium. The method is mild in reaction condition, simple and convenient in post-treatment operation, good in process repeatability and high in yield.

Description

technical field [0001] The invention relates to an intermediate used for preparing sugammadex sodium and a preparation method thereof, in particular to a preparation method of using the intermediate to prepare sugammadex sodium. Background technique [0002] Sodium sugammadex (sugammadex), whose trade name is Britim, and whose original manufacturer is Organon of the Netherlands (incorporated into Schering-Plough in November 2007, and merged into Merck in November 2009 along with Schering-Plough), was released on In July 2008, the EMA first approved the listing, in January 2010 the Japanese PMDA approved the listing, in December 2015 the FDA approved the listing, and in April 2017 the CFDA approved the listing. Brettim is a restorative agent for neuromuscular blockade that does not act by inhibiting acetylcholinesterase, and is the world's first selective relaxation antagonist (SRBA). This medicine is indicated for the recovery of neuromuscular blockade caused by rocuronium ...

Claims

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Application Information

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IPC IPC(8): C08B37/16
CPCC08B37/0012
Inventor 魏来曾桢杨日芳
Owner BEIJING TIDE PHARMA
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