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Purification method for intermediate prepared by sugammadex sodium

A purification method and crude product technology, which is applied in the field of pharmaceutical preparation, can solve problems such as poor purification effect, complex structure of γ-ICD, and difficult intermediates, and achieve the effects of industrial production, cost reduction, and yield improvement

Active Publication Date: 2019-04-09
BRIGHTGENE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, there are basically no reports on the purification of γ-ICD in the open literature, mainly because γ-ICD is relatively polar, but insoluble in water, and organic solvents are only soluble in DMF, DMSO, formamide, N, N-di In solvents such as methylacetamide, it is insoluble in solvents such as acetonitrile and methanol, and the structure of γ-ICD itself is complex, so it is difficult to prepare and purify this intermediate by HPLC, and the purification effect of the general crystallization purification method is not good.

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0017] Preparation of γ-ICD

[0018] In a 2000mL three-neck flask, under nitrogen protection, add 160ml of DMF and triphenylphosphine (30.1g, 15eq), and add iodine (30.5g, 15.6eq), exothermic violently, control the temperature at 25±5°C, and stir for 10min. Add dry good γ-cyclodextrin (10 g, 7.7 mmol), after the addition is complete, raise the temperature to 70° C. and stir for reaction for 24 hours. Cool the reaction solution to 10°C, add sodium methoxide solution (3.1g sodium added to 50ml methanol), stir for 30min, then add methanol 800ml, add 500ml purified water, and filter the solid. Crude γ-ICD 18.5 g was washed with water (3 x 100 ml) and then with acetone (3 x 100 ml).

Embodiment 2

[0020] Purification of γ-ICD

[0021] In a 500ml three-necked flask, under the protection of nitrogen, add 18.5g of γ-ICD obtained in Example 1, add 185g of DMF, raise the temperature to 70°C, add 129.5g of purified water dropwise, after completion of the dropwise addition, a large amount of solids are precipitated, and the temperature is naturally lowered slowly. Stir at 25°C for 4 hours, and filter to obtain a wet product of γ-ICD.

[0022] In a 500ml three-necked flask, under the protection of nitrogen, add the wet product of γ-ICD obtained in the previous step, add 40g of DMF, raise the temperature to 70°C, add 200g of acetone solution, cool down to 25°C, stir for 4h, filter the wet product by suction, and use vacuum drying , the water temperature was set at 70° C., and dried for 8 hours to obtain pure γ-ICD with a yield of 92% and a purity of 99.86%.

Embodiment 3

[0024] Purification of γ-ICD

[0025] In a 500ml three-necked flask, under the protection of nitrogen, add 18.5g of γ-ICD obtained in Example 1, add 92.5g of DMF, raise the temperature to 50°C, add 92.5g of purified water dropwise, after the completion of the dropwise addition, a large amount of solids are precipitated, and the temperature is naturally lowered slowly , stirred at 25°C for 4 hours, and filtered to obtain a wet product of γ-ICD.

[0026] In a 500ml three-necked flask, under the protection of nitrogen, add the wet product of γ-ICD obtained in the previous step, add 27.75g of DMF, heat up to 80°C, add 222g of acetone solution, cool down to 25°C, stir for 4h, filter the wet product, and use a vacuum After drying, the water temperature was set at 70° C. and dried for 8 hours to obtain a pure γ-ICD product with a yield of 85% and a purity of 97.14%.

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Abstract

The invention discloses a purification method for an intermediate gamma-ICD prepared by sugammadex sodium. The method comprises the following steps: (1) crystallizing gamma-ICD by using a DMF-aqueoussolvent system to remove impurities greater in polarity first; and (2) recrystallizing the gamma-ICD again by using a DMF-acetone solvent system to remove impurities smaller in polarity. The method ofpurifying gamma-ICD cancels various complex purification processes and can obtain gamma-ICD relatively high in purity through a simple crystallizing process. The inventory of the follow-up sugammadexsodium reaction is reduced, the yield is improved, the cost is lowered, the environmental pollution is reduced, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a purification method for preparing intermediate 6-perdeoxy-6-periodo-γ-cyclodextrin by sugammadex sodium. Background technique [0002] Sugammadex sodium is a new type of selective muscle relaxant antagonist, which can selectively bind amino carrier muscle relaxants and terminate their muscle relaxant effect. The drug is a modified γ-cyclodextrin, which consists of 8 adjacent glucose molecules forming a ring-shaped molecular structure with a lipophilic inner cavity with an optimal inner diameter for accommodating amino carrier molecules, such as rocuronium bromide. 8 negatively charged hydrophilic carboxyl side chains project outward from the edge of the cyclodextrin molecule, and the acidic functional group (COO—) on the side chain increases the lipophilicity of the inner cavity of sugammadex sodium and can bind with Roku The positively charged nitrogen atoms of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16
CPCC08B37/0003C08B37/0012
Inventor 袁建栋黄仰青池建文葛亮
Owner BRIGHTGENE PHARMA
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