Gamma-cyclodextrin modifier as well as preparation method and use thereof

Abstract

The invention discloses a gamma-cyclodextrin modifier as well as a preparation method and use thereof. The preparation method of the gamma-cyclodextrin modifier comprises the step of carrying out substitution on full halogenated gamma-cyclodextrin and 3-(Chlorosulfonyl)propionate in the presence of alkali to generate 2-ethyl sulfone-gamma-cyclodextrin. The gamma-cyclodextrin modifier can be used for preparing sugammadex. The preparation method is simple and convenient in operation and relatively high in yield and has wide application prospects, and reaction conditions are easily controlled.

Description

technical field

[0001] The invention relates to the field of preparation of polysaccharides, in particular to a modified gamma-cyclodextrin and its preparation method and application. 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 sod...

Examples

preparation example Construction

[0027] A preparation method of γ-cyclodextrin modification, 6-deoxy-6-perhalogenated γ-cyclodextrin and 3-(chlorosulfonyl) propionate are prepared to obtain γ-cyclodextrin modification, preparation route as follows:

[0028]

[0029] 6-Deoxy-6-perhalogenated γ-cyclodextrin is prepared from γ-cyclodextrin with triphenylphosphine and halogen.

[0030] Tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide were added in the preparation reaction of modified γ-cyclodextrin.

[0031] Alkali is added in the preparation reaction of modified γ-cyclodextrin.

[0032] The alkali is sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium amide, sodium hydride, potassium tert-butoxide, n-butyllithium, tert-butyllithium, triethylamine, pyridine, diethylamine, ammonia , Ethylenediamine, tetramethylethylenediamine and diisopropylamine, etc.

[0033] The reaction temperature of the preparation reaction of the γ-cyclodextrin modif...

Embodiment 1

[0042] Example 1: Preparation of 2-carbocarboxyethylsulfone-γ-cyclodextrin

[0043]

[0044] 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%.

[0045] 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

[0046] Example 2: Preparation of 2-carboethoxyethylsulfone-γ-cyclodextrin

[0047]

[0048] 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 solid is precipitated, suction filtered, 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%.

[0049] 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).

technical field

[0001] The invention relates to the field of preparation of polysaccharides, in particular to a modified gamma-cyclodextrin and its preparation method and application. 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 sod...

Examples

preparation example Construction

[0027] A preparation method of γ-cyclodextrin modification, 6-deoxy-6-perhalogenated γ-cyclodextrin and 3-(chlorosulfonyl) propionate are prepared to obtain γ-cyclodextrin modification, preparation route as follows:

[0028]

[0029] 6-Deoxy-6-perhalogenated γ-cyclodextrin is prepared from γ-cyclodextrin with triphenylphosphine and halogen.

[0030] Tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide were added in the preparation reaction of modified γ-cyclodextrin.

[0031] Alkali is added in the preparation reaction of modified γ-cyclodextrin.

[0032] The alkali is sodium hydroxide, potassium hydroxide, sodium methylate, potassium methylate, sodium amide, sodium hydride, potassium tert-butoxide, n-butyllithium, tert-butyllithium, triethylamine, pyridine, diethylamine, ammonia , Ethylenediamine, tetramethylethylenediamine and diisopropylamine, etc.

[0033] The reaction temperature of the preparation reaction of the γ-cyclodextrin modif...

Embodiment 1

[0042] Example 1: Preparation of 2-carbocarboxyethylsulfone-γ-cyclodextrin

[0043]

[0044] 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%.

[0045] 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

[0046] Example 2: Preparation of 2-carboethoxyethylsulfone-γ-cyclodextrin

[0047]

[0048] 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 solid is precipitated, suction filtered, 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%.

[0049] 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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