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Preparation method of NH2-PEG-NHBoc

A technology of polyethylene glycol carbamic acid and polyethylene glycol, applied in the field of preparation of amino-terminated polyethylene glycol tert-butyl carbamate, can solve the problems of low raw material utilization rate, difficult post-processing, unfavorable production, etc., and achieve Conducive to extraction and purification, optimization of synthetic routes, and cost-saving effects

Inactive Publication Date: 2017-12-22
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The invention provides a method for preparing amino-terminated polyethylene glycol tert-butyl carbamate (NH2-PEG-NHBoc, n=1-12), which solves the problems of low utilization rate of raw materials and high yield in the prior art. Low, difficult post-processing, unfavorable for production, this preparation method optimizes the synthesis route of small molecule PEG, makes the purification of the product easier, and improves the yield and purity of small molecule PEG

Method used

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  • Preparation method of NH2-PEG-NHBoc
  • Preparation method of NH2-PEG-NHBoc

Examples

Experimental program
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Effect test

Embodiment 1

[0029] (1) Add 50g of diethylene glycol and 105g of triethylamine to 500ml of dichloromethane, stir, weigh 198g of p-toluenesulfonyl chloride and dissolve in 250ml of dichloromethane, add dropwise to the reaction system under ice-water bath conditions, dropwise After completion, react for 12h at 20°C. TLC showed that the reaction was over, 400ml of water was added to wash, liquid separation, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and then separated and purified by column chromatography to obtain 175g of Intermediate A, the yield: 89%. The nuclear magnetic data are as follows: 1HNMR (400MHz, CDCl 3 ): δ: 7.792 (d, J = 8.4 Hz, 4H); 7.350 (d, J = 8.4 Hz, 4H); 4.158 (t, J = 4.4 Hz, 4H); 3.702 ~ 3.567 (m, 4H); 2.435 (s, 6H);

[0030] (2) Add 175 g of Intermediate A obtained in step (1) to 400 ml of ethanol, and then add 68.6 g of sodium azide, raise the temperature to 80°C, and stir for 10 hours. After the reaction is complete, cool to room temperatur...

Embodiment 2

[0035] (1) Add 50g of diethylene glycol and 82g of pyridine to 500ml of acetonitrile, stir, weigh 198g of p-toluenesulfonyl chloride and dissolve in 250ml of acetonitrile, add dropwise to the reaction system under ice-water bath conditions, and then, at 30°C Reaction for 12h. TLC showed that the reaction was over, 400ml of water was added to wash, liquid separation, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and then separated and purified by column chromatography to obtain 170g of Intermediate A, yield: 88%. The nuclear magnetic data are as follows: 1HNMR (400MHz, CDCl 3 ): δ: 7.782 (d, J=8.4 Hz, 4H); 7.356 (d, J=8.4 Hz, 4H); 4.156 (t, J=4.4 Hz, 4H); 3.710~3.568 (m, 4H); 2.434 (s, 6H);

[0036] (2) Add 170 g of Intermediate A obtained in step (1) to 400 ml of ethanol, and then add 66.6 g of sodium azide, raise the temperature to 80°C, and stir for 10 hours. After the reaction is complete, cool to room temperature, add 200 ml of water, extract with 5...

Embodiment 3

[0041] (1) Add 50g of diethylene glycol and 41g of sodium hydroxide to 500ml of dioxane, stir, weigh 225g of p-toluenesulfonyl chloride, dissolve in 250ml of acetonitrile dioxane, and add dropwise to the reaction system under ice-water bath conditions After dripping, react for 10h at 25°C. TLC indicated the completion of the reaction, 400 ml of water was added, extracted with dichloromethane, liquid separation, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and then separated and purified by column chromatography to obtain 150 g of Intermediate A, yield: 77%. The nuclear magnetic data are as follows: 1HNMR (400MHz, CDCl 3 ): δ: 7.783 (d, J = 8.4 Hz, 4H); 7.366 (d, J = 8.4 Hz, 4H); 4.146 (t, J = 4.4 Hz, 4H); 3.713 ~ 3.560 (m, 4H); 2.435 (s, 6H);

[0042] (2) Add 150 g of Intermediate A obtained in step (1) to 400 ml of DMF, and then add 58.8 g of sodium azide, raise the temperature to 80°C, and stir for 10 hours. After the reaction is complete, cool to ro...

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Abstract

The invention discloses a micromolecular PEG (polyethylene glycol) derivative and relates to a preparation method of NH2-PEG-NHBoc. According to the preparation method, monodisperse di-hydroxyl PEG is taken as a raw material, hydroxyls at two ends of monodisperse di-hydroxyl PEG are converted into amino and tert-butyl carbamate through a series of reactions respectively. By means of the preparation method, the synthesis route of micromolecular PEG is optimized, the product is simpler to purify, the reaction conditions are mild, purification is easy and the yield and the purity of micromolecular PEG are improved.

Description

Technical field [0001] The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of amino-terminated polyethylene glycol tert-butyl carbamate. Background technique [0002] Polyethylene glycol (PEG) is a kind of high molecular water-soluble polyether obtained by the gradual addition polymerization of ethylene oxide and water or ethylene glycol. It is non-corrosive, non-irritating, and non-corrosive. Antigenicity and immunogenicity, good biocompatibility, low protein and low platelet adsorption and low cell adhesion in the body, and has been approved by the FDA for use. [0003] However, unmodified PEG itself cannot be used as a reagent because its terminal hydroxyl groups have limited reactivity. Therefore, in order to prepare useful PEG reagents, the terminal hydroxyl groups must be modified to make them more reactive groups. According to the method of the prior art, one end of the hydroxyl group is first blocked in the form of an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/338C08G65/334C08G65/325C08G65/335C08G65/331C07C247/04C07C303/28C07C309/73C07C309/66C07C269/04C07C269/06C07C271/16
CPCC08G65/338C07C247/04C07C269/04C07C269/06C07C303/28C07C309/73C08G65/325C08G65/331C08G65/3346C08G65/335C07C309/66C07C271/16
Inventor 邓泽平成佳张安林李虎
Owner 湖南华腾制药有限公司
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