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Method for preparing 6-deoxy-6-haloalkyl cyclodextrin

A cyclodextrin and halide technology, applied in the field of pharmaceutical preparation, can solve the problems of strong volatility, low substitution reaction yield, poor stability of succinimide and the like, achieve stable properties, improve reaction quality, and facilitate industrial production. Effect

Active Publication Date: 2015-05-20
CHINA OTSUKA PHARM CO LTD
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This method directly uses bromine to react with cyclodextrin under the condition of triphenylphosphine / N,N-dimethylformamide to generate 6-perdeoxy-6-perbromocyclodextrin, which has obvious defects: ① Bromine The toxicity is very high, the volatility is very strong, and it is difficult to control the reaction dosage; ②The reaction time is as long as 18-24h, and when the reaction temperature is high, bromine volatilizes violently; ③The yield of the substitution reaction of this method is low, and the appearance color of the product is very poor, reddish brown
The reaction time of this method is obviously shortened, and the product yield and appearance are improved, but there are still certain defects in this method: 1. N-bromosuccinimide has poor stability and is easy to absorb moisture and deteriorate; 2. N-bromosuccinimide The bromine content in imine is low, and the amount used in the production process is relatively large, which brings some inconvenience to post-processing; ③The price of N-bromosuccinimide is relatively high, which increases the cost pressure of raw materials

Method used

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  • Method for preparing 6-deoxy-6-haloalkyl cyclodextrin
  • Method for preparing 6-deoxy-6-haloalkyl cyclodextrin
  • Method for preparing 6-deoxy-6-haloalkyl cyclodextrin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of 6-perdeoxy-6-perchloro-α-cyclodextrin

[0030]

[0031] At room temperature, dissolve 50g of dry α-cyclodextrin in 1L of dry N,N-dimethylformamide, add 160g of triphenylphosphine, 1,3-dichloro-5,5-dimethylformamide in sequence Genhydantoin 100g, reacted at 70°C for 5h, dissolved 30g of sodium methoxide in 200mL of methanol, slowly added the solution into the reaction solution, slowly added the reaction solution into 18L of drinking water, a large amount of solid was precipitated, suction filtered, 100mL of cold water The filter cake was washed with N,N-dimethylformamide to obtain 37 g of off-white solid with a yield of 74% and a content of 95.8%.

[0032] The experimental data are as follows: MS (m / z): 1104.5 [M+Na]+. 1H-NMR (d6-DMSO): δ5.90-5.91 (16H, m), δ4.99-5.01 (8H, m), δ3.95-3.99 (8H, m), δ3.85-3.81 (8H, m), δ3.64-3.71 (8H, m), δ3.55-3.60 (8H, m), δ3.31-3.37 (16H, m).

Embodiment 2

[0034] Preparation of 6-perdeoxy-6-perbromo-β-cyclodextrin

[0035]

[0036] At room temperature, dissolve 10 g of dry β-cyclodextrin in 1 L of dry N,N-dimethylformamide, add 32.1 g of triphenylphosphine, 1,3-dibromo-5,5-di Methylhydantoin 17g, reacted at 80°C for 2.5h, dissolved 6.2g of sodium methoxide in 50mL of methanol, slowly added the solution into the reaction solution, slowly added the reaction solution into 10L of drinking water, a large amount of solids were precipitated, and suction filtered , 60mL of cold N,N-dimethylformamide washed the filter cake to obtain 8.3g of off-white solid with a yield of 83% and a content of 95.3%.

[0037] The experimental data are as follows: MS (m / z): 1576.5 [M+Na]+. 1H-NMR (d6-DMSO): δ5.88-5.90 (16H, m), δ4.91-5.04 (8H, m), δ3.91-3.93 (8H, m), δ3.84-3.80 (8H, m), δ3.61-3.72 (8H, m), δ3.53-3.62 (8H, m), δ3.27-3.33 (16H, m).

Embodiment 3

[0039] Preparation of 6-perdeoxy-6-periodo-γ-cyclodextrin

[0040]

[0041] At room temperature, dissolve 100g of dry γ-cyclodextrin in 2L of dry N,N-dimethylformamide, add 323.5g of triphenylphosphine, 1,3-diiodo-5,5-di Methylhydantoin 230g, reacted at 50°C for 4h, dissolved 75g of sodium methoxide in 500mL of methanol, slowly added the solution into the reaction solution, slowly added the reaction solution into 30L of drinking water, a large amount of solids were precipitated, suction filtered, 200mL The filter cake was washed with cold N,N-dimethylformamide to obtain 80 g of a khaki solid with a yield of 80% and a content of 97.8%.

[0042] The experimental data are as follows: MS (m / z): 2198.7 [M+Na]+. 1H-NMR (d6-DMSO): δ5.94-5.97 (16H, m), δ5.01-5.02 (8H, m), δ3.96-3.99 (8H, m), δ3.80-3.83 (8H, m), δ3.66-3.70 (8H, m), δ3.60-3.63 (8H, m), δ3.34-3.40 (16H, m).

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Abstract

The invention discloses a method for preparing 6-deoxy-6-haloalkyl cyclodextrin. The method comprises the following specific steps: in a N, N-dimethylformamide solvent, firstly reacting 1,3-dihalo-5, 5-dimethylhydantoin and triphenylphosphine to form a salt and substituting with cyclodextrin to form halide. The method has the advantages and beneficial effects that compared to the existing preparation method, the reaction quality is significantly improved, the content of a product can be not less than 95% and the product yield can reach 80%; and 1,3-dihalo-5, 5-dimethylhydantoin used in the reaction is cheap and easily available and is stable in property and the 6-deoxy-6-haloalkyl cyclodextrin is conductive to industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation and relates to a preparation method of 6-deoxy-6-halogenated cyclodextrin. 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. At the beginning of the operation, the degree of muscle relaxation is well controlled and the quality of the operation is improved. [0003] In 1996, the literature tetrhedron letters, Vol.37, No.27, 4647-4650 introduced a synthesis method of cyclodextrin analogues, the chemical process is as follows: [0004] [0005] This method directly uses bromine to react with cyclodextrin under the condition of triphenylphosphine / N,N-dimethylformamide...

Claims

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Application Information

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IPC IPC(8): C08B37/16
Inventor 张冲高海春龚莉苗岩王莹莹钟凯旋张轻轻
Owner CHINA OTSUKA PHARM CO LTD
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