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Preparation method of d-alpha-tocopherol polyethylene glycol succinate

A technology of polyethylene glycol succinate and tocopherol, which is applied in the field of preparation of d-α-tocopherol polyethylene glycol succinate, which can solve the problem of unclean separation of impurities, incomplete separation and low monoester content and other problems, to achieve the effect of simplifying the post-reaction processing operation, facilitating automatic operation, and speeding up the synthesis process

Active Publication Date: 2018-10-19
NINGBO WANGLONG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, all methods currently reported in the literature will encounter a common problem:
[0009] 1. The monoester content of TPGS is too low, and contains a large amount of diesterification products;
[0010] 2. Since TPGS has dual characteristics of hydrophilicity and lipophilicity, the post-treatment of the preparation reaction is very difficult and cannot be completed by conventional separation means (due to many reasons such as too much separation loss and incomplete separation at the same time), the reaction process brings The separation of incoming and generated impurities is not clean;
[0011] 3. Unable to prepare high-purity TPGS

Method used

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  • Preparation method of d-alpha-tocopherol polyethylene glycol succinate
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  • Preparation method of d-alpha-tocopherol polyethylene glycol succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: Preparation of d-alpha-tocopheryl polyethylene glycol succinate (TPGS) shown in formula VI

[0046] (1) Preparation of unidirectional loaded PEG1000 resin III

[0047] The reaction formula is as follows:

[0048]

[0049] Add PEG1000II (80g, 80mmol) and 8mL toluene into the reaction flask, heat to 45°C, start stirring, after the PEG1000 melts, add catalyst sodium ethoxide (5.104g, 75mmol) in batches, heat up to 85°C and react for 1 hour. Then add Merrifield resin I (20 g, 1.0 mmol / g chlorine loading) soaked with tetrahydrofuran (THF) and toluene for 3 hours successively in 4 batches, and then raise the temperature to 130° C. to continue the reaction for 5 hours. Stop the reaction, and when the temperature drops to 80°C, filter while it is hot. The filtrate is transferred to a clean container and stored in a sealed container, which can be used in the next similar reaction; the filter cake is washed in the following order: water (100mL×2 times), THF (50...

Embodiment 2

[0064] Embodiment 2: Preparation of d-alpha-tocopherol polyethylene glycol succinate (TPGS) shown in formula VI

[0065] (1) Preparation of unidirectional loaded PEG1000 resin III

[0066] The reaction formula is as follows:

[0067]

[0068] Add PEG1000 (60g, 60mmol) and 5mL THF to the reaction flask, heat to 45°C, and start stirring. After the PEG1000 melts, add the catalyst sodium ethoxide (3.062g, 45mmol) in batches, and heat up to 80°C for 2 hours. Then add Merrifield resin (10 g, 1.5 mmol / g chlorine loading) soaked with THF and toluene for 3 hours successively in 4 batches, and then raise the temperature to 135° C. to continue the reaction for 6 hours. Stop the reaction, and when the temperature drops to 80°C, filter while it is hot. The filtrate was transferred to a clean container and kept tightly closed for the next similar reaction; the filter cake was washed in the following order: water (100mL×2 times), THF (40mL×1 time), THF / water=1:1( v / v, 40mL×3 times), TH...

Embodiment 3

[0077] Example 3: Preparation of d-alpha-tocopheryl polyethylene glycol succinate (TPGS, VI)

[0078] (1) Preparation of unidirectional loaded PEG1000 resin III

[0079] The reaction formula is as follows:

[0080]

[0081] Add PEG1000 (36g, 36mmol) and 5mL toluene into the reaction flask, heat to 45°C, start stirring, add the catalyst sodium ethoxide (2.45g, 36mmol) in batches after the PEG1000 melts, raise the temperature to 80°C for 2 hours. Then add Merrifield resin (10 g, 1.2 mmol / g chlorine loading) soaked with THF and toluene for 3 hours successively in 4 batches, and then raise the temperature to 130° C. to continue the reaction for 8 hours. The following reaction is the same as step (1) in Example 2, and finally 21.54 g of unidirectional loading PEG1000 resin III is obtained, the loading of PEG1000 is 0.556 mmol / g, and the conversion rate of chlorine is 99.8%.

[0082] (2) Preparation of loaded TPGS resin V

[0083] The reaction formula is as follows:

[0084] ...

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Abstract

The invention discloses a preparation method of d-alpha-tocopherol polyethylene glycol succinate. The preparation method comprises the following steps: by taking Merrifield resin and PEG1,000 as raw materials and alkali as a catalyst, performing reaction at 45-135 DEG C in an organic solvent to obtain resin loaded with PEG1,000; under the action of the catalyst, enabling the resin loaded with PEG1,000 and d-alpha-tocopherol succinate to be subjected to water diversion reflux reaction to obtain resin loaded with TPGS; and soaking the resin loaded with TPGS in toluene, then adding ethanol, palladium on carbon and phosphopyridoxal, and performing stirring reaction at 100-110 DEG C for 24 hours in hydrogen gas of 0.8-1.5MPa to obtain the d-alpha-tocopherol polyethylene glycol succinate. By adopting the synthetic method disclosed by the invention, the yield of TPGS is as high as 99%, the monoester content of TPGS is 99%, and the diester content of TPGS is 0.

Description

technical field [0001] The present invention relates to a preparation method of d-alpha-tocopheryl polyethylene glycol succinate represented by formula VI. Background technique [0002] d-α-Tocopheryl Polyethylene Glycol Succinate (d-α-Tocopheryl Polyethylene Glycol Succinate, TPGS) is a water-soluble derivative of tocopherol, which is composed of d-α-tocopheryl succinate and polyethylene glycol 1000 Formed by esterification (VI), TPGSl000 contains polyethylene glycol chains with a degree of polymerization of 23. It is a white to light brown waxy solid that is miscible with water and can exist stably in air. TPGS contains both the lipophilic group of tocopherol and the hydrophilic group of polyethylene glycol long chain. It is a non-ionic surfactant and an effective tocopherol supplement and absorption enhancer. Various excipients have broad application prospects in the food, pharmaceutical and health care products markets. [0003] d-α-tocopherol has strong physiological ...

Claims

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Application Information

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IPC IPC(8): C08G65/332
CPCC08G65/3326
Inventor 王宇光王捍东施红杰施海洪王益挺王国军汪钊
Owner NINGBO WANGLONG TECH
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