Preparation method of sugammadex

A technology of sodium gluconate and sodium hydroxide, applied in the field of polysaccharide preparation, can solve the problems of difficult control of reaction conditions, difficult purification, low process yield and the like, and achieves convenient industrial production, high reaction efficiency and low cost. low cost effect

Active Publication Date: 2017-11-07
CHINA OTSUKA PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present invention is to solve the problems such as low yield of sugammadex sodium preparation process in the prior art, di

Method used

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  • Preparation method of sugammadex

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preparation example Construction

[0026] A preparation method of sugammadex sodium, using 6-deoxy-6-perhalogenated γ-cyclodextrin as a starting material, and preparing sugammadex sodium through the following steps in sequence

[0027] a. Substitution reaction of 6-deoxy-6-perhalogenated γ-cyclodextrin with 3-(chlorosulfonyl) propionate to obtain modified γ-cyclodextrin

[0028]

[0029] In the formula, R refers to 1-12 carbon chain alkanes, naphthenes and aromatic hydrocarbons;

[0030] 6-deoxy-6-perhalogenated γ-cyclodextrin is prepared by γ-cyclodextrin with triphenylphosphine and halogen;

[0031] b. After the γ-cyclodextrin modification and metal and anhydrous alcohol reduce the sulfone group to become a sulfide, then react with sodium hydroxide to obtain sugammadex sodium

[0032]

[0033] a Add tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide to the reaction.

[0034] a base is added to the reaction.

[0035] The alkali is sodium hydroxide, potassium hydroxid...

Embodiment 1

[0039] Example 1: Preparation of 2-carbocarboxyethylsulfone-γ-cyclodextrin

[0040]

[0041] Dissolve 50g of dry 6-deoxy-6-perchloro-γ-cyclodextrin in dry 1L of N,N-dimethylformamide, add 22mL of triethylamine and cool down to -30°C, slowly drop After methyl 3-(chlorosulfonyl)propionate, control the temperature to 0°C and react for 2 hours, then slowly add the solution into the reaction liquid, then slowly add the reaction liquid into 1L of drinking water, a large amount of solids are precipitated, suction filtered, and 10 mL of cold water The filter cake was washed with N,N-dimethylformamide to obtain 55 g of off-white solid with a yield of 110%.

[0042] MS (m / z): 2393.35 [M+Na] + . 1 H-NMR (d6-DMSO): δ5.90-5.91 (16H, m), δ4.99-5.01 (8H, m), δ3.55-3.66 (32H, m), δ3.25-3.41 (16H, m), δ3.04-3.11 (8H, m), δ2.74-2.80 (24H, m), δ2.57-2.60 (16H, m).

Embodiment 2

[0043] Example 2: Preparation of 2-carboethoxyethylsulfone-γ-cyclodextrin

[0044]

[0045] Dissolve 25g of dry 6-deoxy-6-perbromo-γ-cyclodextrin in dry 500mL of N,N-dimethylacetamide, add 10mL of pyridine and cool down to -10°C, slowly add 3- After ethyl (chlorosulfonyl)propionate, control the temperature to 10°C and react for 1.5h, slowly add the solution into the reaction solution, slowly add the reaction solution into 500mL of drinking water, a large amount of solids are precipitated, suction filter, 10mL of cold The filter cake was washed with N,N-dimethylacetamide to obtain 28 g of an off-white solid with a yield of 112%.

[0046] MS(m / z): 2483.57[M+H] + . 1 H-NMR (d6-DMSO): δ5.91-5.93 (16H, m), δ4.99-5.04 (8H, m), δ3.76-4.03 (24H, m), δ3.24-3.43 (16H, m), δ3.09-3.13 (8H, m), δ2.75-2.83 (24H, m), δ2.56-2.60 (16H, m), δ1.27-1.33 (24H, m).

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Abstract

The invention discloses a preparation method of sugammadex. The method comprises the steps of carrying out substitution by adopting fully halogenated gamma-cyclodextrin and 3-(chlorosulfonyl) propionate under the action of alkali to generate 2-ester ethyl sulfuryl-gamma-cyclodextrin; reducing under the action of a reducing agent metal and anhydrous alcohol to generate 2-ester ethyl sulfydryl-gamma-cyclodextrin; and finally adding sodium hydroxide to generate the sugammadex. The preparation method of the sugammadex is simple in operation, the reaction conditions are easy to control, the yield is relatively high and the preparation method has a wide application prospect.

Description

technical field [0001] The invention relates to the field of preparation of polysaccharides, in particular to a preparation method of sugammadex sodium. Background technique [0002] Cyclodextrin modifications can be used as a reversal of conventionally used neuromuscular blocking drugs, antimuscular relaxants. Among them, sugammadex sodium, as a new type of anti-muscle relaxant, can reverse the moderate and deep muscle relaxation induced by rocuronium bromide or vecuronium bromide during general anesthesia within a few minutes. From the beginning to the end of the operation, the degree of muscle relaxation is well controlled to improve the quality of the operation. [0003] Sugammadex sodium was first disclosed in the patent US6670340, using γ-cyclodextrin as the starting material to generate perhalogenated γ-cyclodextrin by substituting with triphenylphosphine and halogen, and then reacting with mercaptopropionic acid under the action of sodium hydride Generate target pr...

Claims

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Application Information

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IPC IPC(8): C08B37/16
Inventor 张冲张轻轻龚莉李正艳李桂龙闫婷
Owner CHINA OTSUKA PHARM CO LTD
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