Preparation method of valproic acid phospholipid derivative

A technology of valproic acid phospholipids and derivatives, which is applied in the direction of edible phospholipid composition, food science, protein food ingredients, etc., can solve the problems of high impurity content, low yield, dark product color, etc., and achieve improved product yield and Purity, reduce the content of by-products, and avoid the effect of high impurity content

Active Publication Date: 2014-12-24
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] But there are some problems in the synthetic route of this method: the preparation of step 1 valproic anhydride is to react with valproic acid and excessive acetic anhydride, then with excessive acetic anhydride and by-product acetic acid, after the catalyst pyridine is evaporated, the product is distilled repeatedly to obtain propane Valeric anhydride
In step 2, the reaction temperature is 90-100°C. The product obtained by the inventors using this temperature has a darker color and higher impurity content. The product is not easy to separate out in the post-treatment, and the yield is reduced. The recrystallization process is time-consuming and laborious, resulting in a decrease in the yield.

Method used

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  • Preparation method of valproic acid phospholipid derivative
  • Preparation method of valproic acid phospholipid derivative
  • Preparation method of valproic acid phospholipid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1C 18 -Synthesis of DP-VPA

[0024] (1) Preparation of valproic anhydride

[0025] Step A: add 1.4L of thionyl chloride to a 2L reaction bottle, add 700g of valproic acid dropwise, after the dropwise addition, heat up to 86°C and reflux for 2 hours, remove excess thionyl chloride by rotary evaporation, and the obtained residue is ready for use.

[0026] Step B: In another 5L reaction bottle, add 2L tetrahydrofuran and 491g triethylamine, slowly add 700g valproic acid under stirring, then add the above residue dropwise, after the dropwise addition, stir and react at 10°C for 4h, suction filter, filter cake Washed with tetrahydrofuran, the filtrate was rotary evaporated to remove tetrahydrofuran, the residue was vacuum distilled, and the fraction at 125-127°C / 54Pa was collected to obtain 1089g of valproic anhydride, the yield of valproic anhydride was 82.8%, and the purity was 99.4%.

[0027] (2) C 18 -DP-VPA preparation

[0028] 190g C was added to the 5L rea...

Embodiment 2

[0034] Example 2C 18 -Synthesis of DP-VPA

[0035] (1) Preparation of valproic anhydride

[0036] Step A: Add 1.4L of dichloromethane into a 2L reaction bottle, add 700g of valproic acid dropwise, after the dropwise addition, raise the temperature to 86°C and reflux for 2h, remove excess thionyl chloride by rotary evaporation, and the obtained residue is ready for use.

[0037] Step B: In another 5L reaction bottle, add 2L tetrahydrofuran and 500g pyridine, slowly add 700g valproic acid under stirring, then add the above residue dropwise, after the dropwise addition is completed, stir at 35°C for 1.5h, filter with suction, and filter the cake with THF After washing, the filtrate was rotary evaporated to remove tetrahydrofuran, the residue was vacuum distilled, and the fraction at 125-127°C / 54Pa was collected to obtain 1059 g of valproic anhydride. The yield of valproic anhydride was 80.6%, and the purity was 99.3%.

[0038] (2) C 18 -DP-VPA preparation

[0039] 190g C was ...

Embodiment 3

[0040] Example 3C 18 -Synthesis of DP-VPA

[0041] (1) Preparation of valproic anhydride

[0042] Step A: Add 1.4L of ethane into a 2L reaction flask, add 700g of valproic acid dropwise, after the dropwise addition, raise the temperature to 88°C and reflux for 2h, remove excess thionyl chloride by rotary evaporation, and the obtained residue is ready for use.

[0043] Step B: In another 5L reaction bottle, add 2L tetrahydrofuran and 491g triethylamine, slowly add 700g valproic acid under stirring, then add the above residue dropwise, after the dropwise addition is completed, stir at 25°C for 1h, suction filter, and the filter cake is THF was washed, the filtrate was rotary evaporated to remove THF, the residue was vacuum distilled, and stable fractions at around 125-127°C / 54Pa were collected to obtain 1070 g of valproic anhydride. The yield of valproic anhydride was 81.5%, and the purity was 99.1%.

[0044] (2) C 18 -DP-VPA preparation

[0045] 190g C was added to the 5L rea...

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Abstract

The invention belongs to the field of organic compound preparation, and discloses a preparation method of a valproic acid phospholipid derivative. The method comprises the following steps: by using tetrahydrofuran as a solvent and triethylamine as an acid-binding agent, reacting propyl valeric chloride and equal mole of valproic acid at 10-50 DEG C, filtering, distilling to obtain valproic acid anhydride, adding lysophosphatidyl choline into the valproic acid anhydride solution, reacting at 60-85 DEG C under the catalytic action of 4-dimethylaminopyridine for 2-6 hours, adding acetone to precipitate the product, and refining with ethanol / acetone to obtain the valproic acid phospholipid derivative. By reacting the valproic acid and propyl valeric chloride to prepare the valproic acid anhydride, no influence of the acetic anhydride exists, and the valproic acid anhydride can be easily purified to obtain the high-purity valproic acid anhydride, thereby preparing the high-purity valproic acid phospholipid derivative.

Description

technical field [0001] The invention belongs to the field of organic compound preparation, and relates to a preparation method of valproic acid phospholipid derivatives. Background technique [0002] Chinese patent application 01815173.6 discloses a phospholipid derivative of valproic acid and its preparation method. The phospholipid derivative (DP-VPA) is a mixture, and its two components are 1-palmitoyl-sn-glyceryl-3-phosphate Choline (C 16 -DP-VPA), 1-stearyl-sn-glyceryl-3-phosphocholine (C 18 -DP-VPA), the structural formula is [0003] [0004] Two-component ratio C 16 -DP-VPA:C 18 -DP-VPA is 15±5%: 85±5%. The drug was developed by Israel D-Pharm for the treatment of epilepsy and is currently in clinical research. [0005] This product is a powerful anticonvulsant. Its essence is to use lysophosphatidylcholine as a carrier, and the active ingredient VPA (valproic acid) is linked to phospholipids through an ester bond at the sn-2 position. Since phospholipids are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/10
Inventor 王勇马彦琴周英珍石涛
Owner NHWA PHARMA CORPORATION
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